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Bonetti C, Silvestri I, Caccioppola A, Meli A, Grasselli G, Panigada M. Viscoelastic Hemostatic Assays in Sepsis: From Pathophysiology to Potential Clinical Implications. Semin Thromb Hemost 2025. [PMID: 40412374 DOI: 10.1055/s-0045-1809373] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/27/2025]
Abstract
Sepsis is a complex syndrome characterized by physiological, pathological, and biochemical abnormalities induced by infection, with up to 70% of patients experiencing coagulation alterations, ranging from subclinical coagulopathy to disseminated intravascular coagulation (DIC). The multifactorial nature of sepsis-related coagulopathy and the limitations of standard diagnostic parameters, such as platelet count and traditional coagulation tests, complicate its definition and management. Assessing coagulopathy related to sepsis presents significant challenges due to current definitions primarily focusing on diagnosing advanced stages of coagulation dysfunction, thereby overlooking the dynamic and evolving nature of the condition. Viscoelastic hemostatic assays (VHAs) have emerged as valuable tools in this context, offering real-time insights into clot formation, stabilization, and lysis by integrating both plasma and cellular contributions to coagulation. Data from clinical studies suggest that early stages of sepsis coagulopathy are characterized by hypercoagulability, while advanced stages may lead to hypocoagulability and DIC. Moreover, specific point-of-care assays can evaluate platelet performance in the clotting mechanism and potentially help the diagnosis of platelet dysfunction in sepsis. Additionally, the phenomenon of fibrinolysis inhibition contributes to the persistence of fibrin clots, promoting tissue ischemia and multiorgan dysfunction. Modified VHAs appear promising for detecting fibrinolysis impairment, which is associated with poorer outcomes, but the standardization of results is still a work in progress. Incorporating VHAs data into treatment strategies could lead to more targeted therapies, potentially improving outcomes in septic patients by addressing both hypercoagulable and hypocoagulable states, as well as fibrinolysis abnormalities.
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Affiliation(s)
- Claudia Bonetti
- Department of Anesthesiology, Critical Care and Emergency. Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan (MI), Italy
- Department of Pathophysiology and Transplantation, University of Milan, Milan (MI), Italy
| | - Ivan Silvestri
- Department of Anesthesiology, Critical Care and Emergency. Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan (MI), Italy
- Department of Pathophysiology and Transplantation, University of Milan, Milan (MI), Italy
| | - Alessio Caccioppola
- Department of Anesthesiology, Critical Care and Emergency. Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan (MI), Italy
| | - Andrea Meli
- Department of Anesthesiology, Critical Care and Emergency. Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan (MI), Italy
| | - Giacomo Grasselli
- Department of Anesthesiology, Critical Care and Emergency. Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan (MI), Italy
- Department of Pathophysiology and Transplantation, University of Milan, Milan (MI), Italy
| | - Mauro Panigada
- Department of Anesthesiology, Critical Care and Emergency. Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan (MI), Italy
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Bendapudi PK, Losman JA. How I diagnose and treat acute infection-associated purpura fulminans. Blood 2025; 145:1358-1368. [PMID: 39786416 DOI: 10.1182/blood.2024025078] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2024] [Revised: 12/19/2024] [Accepted: 12/19/2024] [Indexed: 01/12/2025] Open
Abstract
ABSTRACT Purpura fulminans (PF) is a rare but devastating complication of sepsis characterized by a highly thrombotic subtype of disseminated intravascular coagulation (DIC). A medical emergency, PF often requires the involvement of consultant hematologists to assist with diagnosis and management of patients who are in a highly dynamic and deteriorating clinical situation. Patients who survive past the first 24 to 72 hours often die from complications of unchecked thrombosis rather than shock, and survivors are usually left with severe scarring and tissue loss. Despite these challenging features, PF is a pathophysiologically distinct, homogeneous, and highly predictable form of sepsis-associated DIC for which poor outcomes are not a foregone conclusion. The fundamental pathologic lesion in PF is a failure of the anticoagulant protein C pathway, which leads to uncontrolled microvascular clotting and inadequate protein C-mediated cytoprotective effects, which are vital for survival in sepsis. Herein, we review the clinical features and diagnosis of PF. Drawing from existing clinical literature and recent advances in our understanding of the pathophysiology of PF, we describe rationally designed treatment approaches for this disorder, including repletion of natural circulating anticoagulants, use of therapeutic anticoagulation, and ways to optimize transfusion support, and we outline specific interventions that we would recommend avoiding.
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Affiliation(s)
- Pavan K Bendapudi
- Division of Hematology and Blood Transfusion Service, Massachusetts General Hospital, Boston, MA
- Division of Hemostasis and Thrombosis, Beth Israel Deaconess Medical Center, Boston, MA
- Center for the Development of Therapeutics, The Broad Institute of MIT and Harvard, Cambridge, MA
- Harvard Medical School, Boston, MA
| | - Julie-Aurore Losman
- Harvard Medical School, Boston, MA
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
- Division of Hematology, Brigham and Women's Hospital, Boston, MA
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Fang S, Wang Y, Nan W, Feng Y, Su W, Wang Y, Jiang X. Unfractionated heparin may improve near-term survival in patients admitted to the ICU with sepsis attributed to pneumonia: an observational study using the MIMIC-IV database. Front Pharmacol 2025; 16:1518716. [PMID: 40083381 PMCID: PMC11903409 DOI: 10.3389/fphar.2025.1518716] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2024] [Accepted: 02/11/2025] [Indexed: 03/16/2025] Open
Abstract
Introduction Limited data are available on the use, duration, and dosage of anticoagulant therapy in patients with pneumonia-induced sepsis, and the survival benefits of heparin remain uncertain. This study aimed to assess whether heparin administration improves near-term survival in critically ill patients with pneumonia-induced sepsis and identify the optimal dosage and treatment duration. Methods This study utilized the Medical Information Mart for Intensive Care-IV (MIMIC-IV) database. The variance inflation factor was employed to exclude highly collinear variables. Propensity score matching (PSM), the Cox proportional hazards model, and Cox regression subgroup analysis were used to evaluate the outcomes of subcutaneous heparin prophylactic anticoagulation after intensive care unit (ICU) admission. The primary outcomes were 30-, 45-, and 60-d mortality rates. Secondary outcomes included ICU length of stay (LOS_ICU), hospital length of stay (LOS_Hospital), in-hospital mortality, and the incidence of gastrointestinal bleeding. Results We enrolled 1,586 adult patients with pneumonia-induced sepsis. After PSM, 1,176 patients remained (588 in the heparin group and 588 in the non-heparin group). The 45-d survival rate was significantly higher in the heparin-treated group than that in the non-heparin group (84.4% vs. 79.4%; HR: 0.75; 95% CI: 0.572-0.83; adjusted HR: 0.73, 95% CI: 0.563-0.964; P < 0.05). LOS_ICU and LOS_Hospital were significantly shorter in the heparin group (P < 0.001), with no significant difference in gastrointestinal bleeding incidence between the two groups. Cox proportional hazards models demonstrated that heparin dose and duration were strongly associated with 45-d survival. Subgroup analysis indicated a significant survival advantage in patients aged 18-60 years, without diabetes, chronic obstructive pulmonary disease, or stage 1 acute kidney injury, who received a daily heparin dose of 3 mL for more than 7 d. Conclusion Our study found that early administration of heparin, particularly in sufficient doses (Heparin Sodium 5,000 units/mL, 1 mL per dose, three times daily (TID)) for more than 7 d, was associated with reduced near-term mortality in critically ill patients with pneumonia-induced sepsis. These findings underscore the potential benefits of anticoagulant therapy in this high-risk patient population.
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Affiliation(s)
| | | | | | | | | | | | - Xiaodong Jiang
- The Second Hospital of Dalian Medical University, Dalian Medical University, Dalian, Liaoning, China
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Gong F, Zheng X, Zhao S, Liu H, Chen E, Xie R, Li R, Chen Y. Disseminated intravascular coagulation: cause, molecular mechanism, diagnosis, and therapy. MedComm (Beijing) 2025; 6:e70058. [PMID: 39822757 PMCID: PMC11733103 DOI: 10.1002/mco2.70058] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2024] [Revised: 12/12/2024] [Accepted: 12/13/2024] [Indexed: 01/19/2025] Open
Abstract
Disseminated intravascular coagulation (DIC) is a complex and serious condition characterized by widespread activation of the coagulation cascade, resulting in both thrombosis and bleeding. This review aims to provide a comprehensive overview of DIC, emphasizing its clinical significance and the need for improved management strategies. We explore the primary causes of DIC, including sepsis, trauma, malignancies, and obstetric complications, which trigger an overactive coagulation response. At the molecular level, DIC is marked by excessive thrombin generation, leading to platelet and fibrinogen activation while simultaneously depleting clotting factors, creating a paradoxical bleeding tendency. Diagnosing DIC is challenging and relies on a combination of existing diagnostic criteria and laboratory tests. Treatment strategies focus on addressing the underlying causes and may involve supportive care, anticoagulation therapy, and other supportive measures. Recent advances in understanding the pathophysiology of DIC are paving the way for more targeted therapeutic approaches. This review highlights the critical need for ongoing research to enhance diagnostic accuracy and treatment efficacy, ultimately improving patient outcomes in those affected by DIC.
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Affiliation(s)
- Fangchen Gong
- Department of EmergencyRuijin Hospital, Shanghai Jiao Tong University School of MedicineShanghaiChina
| | - Xiangtao Zheng
- Department of EmergencyRuijin Hospital, Shanghai Jiao Tong University School of MedicineShanghaiChina
| | - Shanzhi Zhao
- Department of EmergencyRuijin Hospital, Shanghai Jiao Tong University School of MedicineShanghaiChina
| | - Huan Liu
- Department of EmergencyRuijin Hospital, Shanghai Jiao Tong University School of MedicineShanghaiChina
| | - Erzhen Chen
- Department of EmergencyRuijin Hospital, Shanghai Jiao Tong University School of MedicineShanghaiChina
- Shanghai Institute of Aviation Medicine, Shanghai Jiao Tong University Medical School Affiliated Ruijin HospitalShanghaiChina
| | - Rongli Xie
- Department of General SurgeryRuijin Hospital Lu Wan Branch, Shanghai Jiaotong University School of MedicineShanghaiChina
| | - Ranran Li
- Department of Critical Care MedicineRuijin Hospital, Shanghai Jiao Tong University School of MedicineShanghaiChina
| | - Ying Chen
- Department of EmergencyRuijin Hospital, Shanghai Jiao Tong University School of MedicineShanghaiChina
- Department of Emergency and Critical Care MedicineRuijin Hospital Wuxi Branch, Shanghai Jiao Tong University School of MedicineWuxiChina
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Almeida TML, Freitas FGR, Figueiredo RC, Houly SG, Azevedo LCP, Cavalcanti AB, Damiani LP, Svicero BS, Souza MA, Bustamante CLS, Ramos FJS, Alves RSV, Atallah FC, Jackiu M, Pacheco ES, Schmidt RC, Serra FSC, Tomotani DYV, Zampieri FG, Machado FR. Acetylsalicylic Acid Treatment in Patients With Sepsis and Septic Shock: A Phase 2, Placebo-Controlled, Randomized Clinical Trial. Crit Care Med 2025; 53:e269-e281. [PMID: 39982179 DOI: 10.1097/ccm.0000000000006564] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/22/2025]
Abstract
OBJECTIVES Platelets play a critical role in the inflammatory response and coagulation. We aimed to evaluate whether the use of acetylsalicylic acid (ASA) would reduce the intensity of organ dysfunction in septic patients. DESIGN Randomized, blinded, parallel-group, placebo-controlled trial. SETTING Five general ICUs in Brazil. PATIENTS Adults with sepsis for no longer than 48 hours who had at least one severe organ dysfunction (lactate > 4 mmol/L, platelets < 100,000/mm3, Pao2/Fio2 ratio < 200, or septic shock). INTERVENTIONS Patients were randomized to receive 200 mg of ASA or placebo for 7 days. MEASUREMENTS AND MAIN RESULTS The primary outcome was the change in the Sequential Organ Failure Assessment (SOFA) score between day 0 and day 7 or date of discharge/death. Safety outcomes were major bleeding and the number of blood transfusions within 14 days. The planned sample size was 218 with interim safety analyses after enrolling 109 and 163 patients. The study was discontinued due to higher frequency of major bleeding in the ASA group. We included 166 patients (ASA: 82 patients, placebo: 84). In the adjusted analysis, there was no difference in the SOFA change between the groups (mean placebo to ASA group difference, 0.60; 95% CI, -0.55 to 1.75; p = 0.30). There were no differences in any of the secondary outcomes. In the intervention group, there were a higher number of serious adverse events (9 [11%] vs. 1 [1.2%]; p = 0.009) and major bleeding (8 [8.5%] vs. 1 [1.2%]; p = 0.02). CONCLUSIONS In this population of septic patients, ASA did not reduce the intensity of organ dysfunction. ASA increased the risk of severe bleeding compared with placebo.
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Affiliation(s)
- Thiago M L Almeida
- Intensive Care Department, Hospital São Paulo, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil
- Programa de Pós-graduação em Medicina Translacional, Pró-Reitoria de Pós-Graduação e Pesquisa, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil
- Brazilian Research in Intensive Care Network, BRICNET, São Paulo, Brazil
- Intensive Care Unit, Hospital Japonês Santa Cruz, São Paulo, Brazil
| | - Flávio G R Freitas
- Intensive Care Department, Hospital São Paulo, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil
- Programa de Pós-graduação em Medicina Translacional, Pró-Reitoria de Pós-Graduação e Pesquisa, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil
- Brazilian Research in Intensive Care Network, BRICNET, São Paulo, Brazil
- Intensive Care Unit, Hospital SEPACO, São Paulo, Brazil
| | | | - Sandra G Houly
- Internal Medicine Department, Hospital São Paulo, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil
| | | | | | - Lucas P Damiani
- Brazilian Research in Intensive Care Network, BRICNET, São Paulo, Brazil
| | - Bianca S Svicero
- Intensive Care Department, Hospital São Paulo, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil
| | - Maria A Souza
- Intensive Care Department, Hospital São Paulo, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil
| | | | - Fernando J S Ramos
- Intensive Care Department, Hospital São Paulo, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil
- Programa de Pós-graduação em Medicina Translacional, Pró-Reitoria de Pós-Graduação e Pesquisa, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil
- Brazilian Research in Intensive Care Network, BRICNET, São Paulo, Brazil
| | - Rafael S V Alves
- Intensive Care Department, Hospital São Paulo, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil
- Programa de Pós-graduação em Medicina Translacional, Pró-Reitoria de Pós-Graduação e Pesquisa, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil
| | - Fernanda C Atallah
- Intensive Care Department, Hospital São Paulo, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil
| | - Míriam Jackiu
- Intensive Care Department, Hospital São Paulo, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil
| | - Eduardo S Pacheco
- Intensive Care Department, Hospital São Paulo, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil
| | - Raysa C Schmidt
- Intensive Care Department, Hospital São Paulo, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil
- Programa de Pós-graduação em Medicina Translacional, Pró-Reitoria de Pós-Graduação e Pesquisa, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil
| | - Felipe S C Serra
- Intensive Care Department, Hospital São Paulo, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil
| | - Daniere Y V Tomotani
- Intensive Care Department, Hospital São Paulo, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil
- Brazilian Research in Intensive Care Network, BRICNET, São Paulo, Brazil
| | - Fernando G Zampieri
- Intensive Care Department, Hospital São Paulo, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil
- Brazilian Research in Intensive Care Network, BRICNET, São Paulo, Brazil
| | - Flávia R Machado
- Intensive Care Department, Hospital São Paulo, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil
- Programa de Pós-graduação em Medicina Translacional, Pró-Reitoria de Pós-Graduação e Pesquisa, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil
- Brazilian Research in Intensive Care Network, BRICNET, São Paulo, Brazil
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Curtiaud A, Iba T, Angles-Cano E, Meziani F, Helms J. Biomarkers of sepsis-induced coagulopathy: diagnostic insights and potential therapeutic implications. Ann Intensive Care 2025; 15:12. [PMID: 39821561 PMCID: PMC11739444 DOI: 10.1186/s13613-025-01434-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2024] [Accepted: 01/06/2025] [Indexed: 01/19/2025] Open
Abstract
Diagnosing coagulopathy in septic patients remains challenging in intensive care. Disseminated intravascular coagulation (DIC) indeed presents with complex pathophysiology, complicating timely diagnosis. Epidemiological data indicate a significant prevalence of DIC in septic patients, with mortality rates up to 60%. Despite advances, current biomarker-based diagnostic tools often fail to provide early and accurate detection. This review evaluates the utility and limitations of traditional and emerging biomarkers for diagnosing sepsis-induced coagulopathy (SIC) and DIC. We also assess the effectiveness of anticoagulant therapy guided by biomarker-based diagnostic criteria.
