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Ogiwara K, Furukawa S, Inaba K, Sasai K, Nakajima Y, Shimonishi N, Kitazawa T, Nogami K. Insights from in vitro global assays on possible doses of concomitant hemostatic agents in the presence of NXT007 in hemophilia A. J Thromb Haemost 2025:S1538-7836(25)00214-4. [PMID: 40199443 DOI: 10.1016/j.jtha.2025.03.034] [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: 01/21/2025] [Revised: 03/23/2025] [Accepted: 03/25/2025] [Indexed: 04/10/2025]
Abstract
BACKGROUND Concomitant administration of activated prothrombin complex concentrate (APCC) at doses >100 U/kg/d is associated with thrombotic risk under emicizumab prophylaxis. In vitro global assay data on the effects of concomitant coagulation factor agents in the presence of NXT007, an emicizumab-based engineered bispecific antibody under clinical development, may serve as a basis for addressing this potential risk. OBJECTIVES This study aimed to investigate the in vitro effects of recombinant factor (rF)VIII, rFVIIa, and APCC during NXT007 treatment and estimate tolerable doses with reference to emicizumab. METHODS Thrombin generation assays, clot waveform analysis, and rotational thromboelastometry were performed using hemophilia A plasma and blood samples spiked with NXT007 and others. RESULTS A single dose of NXT007 at ≥10.0 μg/mL (plasma) achieved a nonhemophiliac coagulation potential. The concomitant addition of rFVIII, rFVIIa, and APCC each boosted various parameters following NXT007 levels at 0.1 to 50.0 μg/mL. In the copresence of NXT007 at 15.0 μg/mL (blood) and APCC at 0.13 U/mL, with the blood level immediately following the administration of 10.0 U/kg, the rotational thromboelastometry parameters were comparable with those observed with clinical emicizumab level and APCC at 0.63 U/mL, corresponding to the blood level immediately after administrating 50.0 U/kg (recommended initial dose). CONCLUSION Concomitant addition of coagulation agents increased coagulation potentials in vitro in the presence of NXT007. A dose of 10.0 U/kg may serve as a rough indicator for the initial dose when exploring the concomitant use of APCC at plasma NXT007 levels of ∼30.0 μg/mL. Importantly, plasma NXT007 at ≥10.0 μg/mL demonstrated non-hemophiliac coagulation potentials in vitro.
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Affiliation(s)
- Kenichi Ogiwara
- Department of Pediatrics, Nara Medical University, Kashihara, Japan.
| | - Shoko Furukawa
- Department of Pediatrics, Nara Medical University, Kashihara, Japan
| | - Keito Inaba
- Research Division, Chugai Pharmaceutical, Yokohama, Japan
| | - Kana Sasai
- Department of Pediatrics, Nara Medical University, Kashihara, Japan
| | - Yuto Nakajima
- Department of Pediatrics, Nara Medical University, Kashihara, Japan
| | - Naruto Shimonishi
- Department of Pediatrics, Nara Medical University, Kashihara, Japan; The Course of Thrombosis and Hemostasis Molecular Pathology, Nara Medical University, Kashihara, Japan
| | | | - Keiji Nogami
- Department of Pediatrics, Nara Medical University, Kashihara, Japan
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Wu X, Liu Y, Zou C, He F, Guo F, Liu S, Fan Y, Zhu X, Zhou Q, Shu D. Nicotine's impact on platelet function: insights into hemostasis mechanisms. Front Pharmacol 2025; 15:1512142. [PMID: 39902074 PMCID: PMC11788582 DOI: 10.3389/fphar.2024.1512142] [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: 10/16/2024] [Accepted: 12/18/2024] [Indexed: 02/05/2025] Open
Abstract
Introduction Traditional Miao and Dai Chinese medicines have used nicotine-rich leaf tobacco to treat traumatic injuries by promoting hemostasis. While nicotine is known to enhance platelet aggregation, its effects on other platelet functions and underlying mechanisms remain unclear. Methods and Results This study aimed to thoroughly investigate nicotine's effects on human platelets and its pharmacological mechanisms, using thromboelastography to assess nicotine's impact on platelet function during coagulation. This study aimed to investigate the functional effects of nicotine on human platelets and elucidate its pharmacological mechanisms. The impact of nicotine on platelet function during the coagulation process was assessed using thromboelastography. Further studies showed that nicotine fully activates washed platelets, promoting aggregation, granule release, adhesion, spreading, and plaque retraction. Concurrently, nicotine was found to enhance the intracellular concentration of calcium ions in platelets ([Ca2+]i). To explore the underlying mechanisms, molecular docking software was employed to identify the platelet membrane receptors PAR1 and PAR4, which exhibited the highest docking scores with nicotine. Intervention with two receptor inhibitors demonstrated that only the PAR4 inhibitor could reverse the stimulatory effects of nicotine on platelet granule release. Through the examination of alterations in the downstream signaling pathways of PAR4 receptors, it was determined that nicotine promo-facilitates the phosphorylation of PI3K, AKT, and ERK1/2 proteins, subsequently contributing to the activation of αIIbβ3 receptors in platelets. Conversely, the application of PAR4 inhibitors was found to reverse these effects. Discussion In conclusion, nicotine activates αIIbβ3 receptors and significantly enhances platelet function by promoting the phosphorylation of the platelet PAR4 receptor signaling pathway. These findings suggest the potential utility of nicotine as a hemostatic agent.
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Affiliation(s)
- Xiayu Wu
- Institute of Pharmaceutical Innovation, Hubei Province Key Laboratory of Occupational Hazard Identification and Control, School of Medicine, Wuhan University of Science and Technology, Wuhan, China
- Institute of Cardiovascular Diseases, Hubei Province Key Laboratory of Occupational Hazard Identification and Control, School of Medicine, Wuhan University of Science and Technology, Wuhan, China
| | - Yongjun Liu
- Hunan Tobacco Science Research Institute, Changsha, China
| | - Changhao Zou
- Institute of Pharmaceutical Innovation, Hubei Province Key Laboratory of Occupational Hazard Identification and Control, School of Medicine, Wuhan University of Science and Technology, Wuhan, China
- Institute of Cardiovascular Diseases, Hubei Province Key Laboratory of Occupational Hazard Identification and Control, School of Medicine, Wuhan University of Science and Technology, Wuhan, China
| | - Fuqin He
- Institute of Pharmaceutical Innovation, Hubei Province Key Laboratory of Occupational Hazard Identification and Control, School of Medicine, Wuhan University of Science and Technology, Wuhan, China
- Institute of Cardiovascular Diseases, Hubei Province Key Laboratory of Occupational Hazard Identification and Control, School of Medicine, Wuhan University of Science and Technology, Wuhan, China
| | - Fang Guo
- Institute of Pharmaceutical Innovation, Hubei Province Key Laboratory of Occupational Hazard Identification and Control, School of Medicine, Wuhan University of Science and Technology, Wuhan, China
- Institute of Cardiovascular Diseases, Hubei Province Key Laboratory of Occupational Hazard Identification and Control, School of Medicine, Wuhan University of Science and Technology, Wuhan, China
| | - Sijia Liu
- Institute of Pharmaceutical Innovation, Hubei Province Key Laboratory of Occupational Hazard Identification and Control, School of Medicine, Wuhan University of Science and Technology, Wuhan, China
- Institute of Cardiovascular Diseases, Hubei Province Key Laboratory of Occupational Hazard Identification and Control, School of Medicine, Wuhan University of Science and Technology, Wuhan, China
| | - Yi Fan
- Institute of Pharmaceutical Innovation, Hubei Province Key Laboratory of Occupational Hazard Identification and Control, School of Medicine, Wuhan University of Science and Technology, Wuhan, China
- Institute of Cardiovascular Diseases, Hubei Province Key Laboratory of Occupational Hazard Identification and Control, School of Medicine, Wuhan University of Science and Technology, Wuhan, China
| | - Xuedong Zhu
- Institute of Pharmaceutical Innovation, Hubei Province Key Laboratory of Occupational Hazard Identification and Control, School of Medicine, Wuhan University of Science and Technology, Wuhan, China
- Institute of Cardiovascular Diseases, Hubei Province Key Laboratory of Occupational Hazard Identification and Control, School of Medicine, Wuhan University of Science and Technology, Wuhan, China
| | - Qianyi Zhou
- Institute of Pharmaceutical Innovation, Hubei Province Key Laboratory of Occupational Hazard Identification and Control, School of Medicine, Wuhan University of Science and Technology, Wuhan, China
- Institute of Cardiovascular Diseases, Hubei Province Key Laboratory of Occupational Hazard Identification and Control, School of Medicine, Wuhan University of Science and Technology, Wuhan, China
| | - Dan Shu
- Institute of Pharmaceutical Innovation, Hubei Province Key Laboratory of Occupational Hazard Identification and Control, School of Medicine, Wuhan University of Science and Technology, Wuhan, China
- Institute of Cardiovascular Diseases, Hubei Province Key Laboratory of Occupational Hazard Identification and Control, School of Medicine, Wuhan University of Science and Technology, Wuhan, China
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Mizumachi K, Ogiwara K, Nakajima Y, Shimonishi N, Furukawa S, Takeyama M, Nogami K. Factor X consumption attenuates the coagulation effect of emicizumab: a case of severe hemophilia A treated with emicizumab and factor VIII-bypassing agents. Int J Hematol 2025; 121:126-130. [PMID: 39476172 DOI: 10.1007/s12185-024-03860-7] [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: 05/09/2024] [Revised: 10/04/2024] [Accepted: 10/16/2024] [Indexed: 01/19/2025]
Abstract
In patients with hemophilia A with inhibitor (PwHA-I), emicizumab drastically reduces bleeding events. However, few studies have investigated the behavior and effects of factor X (FX) in patients who require intensive treatment with factor VIII-bypassing agents (BPA) and emicizumab. A 59-year-old man with HA-I receiving emicizumab prophylaxis was admitted to our hospital because of acute gangrenous cholecystitis. He received percutaneous transhepatic gallbladder drainage and laparoscopic cholecystectomy along with repeated administration of recombinant activated factor VII (rFVIIa). On day 10, a large hematoma developed around the residual gallbladder. Rotational thromboelastometry (ROTEM) suggested poor effect of rFVIIa and reduced activity of emicizumab. Considering that this could be due to consumption of FX, plasma-derived FVIIa/FX agent (pdFVIIa/X) was administered, and ROTEM parameters recovered considerably. The patient was discharged on day 19 uneventfully. Plasma assays revealed that FX antigen level (FX:Ag) was 107.5% at baseline but then decreased. Administration of pdFVIIa/FX restored FX:Ag (pre/post 47.2%/125.5%). ROTEM and thrombin generation assay with in vitro addition of anti-emicizumab antibody suggested that low FX:Ag was responsible for attenuating the effect of emicizumab, and pdFVIIa/FX administration restored coagulation potentials. In PwHA-I receiving intensive treatment with rFVIIa under emicizumab prophylaxis, FX consumption might attenuate the effect of emicizumab.