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Affiliation(s)
- Anaïs Curtiaud
- Faculté de Médecine, Service de Médecine Intensive-Réanimation, Université de Strasbourg (UNISTRA), Hôpitaux universitaires de Strasbourg, Nouvel Hôpital Civil, 1, place de l'Hôpital, Strasbourg, F-67091, cedex, France
- INSERM (French National Institute of Health and Medical Research), UMR 1260, Regenerative Nanomedicine (RNM), FMTS, Strasbourg, France
| | - Toshiaki Iba
- Department of Emergency and Disaster Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Eduardo Angles-Cano
- Innovative Therapies in Haemostasis, Université Paris Cité - INSERM U-1140, Paris, 75006, France
| | - Ferhat Meziani
- Faculté de Médecine, Service de Médecine Intensive-Réanimation, Université de Strasbourg (UNISTRA), Hôpitaux universitaires de Strasbourg, Nouvel Hôpital Civil, 1, place de l'Hôpital, Strasbourg, F-67091, cedex, France
- INSERM (French National Institute of Health and Medical Research), UMR 1260, Regenerative Nanomedicine (RNM), FMTS, Strasbourg, France
| | - Julie Helms
- Faculté de Médecine, Service de Médecine Intensive-Réanimation, Université de Strasbourg (UNISTRA), Hôpitaux universitaires de Strasbourg, Nouvel Hôpital Civil, 1, place de l'Hôpital, Strasbourg, F-67091, cedex, France.
- INSERM (French National Institute of Health and Medical Research), UMR 1260, Regenerative Nanomedicine (RNM), FMTS, Strasbourg, France.
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Yu S, Chi Y, Ma X, Li X. Heparin in sepsis: current clinical findings and possible mechanisms. Front Immunol 2024; 15:1495260. [PMID: 39712008 PMCID: PMC11659142 DOI: 10.3389/fimmu.2024.1495260] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2024] [Accepted: 11/22/2024] [Indexed: 12/24/2024] Open
Abstract
Sepsis is a clinical syndrome resulting from the interaction between coagulation, inflammation, immunity and other systems. Coagulation activation is an initial factor for sepsis to develop into multiple organ dysfunction. Therefore, anticoagulant therapy may be beneficial for sepsis patients. Heparin possesses a variety of biological activities, so it has a broad prospect in sepsis. Previous studies suggested that patients with sepsis-induced disseminated intravascular coagulation and high disease severity might be suitable for anticoagulant therapy. With the development of artificial intelligence (AI), recent studies have shown that patients with severe coagulation activation represent the targeted patients for anticoagulant therapy in sepsis. However, it remains necessary to accurately define the relevant biomarkers indicative of this phenotype and validate their clinical utility by large randomized controlled trials (RCTs). Analyses of data from early small RCTs, subgroup analyses of large RCTs and meta-analyses have collectively suggested that anticoagulant therapy, particularly the use of heparin, may be an effective approach for managing sepsis patients. Concurrently, debate persists regarding the optimal selection of anticoagulants, proper timing, usage and dosage of administration that should be employed to assess treatment efficacy. The primary mechanisms of heparin are acting on heparan sulfate, histones, high mobility group box 1 and heparin-binding protein, which interfere with the regulation of inflammation, vascular permeability, coagulation, endothelial function and other biological activities. However, the underlying pathophysiological processes mediating the potential therapeutic effects of heparin in the context of sepsis remain incompletely understood and warrant additional rigorous investigation to establish the mechanism more conclusively.
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Affiliation(s)
| | | | | | - Xu Li
- Department of Critical Care Medicine, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
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Allam S, Na J, Moon J, Desai Y, Messner C, Potenza R, Sonbol M, Abushullaih F, Aljudaibi A, Abraham M, Chen K, Kotloff E, Hossain S, Esmati E, Kutner T, Norcross G, Childress J, Han P, Welch I, Sokolow M, See V, Wang L. Bleeding, stroke, and mortality risk of patients with septic shock receiving anticoagulation for atrial fibrillation. Heart Rhythm 2024:S1547-5271(24)03638-5. [PMID: 39647561 DOI: 10.1016/j.hrthm.2024.12.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2024] [Revised: 11/13/2024] [Accepted: 12/02/2024] [Indexed: 12/10/2024]
Abstract
BACKGROUND There are limited data on the effects of therapeutic anticoagulation (AC) on stroke and bleeding risk in patients with sepsis-induced atrial fibrillation (AF). OBJECTIVE This study aimed to determine the effect of therapeutic AC on the development of inpatient strokes and significant bleeding in hospitalized patients with septic shock and AF. METHODS This single-center, retrospective study examined 604 patients with septic shock and AF. The total AF population was further subdivided into new-onset AF. Propensity score matching was used to match patients with similar comorbidities who received and did not receive AC. The risks of bleeding, in-hospital stroke, increased length of stay, and mortality were compared between propensity score-matched cohorts. RESULTS Bleeding Academic Research Consortium 2 and 3a bleeding events were the most common. After propensity score matching, the relative risk of bleeding on AC was not significantly higher in either group (AF, 1.33 [95% confidence interval, 0.81-2.17]; new-onset AF, 1.60 [95% confidence interval, 0.72-3.54]). AC also did not decrease the number of ischemic strokes (AF, 1.34% with AC vs 1.34% without AC [P = 1]; new-onset AF, 0.89% with AC vs 1.79% without AC [P = .56]). There was significantly reduced mortality of patients who received AC (AF, 52.35% with AC vs 66.44% without AC [P = .01]; new-onset AF, 46.43% with AC vs 66.07% without AC [P = .04]). CONCLUSION In patients with septic shock and AF, AC was not associated with a higher incidence of bleeding or lowering of in-hospital strokes but was associated with decreased mortality, potentially protecting against disseminated intravascular coagulopathy or other embolic phenomena.
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Affiliation(s)
- Sahitya Allam
- Department of Internal Medicine, University of Maryland School of Medicine, Baltimore, Maryland.
| | - Jonathan Na
- Department of Internal Medicine, University of Maryland School of Medicine, Baltimore, Maryland
| | - Joanne Moon
- Department of Internal Medicine, University of Maryland School of Medicine, Baltimore, Maryland
| | - Yash Desai
- Department of Internal Medicine, University of Maryland School of Medicine, Baltimore, Maryland
| | - Christopher Messner
- Department of Internal Medicine, University of Maryland School of Medicine, Baltimore, Maryland
| | - Robert Potenza
- Department of Internal Medicine, University of Maryland School of Medicine, Baltimore, Maryland
| | - Mark Sonbol
- Department of Internal Medicine, University of Maryland School of Medicine, Baltimore, Maryland
| | - Faisal Abushullaih
- Department of Internal Medicine, University of Maryland School of Medicine, Baltimore, Maryland
| | - Abdullah Aljudaibi
- Department of Internal Medicine, University of Maryland School of Medicine, Baltimore, Maryland
| | - Maria Abraham
- Department of Internal Medicine, University of Maryland School of Medicine, Baltimore, Maryland
| | - Kevin Chen
- Department of Internal Medicine, University of Maryland School of Medicine, Baltimore, Maryland
| | - Ethan Kotloff
- Department of Internal Medicine, University of Maryland School of Medicine, Baltimore, Maryland
| | - Simin Hossain
- Department of Internal Medicine, University of Maryland School of Medicine, Baltimore, Maryland
| | - Elnaz Esmati
- Department of Internal Medicine, University of Maryland School of Medicine, Baltimore, Maryland
| | - Thomas Kutner
- Department of Internal Medicine, University of Maryland School of Medicine, Baltimore, Maryland
| | - Gregory Norcross
- Department of Internal Medicine, University of Maryland School of Medicine, Baltimore, Maryland
| | - James Childress
- Department of Internal Medicine, University of Maryland School of Medicine, Baltimore, Maryland
| | - Paul Han
- Department of Internal Medicine, University of Maryland School of Medicine, Baltimore, Maryland
| | - Ian Welch
- Department of Internal Medicine, University of Maryland School of Medicine, Baltimore, Maryland
| | - Michael Sokolow
- Quality Management Department, University of Maryland Medical System, Baltimore, Maryland
| | - Vincent See
- Division of Cardiovascular Medicine, Department of Internal Medicine, University of Maryland School of Medicine, Baltimore, Maryland
| | - Libin Wang
- Division of Cardiovascular Medicine, Department of Internal Medicine, University of Maryland School of Medicine, Baltimore, Maryland
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9
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Iba T, Helms J, Totoki T, Levy JH. Heparins May Not Be the Optimal Anticoagulants for Sepsis and Sepsis-Associated Disseminated Intravascular Coagulation. Semin Thromb Hemost 2024; 50:1012-1018. [PMID: 38733977 DOI: 10.1055/s-0044-1786754] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/13/2024]
Abstract
Historically, heparin has had the longest historical use as an anticoagulant and continues this day to be the primary therapeutic option for preventing thrombosis and thromboembolism in critically ill hospitalized patients. Heparin is also used to treat sepsis and sepsis-associated disseminated intravascular coagulation (DIC) in various countries. However, the efficacy and safety of heparin for this indication remains controversial, as adequately powered randomized clinical studies have not demonstrated as yet a survival benefit in sepsis and sepsis-associated DIC, despite meta-analyses and propensity analyses reporting improved outcomes without increasing bleeding risk. Further, activated protein C and recombinant thrombomodulin showed greater improvements in outcomes compared with heparin, although these effects were inconclusive. In summary, further research is warranted, despite the ongoing clinical use of heparin for sepsis and sepsis-associated DIC. Based on Japanese guidelines, antithrombin or recombinant thrombomodulin may be a preferable choice if they are accessible.
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Affiliation(s)
- Toshiaki Iba
- Department of Emergency and Disaster Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Julie Helms
- Strasbourg University Hospital, Medical Intensive Care Unit - NHC, INSERM (French National Institute of Health and Medical Research), Strasbourg University (UNISTRA), UMR 1260, Regenerative Nanomedicine (RNM), FMTS, Strasbourg, France
| | - Takaaki Totoki
- Department of Anesthesiology and Critical Care Medicine, Kyushu University, Fukuoka, Japan
| | - Jerrold H Levy
- Department of Anesthesiology, Critical Care, and Surgery, Duke University School of Medicine, Durham, North Carolina
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10
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Guo QY, Peng J, Shan TC, Xu M. Risk Factors for Mortality in Critically Ill Patients with Coagulation Abnormalities: A Retrospective Cohort Study. Curr Med Sci 2024; 44:912-922. [PMID: 39285052 DOI: 10.1007/s11596-024-2920-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2024] [Accepted: 07/18/2024] [Indexed: 10/25/2024]
Abstract
OBJECTIVE Coagulation abnormalities are common and prognostically significant in intensive care units (ICUs) and are associated with increased mortality. This study aimed to explore the association between the levels of coagulation markers and the risk of mortality among ICU patients with coagulation abnormalities. METHODS This retrospective study investigated patients with coagulation abnormalities in the ICU between January 2021 and December 2022. The initial point for detecting hemostatic biomarkers due to clinical assessment of coagulation abnormalities was designated day 0. Patients were followed up for 28 days, and multivariate logistic regression analysis was utilized to identify risk factors for mortality. RESULTS Of the 451 patients analyzed, 115 died, and 336 were alive at the end of the 28-day period. Multivariate analysis revealed that elevated thrombin-antithrombin complex (TAT), tissue plasminogen activator inhibitor complex (tPAIC), prolonged prothrombin time, and thrombocytopenia were independent risk factors for mortality. For nonovert disseminated intravascular coagulation (DIC) patients, older age and thrombocytopenia were associated with increased risks of mortality, whereas elevated levels of plasmin α2-plasmin inhibitor complex (PIC) were found to be independent predictors of survival. In patients with overt DIC, elevated levels of tPAIC were independently associated with increased risks of mortality. Nevertheless, thrombocytopenia was independently associated with increased risks of mortality in patients with pre-DIC. CONCLUSION Coagulation markers such as the TAT, tPAIC, PIC, and platelet count were significantly associated with mortality, underscoring the importance of maintaining a balance between coagulation and fibrinolysis. These findings highlight the potential for targeted therapeutic interventions based on specific coagulation markers to improve patient outcomes.
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Affiliation(s)
- Qiu-Yu Guo
- Department of Hematology, Qilu Hospital of Shandong University, Jinan, 250012, China
| | - Jun Peng
- Department of Hematology, Qilu Hospital of Shandong University, Jinan, 250012, China
| | - Ti-Chao Shan
- Department of Critical Care Medicine, Qilu Hospital of Shandong University, Jinan, 250012, China.
| | - Miao Xu
- Department of Hematology, Qilu Hospital of Shandong University, Jinan, 250012, China.
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Totoki T, Koami H, Makino Y, Wada T, Ito T, Yamakawa K, Iba T. Heparin therapy in sepsis and sepsis-associated disseminated intravascular coagulation: a systematic review and meta-analysis. Thromb J 2024; 22:84. [PMID: 39350146 PMCID: PMC11440886 DOI: 10.1186/s12959-024-00653-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2024] [Accepted: 09/12/2024] [Indexed: 10/04/2024] Open
Abstract
BACKGROUND Sepsis is a life-threatening condition that affects 49 million people annually. Managing sepsis-associated coagulopathy poses a significant challenge due to its high mortality rates in intensive care. Recent reports suggest that administering heparin may offer potential survival benefits in sepsis and coronavirus disease cases. However, there is currently no established evidence supporting the use of heparin for sepsis. Thus, in this study, we aimed to assess the efficacy of heparin administration in patients with sepsis. METHODS A systematic review was conducted following the PRISMA guidelines. The searches included MEDLINE, Cochrane, and Japanese databases up to January 2023. The inclusion criteria consisted of randomized control trials (RCTs) involving adult sepsis patients receiving heparin. The risk of bias was assessed using RoB2, and the data extraction included 28-day mortality and bleeding complications. RESULTS Out of 1733 initial articles, only three studies met the inclusion criteria. The analysis, which included 426 patients, showed no significant difference in 28-day and in-hospital mortality between the heparin and control groups (risk ratio [RR] = 0.86, 95% confidence interval [CI]: 0.60-1.24). Subgroup analysis of sepsis-associated disseminated intravascular coagulation (DIC) patients (n = 109) also did not show a significant reduction in mortality (RR = 0.84, 95% CI: 0.51-1.38). Heterogeneity was zero, and no publication bias was observed. Additionally, there was significant difference in bleeding complications (RR = 0.49, 95% CI: 0.24-0.99, p = 0.047). CONCLUSIONS This meta-analysis did not demonstrate a survival benefit of heparin administration in patients with sepsis and sepsis-associated DIC. Further investigation into the potential benefits of heparin is warranted. Moreover, the analysis revealed no increase in bleeding risks with heparin administration; instead, a significant reduction in the risk of bleeding was noted. TRIAL REGISTRATION This review was preregistered with PROSPERO (registration: CRD42023385091).
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Affiliation(s)
- Takaaki Totoki
- Department of Emergency and Critical Care Medicine, Osaka Medical and Pharmaceutical University, Osaka, Japan.
| | - Hiroyuki Koami
- Advanced Emergency Care Center, Saga University Hospital, Saga, Japan
| | - Yuto Makino
- Department of Anesthesiology and Intensive Care Medicine, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Takeshi Wada
- Division of Acute and Critical Care Medicine, Department of Anesthesiology and Critical Care Medicine, Hokkaido University Faculty of Medicine, Sapporo, Japan
| | - Takashi Ito
- Department of Hematology and Immunology, Faculty of Life Sciences Kumamoto University, Kumamoto, Japan
| | - Kazuma Yamakawa
- Department of Emergency and Critical Care Medicine, Osaka Medical and Pharmaceutical University, Osaka, Japan
| | - Toshiaki Iba
- Department of Emergency and Disaster Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan
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Zhang H, Song X, Ge S, Song W, Wang F, Yin Q, Zhang M, Zhuang P, Zhang Y. Zixue Powder attenuates septic thrombosis via reducing neutrophil extracellular trap through blocking platelet STING activation. JOURNAL OF ETHNOPHARMACOLOGY 2024; 331:118337. [PMID: 38740110 DOI: 10.1016/j.jep.2024.118337] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/18/2024] [Revised: 05/09/2024] [Accepted: 05/10/2024] [Indexed: 05/16/2024]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Microthrombosis is commonly seen in sepsis and COVID-19. Zixue Powder (ZXP) is a traditional Chinese herbal formula with the potential to treat microvascular and infectious diseases. However, the role and mechanism of ZXP in sepsis-associated thrombosis remain unclear. AIM OF THE STUDY Investigating the therapeutic effectiveness and underlying mechanisms of ZXP in septic thrombosis. MATERIALS AND METHODS ZXP's compositions were examined with UPLC-QTOF-MS. The efficacy of ZXP on sepsis-induced thrombosis was assessed through various methods: liver tissue pathology was examined using hematoxylin-eosin staining, platelet count was determined by a blood cell analyzer, and an enzyme-linked immunosorbent assay (ELISA) was used to detect the levels of serum tissue factor (TF), thromboxane B2 (TXB2), D-Dimer, and plasminogen activator inhibitor-1 (PAI-1). Neutrophil extracellular traps (NETs) were localized and expressed in liver tissues by immunofluorescence, and the number of NETs in peripheral blood was evaluated by ELISA, which measured the quantity of cf-DNA and MPO-DNA in serum. Platelet P-selectin expression and platelet-neutrophil aggregation were measured by flow cytometry, and plasma P-selectin expression was measured by ELISA. Furthermore, the mechanism of the stimulator of interferon genes (STING) signaling pathway in ZXP's anti-sepsis thrombosis effect was investigated using the STING agonist, Western blot experiments, and immunoprecipitation experiments. RESULTS UPLC-QTOF-MS identified 40 chemical compositions of ZXP. Administration of ZXP resulted in significant improvements in liver thrombosis, platelet counts, and levels of TXB2, TF, PAI-1, and D-Dimer in septic rats. Moreover, ZXP inhibited NETs formation in both liver tissue and peripheral blood. Additionally, ZXP decreased the levels of P-selectin in both platelets and plasma, as well as the formation of platelet-neutrophil aggregates, thereby suppressing P-selectin-mediated NETs release. Immunoprecipitation and immunofluorescence staining experiments revealed that ZXP attenuated P-selectin secretion by inhibiting STING-mediated assembly of platelet soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs) complex, ultimately preventing inhibition of NETs formation. CONCLUSION Our study showed that ZXP effectively mitigates platelet granule secretion primarily through modulation of the STING pathway, consequently impeding NET-associated thrombosis in sepsis. These findings offer valuable insights for future research on the development and application of ZXP.