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Affiliation(s)
- Kuniyoshi Mizumachi
- Department of Pediatrics, Nara Medical University, 840 Shijo-cho, Kashihara, Nara, 634-8522, Japan
| | - Kenichi Ogiwara
- Department of Pediatrics, Nara Medical University, 840 Shijo-cho, Kashihara, Nara, 634-8522, Japan.
| | - Yuto Nakajima
- Department of Pediatrics, Nara Medical University, 840 Shijo-cho, Kashihara, Nara, 634-8522, Japan
- Advanced Medical Science of Thrombosis and Hemostasis, Nara Medical University, Kashihara, Nara, Japan
| | - Naruto Shimonishi
- Department of Pediatrics, Nara Medical University, 840 Shijo-cho, Kashihara, Nara, 634-8522, Japan
- The Course of Thrombosis and Hemostasis Molecular Pathology, Nara Medical University, Kashihara, Nara, Japan
| | - Shoko Furukawa
- Department of Pediatrics, Nara Medical University, 840 Shijo-cho, Kashihara, Nara, 634-8522, Japan
| | - Masahiro Takeyama
- Department of Pediatrics, Nara Medical University, 840 Shijo-cho, Kashihara, Nara, 634-8522, Japan
| | - Keiji Nogami
- Department of Pediatrics, Nara Medical University, 840 Shijo-cho, Kashihara, Nara, 634-8522, Japan
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Raventós A, Arias-Salgado EG, Pérez A, Alvarez-Román MT, Butta NV, Monzon Manzano E, Acuña P, Jiménez-Yuste V, Costa M, Bravo MI. Ex vivo evaluation of the effect of plasma-derived factor VIII/von Willebrand factor in patients with severe hemophilia A on emicizumab prophylaxis. Clin Exp Med 2024; 25:14. [PMID: 39708197 DOI: 10.1007/s10238-024-01528-4] [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: 08/01/2024] [Accepted: 11/22/2024] [Indexed: 12/23/2024]
Abstract
Hemophilia A (HA) patients under emicizumab prophylaxis may require the concomitant use of procoagulant factors for breakthrough bleedings or immune tolerance induction (ITI). The aim of this study is to evaluate the ex vivo procoagulant effect of plasma-derived FVIII concentrates containing von Willebrand factor (pdFVIII/VWF) in samples from patients with severe HA without inhibitors on emicizumab prophylaxis. Samples from healthy controls (HC) and HA patients were drawn in sodium citrate plus corn trypsin inhibitor tubes and spiked with increasing concentrations of pdFVIII/VWF concentrates (10-400 IU/dL) (Fanhdi®/Alphanate®, Grifols), activated prothrombin complex concentrate (aPCC, 0.5 U/mL) or recombinant activated factor VII (rFVIIa, 0.9 µg/mL). Global coagulation was measured by rotational thromboelastometry (ROTEM) (clotting time [CT] and time to maximum clot formation velocity [MAXV-t]) and thrombin generation (TG) assay (thrombin peak [TP] and endogenous thrombin potential [ETP]). Samples from HA patients under emicizumab prophylaxis showed CT and MAXV-t values above HC levels, while TP and ETP were below HC levels. Ex vivo pdFVIII/VWF supplementation increased TP and ETP and shortened CT and MAXV-t dose-dependently. At 50 IU/dL (≈25 IU/kg), pdFVIII/VWF normalized clot formation and restored TG within HC normal range. The highest pdFVIII/VWF concentration (400 IU/dL) and rFVIIa did not result in an excessive procoagulant profile. However, aPCC induced ex vivo an excessive TG and markedly decreased ROTEM parameters (CT and MAXV-t). Coagulation parameters of both methods significantly correlated at baseline and with increasing concentrations of pdFVIII/VWF. High doses of pdFVIII/VWF concentrates, similar to those used for ITI, did not trigger a multiplying procoagulant effect to samples from HA patients on emicizumab prophylaxis, evidencing their low thrombotic risk in these patients.
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Affiliation(s)
- Aida Raventós
- Discovery Research, Scientific Innovation Office, Grifols, Palou 3, 08150, Parets del Vallès, Barcelona, Spain.
| | | | - Alba Pérez
- Discovery Research, Scientific Innovation Office, Grifols, Palou 3, 08150, Parets del Vallès, Barcelona, Spain
| | - María Teresa Alvarez-Román
- Hematology and Hemotherapy Unit, La Paz University Hospital-IdiPAZ, Madrid, Spain
- Universidad Autónoma de Madrid, Madrid, Spain
| | - Nora V Butta
- Hematology and Hemotherapy Unit, La Paz University Hospital-IdiPAZ, Madrid, Spain
| | - Elena Monzon Manzano
- Hematology and Hemotherapy Unit, La Paz University Hospital-IdiPAZ, Madrid, Spain
| | - Paula Acuña
- Hematology and Hemotherapy Unit, La Paz University Hospital-IdiPAZ, Madrid, Spain
| | - Víctor Jiménez-Yuste
- Hematology and Hemotherapy Unit, La Paz University Hospital-IdiPAZ, Madrid, Spain
- Universidad Autónoma de Madrid, Madrid, Spain
| | - Montserrat Costa
- Discovery Research, Scientific Innovation Office, Grifols, Palou 3, 08150, Parets del Vallès, Barcelona, Spain
| | - María Isabel Bravo
- Discovery Research, Scientific Innovation Office, Grifols, Palou 3, 08150, Parets del Vallès, Barcelona, Spain
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Zrimsek M, Gubensek J, Marn Pernat A. A Pilot Study on the Replacement of Fibrinogen with Fibrinogen Concentrates During Therapeutic Plasma Exchange with Mild to Moderate Bleeding Risk-A Comparison with Fresh Frozen Plasma and Albumin Replacement. J Clin Med 2024; 13:7662. [PMID: 39768590 PMCID: PMC11676064 DOI: 10.3390/jcm13247662] [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: 11/24/2024] [Revised: 12/07/2024] [Accepted: 12/13/2024] [Indexed: 01/11/2025] Open
Abstract
Background: Therapeutic plasma exchange (TPE) removes coagulation factors and leads to depletion coagulopathy. The aim of the study was to compare hemostasis between TPE procedures without coagulation factor replacement (electrolyte group), the partial replacement of fibrinogen with fibrinogen concentrates (fibrinogen group) and partial coagulation factors replacement with fresh frozen plasma (partial FFP group). Methods: A total of 73 TPE procedures in patients with fibrinogen levels 1-2 g/L were divided into three study groups depending on clinically estimated bleeding risk. Standard coagulation and ROTEM® tests were performed before and after TPE. Results: Fibrinogen levels before TPE (p = 0.88) and after TPE (p = 0.33) were comparable between the fibrinogen and partial FFP groups. INR and ROTEM® parameters reflected moderately worse hemostasis after TPE with fibrinogen-only replacement compared to partial FFP replacement, which could result in increased bleeding risk. In the electrolyte group, most laboratory tests confirmed the most deranged hemostasis after TPE, as compared to fibrinogen or partial FFP replacement. A mild allergic reaction to FFP infusion was noted during one TPE. No clinically significant bleeding occurred in any of the study groups. Conclusions: Fibrinogen concentrate supplementation and partial FFP replacement can both maintain fibrinogen levels > 1 g/L after TPE, but modest differences in classical coagulation tests and bedside ROTEM® tests favor FFP replacement (NCT03801135).
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Affiliation(s)
- Matej Zrimsek
- Department of Nephrology, University Medical Centre Ljubljana, Zaloska cesta 7, 1000 Ljubljana, Slovenia
- Faculty of Medicine, University of Ljubljana, Vrazov Trg 2, 1000 Ljubljana, Slovenia
| | - Jakob Gubensek
- Department of Nephrology, University Medical Centre Ljubljana, Zaloska cesta 7, 1000 Ljubljana, Slovenia
- Faculty of Medicine, University of Ljubljana, Vrazov Trg 2, 1000 Ljubljana, Slovenia
| | - Andreja Marn Pernat
- Department of Nephrology, University Medical Centre Ljubljana, Zaloska cesta 7, 1000 Ljubljana, Slovenia
- Faculty of Medicine, University of Ljubljana, Vrazov Trg 2, 1000 Ljubljana, Slovenia
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Mehic D, Assinger A, Gebhart J. Utility of Global Hemostatic Assays in Patients with Bleeding Disorders of Unknown Cause. Hamostaseologie 2024; 44:358-367. [PMID: 38950624 DOI: 10.1055/a-2330-9112] [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: 07/03/2024] Open
Abstract
Bleeding disorder of unknown cause (BDUC) is a diagnosis of exclusion after exhaustive evaluation of plasmatic coagulation and platelet function. This review explores the utility of global hemostatic assays as confirmatory tests and in elucidating the pathophysiology of BDUC. Unlike traditional hemostatic tests that focus on coagulation factors, global assays are conducted both in plasma and also whole blood. These assays provide a more comprehensive understanding of the cell-based model of coagulation, aid in the identification of plasmatic factor abnormalities that may reduce hemostatic capacity, and allow for the assessment of impaired platelet-endothelial interactions under shear stress, as well as hyperfibrinolytic states. While clinical tests such as skin bleeding time and global assays such as PFA-100 exhibit limited diagnostic capacity, the role of viscoelastic testing in identifying hemostatic dysfunction in patients with BDUC remains unclear. Thrombin generation assays have shown variable results in BDUC patients; some studies demonstrate differences compared with healthy controls or reference values, whereas others question its clinical utility. Fibrinolysis assessment in vitro remains challenging, with studies employing euglobulin clot lysis time, plasma clot lysis time, and fluorogenic plasmin generation yielding inconclusive or conflicting results. Notably, recent studies suggest that microfluidic analysis unveils shear-dependent platelet function defects in BDUC patients, undetected by conventional platelet function assays. Overall, global assays might be helpful for exploring underlying hemostatic impairments, when conventional hemostatic laboratory tests yield no results. However, due to limited data and/or discrepant results, further research is needed to evaluate the utility of global assays as screening tools.
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Affiliation(s)
- Dino Mehic
- Clinical Division of Hematology and Hemostaseology, Department of Medicine I, Medical University of Vienna, Vienna, Austria
| | - Alice Assinger
- Institute of Vascular Biology and Thrombosis Research, Centre of Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria
| | - Johanna Gebhart
- Clinical Division of Hematology and Hemostaseology, Department of Medicine I, Medical University of Vienna, Vienna, Austria
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Yoon U, Haley S, Huffnagle S, Huffnagle J. Viscoelastic testing guided coagulation management in factor VII deficiency for spinal anaesthesia and caesarean section. BMJ Case Rep 2024; 17:e259464. [PMID: 38901856 DOI: 10.1136/bcr-2023-259464] [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: 06/22/2024] Open
Abstract
The risks and benefits of spinal anaesthesia must be assessed in patients with coagulation disorders. A woman in her 20s with congenital factor VII (FVII) deficiency (31%) was admitted at 38 weeks for caesarean delivery. A rotational thromboelastometry (ROTEM) analysis showed normal coagulation and spinal anaesthesia was performed safely. A repeated ROTEM analysis after haemostasis and uterine closure showed normal coagulation without fibrinolysis. No prophylactic FVII was administered, resulting in a cost savings of US$12 884. FVII level did not predict bleeding or fibrinolysis and FVII and tranexamic acid were not indicated.
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Affiliation(s)
- Uzung Yoon
- Department of Anesthesiology, Thomas Jefferson University Hospital, Philadelphia, Pennsylvania, USA
| | - Shannon Haley
- Department of Anesthesiology, Thomas Jefferson University Hospital, Philadelphia, Pennsylvania, USA
| | - Suzanne Huffnagle
- Department of Anesthesiology, Thomas Jefferson University Hospital, Philadelphia, Pennsylvania, USA
| | - Jane Huffnagle
- Department of Anesthesiology, Thomas Jefferson University Hospital, Philadelphia, Pennsylvania, USA
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Gupta D, Arya V, Dass J, Gupta N, Kalra M, Sachdeva A, Kotwal J. Assessment of the phenotypic severity of hemophilia A: using rotational thromboelastometry (ROTEM) and APTT-clot waveform analysis. Blood Res 2024; 59:19. [PMID: 38743166 PMCID: PMC11093952 DOI: 10.1007/s44313-024-00018-6] [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: 10/21/2023] [Accepted: 04/01/2024] [Indexed: 05/16/2024] Open
Abstract
BACKGROUND Hemophilia A (HA) is an X-linked inherited bleeding disorder caused by reduced factor VIII (FVIII) levels. Approximately 10-15% of patients with severe HA (SHA) do not present with the anticipated bleeding pattern. Here, we assessed the phenotypic severity of hemophilia A using rotational thromboelastometry (ROTEM) and activated partial thromboplastin time-clot waveform analysis (APTT-CWA). METHODS Patients diagnosed with hemophilia A were enrolled. Clinical phenotype assignment was performed according to the published literature, and patients were classified into four phenotypic subgroups. The whole blood sample was first run on ROTEM in INTEM mode using platelet-poor plasma, APTT was run, and the APTT-CWA graph was simultaneously recorded. RESULTS A total of 66 patients were recruited for this study. Statistically significant differences were observed between the four phenotypically categorized groups using ROTEM and APTT-CWA. On comparing patients with mild/moderate-to-severe phenotypes (Group II) with SHA without inhibitors (Group IV), no significant difference was found for all parameters of ROTEM or APTT-CWA. The MCF, MA30, MAXV, and Alpha angle values using ROTEM were found to be the lowest in patients with SHA with inhibitors, which helped differentiate them from those with SHA without inhibitors. However, these two groups could not be differentiated using the APTT-CWA parameters. CONCLUSION ROTEM can be used to distinguish patients with SHA with inhibitors from those with SHA without inhibitors using a combination of parameters with high sensitivity and specificity. However, APTT-CWA cannot be used to differentiate these patient groups.
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Affiliation(s)
- Deepika Gupta
- Department of Hematology, Sir Gangaram Hospital, Old Rajinder Nagar, New Delhi, 110060, India
| | - Vandana Arya
- Department of Hematology, Sir Gangaram Hospital, Old Rajinder Nagar, New Delhi, 110060, India
| | - Jasmita Dass
- Department of Lab Hematology, All India Institute of Medical Sciences, New Delhi, India
| | - Nitin Gupta
- Department of Hematology, Sir Gangaram Hospital, Old Rajinder Nagar, New Delhi, 110060, India
| | - Manas Kalra
- Department of Pediatric Hemato Oncology, Sir Gangaram Hospital, New Delhi, India
| | - Anupam Sachdeva
- Department of Pediatric Hemato Oncology, Sir Gangaram Hospital, New Delhi, India
| | - Jyoti Kotwal
- Department of Hematology, Sir Gangaram Hospital, Old Rajinder Nagar, New Delhi, 110060, India.
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Yada K, Fujitate N, Ogiwara K, Soeda T, Kitazawa T, Nogami K. Reduced plasma factor X is associated with a lack of response to recombinant activated factor VII in patients with hemophilia A and inhibitor, but does not impair emicizumab-driven hemostasis in vitro. Thromb Res 2024; 237:37-45. [PMID: 38547693 DOI: 10.1016/j.thromres.2024.03.023] [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: 10/29/2023] [Revised: 03/14/2024] [Accepted: 03/21/2024] [Indexed: 04/29/2024]
Abstract
BACKGROUND The hemostatic effect of recombinant (r) factor (F)VIIa after repetitive intermittent administration may be attenuated in patients with hemophilia A (PwHA) with inhibitors (PwHAwI) creating a clinically unresponsive status, although mechanism(s) remain to be clarified. In patients receiving prophylaxis treatment with emicizumab, concomitant rFVIIa is sometimes utilized in multiple doses for surgical procedures or breakthrough bleeding. AIM AND METHODS We identified 'unresponsiveness' to rFVIIa, based on global coagulation function monitored using rotational thromboelastometry (ROTEM) in 11 PwHAwI and 5 patients with acquired HA, and investigated possible mechanisms focusing on the association between plasma FX levels and rFVIIa-mediated interactions. RESULTS Our data demonstrated that FX antigen levels were lower in the rFVIIa-unresponsive group than in the rFVIIa-responsive group (0.46 ± 0.14 IU/mL vs. 0.87 ± 0.15 IU/mL, p < 0.01). This relationship was further examined by thrombin generation assays using a FX-deficient PwHAwI plasma model. The addition of FX with rFVIIa was associated with increased peak thrombin (PeakTh) generation. At low levels of FX (<0.5 IU/mL), rFVIIa failed to increase PeakTh to the normal range, consistent with clinical rFVIIa-unresponsiveness. In the presence of emicizumab (50 μg/mL), PeakTh was increased maximally to 80 % of normal, even at low levels of FX (0.28 IU/mL). CONCLUSIONS Unresponsiveness to rFVIIa was associated with reduced levels of FX in PwHAwI. Emicizumab exhibited in vitro coagulation potential in the presence of FX at concentrations that appeared to limit the clinical response to rFVIIa therapy.
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Affiliation(s)
- Koji Yada
- Department of Pediatrics, Nara Medical University, Kashihara, Nara, Japan.
| | | | - Kenichi Ogiwara
- Department of Pediatrics, Nara Medical University, Kashihara, Nara, Japan
| | - Tetsuhiro Soeda
- Research Division, Chugai Pharmaceutical Co., Ltd., Yokohama, Japan
| | | | - Keiji Nogami
- Department of Pediatrics, Nara Medical University, Kashihara, Nara, Japan
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Simurda T, Drotarova M, Skornova I, Dobrotova M, Brunclikova M, Necas L, Cibula Z, Kubisz P, Stasko J. Perioperative Monitoring with Rotational Thromboelastometry in a Severe Hemophilia A Patient Undergoing Elective Ankle Surgery. Semin Thromb Hemost 2024; 50:310-313. [PMID: 37075775 DOI: 10.1055/s-0043-57009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/21/2023]
Affiliation(s)
- Tomas Simurda
- National Centre of Hemostasis and Thrombosis, Department of Hematology and Transfusiology, Comenius University in Bratislava, Jessenius Faculty of Medicine in Martin and University Hospital in Martin, Martin, Slovakia
| | - Miroslava Drotarova
- National Centre of Hemostasis and Thrombosis, Department of Hematology and Transfusiology, Comenius University in Bratislava, Jessenius Faculty of Medicine in Martin and University Hospital in Martin, Martin, Slovakia
| | - Ingrid Skornova
- National Centre of Hemostasis and Thrombosis, Department of Hematology and Transfusiology, Comenius University in Bratislava, Jessenius Faculty of Medicine in Martin and University Hospital in Martin, Martin, Slovakia
| | - Miroslava Dobrotova
- National Centre of Hemostasis and Thrombosis, Department of Hematology and Transfusiology, Comenius University in Bratislava, Jessenius Faculty of Medicine in Martin and University Hospital in Martin, Martin, Slovakia
| | - Monika Brunclikova
- National Centre of Hemostasis and Thrombosis, Department of Hematology and Transfusiology, Comenius University in Bratislava, Jessenius Faculty of Medicine in Martin and University Hospital in Martin, Martin, Slovakia
| | - Libor Necas
- Department of Orthopedics, Comenius University in Bratislava, Jessenius Faculty of Medicine in Martin and University Hospital in Martin, Martin, Slovakia
| | - Zoltan Cibula
- Department of Orthopedics, Comenius University in Bratislava, Jessenius Faculty of Medicine in Martin and University Hospital in Martin, Martin, Slovakia
| | - Peter Kubisz
- National Centre of Hemostasis and Thrombosis, Department of Hematology and Transfusiology, Comenius University in Bratislava, Jessenius Faculty of Medicine in Martin and University Hospital in Martin, Martin, Slovakia
| | - Jan Stasko
- National Centre of Hemostasis and Thrombosis, Department of Hematology and Transfusiology, Comenius University in Bratislava, Jessenius Faculty of Medicine in Martin and University Hospital in Martin, Martin, Slovakia
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11
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Katz D, Farber M, Getrajdman C, Hamburger J, Reale S, Butwick A. The role of viscoelastic hemostatic assays for postpartum hemorrhage management and bedside intrapartum care. Am J Obstet Gynecol 2024; 230:S1089-S1106. [PMID: 38462250 DOI: 10.1016/j.ajog.2022.09.008] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Revised: 09/06/2022] [Accepted: 09/06/2022] [Indexed: 03/12/2024]
Abstract
Viscoelastic hemostatic assays are point-of-care devices that assess coagulation and fibrinolysis in whole blood samples. These technologies provide numeric and visual information of clot initiation, clot strength, and clot lysis under low-shear conditions, and have been used in a variety of clinical settings and subpopulations, including trauma, cardiac surgery, and obstetrics. Emerging data indicate that these devices are useful for detecting important coagulation defects during major postpartum hemorrhage (especially low plasma fibrinogen concentration [hypofibrinogenemia]) and informing clinical decision-making for blood product use. Data from observational studies suggest that, compared with traditional formulaic approaches to transfusion management, targeted or goal-directed transfusion approaches using data from viscoelastic hemostatic assays are associated with reduced hemorrhage-related morbidity and lower blood product requirement. Viscoelastic hemostatic assays can also be used to identify and treat coagulation defects in patients with inherited or acquired coagulation disorders, such as factor XI deficiency or immune-mediated thrombocytopenia, and to assess hemostatic profiles of patients prescribed anticoagulant medications to mitigate the risk of epidural hematoma after neuraxial anesthesia and postpartum hemorrhage after delivery.