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Affiliation(s)
- Hanyu Zhang
- State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China; Haihe Laboratory of Modern Chinese Medicine, Tianjin, 301617, China
| | - Xuejiao Song
- State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China; Haihe Laboratory of Modern Chinese Medicine, Tianjin, 301617, China
| | - Shining Ge
- State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China; Haihe Laboratory of Modern Chinese Medicine, Tianjin, 301617, China
| | - Wen Song
- Tianjin Hongrentang Pharmaceutical Co., Ltd, Tianjin, 300193, China
| | - Fan Wang
- Tianjin Hongrentang Pharmaceutical Co., Ltd, Tianjin, 300193, China
| | - Qingsheng Yin
- State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China; Haihe Laboratory of Modern Chinese Medicine, Tianjin, 301617, China
| | - Mixia Zhang
- College of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China
| | - Pengwei Zhuang
- State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China; Haihe Laboratory of Modern Chinese Medicine, Tianjin, 301617, China; First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, 300193, China; National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, 300193, China.
| | - Yanjun Zhang
- State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China; Haihe Laboratory of Modern Chinese Medicine, Tianjin, 301617, China; First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, 300193, China; National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, 300193, China.
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Xu ZY, Peng M, Fan MM, Zou QF, Li YR, Jiang D. Heparin is an effective treatment for preventing liver failure after hepatectomy. World J Gastroenterol 2024; 30:2881-2892. [PMID: 38947296 PMCID: PMC11212721 DOI: 10.3748/wjg.v30.i22.2881] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2024] [Revised: 04/26/2024] [Accepted: 05/20/2024] [Indexed: 06/05/2024] Open
Abstract
BACKGROUND Posthepatectomy liver failure (PHLF) is one of the most important causes of death following liver resection. Heparin, an established anticoagulant, can protect liver function through a number of mechanisms, and thus, prevent liver failure. AIM To look at the safety and efficacy of heparin in preventing hepatic dysfunction after hepatectomy. METHODS The data was extracted from Multiparameter Intelligent Monitoring in Intensive Care III (MIMIC-III) v1. 4 pinpointed patients who had undergone hepatectomy for liver cancer, subdividing them into two cohorts: Those who were injected with heparin and those who were not. The statistical evaluations used were unpaired t-tests, Mann-Whitney U tests, chi-square tests, and Fisher's exact tests to assess the effect of heparin administration on PHLF, duration of intensive care unit (ICU) stay, need for mechanical ventilation, use of continuous renal replacement therapy (CRRT), incidence of hypoxemia, development of acute kidney injury, and ICU mortality. Logistic regression was utilized to analyze the factors related to PHLF, with propensity score matching (PSM) aiming to balance the preoperative disparities between the two groups. RESULTS In this study, 1388 patients who underwent liver cancer hepatectomy were analyzed. PSM yielded 213 matched pairs from the heparin-treated and control groups. Initial univariate analyses indicated that heparin potentially reduces the risk of PHLF in both matched and unmatched samples. Further analysis in the matched cohorts confirmed a significant association, with heparin reducing the risk of PHLF (odds ratio: 0.518; 95% confidence interval: 0.295-0.910; P = 0.022). Additionally, heparin treatment correlated with improved short-term postoperative outcomes such as reduced ICU stay durations, diminished requirements for respiratory support and CRRT, and lower incidences of hypoxemia and ICU mortality. CONCLUSION Liver failure is an important hazard following hepatic surgery. During ICU care heparin administration has been proved to decrease the occurrence of hepatectomy induced liver failure. This indicates that heparin may provide a hopeful option for controlling PHLF.
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Affiliation(s)
- Zhi-Ying Xu
- Hepatic Surgery IV, Shanghai Eastern Hepatobiliary Surgery Hospital, The Third Affiliated Hospital of Naval Medical University, Shanghai 200433, China
| | - Min Peng
- Ultrasound Diagnosis, PLA Naval Medical Center, Shanghai 200437, China
| | - Ming-Ming Fan
- Hepatic Surgery IV, Shanghai Eastern Hepatobiliary Surgery Hospital, The Third Affiliated Hospital of Naval Medical University, Shanghai 200433, China
| | - Qi-Fei Zou
- Hepatic Surgery IV, Shanghai Eastern Hepatobiliary Surgery Hospital, The Third Affiliated Hospital of Naval Medical University, Shanghai 200433, China
| | - Yi-Ran Li
- Department of Ultrasound, Eastern Hepatobiliary Surgery Hospital, The Third Affiliated Hospital of Naval Medical University, Shanghai 200433, China
| | - Dong Jiang
- Department of Ultrasound, Eastern Hepatobiliary Surgery Hospital, The Third Affiliated Hospital of Naval Medical University, Shanghai 200433, China
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Zhong T, Chen S, Deng K, Guan J, Zhang J, Lu F, Shichen M, Lv R, Liu Z, Liu Y, Chang P, Liu Z. Magnesium alleviates extracellular histone-induced apoptosis and defective bacterial phagocytosis in macrophages by regulating intracellular calcium signal. Int Immunopharmacol 2024; 132:111870. [PMID: 38547771 DOI: 10.1016/j.intimp.2024.111870] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2024] [Revised: 02/18/2024] [Accepted: 03/12/2024] [Indexed: 05/01/2024]
Abstract
Extracellular histones have been determined as important mediators of sepsis, which induce excessive inflammatory responses in macrophages and impair innate immunity. Magnesium (Mg2+), one of the essential nutrients of the human body, contributes to the proper regulation of immune function. However, no reports indicate whether extracellular histones affect survival and bacterial phagocytosis in macrophages and whether Mg2+ is protective against histone-induced macrophage damage. Our clinical data revealed a negative correlation between circulating histone and monocyte levels in septic patients, and in vitro experiments confirmed that histones induced mitochondria-associated apoptosis and defective bacterial phagocytosis in macrophages. Interestingly, our clinical data also indicated an association between lower serum Mg2+ levels and reduced monocyte levels in septic patients. Moreover, in vitro experiments demonstrated that Mg2+ attenuated histone-induced apoptosis and defective bacterial phagocytosis in macrophages through the PLC/IP3R/STIM-mediated calcium signaling pathway. Importantly, further animal experiments proved that Mg2+ significantly improved survival and attenuated histone-mediated lung injury and macrophage damage in histone-stimulated mice. Additionally, in a cecal ligation and puncture (CLP) + histone-induced injury mouse model, Mg2+ inhibited histone-mediated apoptosis and defective phagocytosis in macrophages and further reduced bacterial load. Overall, these results suggest that Mg2+ supplementation may be a promising treatment for extracellular histone-mediated macrophage damage in sepsis.
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Affiliation(s)
- Tao Zhong
- Department of Critical Care Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Sainan Chen
- Department of Critical Care Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Ke Deng
- Department of Critical Care Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Jianbin Guan
- Department of Critical Care Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Jiaqi Zhang
- Department of Critical Care Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Furong Lu
- Department of Critical Care Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Maoyou Shichen
- Department of Critical Care Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Ronggui Lv
- Department of Intensive Care Unit, Shenzhen Hospital, Southern Medical University, Shenzhen, Guangdong, China
| | - Zhifeng Liu
- Department of Medicine Intensive Care Units, General Hospital of Southern Theatre Command of PLA, Guangzhou, Guangdong, China.
| | - Yong Liu
- Department of Intensive Care Unit, Shenzhen Hospital, Southern Medical University, Shenzhen, Guangdong, China.
| | - Ping Chang
- Department of Critical Care Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China.
| | - Zhanguo Liu
- Department of Critical Care Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China.
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Chanthong S, Choed-Amphai C, Manowong S, Tuntivate P, Tansriratanawong S, Makonkawkeyoon K, Natesirinilkul R. Rotational Thromboelastometry and Clot Waveform Analysis as Point-of-Care Tests for Diagnosis of Disseminated Intravascular Coagulation in Critically Ill Children in Thailand. Pediatr Crit Care Med 2024; 25:e221-e231. [PMID: 38299935 DOI: 10.1097/pcc.0000000000003452] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/02/2024]
Abstract
OBJECTIVES This study aimed to determine the test performances of rotational thromboelastometry (ROTEM) and activated partial thromboplastin time-based clot waveform analysis (aPTT-CWA) compared with the International Society on Thrombosis and Hemostasis disseminated intravascular coagulation (ISTH-DIC) score for diagnosis of overt disseminated intravascular coagulation (ODIC) in critically ill children. Prognostic indicators of DIC complications were also evaluated. DESIGN A prospective cross-sectional observational study was conducted. ROTEM and aPTT-CWA were assessed alongside standard parameters based on the ISTH-DIC score and natural anticoagulants. Both conventional and global hemostatic tests were repeated on days 3-5 for nonovert DIC. SETTING PICU of the Department of Pediatrics, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand. SUBJECTS Infants and children who were admitted to PICU with underlying diseases predisposed to DIC, such as sepsis, malignancy, major surgery, trauma, or severe illness, were included in the study between July 1, 2021, and November 30, 2022. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS Sixty-four children were enrolled in this study. The prevalence of ODIC was 20.3%. Regarding ROTEM parameters, using EXTEM clot formation time (CFT) cutoff of greater than 102 seconds provided sensitivity and specificity of 90.9% and 80.9%, respectively, for diagnosing ODIC, with the area under the curve (AUC) of 0.86. In the case of aPTT-CWA performance, no biphasic waveform was observed, whereas both maximum coagulation acceleration (Min2) of less than 0.35%/s 2 and maximum coagulation deceleration of less than 0.25%/s 2 demonstrated identical sensitivities of 76.9% and specificities of 79.6%. Combining two global hemostatic tests significantly improved the diagnostic performance (INTEM CFT + EXTEM CFT + Min2 AUC 0.92 [95% CI, 0.80-1.00] vs. EXTEM CFT AUC 0.86 [95% CI, 0.75-0.96], p = 0.034). Bleeding was the most common consequence. In multivariable logistic regression analysis, Min2 of less than 0.36%/s 2 was an independent risk factor for bleeding complications, with an adjusted odds ratio of 15.08 (95% CI, 1.08-211.15, p = 0.044). CONCLUSIONS ROTEM and aPTT-CWA were valuable diagnostic tools in critically ill children who might require point-of-care tests. Min2 showed significant clinical implications for predicting bleeding events in this population.
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Affiliation(s)
- Supapitch Chanthong
- Department of Pediatrics, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| | - Chane Choed-Amphai
- Department of Pediatrics, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| | - Suphara Manowong
- Department of Pediatrics, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| | - Pakinee Tuntivate
- Hematology Laboratory, Department of Internal Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| | | | - Krit Makonkawkeyoon
- Department of Pediatrics, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
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Alana NB, Ciurylo WA, Hurlock N. HMG-CoA reductase inhibitors and the attenuation of risk for disseminated intravascular coagulation in patients with sepsis. J Thromb Thrombolysis 2024; 57:260-268. [PMID: 37945940 DOI: 10.1007/s11239-023-02910-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 10/22/2023] [Indexed: 11/12/2023]
Abstract
BACKGROUND Disseminated Intravascular Coagulation (DIC) is a syndrome of dysregulated coagulation. Patients with sepsis are at increased risk for DIC. HMG-CoA Reductase Inhibitors (Statins) are primarily used as lipid-lowering agents; however, studies have suggested statins may possess anti-inflammatory, antithrombotic, anticoagulant, and endothelial stabilizing properties. These mechanisms may oppose those that underlie the pathogenesis of septic DIC. METHODS To evaluate whether statins may be protective against the development of DIC, we conducted a multi-center, retrospective case-control study where 86,638 critically ill patients admitted to the ICU with sepsis, severe sepsis or septic shock were identified during a 3-year period. Patients who developed DIC during their hospitalization were identified and stratified by whether they received a statin or not during their hospitalization. Odds ratios for development of DIC was calculated by composite of any statin, as well as low, moderate, and high intensity statins. RESULTS 2236 patients would develop DIC compared to 84,402 who did not. The use of any statin was associated with a reduced likelihood for developing DIC (odds ratio [OR], 0.69; 95% CI, 0.61-0.78). This was observed with use of both moderate (OR, 0.64; 95% CI, 0.53-0.77) and high (OR, 0.72; 95% CI, 0.61-0.84) but not low intensity statins (OR, 0.84; 95% CI, 0.53-1.32). CONCLUSIONS The use of moderate and high intensity statins was associated with a significantly reduced odds of developing DIC in critically ill patients with sepsis. This present study may be the first to suggest that statin medications may independently reduce the frequency of DIC in critically ill patients with severe sepsis or septic shock. More research is needed to investigate the potential for this class of medication to be protective against DIC.
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Affiliation(s)
- Nicholas B Alana
- Portsmouth Regional Hospital Internal Medicine Residency Program, HCA Healthcare/Tufts University School of Medicine, 333 Borthwick Ave. Portsmouth, New Hampshire, 03801, USA.
| | - William A Ciurylo
- Portsmouth Regional Hospital Internal Medicine Residency Program, HCA Healthcare/Tufts University School of Medicine, 333 Borthwick Ave. Portsmouth, New Hampshire, 03801, USA
| | - Natalie Hurlock
- HCA Healthcare, 2000 Health Park Drive, Brentwood, TN, 37027, UK
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Liu X, Li T, Chen H, Yuan L, Ao H. Role and intervention of PAD4 in NETs in acute respiratory distress syndrome. Respir Res 2024; 25:63. [PMID: 38291476 PMCID: PMC10829387 DOI: 10.1186/s12931-024-02676-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2023] [Accepted: 01/03/2024] [Indexed: 02/01/2024] Open
Abstract
BACKGROUND Sepsis is life-threatening organ dysfunction caused by a dysregulated host response to infection. Acute respiratory distress syndrome (ARDS) is a common sepsis-associated injury that can increase postoperative mortality but the mechanism is still unclear. MAIN TEXT The role of neutrophils in the pathophysiology of sepsis was deeply challenged after the discovery of NETosis, a process resulting in neutrophil extracellular traps (NETs) release. NETs can support thrombin generation and the concept of immunothrombosis has emerged as a new innate response to infection. Immunothrombosis leads to thrombosis in microvessels and supports immune cells together with specific thrombus-related molecules. ARDS is a common sepsis-associated organ injury. Immunothrombosis participates in thrombosis in pulmonary capillaries. Intervention regarding immunothrombosis in ARDS is a key scientific problem. PAD4 is the key enzyme regulating the NET skeleton protein histone H3 to citrulline histone to form NETs in immune thrombosis. This review summarizes NETosis and immunohaemostasis, ARDS and therapeutic opportunities targeting PAD4 via PAD4 inhibitors and lncRNAs potentially, providing future therapies. CONCLUSIONS We identified and summarized the fundamental definition of ARDS and the concept of immune thrombosis and its composition. NETs activation has become particularly relevant in the formation of immune thrombosis. The taskforce highlighted the intervention targets of PAD4, including noncoding RNAs, potentially providing future therapeutic targets to confront the high postoperative mortality of ARDS.
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Affiliation(s)
- Xiaojie Liu
- Department of Anesthesiology, The Affiliated Hospital of Qingdao University, No. 16, Jiangsu Road, Qingdao, Shandong, China
| | - Tianjun Li
- Department of Oncology, The Affiliated Hospital of Qingdao University, No. 59, Haier Road, Qingdao, Shandong, China
| | - Huailong Chen
- Department of Anestheiology, The Qingdao Eighth People's Hospital, No. 210 Jinshui Road, Licang District, Qingdao City, Shandong, China
| | - Li Yuan
- Department of Anesthesiology, The Affiliated Hospital of Qingdao University, No. 16, Jiangsu Road, Qingdao, Shandong, China.
| | - Hushan Ao
- Department of Anesthesiology, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No.167 North Lishi Road, Xicheng District, Beijing, China.