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Affiliation(s)
- Daniel Katz
- Department of Anesthesiology, Perioperative, and Pain Medicine, Icahn School of Medicine at Mount Sinai, New York, NY; Department of Obstetrics, Gynecology and Reproductive Science, Icahn School of Medicine at Mount Sinai, New York, NY.
| | - Michaela Farber
- Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Boston, MA
| | - Chloe Getrajdman
- Department of Obstetrics, Gynecology and Reproductive Science, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Joshua Hamburger
- Department of Anesthesiology, Perioperative, and Pain Medicine, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Sharon Reale
- Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Boston, MA
| | - Alexander Butwick
- Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Stanford, CA
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12
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Mizumachi K, Nakajima Y, Shimonishi N, Furukawa S, Ogiwara K, Takeyama M, Nogami K. Hybrid human-porcine factor VIII proteins partially escape the inhibitory effects of anti-factor VIII inhibitor alloantibodies having A2 or C2 domain specificity. Haemophilia 2024; 30:140-150. [PMID: 38058226 DOI: 10.1111/hae.14911] [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: 06/14/2023] [Revised: 10/29/2023] [Accepted: 11/28/2023] [Indexed: 12/08/2023]
Abstract
INTRODUCTION Porcine factor (pF)VIII has low cross-reactivity with anti-human (h)FVIII inhibitor alloantibodies. Clinical trials of pFVIII in congenital haemophilia A patients with inhibitor (PwHA-I) are in progress. Most polyclonal anti-hFVIII inhibitors recognize its A2 and/or C2 domain(s), and recombinant human-porcine hybrid (hp)FVIII proteins may escape neutralization by these inhibitors. AIM To evaluate the ability of hpFVIII to limit the anti-FVIII activity of inhibitor alloantibodies. METHODS Three hybrid proteins were created by substituting the hFVIII A2, C2 domain or both with the corresponding domains of pFVIII [termed hp(A2), hp(C2) and hp(A2/C2), respectively]. The reactivity of these hybrids was assessed by one-stage clotting assays (OSA), thrombin generation assays (TGA) and rotational thromboelastometry (ROTEM) by adding them to FVIII-deficient samples. RESULTS OSA demonstrated that the hybrid proteins avoided neutralization by anti-FVIII A2 or C2 monoclonal antibodies (mAb) and polyclonal inhibitor-antibodies (polyAb) from PwHA-I. In TGA, thrombin generation with hp(A2) and hp(A2/C2) was not attenuated in the presence of patient IgG recognizing anti-A2 domain. In contrast, that with hFVIII and hp(C2) was suppressed by this IgG to levels equivalent to those of FVIII-deficient plasma. With anti-A2/C2 polyAb, the activity of hp(A2/C2) was unaffected. ROTEM demonstrated that the addition of hp(A2) or hp(A2/C2) to anti-A2 polyAb shortened clot times/clot formation times, whilst hFVIII or hp(C2) were ineffective. Similarly with anti-A2/C2 polyAb, hp(A2/C2) restored coagulation potential to a greater extent than hp(A2) and hp(C2). CONCLUSION Hybrid FVIII proteins containing porcine FVIII A2 and/or C2 domain(s) could support effective therapy in PwHA-I by avoiding neutralization.
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Affiliation(s)
| | - Yuto Nakajima
- Department of Pediatrics, Nara Medical University, Kashihara, Nara, Japan
- Advanced Medical Science of Thrombosis and Hemostasis, Nara Medical University, Kashihara, Nara, Japan
| | - Naruto Shimonishi
- Department of Pediatrics, Nara Medical University, Kashihara, Nara, Japan
- The Course of Thrombosis and Hemostasis Molecular Pathology, Nara Medical University, Kashihara, Nara, Japan
| | - Shoko Furukawa
- Department of Pediatrics, Nara Medical University, Kashihara, Nara, Japan
| | - Kenichi Ogiwara
- Department of Pediatrics, Nara Medical University, Kashihara, Nara, Japan
| | - Masahiro Takeyama
- Department of Pediatrics, Nara Medical University, Kashihara, Nara, Japan
| | - Keiji Nogami
- Department of Pediatrics, Nara Medical University, Kashihara, Nara, Japan
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13
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Nepal C, Kc O, Koirala M, Subedi A, Sharma R, Annangi S, Jabak S, Chaaban S. A Retrospective Study Comparing the Effect of Conventional Coagulation Parameters Vs. Thromboelastography-Guided Blood Product Utilization in Patients With Major Gastrointestinal Bleeding. J Clin Med Res 2023; 15:431-437. [PMID: 38189039 PMCID: PMC10769601 DOI: 10.14740/jocmr5022] [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: 09/06/2023] [Accepted: 10/28/2023] [Indexed: 01/09/2024] Open
Abstract
Background The use of thromboelastography (TEG) has demonstrated decreased blood product utilization in patients with specific etiologies of major gastrointestinal bleeding (GIB), such as variceal and non-variceal bleeding in cirrhosis patients; however, in a non-cirrhosis patient with GIB, there is far less evidence in the literature. Our retrospective study compares the effect of TEG-guided blood product utilization in patients with major GIB with all etiologies, including cirrhosis, admitted to medical intensive care unit (MICU). Methods A retrospective chart review was conducted on patients admitted to the MICU of a tertiary academic medical center diagnosed with GIB using ICD-9/10 codes from 2014 to 2018. A total of 1,889 patients were identified, and validation criteria such as "GI or hepatology consult note", type and screen, pantoprazole, or octreotide drip" were used, which resulted in 997 patients, out of which 369 had a diagnosis of cirrhosis. Propensity score matching was done for baseline variables (age, sex, and race), ICU length of stay, hospital length of stay, ventilator days, and vasopressor use. As a result, 88 patients were included in the final analysis, with 44 in TEG and 44 in non-TEG group. A sub-group analysis was done in 46 patients with cirrhosis, 23 in TEG group and 23 in non-TEG group after propensity score matching. Results There was significantly higher total blood volume (4,207 mL vs. 2,568 mL, P = 0.04) in the TEG group as compared to the non-TEG group, including total volume of cryoprecipitate (80 mL vs. 55 mL, P = 0.03) and total volume of platelet (543 mL vs. 327 mL, P = 0.03). In the cirrhosis sub-group, there was no significant difference in the amount of blood products transfused between the two groups. Conclusion This study revealed that TEG is not superior to conventional coagulation parameters in limiting the volume of blood product transfusion in major GIB patients in ICU settings.
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Affiliation(s)
- Chhabindra Nepal
- Department of Pulmonology and Critical Care, Faith Regional Health Services, Norfolk, NE, USA
| | - Ojbindra Kc
- Department of Hospital Medicine, Faith Regional Health Services, Norfolk, NE, USA
| | - Manisha Koirala
- Department of Hospital Medicine, Faith Regional Health Services, Norfolk, NE, USA
| | - Ananta Subedi
- Department of Hospital Medicine, Avera McKennan Hospital and University Health Center, Sioux Falls, SD, USA
| | - Rakshya Sharma
- Department of Hospital Medicine, Avera McKennan Hospital and University Health Center, Sioux Falls, SD, USA
| | - Srinadh Annangi
- Division of Pulmonary and Critical Care, University of Kentucky, Lexington, KY, USA
| | - Suha Jabak
- Division of Gastroenterology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Said Chaaban
- Division of Pulmonary and Critical Care Medicine, University of Nebraska Medical Center, Omaha, NE, USA
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14
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Hendren C, Li W, Stegemann JP, Hall TL, Deng CX. Multichannel resonant acoustic rheometry system for quantification of coagulation of multiple human plasma samples. Sci Rep 2023; 13:19237. [PMID: 37935776 PMCID: PMC10630367 DOI: 10.1038/s41598-023-46518-w] [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: 07/02/2023] [Accepted: 11/02/2023] [Indexed: 11/09/2023] Open
Abstract
Resonant Acoustic Rheometry (RAR), a newly developed ultrasound-based technique for non-contact characterization of soft viscoelastic materials, has shown promise for quantitative viscoelastic assessment of temporally changing soft biomaterials in real time, and may be used to monitor blood coagulation process. Here, we report the development of a novel, multichannel RAR (mRAR) system for simultaneous measurements of multiple temporally evolving samples and demonstration of its use for monitoring the coagulation of multiple small-volume plasma samples. The mRAR system was constructed using an array of 4 custom-designed ultrasound transducers at 5.0 MHz and a novel electronic driving system that controlled the generation of synchronized ultrasound pulses for real time assessment of multiple samples simultaneously. As a proof-of-concept of the operation of the mRAR system, we performed tests using pooled normal human plasma samples and anti-coagulated plasma samples from patients treated with warfarin with a range of International Normalized Ratio (INR) values as well-characterized samples with different coagulation kinetics. Our results show that simultaneous tracking of dynamic changes in 4 plasma samples triggered by either kaolin or tissue factor was achieved for the entire duration of coagulation. The mRAR system captured distinct changes in the samples and identified parameters including the clotting start time and parameters associated with the stiffness of the final clots that were consistent with INR levels. Data from this study demonstrate the feasibility of the mRAR system for efficient characterization of the kinetic coagulation processes of multiple plasma samples.
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Affiliation(s)
- Christina Hendren
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA
| | - Weiping Li
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA
| | - Jan P Stegemann
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA
| | - Timothy L Hall
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA.
| | - Cheri X Deng
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA.
- Department of Mechanical Engineering, University of Michigan, Ann Arbor, MI, USA.
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15
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Chikasawa Y, Amano K, Shinozawa K, Bingo M, Miyashita R, Yamaguchi T, Mitsuhashi A, Inaba H, Hagiwara T, Kinai E. Comprehensive comparison of global coagulation assays to differentiate lupus anticoagulant from acquired hemophilia A in patients with prolonged APTT. Int J Hematol 2023; 118:577-588. [PMID: 37751038 DOI: 10.1007/s12185-023-03659-y] [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: 05/10/2023] [Revised: 08/31/2023] [Accepted: 09/06/2023] [Indexed: 09/27/2023]
Abstract
There is no established method for differentiating acquired hemophilia A (AHA) from lupus anticoagulant (LA) positivity because both present with prolonged activated partial thromboplastin time. We compared various parameters of rotational thromboelastometry (ROTEM), thrombin generation assay (TGA), and clot waveform analysis (CWA) in patients with AHA (n = 10) and LA (n = 44). Compared with AHA, possible (n = 12) and definite (n = 32) LA showed significantly shorter clotting time (CT) in NATEM mode of ROTEM (> 3600 vs. 501/533). In TGA, peak height was significantly lower in AHA (16 vs. 242/174 nM). In CWA, CT was significantly longer (81 vs. 36/41 s) and Ad|min1| was lower (2.1 vs. 8.7/6.7) in AHA. Notably, CT by NATEM and peak height in TGA completely discriminated between AHA and LA, whereas Ad|min1| did not discriminate between them in 4 cases of AHA and 1 of LA. Comparison of 3 patients with both AHA and LA against a patient with only LA and markedly low FVIII activity (3.5%) showed that both CT by NATEM and peak height of TGA precisely classified the former 3 cases as AHA and the latter 1 case as LA, whereas Ad|min1| classified all 4 cases as AHA. ROTEM and TGA can comparably distinguish between AHA and LA.
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Affiliation(s)
- Yushi Chikasawa
- Department of Laboratory Medicine, Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo, 160-0023, Japan.
| | - Kagehiro Amano
- Department of Laboratory Medicine, Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo, 160-0023, Japan
| | - Keiko Shinozawa
- Department of Laboratory Medicine, Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo, 160-0023, Japan
| | - Masato Bingo
- Department of Laboratory Medicine, Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo, 160-0023, Japan
| | - Ryui Miyashita
- Department of Laboratory Medicine, Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo, 160-0023, Japan
| | - Tomoko Yamaguchi
- Department of Laboratory Medicine, Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo, 160-0023, Japan
| | - Ayano Mitsuhashi
- Department of Gene Research of Coagulation Disorders, Tokyo Medical University, Tokyo, Japan
| | - Hiroshi Inaba
- Department of Laboratory Medicine, Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo, 160-0023, Japan
| | - Takeshi Hagiwara
- Department of Laboratory Medicine, Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo, 160-0023, Japan
| | - Ei Kinai
- Department of Laboratory Medicine, Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo, 160-0023, Japan
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16
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Pruthi RK. Testing strategies used in the diagnosis of rare inherited bleeding disorders. Expert Rev Hematol 2023:1-15. [PMID: 37144355 DOI: 10.1080/17474086.2023.2211257] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/06/2023]
Abstract
INTRODUCTION Rare Bleeding Disorders have a low population prevalence and may not be recognized by most clinicians. In addition, knowledge gaps of the indicated laboratory tests and their availability add to the potential for delayed diagnosis or misdiagnosis. The lack of widely available commercial, regulatory body approved esoteric tests limit them to reference laboratories, thus limiting easy access for patients. AREAS COVERED A literature search of Pubmed, Medline, Embase and review of international society guidelines was performed. Additional references from published articles were reviewed. A patient-centered approach to recognition and evaluation of RBD is discussed. EXPERT OPINION Recognition of RBD relies on obtaining a detailed patient personal and family hemostatic history. Inquiry into a history of involvement of other organ systems is important and if present should lead to suspicion of an inherited platelet disorder or a variant of Ehlers Danlos Syndrome. Multiple factors contribute to the complexity of development of efficient algorithms for diagnostic testing. Limitations in diagnostic sensitivity and specificity of screening tests, diagnostic tests, and esoteric tests further compound the complexity of establishing a diagnosis. Educational efforts focusing on clinician awareness of RBDs and available testing options are vital for optimal management of such patients.
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Affiliation(s)
- Rajiv K Pruthi
- Mayo Comprehensive Hemophilia Center, Division of Hematology, Department of Internal Medicine, Mayo Clinic College of Medicine, Rochester, MN, USA
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17
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Eskildsen MPR, Kalliokoski O, Boennelycke M, Lundquist R, Settnes A, Loekkegaard E. An autologous blood-derived patch as a hemostatic agent: evidence from thromboelastography experiments and a porcine liver punch biopsy model. JOURNAL OF MATERIALS SCIENCE. MATERIALS IN MEDICINE 2023; 34:20. [PMID: 37074487 PMCID: PMC10115690 DOI: 10.1007/s10856-023-06726-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/25/2022] [Accepted: 04/03/2023] [Indexed: 05/03/2023]
Abstract
Perioperative bleeding is a common complication in surgeries that increases morbidity, risk of mortality, and leads to increased socioeconomic costs. In this study we investigated a blood-derived autologous combined leukocyte, platelet, and fibrin patch as a new means of activating coagulation and maintaining hemostasis in a surgical setting. We evaluated the effects of an extract derived from the patch on the clotting of human blood in vitro, using thromboelastography (TEG). The autologous blood-derived patch activated hemostasis, seen as a reduced mean activation time compared to both non-activated controls, kaolin-activated samples, and fibrinogen/thrombin-patch-activated samples. The accelerated clotting was reproducible and did not compromise the quality or stability of the resulting blood clot. We also evaluated the patch in vivo in a porcine liver punch biopsy model. In this surgical model we saw 100% effective hemostasis and a significant reduction of the time-to-hemostasis, when compared to controls. These results were comparable to the hemostatic properties of a commercially available, xenogeneic fibrinogen/thrombin patch. Our findings suggest clinical potential for the autologous blood-derived patch as a hemostatic agent.
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Affiliation(s)
- Morten P R Eskildsen
- Department of Obstetrics and Gynecology, Copenhagen University Hospital - North Zealand, Hilleroed, Denmark.
- Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.
- Department of Experimental Medicine, University of Copenhagen, Copenhagen, Denmark.
| | - Otto Kalliokoski
- Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
- Department of Experimental Medicine, University of Copenhagen, Copenhagen, Denmark
| | - Marie Boennelycke
- Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
- Department of Pathology, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark
| | | | - Annette Settnes
- Department of Obstetrics and Gynecology, Copenhagen University Hospital - North Zealand, Hilleroed, Denmark
- Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
| | - Ellen Loekkegaard
- Department of Obstetrics and Gynecology, Copenhagen University Hospital - North Zealand, Hilleroed, Denmark
- Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
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18
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Japanese high bleeding risk criteria status predicts low thrombogenicity and bleeding events in patients undergoing percutaneous coronary intervention. Cardiovasc Interv Ther 2023:10.1007/s12928-023-00920-3. [PMID: 36877333 DOI: 10.1007/s12928-023-00920-3] [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: 10/13/2022] [Accepted: 02/13/2023] [Indexed: 03/07/2023]
Abstract
Although the Japanese high bleeding risk criteria (J-HBR) were established to predict bleeding risk in patients undergoing percutaneous coronary intervention (PCI), the thrombogenicity in the J-HBR status remains unknown. Here, we examined the relationships among J-HBR status, thrombogenicity and bleeding events. This study was a retrospective analysis of 300 consecutive patients who underwent PCI. Blood samples obtained on the day of PCI were used in the total thrombus-formation analysis system (T-TAS) to investigate the thrombus-formation area under the curve (AUC; PL18-AUC10 for platelet chip; AR10-AUC30 for atheroma chip). The J-HBR score was calculated by adding 1 point for any major criterion and 0.5 point for any minor criterion. We assigned patients to three groups based on J-HBR status: a J-HBR-negative group (n = 80), a low score J-HBR-positive group (positive/low, n = 109), and a high score J-HBR-positive group (positive/high, n = 111). The primary end point was the 1-year incidence of bleeding events defined by the Bleeding Academic Research Consortium types 2, 3, or 5. Both PL18-AUC10 and AR10-AUC30 levels were lower in the J-HBR-positive/high group than the negative group. Kaplan-Meier analysis showed worse 1-year bleeding event-free survival in the J-HBR-positive/high group compared with the negative group. In addition, both T-TAS levels in J-HBR positivity were lower in those with bleeding events than in those without bleeding events. In multivariate Cox regression analyses, the J-HBR-positive/high status was significantly associated with 1-year bleeding events. In conclusion, the J-HBR-positive/high status could reflect low thrombogenicity as measured by T-TAS and high bleeding risk in patients undergoing PCI.