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Ge G, Bo D, Jiang R, Zhao W, Lu Y. Oral anticoagulants increased 30-day survival in sepsis patients complicated with atrial fibrillation: a retrospective analysis from MIMIC-IV database. Front Cardiovasc Med 2024; 11:1322045. [PMID: 38304138 PMCID: PMC10830619 DOI: 10.3389/fcvm.2024.1322045] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2023] [Accepted: 01/05/2024] [Indexed: 02/03/2024] Open
Abstract
Background The severity of sepsis is associated with systemic clotting activation. Atrial fibrillation (AF) is the most commonly observed arrhythmia in patients with sepsis and can lead to a poor prognosis. The aim of this study is to elucidate the association between oral anticoagulants and survival from septic patients complicated with AF. Methods The data of 8,828 septic patients, including 2,955 AF and 5,873 without AF, were all originated from the Medical Information Mart for Intensive Care IV (MIMIC-IV) database. Patients with sepsis and AF are divided into OAC- group (n = 1,774) and OAC+ group (n = 1,181) based on OAC therapy. Septic patients with no AF were considered as the control group (n = 5,873, sepsis and no AF group). The main outcome endpoint was the survival rate of 30 day. The secondary outcome endpoint was the length of stay (LOS) from intensive care unit and hospital. Propensity score matching (PSM) was used to adjust the influence of superfluous factors, and a restricted mean survival time (RMST) analysis was used for calculating the benefit of survival time and survival rate. Analysis including univariate and multivariate logistic regression analysis was conducted to find prognosis-related predictors. Results After PSM, the OAC+group had a higher 30-day survival rate compared to the OAC- group (81.59% vs. 58.10%; P < 0.001) in the ICU. Despite the higher survival, the hospital LOS (14.65 days vs. 16.66 days; P = 0.15) and ICU LOS (6.93 days vs. 5.92 days; P = 0.02) were prolonged at OAC+ group than OAC- group. No difference was found in survival rate of 30 day between the sepsis patients using warfarin and patients using NOAC (85.60% vs. 79.84%, P = 0.12). The sepsis patients using warfarin had a prolonged LOS in ICU and hospital compared with the sepsis patients using NOAC. In the vasopressor subgroup, patients who received NOAC therapy were associated with a reduced 30-day survival rate (73.57% vs. 84.03%; P = 0.04) and reduced LOS in ICU and hospital than those on warfarin therapy. Conclusion This study demonstrated that oral anticoagulants may increase the 30-day survival rate of patients with sepsis and AF.
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Affiliation(s)
- Gaoyuan Ge
- Department of Cardiology, The Affiliated Hospital of Yangzhou University, Yangzhou, Jiangsu, China
| | - Dan Bo
- Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Rongli Jiang
- Department of Geriatric, The Affiliated Hospital of Yangzhou University, Yangzhou, Jiangsu, China
| | - Wei Zhao
- Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Yao Lu
- Department of Cardiology, Xuzhou Central Hospital, Xuzhou Institute of Cardiovascular Disease, Xuzhou Clinical School of Nanjing Medical University, Xuzhou, Jiangsu, China
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Sun Y, Ding R, Sun H, Liang Y, Ma X. Efficacy and safety of heparin for sepsis-induced disseminated intravascular coagulation (HepSIC): study protocol for a multicenter randomized controlled trial. Trials 2024; 25:4. [PMID: 38167115 PMCID: PMC10759642 DOI: 10.1186/s13063-023-07853-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2023] [Accepted: 12/06/2023] [Indexed: 01/05/2024] Open
Abstract
BACKGROUND Disseminated intravascular coagulation (DIC) occurs in 30-50% of septic patients and contributes to high mortality in the intensive care unit (ICU). However, there are few proven interventions for coagulation disorder management in sepsis. Experimental and clinical data have demonstrated that sepsis could benefit from unfractionated heparin (UFH) treatment. To date, there are no large multicenter trials to determine the safety and efficacy of UFH in septic patients with suspected DIC. METHODS A multicenter, double-blinded, placebo-controlled randomized trial is designed to recruit 600 patients who met sepsis 3.0 criteria and suspected DIC. Participants will be randomized (1:1) to receive UFH or saline via continuous intravenous administration for 7 days within 6 h of enrolment. The primary outcome is ICU mortality. The secondary outcome includes 28-day all-cause mortality, the improvement of Sequential Organ Failure Assessment scores, and the incidence of major hemorrhage. Investigators, participants, and statisticians will be blinded to the allocation. DISCUSSION The HepSIC trial is to evaluate the efficacy and safety of UFH on sepsis-related DIC across different areas of China. The small dosage of UFH administration would offer a new potential approach for treating sepsis-related coagulation disorders. ETHICS AND DISSEMINATION Ethical approval was granted by all the ethics committees of 20 participant centers. Results will be disseminated via peer-reviewed publications and presented at conferences. TRIAL REGISTRATION ClinicalTrials.gov NCT02654561. Registered on 13 January 2016.
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Affiliation(s)
- Yini Sun
- Department of Critical Care Medicine, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Renyu Ding
- Department of Critical Care Medicine, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Hao Sun
- Department of Clinical Epidemiology and Evidence-based Medicine, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Yingjian Liang
- Department of Critical Care Medicine, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Xiaochun Ma
- Department of Critical Care Medicine, The First Affiliated Hospital of China Medical University, Shenyang, China.
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20
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Zhong T, Zhang J, Chen S, Chen S, Deng K, Guan J, Yang J, Lv R, Liu Z, Liu Y, Chang P, Liu Z. MAGNESIUM SULFATE AMELIORATES HISTONE-INDUCED COAGULATION DYSFUNCTION AND LUNG DAMAGE IN MICE. Shock 2024; 61:132-141. [PMID: 37988072 PMCID: PMC11841720 DOI: 10.1097/shk.0000000000002263] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2023] [Accepted: 10/19/2023] [Indexed: 11/22/2023]
Abstract
ABSTRACT Introduction: Extracellular histones have been determined as significant mediators of sepsis, which can induce endothelial cell injury and promote coagulation activation, and ultimately contribute to multiorgan failure. Evidence suggests that magnesium sulfate (MgSO 4 ) exerts a potential coagulation-modulating activity; however, whether MgSO 4 ameliorates histone-induced coagulation dysfunction and organ damage remains unclear. Methods: To measure circulating histone levels, blood specimens were collected from septic patients and mice, and the relationship between circulating histone levels, coagulation parameters, and Mg 2+ levels in sepsis was investigated. Furthermore, to explore the possible protective effects of MgSO 4 , we established a histone-induced coagulation model in mice by intravenous histone injection. The survival rate of mice was assessed, and the histopathological damage of the lungs (including endothelial cell injury and coagulation status) was evaluated using various methods, including hematoxylin and eosin staining, immunohistochemistry, immunofluorescence, electron microscopy, and quantitative polymerase chain reaction. Results: The circulating histone levels in septic patients and mice were significantly associated with several coagulation parameters. In septic patients, histone levels correlated negatively with platelet counts and positively with prothrombin time and D-dimer levels. Similarly, in cecal ligation and puncture mice, histones correlated negatively with platelet counts and positively with D-dimer levels. Interestingly, we also observed a positive link between histones and Mg 2+ levels, suggesting that Mg 2+ with anticoagulant activity is involved in histone-mediated coagulation alterations in sepsis. Further animal experiments confirmed that MgSO 4 administration significantly improved survival and attenuated histone-mediated endothelial cell injury, coagulation dysfunction, and lung damage in mice. Conclusion: These results suggest that therapeutic targeting of histone-mediated endothelial cell injury, coagulation dysfunction, and lung damage, for example, with MgSO 4 , may be protective in septic individuals with elevated circulating histone levels.
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Affiliation(s)
- Tao Zhong
- Department of Critical Care Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Jiaqi Zhang
- Department of Critical Care Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Shanjia Chen
- Department of Critical Care Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Sainan Chen
- Department of Critical Care Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Ke Deng
- Department of Critical Care Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Jianbin Guan
- Department of Critical Care Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Jingjing Yang
- Department of Critical Care Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Ronggui Lv
- Department of Intensive Care Unit, Shenzhen Hospital, Southern Medical University, Shenzhen, China
| | - Zhifeng Liu
- Department of Medicine Intensive Care Units, General Hospital of Southern Theatre Command of PLA, Guangzhou, Guangdong, China
| | - Yong Liu
- Department of Intensive Care Unit, Shenzhen Hospital, Southern Medical University, Shenzhen, China
| | - Ping Chang
- Department of Critical Care Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Zhanguo Liu
- Department of Critical Care Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
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21
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Guo JY, Lin HY. Why anticoagulant studies on sepsis fail frequently --- start with SCARLET. Chin J Traumatol 2023; 26:297-302. [PMID: 37321903 PMCID: PMC10533541 DOI: 10.1016/j.cjtee.2023.04.006] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2022] [Revised: 03/17/2023] [Accepted: 04/23/2023] [Indexed: 06/17/2023] Open
Abstract
The Sepsis Coagulopathy Asahi Recombinant LE Thrombomodulin (SCARLET) trial has many defects, and thus cannot be the terminator of recombinant thrombomodulin (rTM). On the contrary, it provides sufficient evidence for further research. Based on analysis focusing on the failure of SCARLET and several previous anticoagulant studies, it is most important for new studies to grasp the following two points: (1) The enrolled cases should have sufficient disease severity and a clear standard for disseminated intravascular coagulation; (2) Heparin should not be used in combination with the investigated drugs. Multiple post-hoc analyses show that no combination of heparin will not increase the risk of thromboembolism. In fact, the combination of heparin can mask the true efficacy of the investigated drug. Due to the complexity of sepsis treatment and the limitations of clinical studies, the results of all treatment studies should be repeatedly verified, rather than be determined at one stroke. Some research conclusions contrary to disease physiology, pharmacology and clinical practice may be deceptive, and should be cautious rather than be simply accepted. On the other hand, the dissenting voices in the "consensus" scene are often well discussed by the authors and should be highly valued.
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Affiliation(s)
- Jian-Ying Guo
- Department of the Intensive Care Unit, The Fourth Medical Center of General Hospital of PLA, 100048, Beijing, China
| | - Hong-Yuan Lin
- Department of the Intensive Care Unit, The Fourth Medical Center of General Hospital of PLA, 100048, Beijing, China.
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22
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Tew ZY, Johnson D, Louis G, Bhowmick K. Purpura fulminans in a hyposplenic patient arising from pneumococcal sinusitis. BMJ Case Rep 2023; 16:e253043. [PMID: 37460246 PMCID: PMC10357718 DOI: 10.1136/bcr-2022-253043] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/20/2023] Open
Abstract
We report a previously healthy woman in her 50s who presented with sepsis, rapidly progressive purpuric rash and disseminated intravascular coagulation. She was diagnosed with acute infective purpura fulminans due to invasive pneumococcal infection likely secondary to sinusitis. Our case report discusses our initial diagnostic uncertainty and approach in investigating and treating such a critically unwell patient.
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Affiliation(s)
- Zi Yi Tew
- Department of Anaesthesia, West Suffolk NHS Foundation Trust, Bury Saint Edmunds, UK
| | - Daniel Johnson
- Department of General Medicine, West Suffolk NHS Foundation Trust, Bury Saint Edmunds, UK
| | - Gerard Louis
- Department of Emergency Medicine, Addenbrooke's Hospital, Cambridge, Cambridgeshire, UK
| | - Kaushik Bhowmick
- Department of Anaesthesia, West Suffolk NHS Foundation Trust, Bury Saint Edmunds, UK
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23
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Al-Husinat L, Abu Hmaid A, Abbas H, Abuelsamen B, Albelbisi M, Haddad S, Qamileh I, Quneis O, Al Modanat ZJ, Ferrara G, Dias FS, Cinnella G. Role of aspirin, beta-blocker, statins, and heparin therapy in septic patients under mechanical ventilation: a narrative review. Front Med (Lausanne) 2023; 10:1143090. [PMID: 37492248 PMCID: PMC10364600 DOI: 10.3389/fmed.2023.1143090] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2023] [Accepted: 06/22/2023] [Indexed: 07/27/2023] Open
Abstract
Sepsis is the main cause of death among patients admitted to intensive care units. Management of sepsis includes fluid resuscitation, vasopressors, intravenous antimicrobials, source control, mechanical ventilation, and others. New insights into the potential benefits of non-antimicrobial drugs in sepsis have evolved based on the pathophysiology of the disease and the mechanism of action of some drugs, but the findings are still controversial. In this study, we aimed to evaluate the effect of beta-blockers, aspirin, statins, and heparin as adjunctive treatments in septic patients under mechanical ventilation with non-cardiovascular diseases and their effect on mortality. We searched PubMed with relevant keywords (beta-blockers, aspirin, statins, or heparin, and critically ill or sepsis) for the last 10 years and some personal collection of relevant articles, and then we assessed studies according to prespecified inclusion and exclusion criteria. Our results show that beta-blockers, aspirin, and heparin may have promising feedback on reducing mortality. However, new well-controlled, randomized, multicenter studies are needed to confirm that, and multiple issues regarding their usage need to be addressed. On the other hand, the feedback regarding the effectiveness of statins was not as strong as that of the other drugs studied, and we suggest that further research is needed to confirm these results.
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Affiliation(s)
- Lou'i Al-Husinat
- Department of Clinical Medical Sciences, Faculty of Medicine, Yarmouk University, Irbid, Jordan
| | | | - Hadeel Abbas
- Faculty of Medicine, Yarmouk University, Irbid, Jordan
| | | | | | - Said Haddad
- Faculty of Medicine, Jordan University of Science and Technology, Irbid, Jordan
| | - Ibrahim Qamileh
- Department of Anesthesia and Intensive Care, Al-Maqasid Charity Hospital, Amman, Jordan
| | - Ossaid Quneis
- Faculty of Medicine, Yarmouk University, Irbid, Jordan
| | - Zaid Jehad Al Modanat
- Department of Clinical Medical Sciences, Faculty of Medicine, Yarmouk University, Irbid, Jordan
| | - Giuseppe Ferrara
- Department of Anesthesia and Intensive Care, University of Foggia, Foggia, Italy
| | | | - Gilda Cinnella
- Department of Anesthesia and Intensive Care, University of Foggia, Foggia, Italy
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24
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Zhang Z, Yan T, Ren D, Zhou J, Liu L, Li J, Fu S, Ni T, Xu W, Yang Y, Chen T, He Y, Zhao Y, Liu J. Low-molecular-weight heparin therapy reduces 28-day mortality in patients with sepsis-3 by improving inflammation and coagulopathy. Front Med (Lausanne) 2023; 10:1157775. [PMID: 37359014 PMCID: PMC10289000 DOI: 10.3389/fmed.2023.1157775] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Accepted: 05/02/2023] [Indexed: 06/28/2023] Open
Abstract
Background and aim Sepsis is a syndromic response to infection and is associated with high mortality, thus imposing a significant global burden of disease. Although low-molecular-weight heparin (LMWH) has been recommended to prevent venous thromboembolism, its anticoagulant and anti-inflammatory effects in sepsis remain controversial. Owing to the modification of the Sepsis-3 definition and diagnostic criteria, further evaluation of the efficacy and benefit population of LMWH is required. Methods We performed a retrospective cohort study to assess whether LMWH improved the inflammation, coagulopathy, and clinical outcomes against Sepsis-3 and to identify the target patients. All patients diagnosed with sepsis at the First Affiliated Hospital of Xi'an Jiaotong University (the largest general hospital in northwest China) from January 2016 to December 2020 were recruited and re-evaluated using Sepsis-3 criteria. Results After 1:1 propensity score matching, 88 pairs of patients were categorized into the treatment and control groups based on subcutaneous LMWH administration. Compared with the control group, a significantly lower 28-day mortality was observed in the LMWH group (26.1 vs. 42.0%, p = 0.026) with a comparable incidence of major bleeding events (6.8 vs. 8.0%, p = 0.773). Cox regression analysis showed that LMWH administration was the independent protective factor for septic patients (aHR, 0.48; 95% CI, 0.29-0.81; p = 0.006). Correspondingly, the LMWH treatment group showed a significant improvement in inflammation and coagulopathy. Further subgroup analysis showed that LMWH therapy was associated with favorable outcomes in patients younger than 60 years and diagnosed with sepsis-induced coagulopathy (SIC), ISTH overt DIC, non-septic shock, or non-diabetics and in patients included in the moderate-risk group (APACHE II score 20-35 or SOFA score 8-12). Conclusion Our study results showed that LMWH improves 28-day mortality by improving inflammatory response and coagulopathy in patients meeting Sepsis-3 criteria. The SIC and ISTH overt DIC scoring systems can better identify septic patients who are likely to benefit more from LMWH administration.