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19
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Furukawa S, Ogiwara K, Yada K, Takeyama M, Niino T, Shima M, Keiji N. Decrease in in vivo coagulant potential of emicizumab in a patient with hemophilia A and inhibitor complicated with infectious mononucleosis. Blood Coagul Fibrinolysis 2023; 34:122-128. [PMID: 36719809 DOI: 10.1097/mbc.0000000000001177] [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: 02/01/2023]
Abstract
Emicizumab prophylaxis significantly reduces bleeding episodes in patients with hemophilia A (PwHA). There is little information on coagulant potentials in emicizumab-treated PwHA with infection, however. We encountered an emicizumab-treated PwHA with inhibitor, complicated with Epstein-Barr virus-associated infectious mononucleosis (IM) in phase 1/2 study (ACE001JP/ACE002JP). Although it was a typical clinical course of IM, activated partial thromboplastin time was mildly prolonged but rotational thromboelastometry revealed severely impaired coagulant potential. The blood concentration of emicizumab decreased moderately in the low concentration range, resulting in an increased risk of bleeding and possibly leading to severe ileocecal bleeds requiring coil embolization. The blood concentrations of factors IX/X little decreased and antiemicizumab antibodies did not develop, however. After the influence by IM resolved, his coagulant potentials gradually recovered with the recovery of emicizumab concentration, and parameters by global coagulation assays improved. An IM case for emicizumab-treated PwHA may need to monitor using global coagulation assays.
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Affiliation(s)
- Shoko Furukawa
- Department of Pediatrics, Nara Medical University, Kashihara, Nara
| | - Kenichi Ogiwara
- Department of Pediatrics, Nara Medical University, Kashihara, Nara
| | - Koji Yada
- Department of Pediatrics, Nara Medical University, Kashihara, Nara
- Department of Haemophilia, National Hospital Organization Osaka National Hospital, Osaka
| | | | | | - Midori Shima
- Department of Pediatrics, Nara Medical University, Kashihara, Nara
| | - Nogami Keiji
- Department of Pediatrics, Nara Medical University, Kashihara, Nara
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20
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Li W, Hobson EC, Bunch CM, Miller JB, Nehme J, Kwaan HC, Walsh MM, McCurdy MT, Aversa JG, Thomas AV, Zackariya N, Thomas SJ, Smith SA, Cook BC, Boyd B, Stegemann JP, Deng CX. Resonant Acoustic Rheometry to Measure Coagulation Kinetics in Hemophilia A and Healthy Plasma: A Novel Viscoelastic Method. Semin Thromb Hemost 2023; 49:201-208. [PMID: 36318959 PMCID: PMC9898113 DOI: 10.1055/s-0042-1757896] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Compared with conventional coagulation tests and factor-specific assays, viscoelastic hemostatic assays (VHAs) can provide a more thorough evaluation of clot formation and lysis but have several limitations including clot deformation. In this proof-of-concept study, we test a noncontact technique, termed resonant acoustic rheometry (RAR), for measuring the kinetics of human plasma coagulation. Specifically, RAR utilizes a dual-mode ultrasound technique to induce and detect surface oscillation of blood samples without direct physical contact and measures the resonant frequency of the surface oscillation over time, which is reflective of the viscoelasticity of the sample. Analysis of RAR results of normal plasma allowed defining a set of parameters for quantifying coagulation. RAR detected a flat-line tracing of resonant frequency in hemophilia A plasma that was corrected with the addition of tissue factor. Our RAR results captured the kinetics of plasma coagulation and the newly defined RAR parameters correlated with increasing tissue factor concentration in both healthy and hemophilia A plasma. These findings demonstrate the feasibility of RAR as a novel approach for VHA, providing the foundation for future studies to compare RAR parameters to conventional coagulation tests, factor-specific assays, and VHA parameters.
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Affiliation(s)
- Weiping Li
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, Michigan
| | - Eric C. Hobson
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, Michigan
| | - Connor M. Bunch
- Department of Emergency Medicine and Internal Medicine, Henry Ford Hospital, Detroit, Michigan
| | - Joseph B. Miller
- Department of Emergency Medicine and Internal Medicine, Henry Ford Hospital, Detroit, Michigan
| | - Jimmy Nehme
- Department of Emergency Medicine and Internal Medicine, Henry Ford Hospital, Detroit, Michigan
| | - Hau C. Kwaan
- Division of Hematology and Oncology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Mark M. Walsh
- Department of Emergency Medicine, St. Joseph Regional Medical Center, Mishawaka, Indiana
| | - Michael T. McCurdy
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland
| | - John G. Aversa
- Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana
| | - Anthony V. Thomas
- Indiana University School of Medicine South Bend Campus, Notre Dame, Indiana
| | - Nuha Zackariya
- Indiana University School of Medicine South Bend Campus, Notre Dame, Indiana
| | - Samuel J. Thomas
- Department of Emergency Medicine, St. Joseph Regional Medical Center, Mishawaka, Indiana
| | - Stephanie A. Smith
- Department of Biological Chemistry, Michigan Medicine, Ann Arbor, Michigan
| | - Bernard C. Cook
- Department of Pathology, Henry Ford Hospital, Detroit, Michigan
| | - Bryan Boyd
- Department of Pathology, Henry Ford Hospital, Detroit, Michigan
| | - Jan P. Stegemann
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, Michigan
| | - Cheri X. Deng
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, Michigan
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Bruno L, Lenberg J, Le D, Dimmock D, Thornburg CD, Briggs B. Novel Approach to Improve the Identification of the Bleeding Phenotype in Noonan Syndrome and Related RASopathies. J Pediatr 2023:S0022-3476(23)00019-7. [PMID: 36646249 DOI: 10.1016/j.jpeds.2022.12.036] [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: 09/27/2022] [Revised: 11/10/2022] [Accepted: 12/01/2022] [Indexed: 01/14/2023]
Abstract
OBJECTIVES To characterize bleeding phenotype in Noonan Syndrome, to test the utility of following national guidelines in detecting this phenotype, to evaluate thromboelastography (TEG) as a diagnostic tool and to evaluate the cohort for genotype-phenotype correlations. STUDY DESIGN Participants with a clinical diagnosis NS or related RASopathy were enrolled in a cohort study. Study procedures included clinical bleeding assessment, coagulation testing per guidelines and hematology consultation. TEG was completed in a subset and genetic testing was conducted for those without a molecular diagnosis. International Society of Haemostasis and Thrombosis Bleeding Assessment Tool (ISTH-BAT) scores were calculated with hematology consultation. Bleeding phenotype was defined as abnormal bleeding score. RESULTS Twenty participants enrolled; 12completed clinical and laboratory evaluation, five of whom met the definition for bleeding phenotype. Four of the five participants with a bleeding phenotype had platelet aggregation defects and at least one additional coagulation defect. TEG was performed in nine participants, four with bleeding phenotype and five without, and results were normal in all cases. No genotype-phenotype correlation was found. CONCLUSION Five of 20 participants had a bleeding phenotype identified. Based on available data we do not recommend incorporating TEG into clinical practice for NS patients. Platelet aggregation defects were the most common abnormalities, which would not be detected on Tier 1 testing of current guidelines, therefore we propose a new algorithm.
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Affiliation(s)
- Leah Bruno
- Department of Pediatrics, Division of Hematology and Oncology, University of California San Diego, La Jolla, California; Rady Children's Institute of Genomic Medicine, San Diego, California
| | - Jerica Lenberg
- Rady Children's Institute of Genomic Medicine, San Diego, California
| | - Dzung Le
- Department of Pathology, University of California San Diego, La Jolla, California
| | - David Dimmock
- Rady Children's Institute of Genomic Medicine, San Diego, California
| | - Courtney D Thornburg
- Department of Pediatrics, Division of Hematology and Oncology, University of California San Diego, La Jolla, California; Hemophilia and Thrombosis Treatment Center, Rady Children's Hospital San Diego, San Diego, California
| | - Benjamin Briggs
- Rady Children's Institute of Genomic Medicine, San Diego, California.
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22
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High levels of factor VIII activity in patients with acquired hemophilia A in remission are associated with unusually low coagulation potentials. Int J Hematol 2023; 117:669-677. [PMID: 36607560 DOI: 10.1007/s12185-022-03528-0] [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: 10/19/2022] [Revised: 12/15/2022] [Accepted: 12/25/2022] [Indexed: 01/07/2023]
Abstract
BACKGROUND Elevated factor VIII activity (FVIII:C) is often observed in patients with acquired hemophilia A (PwAHA) in remission. However, comprehensive coagulation potentials in this patient group remain to be investigated. AIM To evaluate comprehensive coagulation potentials in PwAHA. METHODS We investigated coagulation function in eleven PwAHA with high FVIII:C (> 150 IU/dL) using thrombin generation assay (TGA) and/or rotational thromboelastometry (ROTEM), and compared findings with results obtained from contrived samples generated by spiking recombinant FVIII. RESULTS The median FVIII:C and FVIII inhibitor titers during remission in enrolled PwAHA were 206 IU/dL and 0.44 BU/mL, respectively. In all patients, lag time and time to peak were either prolonged or normal compared to contrived samples corresponding to their FVIII:C. However, higher values of peak thrombin and endogenous thrombin potentials compared to contrived samples were observed in two patients. ROTEM parameters were within normal ranges in all cases. One patient (FVIII:C 171 IU/dL) developed venous thrombosis and pulmonary embolism, but TGA parameters showed low or normal coagulation potential compared to contrived samples corresponding to his FVIII:C. CONCLUSION PwAHA with high FVIII:C could exhibit lower coagulation potentials than those corresponding to their FVIII:C.
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23
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Lopez-Delgado JC, Putzu A, Landoni G. The importance of liver function assessment before cardiac surgery: A narrative review. Front Surg 2022; 9:1053019. [PMID: 36561575 PMCID: PMC9764862 DOI: 10.3389/fsurg.2022.1053019] [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: 09/24/2022] [Accepted: 11/15/2022] [Indexed: 12/12/2022] Open
Abstract
The demand for cardiac surgery procedures is increasing globally. Thanks to an improvement in survival driven by medical advances, patients with liver disease undergo cardiac surgery more often. Liver disease is associated with the development of heart failure, especially in patients with advanced cirrhosis. Cardiovascular risk factors can also contribute to the development of both cardiomyopathy and liver disease and heart failure itself can worsen liver function. Despite the risk that liver disease and cirrhosis represent for the perioperative management of patients who undergo cardiac surgery, liver function is often not included in common risk scores for preoperative evaluation. These patients have worse short and long-term survival when compared with other cardiac surgery populations. Preoperative evaluation of liver function, postoperative management and close postoperative follow-up are crucial for avoiding complications and improving results. In the present narrative review, we discuss the pathophysiological components related with postoperative complications and mortality in patients with liver disease who undergo cardiac surgery and provide recommendations for the perioperative management.
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Affiliation(s)
- Juan C. Lopez-Delgado
- Hospital Clinic de Barcelona, Area de Vigilancia Intensiva (ICMiD), Barcelona, Spain,IDIBELL (Institut d’Investigació Biomèdica Bellvitge; Biomedical Investigation Institute of Bellvitge), L’Hospitalet de Llobregat, Barcelona, Spain,Correspondence: Juan C. Lopez-Delgado Alessandro Putzu
| | - Alessandro Putzu
- Division of Anesthesiology, Department of Acute Medicine, Geneva University Hospitals, Geneva, Switzerland,Correspondence: Juan C. Lopez-Delgado Alessandro Putzu
| | - Giovanni Landoni
- Department of Anesthesia and Intensive Care, IRCCS San Raffaele Scientific Institute, Milan, Italy,Vita-Salute San Raffaele University, Milan, Italy
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24
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Hosoi H, Tane M, Kosako H, Ibe M, Takeyama M, Murata S, Mushino T, Sonoki T. Acute-type acquired hemophilia A after COVID-19 mRNA vaccine administration: A new disease entity? J Autoimmun 2022; 133:102915. [PMID: 36155279 PMCID: PMC9485432 DOI: 10.1016/j.jaut.2022.102915] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2022] [Revised: 09/06/2022] [Accepted: 09/12/2022] [Indexed: 12/13/2022]
Abstract
Acquired hemophilia A (AHA) is a rare autoimmune bleeding disorder. Various autoimmune diseases, including AHA, have been reported to occur after the administration of mRNA COVID-19 vaccines. However, the characteristics of these AHA cases remain unclear. We report a case in which AHA arose in a young patient after the administration of an mRNA COVID-19 vaccine, but improved rapidly. The patient's factor VIII (FVIII) inhibitor titer spontaneously decreased to less than half of that seen at diagnosis. One week after the initial immunosuppressive therapy, the FVIII inhibitor had disappeared. Our case suggests that AHA that arises in young patients after COVID-19 vaccination may resolve spontaneously, and the levels of FVIII inhibitors may decrease more rapidly in such cases than in idiopathic AHA. Unlike for immune thrombocytopenic purpura (ITP), no acute type of AHA has been recognized. This case suggests that just as there is an acute type of ITP that develops in children/after vaccination, there may be an acute type of AHA that arises in young patients that receive mRNA COVID-19 vaccines.
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Affiliation(s)
- Hiroki Hosoi
- Department of Hematology/Oncology, Wakayama Medical University, Wakayama, Japan.
| | - Misato Tane
- Department of Hematology/Oncology, Wakayama Medical University, Wakayama, Japan
| | - Hideki Kosako
- Department of Hematology/Oncology, Wakayama Medical University, Wakayama, Japan
| | - Masaki Ibe
- Department of Hematology/Oncology, Wakayama Medical University, Wakayama, Japan
| | | | - Shogo Murata
- Department of Hematology/Oncology, Wakayama Medical University, Wakayama, Japan
| | - Toshiki Mushino
- Department of Hematology/Oncology, Wakayama Medical University, Wakayama, Japan
| | - Takashi Sonoki
- Department of Hematology/Oncology, Wakayama Medical University, Wakayama, Japan
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25
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Hemostatic Abnormalities in Gaucher Disease: Mechanisms and Clinical Implications. J Clin Med 2022; 11:jcm11236920. [PMID: 36498496 PMCID: PMC9735904 DOI: 10.3390/jcm11236920] [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: 10/14/2022] [Revised: 11/08/2022] [Accepted: 11/20/2022] [Indexed: 11/25/2022] Open
Abstract
Gaucher disease (GD) is a rare inherited lysosomal metabolism disorder, characterized by an accumulation into lysosomes of reticuloendothelial cells, especially in the bone marrow, spleen, and liver of β-glucosylceramide and glucosyl sphingosine, which is its deacylated product. Impaired storage is responsible for a chronic inflammatory state at the sites of accumulation and together represents the pathophysiological cause of GD. GD is a progressive, multi-organ chronic disorder. Type 1 GD is the most prevalent form, with heterogeneous multisystem involvement and different severity of symptoms at any age. Hematological involvement is consistent, and a bleeding tendency is frequent, particularly at diagnosis. Several coagulation and primary hemostasis abnormalities are observed in GD. Bleeding manifestations are rarely severe and usually mucocutaneous. Post-operative, delivery, and post-partum hemorrhages are also common. Thrombocytopenia, platelet function defects, and clotting abnormalities, alone or variably associated, contribute to increase the risk of bleeding in GD. Enzyme replacement therapy (ERT) or substrate reduction therapy (SRT) are the two specific available treatments effective in improving typical hematological symptoms and abnormalities, including those of hemostasis. However, the use of medication to potentiate hemostasis may be also useful in defined clinical situations: recent starting of ERT/SRT, surgery, delivery, and life-threatening bleeding.
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26
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Zhou Y, Yu J, Zhou H. Changes in Thrombelastography in Patients with Acute Exacerbation of Chronic Obstructive Pulmonary Disease and the Relationship with Lung Function. Emerg Med Int 2022; 2022:4313394. [PMID: 36406934 PMCID: PMC9671723 DOI: 10.1155/2022/4313394] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Accepted: 09/22/2022] [Indexed: 02/02/2024] Open
Abstract
Purpose To analyze the changes in thrombelastography (TEG) in patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD) and the relationship with indicators related to lung function. Methods 100 patients with AECOPD admitted to our hospital from May 2021 to May 2022 were selected as the AE group, and another 80 patients with a stable phase of COPD in the same period were selected as the SP group. Fresh blood specimens were collected from both groups, and TEG-related indicators (R value, K value, α-angle, MA value) were measured using the TEG technique, and lung function-related indicators (FEV1, FVC, FEV1/FVC, FEV1%) were measured using a lung function meter, and the correlation between TEG-related indicators and lung function-related indicators was analyzed. Results Patients in the AE group had lower R and K values and higher α-angle and MA values than those in the SP group, all with statistically significant differences (P < 0.05). Patients in the AE group had lower FEV1, FVC, FEV1/FVC, and FEV1% levels than those in the SP group, all with statistically significant differences (P < 0.05). Correlation analysis showed that the R value in TEG of AECOPD patients was positively correlated with pulmonary function-related indicators (FEV1, FVC, FEV1/FVC, FEV1%) (r = 0.565, 0.529, 0.447, 0.527, all P < 0.001); K value was positively correlated with pulmonary function-related indicators (FEV1, FVC, FEV1/FVC, FEV1%) (r = 0.512, 0.567, 0.459, 0.439, all P < 0.001); α-angle was inversely correlated with pulmonary function-related indicators (FEV1, FVC, FEV1/FVC, FEV1%) (r = -0.498, -0.372, -0.408, -0.424, all P < 0.001); MA value was inversely correlated with lung function-related indicators (FEV1, FVC, FEV1/FVC, FEV1%) (r = -0.459, -0.429, -0.394, -0.403, all P < 0.001). Conclusion There is a correlation between TEG-related indicators and lung function-related indicators in AECOPD patients, both of which can guide the diagnosis and treatment process of the disease and are worthy of clinical promotion. The clinical registration number is EA2021086.
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Affiliation(s)
- Yan Zhou
- Department of Respiratory and Critical Care Medicine, Zhuji People's Hospital, Zhuji, Zhejiang Province 311800, China
| | - Jing Yu
- Department of Respiratory and Critical Care Medicine, Zhuji People's Hospital, Zhuji, Zhejiang Province 311800, China
| | - Haiying Zhou
- Department of Respiratory and Critical Care Medicine, Zhuji People's Hospital, Zhuji, Zhejiang Province 311800, China
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27
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Tinchon A, Freydl E, Fitzgerald RD, Duarte C, Weber M, Calabek-Wohinz B, Waiß C, Oberndorfer S. Real-time monitoring of intravenous thrombolysis in acute ischemic stroke using rotational thromboelastometry: a feasibility pilot study. J Neurol 2022; 269:6129-6138. [PMID: 35852602 PMCID: PMC9553850 DOI: 10.1007/s00415-022-11271-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2022] [Revised: 07/03/2022] [Accepted: 07/04/2022] [Indexed: 11/03/2022]
Abstract
INTRODUCTION Rotational thromboelastometry (ROTEM) records whole blood coagulation in vitro. Data on dynamic changes of clot patterns during intravenous thrombolysis (IVT) in acute ischemic stroke is scarce. We investigated the feasibility of ROTEM as a potential point-of-care assessment tool for IVT. METHODS In this prospective pilot study, patients with acute stroke symptoms received IVT. Whole blood coagulation was tracked on the ROTEM analyzer. Blood samples were analyzed before, and then 2, 15, 30 and 60 min after beginning IVT. In vitro clots (iCLs) were described by their maximum clot firmness (MCF), the time needed to reach MCF (MCF-t), as well as the area under the curve (AR10). National Institutes of Health Stroke Scale (NIHSS) was used as early clinical outcome parameter. RESULTS We analyzed 288 iCLs from 12 patients undergoing IVT. In all iCLs, an early fibrinolysis (91% within the first 10 min) was detected during IVT. Three different curve progression patterns were observed: a low-responder pattern with a continuous clot increase, a high-responder pattern with a sustained clot decrease or total clotting suppression and an intermediate-responder pattern with alternating clot characteristics. There was a difference among these groups in early clinical outcome (AR10 and MCF each p = 0.01, MCF-t p = 0.02, Kruskal-Wallis Test). CONCLUSION The fibrinolysis patterns determined using ROTEM allow for the monitoring of IVT in patients with acute ischemic stroke. This pilot study found a correlation between the in vitro fibrinolysis patterns and early clinical outcomes. These findings support a potential for individualization of IVT in the future.