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Affiliation(s)
- Ze Zhang
- The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China
- Shaanxi Clinical Medical Research Center of Infectious Diseases, Xi'an, China
| | - Taotao Yan
- The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China
- Shaanxi Clinical Medical Research Center of Infectious Diseases, Xi'an, China
| | - Danfeng Ren
- The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China
- Shaanxi Clinical Medical Research Center of Infectious Diseases, Xi'an, China
| | - Jingwen Zhou
- The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China
- Shaanxi Clinical Medical Research Center of Infectious Diseases, Xi'an, China
| | - Liangru Liu
- Shaanxi Clinical Medical Research Center of Infectious Diseases, Xi'an, China
| | - Juan Li
- The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China
- Shaanxi Clinical Medical Research Center of Infectious Diseases, Xi'an, China
| | - Shan Fu
- Shaanxi Clinical Medical Research Center of Infectious Diseases, Xi'an, China
| | - Tianzhi Ni
- Shaanxi Clinical Medical Research Center of Infectious Diseases, Xi'an, China
| | - Weicheng Xu
- Shaanxi Clinical Medical Research Center of Infectious Diseases, Xi'an, China
| | - Yuan Yang
- The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China
- Institution of Hepatology, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China
| | - Tianyan Chen
- The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China
- Institution of Hepatology, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China
| | - Yingli He
- The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China
- Institution of Hepatology, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China
| | - Yingren Zhao
- Shaanxi Clinical Medical Research Center of Infectious Diseases, Xi'an, China
- Institution of Hepatology, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China
| | - Jinfeng Liu
- The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China
- Shaanxi Clinical Medical Research Center of Infectious Diseases, Xi'an, China
- Institution of Hepatology, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China
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25
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Huang JJ, Zou ZY, Zhou ZP, Liu Y, Yang ZJ, Zhang JJ, Luan YY, Yao YM, Wu M. Effectiveness of early heparin therapy on outcomes in critically ill patients with sepsis-induced coagulopathy. Front Pharmacol 2023; 14:1173893. [PMID: 37256226 PMCID: PMC10225678 DOI: 10.3389/fphar.2023.1173893] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2023] [Accepted: 05/03/2023] [Indexed: 06/01/2023] Open
Abstract
Background: This study aimed to investigate whether early unfractionated heparin (UFH) administration provides a survival advantage for patients with sepsis-induced coagulopathy (SIC). Methods: Patients hospitalized with sepsis-induced coagulopathy from the Medical Information Mart for Intensive Care (MIMIC)-IV database were identified. Patients were divided into two groups, who received unfractionated heparin (UFH) subcutaneously within 24 h after intensive care unit (ICU) admission, and the control group, who received not. The primary endpoint was intensive care unit mortality, the secondary outcomes were 7, 14, and 28-day and hospital mortality. Propensity score matching (PSM) the marginal structural Cox model (MSCM) and E-value analysis were used to account for baseline differences, time-varying and unmeasured confounding factors. Results: A total of 3,377 patients with sepsis-induced coagulopathy were enrolled in the study, of which 815 in unfractionated heparin group and 2,562 in control group. There was significant effect on primary and secondary outcomes with unfractionated heparin after propensity score matching (intensive care unit mortality, hazard ratio [HR] 0.69, 95% confidence interval [CI] 0.52-0.92; 7-day, HR 0.70, 95% CI 0.49-0.99; 14-day, HR 0.68.95% CI 0.50-0.92; 28-day, HR 0.72, 95% CI 0.54-0.96; hospital mortality, HR 0.74, 95% CI 0.57-0.96), marginal structural Cox model manifested unfractionated heparin associated with decreased intensive care unit mortality in all populations (HR 0.64, 95% CI 0.49-0.84), and stratification with the marginal structural Cox model indicated analysis further indicated the survival advantage only among patients with an sepsis-induced coagulopathy score of 4 (HR 0.56, 95% CI 0.38-0.81). Further analysis showed that treatment with 6,250-13750 IU/day of unfractionated heparin associated with a decreased risk of intensive care unit mortality. Similar results were replicated in subgroup analysis with propensity score matching only for patients with an sepsis-induced coagulopathy score of 4 (intensive care unit mortality, HR 0.51, 95% CI 0.34-0.76). Conclusion: This study found early unfractionated heparin therapy to patients with sepsis-induced coagulopathy appears to be associated with improved outcomes. Subgroup analysis further demonstrates heparin therapy decreased intensive care unit mortality primarily in patients only with SIC score of 4.
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Affiliation(s)
- Jia-Jia Huang
- Department of Infection and Critical Care Medicine, Health Science Center, Shenzhen Second People’s Hospital and First Affiliated Hospital of Shenzhen University, Shenzhen, China
- Postgraduate Education, Shantou University Medical College, Shantou, China
| | - Zhi-Ye Zou
- Department of Infection and Critical Care Medicine, Health Science Center, Shenzhen Second People’s Hospital and First Affiliated Hospital of Shenzhen University, Shenzhen, China
| | - Zhi-Peng Zhou
- Department of Infection and Critical Care Medicine, Health Science Center, Shenzhen Second People’s Hospital and First Affiliated Hospital of Shenzhen University, Shenzhen, China
| | - Yan Liu
- Department of Infection and Critical Care Medicine, Health Science Center, Shenzhen Second People’s Hospital and First Affiliated Hospital of Shenzhen University, Shenzhen, China
| | - Zhen-Jia Yang
- Department of Infection and Critical Care Medicine, Health Science Center, Shenzhen Second People’s Hospital and First Affiliated Hospital of Shenzhen University, Shenzhen, China
- Postgraduate Education, Shantou University Medical College, Shantou, China
| | - Jing-Jing Zhang
- Department of Infection and Critical Care Medicine, Health Science Center, Shenzhen Second People’s Hospital and First Affiliated Hospital of Shenzhen University, Shenzhen, China
- Department of Critical Care Medicine, Pingshan District People’s Hospital of Shenzhen, Shenzhen, China
| | - Ying-Yi Luan
- Department of Central Laboratory, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, China
| | - Yong-Ming Yao
- Trauma Research Center, Medical Innovation Research Department and Fourth Medical Center of the Chinese PLA General Hospital, Beijing, China
| | - Ming Wu
- Department of Infection and Critical Care Medicine, Health Science Center, Shenzhen Second People’s Hospital and First Affiliated Hospital of Shenzhen University, Shenzhen, China
- Postgraduate Education, Shantou University Medical College, Shantou, China
- Department of Nosocomial Infection Prevention and Control, Shenzhen Second People's Hospital, Shenzhen, China
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26
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Zhu C, Liang Y, Liu Y, Shu W, Luan Z, Ma X. Unfractionated Heparin Protects Microcirculation in Endotoxemic Rats by Antagonizing Histones. J Surg Res 2023; 282:84-92. [PMID: 36257167 DOI: 10.1016/j.jss.2022.09.019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2022] [Revised: 08/11/2022] [Accepted: 09/03/2022] [Indexed: 11/06/2022]
Abstract
INTRODUCTION Levels of extracellular histones are highly increased in sepsis and may facilitate microcirculatory dysfunction. Unfractionated heparin (UFH) binds histones and neutralizes their cytotoxicity. We investigated the effect of UFH on microcirculatory dysfunction by interacting with extracellular histones in endotoxemic rats. METHODS Twenty-four Wistar rats were randomly divided into three groups: control, lipopolysaccharide (LPS) group, and LPS + UFH group. In the LPS and LPS + UFH groups, 10 mg/kg LPS was injected to induce endotoxemia, and 100 IU/kg/h UFH was administered intravenously in the LPS + UFH group. The rats underwent midline laparotomy, and then intestinal microcirculation was evaluated using an incident dark field microscope. Circulating histones and microstructures of the rat intestinal microvascular endothelium were also detected. Additionally, the antagonistic effect of UFH on histone-induced cytotoxicity was investigated in human intestinal microvascular endothelial cells. RESULTS UFH protected the microcirculation of the intestinal serosa and mucosa in endotoxemic rats, as evidenced by increased total vessel density, perfused vessel density, and proportion of perfused vessels of both the serosa and mucosa, and increased microcirculatory flow index of the mucosa in the LPS + UFH group. UFH treatment decreased the levels of circulating histones and alleviated intestinal microvascular endothelial injuries in endotoxemic rats. Furthermore, UFH inhibited histone cytotoxicity in vitro. CONCLUSIONS UFH attenuated microcirculatory dysfunction in endotoxemic rats by antagonizing extracellular histones, thereby providing a potential therapeutic strategy for sepsis.
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Affiliation(s)
- Chengrui Zhu
- Department of Critical Care Medicine, The First Affiliated Hospital, China Medical University, Shenyang, Liaoning Province, China
| | - Yingjian Liang
- Department of Critical Care Medicine, The First Affiliated Hospital, China Medical University, Shenyang, Liaoning Province, China
| | - Yina Liu
- Department of Critical Care Medicine, The First Affiliated Hospital, China Medical University, Shenyang, Liaoning Province, China
| | - Wenqi Shu
- Department of Critical Care Medicine, The First Affiliated Hospital, China Medical University, Shenyang, Liaoning Province, China
| | - Zhenggang Luan
- Department of Critical Care Medicine, The First Affiliated Hospital, China Medical University, Shenyang, Liaoning Province, China
| | - Xiaochun Ma
- Department of Critical Care Medicine, The First Affiliated Hospital, China Medical University, Shenyang, Liaoning Province, China.
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27
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Zou ZY, Huang JJ, Luan YY, Yang ZJ, Zhou ZP, Zhang JJ, Yao YM, Wu M. Early prophylactic anticoagulation with heparin alleviates mortality in critically ill patients with sepsis: a retrospective analysis from the MIMIC-IV database. BURNS & TRAUMA 2022; 10:tkac029. [PMID: 36168402 PMCID: PMC9501718 DOI: 10.1093/burnst/tkac029] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/09/2021] [Revised: 03/14/2022] [Indexed: 02/05/2023]
Abstract
Background Minimal data exist on anticoagulation use and timing and the dose of heparin in patients with sepsis, and whether heparin use improves sepsis survival remains largely unclear. This study was performed to assess whether heparin administration would provide a survival advantage in critically ill patients with sepsis. Methods A retrospective cohort study of patients with sepsis in the Medical Information Mart for Intensive Care (MIMIC)-IV database was conducted. Cox proportional hazards model and propensity score matching (PSM) were used to evaluate the outcomes of prophylactic anticoagulation with heparin administered by subcutaneous injection within 48 h of intensive care unit (ICU) admission. The primary outcome was in-hospital mortality. Secondary outcomes included 60-day mortality, length of ICU stay, length of hospital stay and incidence of acute kidney injury (AKI) on day 7. E-Value analysis were used for unmeasured confounding. Results A total of 6646 adult septic patients were included and divided into an early prophylactic heparin group (n = 3211) and a nonheparin group (n = 3435). In-hospital mortality in the heparin therapy group was significantly lower than that in the nonheparin group (prematched 14.7 vs 20.0%, hazard ratio (HR) 0.77, 95% confidence interval (CI) [0.68-0.87], p < 0.001, and postmatched 14.9 vs 18.3%, HR 0.78, 95% CI [0.68-0.89], p < 0.001). Secondary endpoints, including 60-day mortality and length of ICU stay, differed between the heparin and nonheparin groups (p < 0.01). Early prophylactic heparin administration was associated with in-hospital mortality among septic patients in different adjusted covariates (HR 0.71-0.78, p < 0.001), and only administration of five doses of heparin was associated with decreased in-hospital mortality after PSM (HR 0.70, 95% CI 0.56-0.87, p < 0.001). Subgroup analysis showed that heparin use was significantly associated with reduced in-hospital mortality in patients with sepsis-induced coagulopathy, septic shock, sequential organ failure assessment score ≥ 10, AKI, mechanical ventilation, gram-positive bacterial infection and gram-negative bacterial infection, with HRs of 0.74, 0.70, 0.58, 0.74, 0.73, 0.64 and 0.72, respectively (p <0.001). E-Value analysis suggested robustness to unmeasured confounding. Conclusions This study found an association between early administration prophylactic heparin provided to patients with sepsis and reduced risk-adjusted mortality. A prospective randomized-controlled study should be designed to further assess the relevant findings.
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Affiliation(s)
- Zhi-ye Zou
- Department of Critical Care Medicine and Hospital Infection Prevention and Control, Shenzhen Second People’s Hospital & First Affiliated Hospital of Shenzhen University, Shenzhen 518035, China
| | - Jia-jia Huang
- Department of Critical Care Medicine and Hospital Infection Prevention and Control, Shenzhen Second People’s Hospital & First Affiliated Hospital of Shenzhen University, Shenzhen 518035, China
- Postgraduate Education, Shantou University Medical College, Shantou 515041, China
| | - Ying-yi Luan
- Department of Central Laboratory, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing 100026, China
| | - Zhen-jia Yang
- Department of Critical Care Medicine and Hospital Infection Prevention and Control, Shenzhen Second People’s Hospital & First Affiliated Hospital of Shenzhen University, Shenzhen 518035, China
- Postgraduate Education, Shantou University Medical College, Shantou 515041, China
| | - Zhi-peng Zhou
- Department of Critical Care Medicine and Hospital Infection Prevention and Control, Shenzhen Second People’s Hospital & First Affiliated Hospital of Shenzhen University, Shenzhen 518035, China
| | - Jing-jing Zhang
- Department of Critical Care Medicine and Hospital Infection Prevention and Control, Shenzhen Second People’s Hospital & First Affiliated Hospital of Shenzhen University, Shenzhen 518035, China
- Postgraduate Education, Shantou University Medical College, Shantou 515041, China
| | - Yong-ming Yao
- Trauma Research Center, Medical Innovation Research Department and Fourth Medical Center of the Chinese PLA General Hospital, Beijing 100048, China
| | - Ming Wu
- Department of Critical Care Medicine and Hospital Infection Prevention and Control, Shenzhen Second People’s Hospital & First Affiliated Hospital of Shenzhen University, Shenzhen 518035, China
- Postgraduate Education, Shantou University Medical College, Shantou 515041, China
- Guangxi University of Chinese Medicine, Nanning 530200, China
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Yang R, Zhang X. A potential new pathway for heparin treatment of sepsis-induced lung injury: inhibition of pulmonary endothelial cell pyroptosis by blocking hMGB1-LPS-induced caspase-11 activation. Front Cell Infect Microbiol 2022; 12:984835. [PMID: 36189354 PMCID: PMC9519888 DOI: 10.3389/fcimb.2022.984835] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2022] [Accepted: 08/29/2022] [Indexed: 11/18/2022] Open
Abstract
Sepsis is a significant cause of mortality in critically ill patients. Acute lung injury (ALI) is a leading cause of death in these patients. Endothelial cells exposed to the bacterial endotoxin lipopolysaccharide (LPS) can progress into pyroptosis, a programmed lysis of cell death triggered by inflammatory caspases. It is characterized by lytic cell death induced by the binding of intracellular LPS to caspases 4/5 in human cells and caspase-11 in mouse cells. In mice,caspase-11-dependent pyroptosis plays an important role in endotoxemia. HMGB1 released into the plasma binds to LPS and is internalized into lysosomes in endothelial cells via the advanced glycation end product receptor. In the acidic lysosomal environment, HMGB1 permeates the phospholipid bilayer, which is followed by the leakage of LPS into the cytoplasm and the activation of caspase-11. Heparin is an anticoagulant widely applied in the treatment of thrombotic disease. Previous studies have found that heparin could block caspase-11-dependent inflammatory reactions, decrease sepsis-related mortality, and reduce ALI, independent of its anticoagulant activity. Heparin or modified heparin with no anticoagulant property could inhibit the alarmin HMGB1-LPS interactions, minimize LPS entry into the cytoplasm, and thus blocking caspase-11 activation. Heparin has been studied in septic ALI, but the regulatory mechanism of pulmonary endothelial cell pyroptosis is still unclear. In this paper, we discuss the potential novel role of heparin in the treatment of septic ALI from the unique mechanism of pulmonary endothelial cell pyroptosis.
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Komorowicz E, Kolev K. Fibrin structure, viscoelasticity and lysis face the interplay of biorelevant polyions. Curr Opin Hematol 2022; 29:244-250. [PMID: 35916559 DOI: 10.1097/moh.0000000000000725] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
PURPOSE OF REVIEW In the past 5 decades, heparins have been widely used as anticoagulants in the prevention and treatment of thrombosis. Subsequent development of heparin variants of various size and charge facilitated the discovery of their multiple biological actions and nonanticoagulant benefits. Platelet-derived or microbial polyphosphates, as well as DNA released in the course of neutrophil extracellular trap-formation are additional polyanions, which can modulate the development and stability of thrombi associated with cancer or inflammation. In this review, we focus on the size-dependent and electric charge-dependent modulatory effects of the three polyanions of different chemical structure. RECENT FINDINGS The polycationic histones have been recognized as potential biomarkers and therapeutic targets in several diseases related to inflammation and thrombosis. Since combating histones with activated protein C or heparin could cause unwanted bleeding, the quest for nonanticoagulant histone-neutralizing agents is ongoing. Polyanions may neutralize or exaggerate certain histone-mediated effects depending on their electric charge, size and histone effects under investigation. Several prothrombotic effects of polyphosphates and DNA are also size-dependent. SUMMARY The efficiency of future therapeutics targeting prothrombotic polyanions or histones is not a simple matter of electric charge, but may rely on a delicate combination of size, charge and chemical composition.
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Affiliation(s)
- Erzsébet Komorowicz
- Department of Biochemistry, Institute of Biochemistry and Molecular Biology, Semmelweis University, Budapest, Hungary
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30
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Shapiro L, Scherger S, Franco-Paredes C, Gharamti AA, Fraulino D, Henao-Martinez AF. Chasing the Ghost: Hyperinflammation Does Not Cause Sepsis. Front Pharmacol 2022; 13:910516. [PMID: 35814227 PMCID: PMC9260244 DOI: 10.3389/fphar.2022.910516] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2022] [Accepted: 05/23/2022] [Indexed: 12/15/2022] Open
Abstract
Sepsis is infection sufficient to cause illness in the infected host, and more severe forms of sepsis can result in organ malfunction or death. Severe forms of Coronavirus disease-2019 (COVID-19), or disease following infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are examples of sepsis. Following infection, sepsis is thought to result from excessive inflammation generated in the infected host, also referred to as a cytokine storm. Sepsis can result in organ malfunction or death. Since COVID-19 is an example of sepsis, the hyperinflammation concept has influenced scientific investigation and treatment approaches to COVID-19. However, decades of laboratory study and more than 100 clinical trials designed to quell inflammation have failed to reduce sepsis mortality. We examine theoretical support underlying widespread belief that hyperinflammation or cytokine storm causes sepsis. Our analysis shows substantial weakness of the hyperinflammation approach to sepsis that includes conceptual confusion and failure to establish a cause-and-effect relationship between hyperinflammation and sepsis. We conclude that anti-inflammation approaches to sepsis therapy have little chance of future success. Therefore, anti-inflammation approaches to treat COVID-19 are likewise at high risk for failure. We find persistence of the cytokine storm concept in sepsis perplexing. Although treatment approaches based on the hyperinflammation concept of pathogenesis have failed, the concept has shown remarkable resilience and appears to be unfalsifiable. An approach to understanding this resilience is to consider the hyperinflammation or cytokine storm concept an example of a scientific paradigm. Thomas Kuhn developed the idea that paradigms generate rules of investigation that both shape and restrict scientific progress. Intrinsic features of scientific paradigms include resistance to falsification in the face of contradictory data and inability of experimentation to generate alternatives to a failing paradigm. We call for rejection of the concept that hyperinflammation or cytokine storm causes sepsis. Using the hyperinflammation or cytokine storm paradigm to guide COVID-19 treatments is likewise unlikely to provide progress. Resources should be redirected to more promising avenues of investigation and treatment.
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Affiliation(s)
- Leland Shapiro
- Division of Infectious Diseases, Rocky Mountain Regional Veterans Affairs Medical Center, Aurora, CO, United States
- Division of Infectious Diseases, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
| | - Sias Scherger
- Division of Infectious Diseases, Rocky Mountain Regional Veterans Affairs Medical Center, Aurora, CO, United States
| | - Carlos Franco-Paredes
- Division of Infectious Diseases, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
- Hospital Infantil de México, Federico Gomez, Mexico City, Mexico
| | - Amal A. Gharamti
- Department of Internal Medicine, Yale University, Waterbury, CT, United States
| | - David Fraulino
- Division of Infectious Diseases, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
| | - Andrés F. Henao-Martinez
- Division of Infectious Diseases, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
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31
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Guo F, Zhu X, Wu Z, Zhu L, Wu J, Zhang F. Clinical applications of machine learning in the survival prediction and classification of sepsis: coagulation and heparin usage matter. J Transl Med 2022; 20:265. [PMID: 35690822 PMCID: PMC9187899 DOI: 10.1186/s12967-022-03469-6] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2022] [Accepted: 05/30/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Sepsis is a life-threatening syndrome eliciting highly heterogeneous host responses. Current prognostic evaluation methods used in clinical practice are characterized by an inadequate effectiveness in predicting sepsis mortality. Rapid identification of patients with high mortality risk is urgently needed. The phenotyping of patients will assistant invaluably in tailoring treatments. METHODS Machine learning and deep learning technology are used to characterize the patients' phenotype and determine the sepsis severity. The database used in this study is MIMIC-III and MIMIC-IV ('Medical information Mart for intensive care') which is a large, public, and freely available database. The K-means clustering is used to classify the sepsis phenotype. Convolutional neural network (CNN) was used to predict the 28-day survival rate based on 35 blood test variables of the sepsis patients, whereas a double coefficient quadratic multivariate fitting function (DCQMFF) is utilized to predict the 28-day survival rate with only 11 features of sepsis patients. RESULTS The patients were grouped into four clusters with a clear survival nomogram. The first cluster (C_1) was characterized by low white blood cell count, low neutrophil, and the highest lymphocyte proportion. C_2 obtained the lowest Sequential Organ Failure Assessment (SOFA) score and the highest survival rate. C_3 was characterized by significantly prolonged PTT, high SIC, and a higher proportion of patients using heparin than the patients in other clusters. The early mortality rate of patients in C_3 was high but with a better long-term survival rate than that in C_4. C_4 contained septic coagulation patients with the worst prognosis, characterized by slightly prolonged partial thromboplastin time (PTT), significantly prolonged prothrombin time (PT), and high septic coagulation disease score (SIC). The survival rate prediction accuracy of CNN and DCQMFF models reached 92% and 82%, respectively. The models were tested on an external dataset (MIMIC-IV) and achieved good performance. A DCQMFF-based application platform was established for fast prediction of the 28-day survival rate. CONCLUSION CNN and DCQMFF accurately predicted the sepsis patients' survival, while K-means successfully identified the phenotype groups. The distinct phenotypes associated with survival, and significant features correlated with mortality were identified. The findings suggest that sepsis patients with abnormal coagulation had poor outcomes, abnormal coagulation increase mortality during sepsis. The anticoagulation effects of appropriate heparin sodium treatment may improve extensive micro thrombosis-caused organ failure.
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Affiliation(s)
- Fei Guo
- Ningbo Institute for Medicine & Biomedical Engineering Combined Innovation, Ningbo Medical Treatment Centre Lihuili Hospital, Ningbo University, Ningbo, 315040, Zhejiang, China
| | - Xishun Zhu
- School of Mechatronics Engineering, Nanchang University, Nanchang, 330031, Jiangxi, China
| | - Zhiheng Wu
- School of Information Engineering, Nanchang University, Nanchang, 330031, Jiangxi, China
| | - Li Zhu
- School of Information Engineering, Nanchang University, Nanchang, 330031, Jiangxi, China
| | - Jianhua Wu
- School of Information Engineering, Nanchang University, Nanchang, 330031, Jiangxi, China.
| | - Fan Zhang
- Department of Critical Care Medicine, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China.
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32
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Jimenez D, Rali P, Doerschug K. Rebuttal From Dr David Jimenez et al. Chest 2022; 161:1453-1455. [PMID: 35469672 PMCID: PMC8923524 DOI: 10.1016/j.chest.2022.01.038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2022] [Accepted: 01/20/2022] [Indexed: 11/18/2022] Open
Affiliation(s)
- David Jimenez
- Respiratory Medicine, Ramón y Cajal Hospital (IRYCIS), and CIBER Enfermedades Respiratorias (CIBERES), Madrid, Spain
| | - Parth Rali
- Department of Thoracic Medicine and Surgery, Lewis Katz School of Medicine, Temple University, Philadelphia, PA.
| | - Kevin Doerschug
- Pulmonary, Critical Care, and Occupational Medicine, University of Iowa, Iowa City, IA
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33
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Tritschler T, Le Gal G, Brosnahan S, Carrier M. POINT: Should Therapeutic Heparin Be Administered to Acutely Ill Hospitalized Patients With COVID-19? Yes. Chest 2022; 161:1446-1448. [PMID: 35469670 PMCID: PMC8923527 DOI: 10.1016/j.chest.2022.01.036] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2021] [Accepted: 01/20/2022] [Indexed: 12/05/2022] Open
Affiliation(s)
- Tobias Tritschler
- Department of General Internal Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
| | - Grégoire Le Gal
- Department of Medicine, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, ON, Canada
| | - Shari Brosnahan
- Division of Pulmonary, Critical Care, and Sleep Medicine, New York University Langone Health System, New York, NY
| | - Marc Carrier
- Department of Medicine, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, ON, Canada
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34
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Steiner SE, Edgren G, Melican K, Richter-Dahlfors A, Brauner A. Effect of anticoagulant and platelet inhibition on the risk of bacteremia among patients with acute pyelonephritis: a retrospective cohort study. BMC Infect Dis 2022; 22:509. [PMID: 35641940 PMCID: PMC9158213 DOI: 10.1186/s12879-022-07474-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2022] [Accepted: 05/16/2022] [Indexed: 11/21/2022] Open
Abstract
Background An increasing number of patients are being prescribed anticoagulants and platelet inhibitors (antithrombotic treatment). Basic research has suggested an association between antithrombotic treatment and bacteremia during kidney infection. Here, we investigated the association between antithrombotic treatment, bacteremia and acute kidney injury in patients with acute pyelonephritis. Methods A retrospective cohort study was conducted in a large university hospital in Sweden. Data were retrieved from electronic medical records for adult patients with acute pyelonephritis in 2016. The main outcome was bacteremia and secondary outcome acute kidney injury. Odds ratios (ORs) with 95% confidence intervals (CIs) were estimated through multiple logistic regression. Treatment with different groups of antithrombotic agents were compared to no antithrombotic treatment. Results 1814 patients with acute pyelonephritis were included, in whom bacteremia developed in 336 (18.5%). Low-molecular-weight heparin (LMWH) at prophylactic doses was associated with a lower risk of bacteremia, compared to no antithrombotic treatment (OR 0.5; 95% CI 0.3–0.7). Other antithrombotic treatments were not associated with a risk of bacteremia. Additionally, patients with prophylactic doses of LMWH had a lower risk of acute kidney injury (OR 0.5; 95% CI 0.3–0.8). Conclusions We found no association between antithrombotic treatment and an increased risk of bacteremia during acute pyelonephritis. Conversely, patients with prophylactic doses of LMWH had a slightly reduced risk of bacteremia. LMWH at prophylactic doses was also associated with a lower risk of acute kidney injury. Our results suggest that it is safe to continue antithrombotic treatment during acute pyelonephritis, in regards to bacteremia and acute kidney injury risk. Supplementary Information The online version contains supplementary material available at 10.1186/s12879-022-07474-4.
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Affiliation(s)
- Svava E Steiner
- AIMES - Center for the Advancement of Integrated Medical and Engineering Sciences at Karolinska Institutet and KTH Royal Institute of Technology, Stockholm, Sweden.,Department of Neuroscience, Karolinska Institutet, 171 77, Stockholm, Sweden
| | - Gustaf Edgren
- Department of Medicine Solna, Clinical Epidemiology Division, Karolinska Institutet, 171 77, Stockholm, Sweden.,Department of Cardiology, Södersjukhuset, Stockholm, Sweden
| | - Keira Melican
- AIMES - Center for the Advancement of Integrated Medical and Engineering Sciences at Karolinska Institutet and KTH Royal Institute of Technology, Stockholm, Sweden.,Department of Neuroscience, Karolinska Institutet, 171 77, Stockholm, Sweden
| | - Agneta Richter-Dahlfors
- AIMES - Center for the Advancement of Integrated Medical and Engineering Sciences at Karolinska Institutet and KTH Royal Institute of Technology, Stockholm, Sweden.,Department of Neuroscience, Karolinska Institutet, 171 77, Stockholm, Sweden
| | - Annelie Brauner
- Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, 171 77, Stockholm, Sweden. .,Division of Clinical Microbiology, Karolinska University Hospital, 171 76, Stockholm, Sweden.
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35
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Swan D, Thachil J. Management of haemostatic complications of chimaeric antigen receptor T-cell therapy. Br J Haematol 2022; 197:250-259. [PMID: 35146749 DOI: 10.1111/bjh.18045] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Revised: 01/03/2022] [Accepted: 01/04/2022] [Indexed: 11/28/2022]
Affiliation(s)
- Dawn Swan
- Department of Haematology, St James' Hospital, Dublin, Republic of Ireland
| | - Jecko Thachil
- Department of Haematology, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK
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36
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Chen TT, Lv JJ, Chen L, Gao YW, Liu LP. Role of heparinase in the gastrointestinal dysfunction of sepsis (Review). Exp Ther Med 2022; 23:119. [PMID: 34970342 PMCID: PMC8713170 DOI: 10.3892/etm.2021.11042] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2021] [Accepted: 10/26/2021] [Indexed: 11/23/2022] Open
Abstract
Heparinase (HPA) is a β-D glucuronidase that belongs to the endoglycosidase enzyme family, and plays an important role in numerous pathological and physiological processes, including inflammation, angiogenesis and tumor metastasis. When the expression of HPA is abnormally high, the side chain of heparin sulfate proteoglycans degrades, destroying the cell barrier and leading to the occurrence and development of inflammation, with systemic inflammation occurring in severe cases. Sepsis is a major cause of mortality in critically ill patients. In sepsis, the gastrointestinal tract is the first and most frequently involved target organ, which often leads to gastrointestinal dysfunction. HPA overexpression has been determined to accelerate sepsis progression and gastrointestinal dysfunction; thus, it was hypothesized that HPA may play an important role and may serve as an index for the diagnosis of gastrointestinal dysfunction in sepsis. HPA inhibitors may therefore become applicable as targeted drugs for the treatment of gastrointestinal dysfunction in patients with sepsis. The present review mainly discussed the role of HPA in gastrointestinal dysfunction of sepsis.
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Affiliation(s)
- Ting-Ting Chen
- The First Clinical Medical School of Lanzhou University, Lanzhou, Gansu 730000, P.R. China
| | - Jia-Jun Lv
- The First Clinical Medical School of Lanzhou University, Lanzhou, Gansu 730000, P.R. China
| | - Ling Chen
- Department of Emergency Critical Care Medicine, The First Hospital of Lanzhou University, Lanzhou, Gansu 730000, P.R. China
- Department of Emergency, The First Hospital of Lanzhou University, Lanzhou, Gansu 730000, P.R. China
| | - Yu-Wei Gao
- Department of Emergency Critical Care Medicine, The First Hospital of Lanzhou University, Lanzhou, Gansu 730000, P.R. China
- Department of Emergency, The First Hospital of Lanzhou University, Lanzhou, Gansu 730000, P.R. China
| | - Li-Ping Liu
- Department of Emergency Critical Care Medicine, The First Hospital of Lanzhou University, Lanzhou, Gansu 730000, P.R. China
- Department of Emergency, The First Hospital of Lanzhou University, Lanzhou, Gansu 730000, P.R. China
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Peng JC, Nie F, Li YJ, Xu QY, Xing SP, Li W, Gao Y. Favorable Outcomes of Anticoagulation With Unfractioned Heparin in Sepsis-Induced Coagulopathy: A Retrospective Analysis of MIMIC-III Database. Front Med (Lausanne) 2022; 8:773339. [PMID: 35047524 PMCID: PMC8761617 DOI: 10.3389/fmed.2021.773339] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2021] [Accepted: 11/11/2021] [Indexed: 11/13/2022] Open
Abstract
Backgrounds: Anticoagulation in sepsis-associated disseminated intravascular coagulation (DIC) remains uncertain. The aim of this study was to investigate whether unfractioned heparin (UFH) could improve clinical outcomes in patients with sepsis-induced coagulopathy (SIC). Methods: Septic patients with SIC were identified from the Medical Information Mart for Intensive Care (MIMIC)-III database. Cox-proportional hazards model, logistic regression model and linear regression were used to assess the associations between UFH administration and 28-day mortality, hospital mortality, occurrence of bleeding complications and length of stay, respectively. Propensity score matching (PSM) analysis was used to match the imbalance between patients in the UFH group and the control group. Patients were further stratified according to SIC score and Simplified Acute Physiology Score II (SAPS II). Results: A total of 1,820 septic patients with SIC were included in the data analysis. After PSM, 652 pairs of patients were matched between the patients in the UFH group and the control group. UFH was significantly associated with reduced 28-day mortality (HR, 0.323, 95% CI, 0.258–0.406; p < 0.001) and hospital mortality (HR, 0.380, 95% CI, 0.307–0.472; p < 0.001) without increasing the risks of intracranial hemorrhage (OR, 1.480, 95% CI, 0.955–2.294; p = 0.080) or gastrointestinal bleeding (OR, 1.094, 95% CI, 0.503–2.382; p = 0.820). For subgroup analysis, it didn't change the favorable results of UFH on mortality and UFH didn't increase the risk of hemorrhage in patients with severe disease. Conclusions: The analysis of MIMIC-III database indicated that anticoagulant therapy with UFH may be associated with a survival benefit in patients with SIC.
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Affiliation(s)
- Jiang-Chen Peng
- Department of Critical Care, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Fang Nie
- Department of Critical Care, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Yu-Jie Li
- Department of Critical Care, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Qiao-Yi Xu
- Department of Critical Care, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Shun-Peng Xing
- Department of Critical Care, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Wen Li
- Department of Critical Care, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Yuan Gao
- Department of Critical Care, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
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38
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Fu S, Yu S, Wang L, Ma X, Li X. Unfractionated heparin improves the clinical efficacy in adult sepsis patients: a systematic review and meta-analysis. BMC Anesthesiol 2022; 22:28. [PMID: 35062871 PMCID: PMC8777179 DOI: 10.1186/s12871-021-01545-w] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2021] [Accepted: 12/10/2021] [Indexed: 12/29/2022] Open
Abstract
Background The anticoagulant treatment and clinical efficacy of heparin in sepsis remains controversial. We conducted a meta-analysis to estimate the clinical efficacy of unfractionated heparin (UFH) in adult septic patients. Method A systematic review of Medline, Cochrane Library, PubMed, Embase, WEIPU database, CNKI database, WANFANG database was performed from inception to January 2021. We included Randomized controlled trials (RCTs) and the main outcome was 28 d mortality. Data analysis was performed with Review Manager (RevMan) version 5.3 software. The meta-analysis included 2617 patients from 15 RCTs. Results Comparing to control group, UFH could reduce 28 d mortality (RR: 0.82; 95% CI: 0.72 to 0.94) especially for patient with Acute Physiology and Chronic Health Evaluation II (APACHE II) > 15, (RR: 0.83; 95% CI: 0.72 to 0.96). In UFH group, the platelet (PLT) (MD: 9.18; 95% CI: 0.68 to 17.68) was higher, the activated partial thromboplastin time (APTT) was shorter (MD: -8.01; 95% CI: − 13.84 to − 2.18) and the prothrombin time (PT) results (P > 0.05) failed to reach statistical significance. UFH decreased multiple organ dysfunction syndrome (MODS) incidence (RR: 0.61; 95% CI: 0.45 to 0.84), length of stay (LOS) in ICU (MD: -4.94; 95% CI: − 6.89 to − 2.99) and ventilation time (MD: -3.01; 95% CI: − 4.0 to − 2.02). And UFH had no adverse impact on bleeding (RR: 1.10; 95% CI: 0.54 to 2.23). Conclusion This meta-analysis suggests that UFH may reduce 28 d mortality and improve the clinical efficacy in sepsis patients without bleeding adverse effect. Supplementary Information The online version contains supplementary material available at 10.1186/s12871-021-01545-w.
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Akahoshi T, Kaku N, Shono Y, Yamamoto Y, Takahashi K, Iyonaga T, Momii K, Nishihara M, Maki J, Tokuda K, Yamaura K. Impact of Antithrombin Activity Levels Following Recombinant Antithrombin Gamma Therapy in Patients with Sepsis-Induced Disseminated Intravascular Coagulation. Clin Appl Thromb Hemost 2022; 28:10760296221135790. [PMID: 36380520 PMCID: PMC9676283 DOI: 10.1177/10760296221135790] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
Recombinant antithrombin gamma (rAT) is reported as an effective drug for patients with disseminated intravascular coagulation (DIC) in Japan. As the appropriate dose and targeted AT activity remain unknown, this study aimed to determine these aspects for sepsis-induced DIC. Thirty-one patients with septic shock and DIC with AT levels <70% were treated with rAT between May 2018 and December 2020. The recovery rates from DIC were 32.2% and 63.3% on day 3 and 5 post administration, respectively. Recovery and survival rates were significantly higher in patients who achieved AT activity ≥70% or 80% on day 3 post administration. Receiver operating characteristic curve analysis revealed that the cutoff values of post-treatment AT activity on day 3 for 28-day survival and 5-day recovery from DIC were 79.5% and 81.5%, respectively. Patients who did not achieve AT activity ≥80% on day 3 presented a lower base level of AT activity and lower dose supplementation. Our results suggest that targeted AT activity should be at least 70%, and ideally 80%, and sufficient doses to maintain this activity are required to achieve better outcomes.
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Affiliation(s)
- Tomohiko Akahoshi
- Emergency and Critical Care Center, Kyushu University Hospital, Fukuoka, Japan
| | - Noriyuki Kaku
- Emergency and Critical Care Center, Kyushu University Hospital, Fukuoka, Japan
| | - Yuji Shono
- Emergency and Critical Care Center, Kyushu University Hospital, Fukuoka, Japan
| | - Yuzo Yamamoto
- Emergency and Critical Care Center, Kyushu University Hospital, Fukuoka, Japan
| | - Keita Takahashi
- Department of Anesthesiology and Critical Care Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Takeshi Iyonaga
- Emergency and Critical Care Center, Kyushu University Hospital, Fukuoka, Japan
| | - Kenta Momii
- Emergency and Critical Care Center, Kyushu University Hospital, Fukuoka, Japan
| | - Masaaki Nishihara
- Emergency and Critical Care Center, Kyushu University Hospital, Fukuoka, Japan
| | - Jun Maki
- Department of Anesthesiology and Critical Care Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Kentaro Tokuda
- Department of Anesthesiology and Critical Care Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Ken Yamaura
- Department of Anesthesiology and Critical Care Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
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40
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Wu T, He S, Jiao Z, Liang X, Chen Y, Liu H, Zhang Y, He G. Low Molecular Weight Heparin Improves the Inflammatory State of Acute Sinusitis Rats Through Inhibiting the TLR4-MyD88-NF-κB Signaling Pathway. Front Pharmacol 2021; 12:726630. [PMID: 34867331 PMCID: PMC8635784 DOI: 10.3389/fphar.2021.726630] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2021] [Accepted: 11/02/2021] [Indexed: 01/20/2023] Open
Abstract
Introduction: Low molecular weight heparin (LMWH), a natural sulfated glycosaminoglycan with an affinity for proangiogenic factors, is produced by chemical or enzymatic depolymerization of unfractionated heparin (UFH). Known for its anticoagulant effects, LMWH has recently been reported to have a strong anti-inflammatory effect on colitis, myocarditis, and airway inflammation. However, as a newly-developed drug, its anti-inflammatory mechanism in upper respiratory tract inflammation has not been well-studied. Methods: SD rats were randomly divided into control and experimental groups. The experimental group was established by building an acute nasal sinusitis model with expansion sponges mixed with Streptococcus pneumoniae. Then the experimental group rats were subcutaneously injected with different concentrations of LMWH. After seven consecutive days of injection, some rats were sacrificed, and blood and nasal mucosa samples were taken to determine their inflammation status. The remaining acute sinusitis rats were randomly selected for a week of nasal irrigation with normal saline or saline mixed with different concentrations of LMWH. One week later, rats were sacrificed, and samples of blood and nasal mucosa were taken to determine the inflammation status. Results: Rat nasal mucosa in the model group had obvious inflammation. The degree of nasal mucosa inflammation damage in the experimental group was lower than in the experimental control group, proving that LMWH has a protective effect on the nasal mucosa and that the effect correlates with dosage. Irrigation of the nose with saline mixed with LMWH can improve the anti-inflammatory effect. Protein related to the TLR4-MyD88-NF-κB signaling pathway was activated in the acute sinusitis rat model, and LMWH can significantly inhibit its expression. Conclusion: This is the first report of the anti-inflammatory effect of LMWH in acute upper respiratory tract inflammation, together with an explanation of its anti-inflammatory mechanism. The findings contribute a theoretical basis for its potential anti-tumor effect.
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Affiliation(s)
- Tong Wu
- Department of Otolaryngology-Head Neck Surgery, Third Xiangya Hospital, Central South University, Changsha, China.,Department of Head and Neck Surgery, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Sihan He
- Institute of Molecular Precision Medicine, Xiangya Hospital and Center for Medical Genetics, Central South University, Changsha, China
| | - Zan Jiao
- Department of Head and Neck Surgery, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Xiang Liang
- Department of Otolaryngology-Head Neck Surgery, Third Xiangya Hospital, Central South University, Changsha, China
| | - Yu Chen
- Department of Otolaryngology-Head Neck Surgery, Third Xiangya Hospital, Central South University, Changsha, China
| | - Huow Liu
- Department of Otolaryngology-Head Neck Surgery, Third Xiangya Hospital, Central South University, Changsha, China
| | - Yongq Zhang
- Department of Otolaryngology-Head Neck Surgery, Third Xiangya Hospital, Central South University, Changsha, China
| | - GuangX He
- Department of Otolaryngology-Head Neck Surgery, Third Xiangya Hospital, Central South University, Changsha, China
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Cato LD, Bailiff B, Price J, Ermogeneous C, Hazeldine J, Lester W, Lowe G, Wearn C, Bishop JRB, Lord JM, Moiemen N, Harrison P. Heparin resistance in severe thermal injury: A prospective cohort study. BURNS & TRAUMA 2021; 9:tkab032. [PMID: 34692855 PMCID: PMC8528639 DOI: 10.1093/burnst/tkab032] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Revised: 04/06/2021] [Indexed: 11/23/2022]
Abstract
BACKGROUND Low molecular-weight heparin (LMWH) is routinely administered to burn patients for thromboprophylaxis. Some studies have reported heparin resistance, yet the mechanism(s) and prevalence have not been systematically studied. We hypothesized that nucleosomes, composed of histone structures with associated DNA released from injured tissue and activated immune cells in the form of neutrophil extracellular traps (NETs or NETosis), neutralize LMWH resulting in suboptimal anticoagulation, assessed by reduction in anti-factor Xa activity. METHODS Blood was sampled from >15% total body surface area (TBSA) burn patients receiving LMWH on days 5, 10 and 14. Peak anti-factor Xa (AFXa) activity, anti-thrombin (ATIII) activity, cell-free DNA (cfDNA) levels and nucleosome levels were measured. Mixed effects regression was adjusted for multiple confounders, including injury severity and ATIII activity, and was used to test the association between nucleosomes and AFXa. RESULTS A total of 30 patients with severe burns were included. Mean TBSA 43% (SD 17). Twenty-three (77%) patients were affected by heparin resistance (defined by AFXa activity <0.2 IU/mL). Mean peak AFXa activity across samples was 0.18 IU/mL (SD 0.11). Mean ATIII was 81.9% activity (SD 20.4). Samples taken at higher LWMH doses were found to have significantly increased AFXa activity, though the effect was not observed at all doses, at 8000 IU no samples were heparin resistant. Nucleosome levels were negatively correlated with AFXa (r = -0.29, p = 0.050) consistent with the hypothesis. The final model, with peak AFXa as the response variable, was adjusted for nucleosome levels (p = 0.0453), ATIII activity (p = 0.0053), LMWH dose pre-sample (p = 0.0049), drug given (enoxaparin or tinzaparin) (p = 0.03), and other confounders including severity of injury, age, gender, time point of sample. CONCLUSIONS Heparin resistance is a prevalent issue in severe burns. Nucleosome levels were increased post-burn, and showed an inverse association with AFXa consistent with the hypothesis that they may interfere with the anticoagulant effect of heparin in vivo and contribute to heparin resistance. Accurate monitoring of AFXa activity with appropriate therapy escalation plans are recommended with dose adjustment following severe burn injury.
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Affiliation(s)
- Liam D Cato
- Scar Free Foundation Birmingham Centre for Burns Research, University Hospitals Birmingham Foundation Trust, Queen Elizabeth Hospital Birmingham, Mindelsohn Way, Birmingham, B15 2WB, UK
- Institute of Inflammation and Ageing, University of Birmingham, Birmingham, B15 2TT, UK
| | - Benjamin Bailiff
- Department of Haematology, University Hospitals Birmingham Foundation Trust, Mindelsohn Way, Birmingham, B15 2WB, UK
| | - Joshua Price
- Institute of Inflammation and Ageing, University of Birmingham, Birmingham, B15 2TT, UK
| | - Christos Ermogeneous
- Institute of Inflammation and Ageing, University of Birmingham, Birmingham, B15 2TT, UK
| | - Jon Hazeldine
- Institute of Inflammation and Ageing, University of Birmingham, Birmingham, B15 2TT, UK
| | - William Lester
- Department of Haematology, University Hospitals Birmingham Foundation Trust, Mindelsohn Way, Birmingham, B15 2WB, UK
| | - Gillian Lowe
- Department of Haematology, University Hospitals Birmingham Foundation Trust, Mindelsohn Way, Birmingham, B15 2WB, UK
| | - Christopher Wearn
- Scar Free Foundation Birmingham Centre for Burns Research, University Hospitals Birmingham Foundation Trust, Queen Elizabeth Hospital Birmingham, Mindelsohn Way, Birmingham, B15 2WB, UK
- Institute of Inflammation and Ageing, University of Birmingham, Birmingham, B15 2TT, UK
| | - Jonathan R B Bishop
- NIHR Surgical Reconstruction and Microbiology Research Centre, University Hospitals Birmingham Foundation Trust, Mindelsohn Way, Birmingham, B15 2WB, UK
| | - Janet M Lord
- Scar Free Foundation Birmingham Centre for Burns Research, University Hospitals Birmingham Foundation Trust, Queen Elizabeth Hospital Birmingham, Mindelsohn Way, Birmingham, B15 2WB, UK
- Institute of Inflammation and Ageing, University of Birmingham, Birmingham, B15 2TT, UK
- NIHR Surgical Reconstruction and Microbiology Research Centre, University Hospitals Birmingham Foundation Trust, Mindelsohn Way, Birmingham, B15 2WB, UK
| | - Naiem Moiemen
- Scar Free Foundation Birmingham Centre for Burns Research, University Hospitals Birmingham Foundation Trust, Queen Elizabeth Hospital Birmingham, Mindelsohn Way, Birmingham, B15 2WB, UK
- Institute of Inflammation and Ageing, University of Birmingham, Birmingham, B15 2TT, UK
- NIHR Surgical Reconstruction and Microbiology Research Centre, University Hospitals Birmingham Foundation Trust, Mindelsohn Way, Birmingham, B15 2WB, UK
| | - Paul Harrison
- Scar Free Foundation Birmingham Centre for Burns Research, University Hospitals Birmingham Foundation Trust, Queen Elizabeth Hospital Birmingham, Mindelsohn Way, Birmingham, B15 2WB, UK
- Institute of Inflammation and Ageing, University of Birmingham, Birmingham, B15 2TT, UK
- NIHR Surgical Reconstruction and Microbiology Research Centre, University Hospitals Birmingham Foundation Trust, Mindelsohn Way, Birmingham, B15 2WB, UK
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Martin GL, Trioux T, Gaudry S, Tubach F, Hajage D, Dechartres A. Association Between Lack of Blinding and Mortality Results in Critical Care Randomized Controlled Trials: A Meta-Epidemiological Study. Crit Care Med 2021; 49:1800-1811. [PMID: 33927122 DOI: 10.1097/ccm.0000000000005065] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
OBJECTIVES To investigate whether intervention effect estimates for mortality differ between blinded and nonblinded randomized controlled trials conducted in critical care. We used a meta-epidemiological approach, comparing effect estimates between blinded and nonblinded randomized controlled trials for the same research question. DATA SOURCES Systematic reviews and meta-analyses of randomized controlled trials evaluating a therapeutic intervention on mortality in critical care, published between January 2009 and March 2019 in high impact factor general medical or critical care journals and by Cochrane. DATA EXTRACTION For each randomized controlled trial included in eligible meta-analyses, we evaluated whether the trial was blinded (i.e., double-blinded and/or reporting adequate methods) or not (i.e., open-label, single-blinded, or unclear). We collected risk of bias evaluated by the review authors and extracted trial results. DATA SYNTHESIS Within each meta-analysis, we compared intervention effect estimates between blinded and nonblinded randomized controlled trials by using a ratio of odds ratio (< 1 indicates larger estimates in nonblinded than blinded randomized controlled trials). We then combined ratio of odds ratios across meta-analyses to obtain the average relative difference between nonblinded and blinded trials. Among 467 randomized controlled trials included in 36 meta-analyses, 267 (57%) were considered blinded and 200 (43%) nonblinded. Intervention effect estimates were statistically significantly larger in nonblinded than blinded trials (combined ratio of odds ratio, 0.91; 95% CI, 0.84-0.99). We found no heterogeneity across meta-analyses (p = 0.72; I2 = 0%; τ2 = 0). Sensitivity analyses adjusting the main analysis on risk of bias items yielded consistent results. CONCLUSIONS Intervention effect estimates of mortality were slightly larger in nonblinded than blinded randomized controlled trials conducted in critical care, but confounding cannot be excluded. Blinding of both patients and personnel is important to consider when possible in critical care trials, even when evaluating mortality.
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Affiliation(s)
- Guillaume L Martin
- Sorbonne Université, INSERM, Institut Pierre Louis d'Epidémiologie et de Santé Publique, AP-HP, Hôpital Pitié Salpêtrière, Département de Santé Publique, Paris, France
| | - Théo Trioux
- Sorbonne Université, INSERM, Institut Pierre Louis d'Epidémiologie et de Santé Publique, AP-HP, Hôpital Pitié Salpêtrière, Département de Santé Publique, Paris, France
| | - Stéphane Gaudry
- Département de réanimation médico-chirurgicale, APHP, Hôpital Avicenne, UFR SMBH, Université Sorbonne Paris Nord, Bobigny, France
- Common and Rare Kidney Diseases, Sorbonne Université, INSERM, UMR-S 1155, Paris, France
| | - Florence Tubach
- Sorbonne Université, INSERM, Institut Pierre Louis d'Epidémiologie et de Santé Publique, AP-HP, Hôpital Pitié Salpêtrière, Département de Santé Publique, Paris, France
| | - David Hajage
- Sorbonne Université, INSERM, Institut Pierre Louis d'Epidémiologie et de Santé Publique, AP-HP, Hôpital Pitié Salpêtrière, Département de Santé Publique, Paris, France
| | - Agnès Dechartres
- Sorbonne Université, INSERM, Institut Pierre Louis d'Epidémiologie et de Santé Publique, AP-HP, Hôpital Pitié Salpêtrière, Département de Santé Publique, Paris, France
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Impact of Allogeneic Leukocyte-Depleted Red Blood Cell Transfusion on Inflammatory Response and Blood Coagulation in Patients with Recurrence of Colon Cancer after Operation. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2021; 2021:6957569. [PMID: 34552654 PMCID: PMC8452391 DOI: 10.1155/2021/6957569] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Accepted: 08/26/2021] [Indexed: 11/17/2022]
Abstract
Objective Anemia inevitably affects the survival of cancer patients. In clinical practice, patients with anemia and decreased blood volume are treated by component blood transfusion. Through targeted blood transfusion therapy, the efficacy of blood transfusion treatment can be validly improved, which renders clinical benefits in reducing transfusion-induced adverse reactions (ARs). This research project mainly investigated the impact of allogeneic leukocyte-depleted red blood cell (LDRBC) transfusion on inflammatory response and coagulation status of patients with postoperative recurrence of colon cancer (CC). Methods A total of 80 patients with postoperative recurrence of CC admitted to Changzhou Second People's Hospital affiliated to Nanjing Medical University from September 2017 to December 2020 were selected as the study subjects. 36 patients with allogeneic suspended red blood cell (RBC) transfusion were used as the control group (CG), and 44 patients receiving allogeneic LDRBC transfusion served as the observation group (OG). The two groups were compared regarding alterations in pretransfusion and posttransfusion serum inflammatory factors, stress indicators and coagulation function, incidence of ARs, postoperative infection, and average incision healing time. Results After blood transfusion, serum tumor necrosis interleukin- (IL-) 6, IL-10, factor-α (TNF-α), and C-reactive protein (CRP) decreased in both cohorts, with lower parameters in CG (P < 0.05); the stress indexes, adrenocortical hormone (ACTH), adrenaline (AD), norepinephrine (NE), and cortisol (Cor) increased, especially in CG (P < 0.05); prothrombin time (PT), thrombin time (TT), and activated partial prothrombin time (APTT) in CG were lower than those in OG, and FIB was higher than that in OG with significant differences between two cohorts (all P < 0.05). The two groups had similar cases of lung infection and wound infection (P > 0.05), but the incision healing time was evidently shorter in OG as compared to CG (9.73 ± 1.86 vs 14.67 ± 2.39 d, P < 0.05). The total incidence of ARs was 16.7% in CG and 6.9% in OG, with no significant difference (P > 0.05). Conclusions In the blood transfusion treatment for patients with postoperative recurrence of CC, LDRBC transfusion renders significant clinical benefits, which can effectively improve the coagulation function of patients, reduce stress reaction, and shorten incision healing time without increasing ARs during treatment and postoperative infection rate, which is worth popularizing.
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Möhnle P, Bruegel M, Spannagl M. [Anticoagulation in intensive care medicine]. Med Klin Intensivmed Notfmed 2021; 116:499-507. [PMID: 34432085 PMCID: PMC8385697 DOI: 10.1007/s00063-021-00849-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2021] [Revised: 06/18/2021] [Accepted: 07/12/2021] [Indexed: 11/28/2022]
Abstract
Critically ill patients are at high risk of hemostasis disorders, which can be associated with both an increased risk of bleeding and an increased risk of thromboembolic events. In the case of acute vascular events, specific therapy with drug anticoagulation or platelet aggregation inhibition is essential. In patients with pre-existing conditions, the appropriate continuation of anticoagulation during intensive care treatment is important. Furthermore, in everyday clinical practice, prophylaxis of thromboembolism as well as the question of potential therapeutic options in the treatment of sepsis and infection-triggered disorders of blood coagulation are important. Specific questions arise with the use of extracorporeal devices such as renal replacement and circulatory assist systems. A number of new anticoagulation and anti-platelet drugs have become available in recent years. Laboratory monitoring of anticoagulation is central. In this overview, current aspects of these topics are presented.
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Affiliation(s)
- Patrick Möhnle
- Abteilung für Transfusionsmedizin, Zelltherapeutika und Hämostaseologie, Klinik für Anästhesiologie, LMU Klinikum München, Ziemssenstr. 1, 80336, München, Deutschland.
| | - Mathias Bruegel
- Institut für Laboratoriumsmedizin, LMU Klinikum München, München, Deutschland
| | - Michael Spannagl
- Abteilung für Transfusionsmedizin, Zelltherapeutika und Hämostaseologie, Klinik für Anästhesiologie, LMU Klinikum München, Ziemssenstr. 1, 80336, München, Deutschland
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Schmoch T, Brenner T, Becker-Pennrich A, Hinske LC, Weigand MA, Briegel J, Möhnle P. [Treatment of sepsis-induced coagulopathy : Results of a Germany-wide survey in intensive care units]. Anaesthesist 2021; 70:662-670. [PMID: 33558944 PMCID: PMC7869761 DOI: 10.1007/s00101-021-00916-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2020] [Revised: 12/22/2020] [Accepted: 01/08/2021] [Indexed: 12/17/2022]
Abstract
BACKGROUND In the context of sepsis and septic shock, coagulopathy often occurs due to the close relationship between coagulation and inflammation. Sepsis-induced coagulopathy (SIC) is the most severe and potentially fatal form. Anticoagulants used in prophylactic or therapeutic doses are discussed to potentially exert beneficial effects in patients with sepsis and/or SIC; however, due to the lack of evidence recent guidelines are limited to recommendations for drug prophylaxis of venous thromboembolism (VTE), while treatment of SIC has not been addressed. METHODS In order to determine the status quo of VTE prophylaxis as well as treatment of SIC in German intensive care units (ICU), we conducted a Germany-wide online survey among heads of ICUs from October 2019 to May 2020. In April 2020, the survey was supplemented by an additional block of questions on VTE prophylaxis and SIC treatment in coronavirus disease 2019 (COVID-19) patients. RESULTS A total of 67 senior doctors took part in the survey. The majority (n = 50; 74.6%) of the responses were from ICU under the direction of an anesthesiologist and/or a department of anesthesiology. Most of the participants worked either at a university hospital (n = 31; 47.8%) or an academic teaching hospital (n = 27; 40.3%). The survey results show a pronounced heterogeneity in clinical practice with respect to the prophylaxis of VTE as well as SIC treatment. In an exemplary case of pneumogenic sepsis, low molecular weight heparins (LMWH) were by far the most frequently mentioned group of medications (n = 51; 76.1% of the responding ITS). In the majority of cases (n = 43; 64.2%), anti-FXa activity is not monitored with the use of LMWH in prophylaxis doses. Unfractionated heparin (UFH) was listed as a strategy for VTE prophylaxis in 37.3% of the responses (n = 25). In an exemplary case of abdominal sepsis 54.5% of the participants (n = 36; multiple answers possible) stated the use of UFH or LMWH and UFH with dosage controlled by PTT is used on two participating ICUs. The anti-FXa activity under prophylactic anticoagulation with LMWH is monitored in 7 participating clinics (10.6%) in abdominal sepsis. Systematic screening for sepsis-associated coagulation disorders does not take place in most hospitals and patterns in the use of anticoagulants show significant variability between ICUs. In the case of COVID-19 patients, it is particularly noticeable that in three quarters of the participating ICUs the practice of drug-based VTE prophylaxis and SIC treatment does not differ from that of non-COVID-19 patients. CONCLUSION The heterogeneity of answers collected in the survey suggests that a systematic approach to this topic via clinical trials is urgently needed to underline individualized patient care with the necessary evidence.
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Affiliation(s)
- Thomas Schmoch
- Klinik für Anästhesiologie, Universitätsklinikum Heidelberg, Heidelberg, Deutschland.
- Klinik für Anästhesiologie und Intensivmedizin, Universitätsklinikum Essen, Hufelandstraße 55, 45147, Essen, Deutschland.
| | - Thorsten Brenner
- Klinik für Anästhesiologie und Intensivmedizin, Universitätsklinikum Essen, Hufelandstraße 55, 45147, Essen, Deutschland
| | - Andrea Becker-Pennrich
- Klinik für Anästhesiologie und Abteilung für Transfusionsmedizin, Zelltherapeutika und Hämostaseologie, LMU Klinikum München, München, Deutschland
| | - Ludwig Christian Hinske
- Klinik für Anästhesiologie und Abteilung für Transfusionsmedizin, Zelltherapeutika und Hämostaseologie, LMU Klinikum München, München, Deutschland
- Institut für medizinische Informationsverarbeitung, Biometrie und Epidemiologie, LMU München, München, Deutschland
| | - Markus A Weigand
- Klinik für Anästhesiologie, Universitätsklinikum Heidelberg, Heidelberg, Deutschland
| | - Josef Briegel
- Klinik für Anästhesiologie und Abteilung für Transfusionsmedizin, Zelltherapeutika und Hämostaseologie, LMU Klinikum München, München, Deutschland
| | - Patrick Möhnle
- Klinik für Anästhesiologie und Abteilung für Transfusionsmedizin, Zelltherapeutika und Hämostaseologie, LMU Klinikum München, München, Deutschland
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Abstract
BACKGROUND Circulating complement C3 fragments released during septic shock might contribute to the development of complications such as profound hypotension and disseminated intravascular coagulation. The role of C3 in the course of septic shock varies in the literature, possibly because circulating C3 exists in different forms indistinguishable via traditional ELISA-based methods. We sought to test the relationship between C3 forms, measured by Western blotting with its associated protein size differentiation feature, and clinical outcomes. METHODS Secondary analysis of two prospective cohorts of patients with septic shock: a discovery cohort of 24 patents and a validation cohort of 181 patients. C3 levels were measured by Western blotting in both cohorts using blood obtained at enrollment. Differences between survivors and non-survivors were compared, and the independent prognostic values of C3 forms were assessed. RESULTS In both cohorts there were significantly lower levels of the C3-alpha chain in non-survivors than in survivors, and persisted after controlling for sequential organ failure assessment score. Area under the receiver operating characteristics to predict survival was 0.65 (95% confidence interval: 0.56-0.75). At a best cutoff value (Youden) of 970.6 μg/mL, the test demonstrated a sensitivity of 68.5% and specificity of 61.5%. At this cutoff point, Kaplan-Meier survival analysis showed that patients with lower levels of C3-alpha chain had significantly lower survival than those with higher levels (P < 0.001). CONCLUSION Circulating C3-alpha chain levels is a significant independent predictor of survival in septic shock patients.
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Unfractionated Heparin Improves the Intestinal Microcirculation in a Canine Septic Shock Model. Mediators Inflamm 2021; 2021:9985397. [PMID: 34257522 PMCID: PMC8245220 DOI: 10.1155/2021/9985397] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2021] [Accepted: 05/21/2021] [Indexed: 12/29/2022] Open
Abstract
Background Alterations of microcirculation are associated with organ hypoperfusion and high mortality in septic shock. This study is aimed at investigating the effects of unfractionated heparin (UFH) on intestinal microcirculatory perfusion and systemic circulation in a septic shock model. Methods Twenty-four beagle dogs were randomly allocated into four groups: (a) sham group: healthy controls, (b) shock group: septic shock induced by Escherichia coli, (c) basic therapy group: septic shock animals treated with antibiotics and 10 ml/kg/h saline, and (d) heparin group: septic shock animals treated with basic therapy plus UFH. Hemodynamic variables were measured within 24 h after E. coli administration. The intestinal microcirculation was simultaneously investigated with a sidestream dark-field imaging technique. Additionally, the function of vital organs was evaluated at 12 h postadministration (T12). Results E. coli induced a progressive septic shock in which the mean arterial pressure (MAP) decreased and lactate levels sharply increased, accompanied by deteriorated microvessel perfusion. While basic therapy partially improved the microvascular flow index and the perfused microvessel density in the jejunal villi, UFH significantly restored major microcirculation variables at T12. Physiological variables, including MAP, urine output, and lactate levels, were improved by UFH, whereas some hemodynamic indices were not affected by UFH. With respect to organ function, UFH increased the platelet count and decreased the creatinine level. Conclusions UFH improves microcirculatory perfusion of the small intestine independently of the changes in systemic hemodynamic variables in a canine model of septic shock, thereby improving coagulation and renal function.
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Alfraij A, Elseadawy M, Alghounaim M. The effect of topical nitroglycerin on symmetrical peripheral gangrene in a pediatric patient. Clin Case Rep 2021; 9:e04213. [PMID: 34026189 PMCID: PMC8123546 DOI: 10.1002/ccr3.4213] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2021] [Revised: 04/02/2021] [Accepted: 04/06/2021] [Indexed: 11/17/2022] Open
Abstract
Symmetrical peripheral gangrene is a rare condition associated with significant morbidity and mortality. The use of topical nitroglycerin may have a role in improving patient outcomes and opens a new area for future research regarding the use of topical nitroglycerin in SPG.
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Affiliation(s)
- Abdulla Alfraij
- Department of PediatricsPediatric Intensive Care UnitFarwaniya HospitalFarwaniyaKuwait
| | - Mohammad Elseadawy
- Department of PediatricsPediatric Intensive Care UnitFarwaniya HospitalFarwaniyaKuwait
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Qiu M, Huang S, Luo C, Wu Z, Liang B, Huang H, Ci Z, Zhang D, Han L, Lin J. Pharmacological and clinical application of heparin progress: An essential drug for modern medicine. Biomed Pharmacother 2021; 139:111561. [PMID: 33848775 DOI: 10.1016/j.biopha.2021.111561] [Citation(s) in RCA: 60] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Revised: 03/20/2021] [Accepted: 03/31/2021] [Indexed: 12/22/2022] Open
Abstract
Heparin is the earliest and most widely used anticoagulant and antithrombotic drug that is still used in a variety of clinical indications. Since it was discovered in 1916, after more than a century of repeated exploration, heparin has not been replaced by other drugs, but a great progress has been made in its basic research and clinical application. Besides anticoagulant and antithrombotic effects, heparin also has antitumor, anti-inflammatory, antiviral, and other pharmacological activities. It is widely used clinically in cardiovascular and cerebrovascular diseases, lung diseases, kidney diseases, cancer, etc., as the first anticoagulant medicine in COVID-19 exerts anticoagulant, anti-inflammatory and antiviral effects. At the same time, however, it also leads to a lot of adverse reactions, such as bleeding, thrombocytopenia, elevated transaminase, allergic reactions, and others. This article comprehensively reviews the modern research progress of heparin compounds; discusses the structure, preparation, and adverse reactions of heparin; emphasizes the pharmacological activity and clinical application of heparin; reveals the possible mechanism of the therapeutic effect of heparin in related clinical applications; provides evidence support for the clinical application of heparin; and hints on the significance of exploring the wider application fields of heparin.
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Affiliation(s)
- Min Qiu
- State Key Laboratory of Southwestern Chinese Medicine Resources, Pharmacy School, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, PR China
| | - Shengjie Huang
- State Key Laboratory of Southwestern Chinese Medicine Resources, Pharmacy School, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, PR China
| | - Chuanhong Luo
- State Key Laboratory of Southwestern Chinese Medicine Resources, Pharmacy School, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, PR China
| | - Zhenfeng Wu
- Key Laboratory of Modern Preparation of TCM, Ministry of Education, Jiangxi University of Traditional Chinese Medicine, Nanchang 330004, PR China
| | - Binzhu Liang
- State Key Laboratory of Southwestern Chinese Medicine Resources, Pharmacy School, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, PR China
| | - Haozhou Huang
- State Key Laboratory of Southwestern Chinese Medicine Resources, Pharmacy School, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, PR China
| | - Zhimin Ci
- State Key Laboratory of Southwestern Chinese Medicine Resources, Pharmacy School, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, PR China
| | - Dingkun Zhang
- State Key Laboratory of Southwestern Chinese Medicine Resources, Pharmacy School, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, PR China
| | - Li Han
- State Key Laboratory of Southwestern Chinese Medicine Resources, Pharmacy School, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, PR China.
| | - Junzhi Lin
- TCM Regulating Metabolic Diseases Key Laboratory of Sichuan Province, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 610072, PR China.
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Li Y, Wan D, Luo X, Song T, Wang Y, Yu Q, Jiang L, Liao R, Zhao W, Su B. Circulating Histones in Sepsis: Potential Outcome Predictors and Therapeutic Targets. Front Immunol 2021; 12:650184. [PMID: 33868288 PMCID: PMC8044749 DOI: 10.3389/fimmu.2021.650184] [Citation(s) in RCA: 55] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Accepted: 03/11/2021] [Indexed: 02/05/2023] Open
Abstract
Sepsis is defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection and is associated with high morbidity and mortality. Circulating histones (CHs), a group of damage-associated molecular pattern molecules mainly derived from neutrophil extracellular traps, play a crucial role in sepsis by mediating inflammation response, organ injury and death through Toll-like receptors or inflammasome pathways. Herein, we first elucidate the molecular mechanisms of histone-induced inflammation amplification, endothelium injury and cascade coagulation activation, and discuss the close correlation between elevated level of CHs and disease severity as well as mortality in patients with sepsis. Furthermore, current state-of-the-art on anti-histone therapy with antibodies, histone-binding proteins (namely recombinant thrombomodulin and activated protein C), and heparin is summarized to propose promising approaches for sepsis treatment.
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Affiliation(s)
- Yupei Li
- Department of Nephrology of West China Hospital, Institute for Disaster Management and Reconstruction, Sichuan University, Chengdu, China.,Department of Emergency Medicine of West China Hospital, Disaster Medical Center, Sichuan University, Chengdu, China.,Med-X Center for Materials, Sichuan University, Chengdu, China
| | - Dingyuan Wan
- West China School of Medicine, Sichuan University, Chengdu, China
| | - Xinyao Luo
- West China School of Medicine, Sichuan University, Chengdu, China
| | - Tao Song
- College of Polymer Science and Engineering, State Key Laboratory of Polymer Materials Engineering, Sichuan University, Chengdu, China
| | - Yiran Wang
- College of Polymer Science and Engineering, State Key Laboratory of Polymer Materials Engineering, Sichuan University, Chengdu, China
| | - Qiao Yu
- Department of Nephrology of West China Hospital, Institute for Disaster Management and Reconstruction, Sichuan University, Chengdu, China.,Department of Emergency Medicine of West China Hospital, Disaster Medical Center, Sichuan University, Chengdu, China.,Med-X Center for Materials, Sichuan University, Chengdu, China
| | - Luojia Jiang
- Department of Nephrology of West China Hospital, Institute for Disaster Management and Reconstruction, Sichuan University, Chengdu, China
| | - Ruoxi Liao
- Department of Nephrology of West China Hospital, Institute for Disaster Management and Reconstruction, Sichuan University, Chengdu, China
| | - Weifeng Zhao
- College of Polymer Science and Engineering, State Key Laboratory of Polymer Materials Engineering, Sichuan University, Chengdu, China
| | - Baihai Su
- Department of Nephrology of West China Hospital, Institute for Disaster Management and Reconstruction, Sichuan University, Chengdu, China.,Department of Emergency Medicine of West China Hospital, Disaster Medical Center, Sichuan University, Chengdu, China.,Med-X Center for Materials, Sichuan University, Chengdu, China.,West China School of Medicine, Sichuan University, Chengdu, China
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