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Affiliation(s)
- Alexander Tinchon
- Karl Landsteiner University of Health Sciences, Dr. Karl-Dorrek-Straße 30, 3500, Krems, Austria.
- Department of Neurology, University Hospital St. Pölten, Dunant-Platz 1, 3100, St. Pölten, Austria.
- Karl Landsteiner Institute of Clinical Neurology and Neuropsychology, University Hospital St. Pölten, Dunant-Platz 1, 3100, St. Pölten, Austria.
| | - Elisabeth Freydl
- Karl Landsteiner University of Health Sciences, Dr. Karl-Dorrek-Straße 30, 3500, Krems, Austria
- Department of Neurology, University Hospital St. Pölten, Dunant-Platz 1, 3100, St. Pölten, Austria
- Karl Landsteiner Institute of Clinical Neurology and Neuropsychology, University Hospital St. Pölten, Dunant-Platz 1, 3100, St. Pölten, Austria
| | - Robert D Fitzgerald
- Karl Landsteiner Institute of Anesthesiology and Intensive Care Medicine, Clinic of Hietzing, Wolkersbergenstrasse 1, 1130, Vienna, Austria
| | - Christina Duarte
- Karl Landsteiner University of Health Sciences, Dr. Karl-Dorrek-Straße 30, 3500, Krems, Austria
- Department of Neurology, University Hospital St. Pölten, Dunant-Platz 1, 3100, St. Pölten, Austria
| | - Michael Weber
- Department of General Health Studies, Division Biostatistics and Data Science, Karl Landsteiner University of Health Sciences, Dr. Karl-Dorrek-Straße 30, 3500, Krems, Austria
| | - Bernadette Calabek-Wohinz
- Karl Landsteiner University of Health Sciences, Dr. Karl-Dorrek-Straße 30, 3500, Krems, Austria
- Department of Neurology, University Hospital St. Pölten, Dunant-Platz 1, 3100, St. Pölten, Austria
- Karl Landsteiner Institute of Clinical Neurology and Neuropsychology, University Hospital St. Pölten, Dunant-Platz 1, 3100, St. Pölten, Austria
| | - Christoph Waiß
- Karl Landsteiner University of Health Sciences, Dr. Karl-Dorrek-Straße 30, 3500, Krems, Austria
- Karl Landsteiner Institute of Clinical Neurology and Neuropsychology, University Hospital St. Pölten, Dunant-Platz 1, 3100, St. Pölten, Austria
| | - Stefan Oberndorfer
- Karl Landsteiner University of Health Sciences, Dr. Karl-Dorrek-Straße 30, 3500, Krems, Austria
- Department of Neurology, University Hospital St. Pölten, Dunant-Platz 1, 3100, St. Pölten, Austria
- Karl Landsteiner Institute of Clinical Neurology and Neuropsychology, University Hospital St. Pölten, Dunant-Platz 1, 3100, St. Pölten, Austria
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28
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Shastry S, Mohan G, PA P, Mundkur S, Kurien A, Ahammad J. Role of Thromboelastogram in monitoring the activation of the coagulation pathway and assessing the associated risk factors for hypercoagulable state in transfusion dependent thalassemia patients. Transfus Apher Sci 2022; 62:103583. [PMID: 36344327 DOI: 10.1016/j.transci.2022.103583] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Revised: 10/10/2022] [Accepted: 10/14/2022] [Indexed: 11/06/2022]
Abstract
BACKGROUND Thromboembolic events are rare but one of the fatal complications in thalassemia. Assessment of the hypercoagulable state is not done regularly, and we have assessed the utility of Thromboelastography (TEG) for monitoring the activation of the coagulation pathway in patients with thalassemia. METHODOLOGY A prospective single-center cohort study was conducted in a tertiary care set-up. Transfusion Dependent Thalassemia patients registered with the pediatric unit were screened for hypercoagulability using TEG during six months of the study period and followed up for three years for the development of thromboembolic events. Patient demographics, history of splenectomy, Serum ferritin levels and annual red cell transfusion requirement (mL/kg/year) were assessed. TEG parameters used were R time, K time, alpha angle, Maximum amplitude, Clot index, and Lysis 30. The thrombin generation test (V Curve) obtained from the first-degree derivate of the TEG velocity curve was also used for analysis. RESULTS A total of 34 patients were recruited during the six months study period with an average age of 10.6 years ( ± 5.47). The average pre-transfusion hemoglobin level and the volume of packed red cells received were 7.24 g/dL and 152.82 mL/kg/year respectively. The TEG tracing was suggestive of a hypercoagulable state in 58.82% of patients. The mean values of angle (70.74), MA (64.16), CI (2.65) and TG (774.43) in TDT patients compared to age matched reference range (62.81, 57.99, 0.8, 577.83 respectively) was suggestive of prothrombotic changes. Annual blood transfusion requirement was negatively correlated with hypercoagulable status (-0.344, CI= -0.68 to 0.08). One out of 34 patients developed corona radiata infarct (with annual blood requirement; 112.7 mL/kg/Year). The risk to develop a hypercoagulable state appeared to be higher when the volume of RBCs transfused was less than 154 mL/kg/Year. CONCLUSION TDT patients are at risk of developing thromboembolism, and screening with TEG may be useful to identify those at high risk.
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29
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Bunch CM, Berquist M, Ansari A, McCoy ML, Langford JH, Brenner TJ, Aboukhaled M, Thomas SJ, Peck E, Patel S, Cancel E, Al-Fadhl MD, Zackariya N, Thomas AV, Aversa JG, Greene RB, Seder CW, Speybroeck J, Miller JB, Kwaan HC, Walsh MM. The Choice between Plasma-Based Common Coagulation Tests and Cell-Based Viscoelastic Tests in Monitoring Hemostatic Competence: Not an either-or Proposition. Semin Thromb Hemost 2022; 48:769-784. [PMID: 36174601 DOI: 10.1055/s-0042-1756302] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/14/2022]
Abstract
There has been a significant interest in the last decade in the use of viscoelastic tests (VETs) to determine the hemostatic competence of bleeding patients. Previously, common coagulation tests (CCTs) such as the prothrombin time (PT) and partial thromboplastin time (PTT) were used to assist in the guidance of blood component and hemostatic adjunctive therapy for these patients. However, the experience of decades of VET use in liver failure with transplantation, cardiac surgery, and trauma has now spread to obstetrical hemorrhage and congenital and acquired coagulopathies. Since CCTs measure only 5 to 10% of the lifespan of a clot, these assays have been found to be of limited use for acute surgical and medical conditions, whereby rapid results are required. However, there are medical indications for the PT/PTT that cannot be supplanted by VETs. Therefore, the choice of whether to use a CCT or a VET to guide blood component therapy or hemostatic adjunctive therapy may often require consideration of both methodologies. In this review, we provide examples of the relative indications for CCTs and VETs in monitoring hemostatic competence of bleeding patients.
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Affiliation(s)
- Connor M Bunch
- Department of Emergency Medicine, Henry Ford Hospital, Detroit, Michigan
| | - Margaret Berquist
- Department of Emergency Medicine, Saint Joseph Regional Medical Center, Mishawaka, Indiana
| | - Aida Ansari
- Department of Emergency Medicine, Saint Joseph Regional Medical Center, Mishawaka, Indiana
| | - Max L McCoy
- Department of Emergency Medicine, Saint Joseph Regional Medical Center, Mishawaka, Indiana
| | - Jack H Langford
- Department of Emergency Medicine, Saint Joseph Regional Medical Center, Mishawaka, Indiana
| | - Toby J Brenner
- Department of Emergency Medicine, Saint Joseph Regional Medical Center, Mishawaka, Indiana
| | - Michael Aboukhaled
- Department of Emergency Medicine, Saint Joseph Regional Medical Center, Mishawaka, Indiana
| | - Samuel J Thomas
- Department of Emergency Medicine, Saint Joseph Regional Medical Center, Mishawaka, Indiana
| | - Ethan Peck
- Department of Emergency Medicine, Saint Joseph Regional Medical Center, Mishawaka, Indiana
| | - Shivani Patel
- Department of Emergency Medicine, Saint Joseph Regional Medical Center, Mishawaka, Indiana
| | - Emily Cancel
- Department of Emergency Medicine, Saint Joseph Regional Medical Center, Mishawaka, Indiana
| | - Mahmoud D Al-Fadhl
- Indiana University School of Medicine, Notre Dame Campus, South Bend, Indiana
| | - Nuha Zackariya
- Indiana University School of Medicine, Notre Dame Campus, South Bend, Indiana
| | - Anthony V Thomas
- Indiana University School of Medicine, Notre Dame Campus, South Bend, Indiana
| | - John G Aversa
- Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana
| | - Ryan B Greene
- Department of Interventional Radiology, St. Joseph Regional Medical Center, Mishawaka, Indiana
| | - Christopher W Seder
- Department of Cardiovascular and Thoracic Surgery, Rush University Medical Center, Chicago, Illinois
| | - Jacob Speybroeck
- Department of Orthopedic Surgery, Case Western Medical Center, Cleveland, Ohio
| | - Joseph B Miller
- Department of Emergency Medicine, Henry Ford Hospital, Detroit, Michigan
| | - Hau C Kwaan
- Division of Hematology and Oncology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Mark M Walsh
- Department of Emergency Medicine, Saint Joseph Regional Medical Center, Mishawaka, Indiana.,Indiana University School of Medicine, Notre Dame Campus, South Bend, Indiana
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30
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Hosoi H, Akagi Y, Mushino T, Takeyama M, Minoura N, Hiroi T, Furuya Y, Morimoto M, Murata S, Tamura S, Sonoki T. Use of thromboelastography before the administration of hemostatic agents to safely taper recombinant activated factor VII in acquired hemophilia A: a report of three cases. Thromb J 2022; 20:28. [PMID: 35578257 PMCID: PMC9109301 DOI: 10.1186/s12959-022-00387-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2022] [Accepted: 05/05/2022] [Indexed: 11/11/2022] Open
Abstract
Background Acquired hemophilia A (AHA) is a rare autoimmune disease characterized by bleeding events. Recombinant activated factor VII (rFVIIa) is a first-line bypassing agent, which is effective against clinically significant bleeding. However, there is no standard way of tapering and discontinuing rFVIIa, mainly because there is no established method for monitoring rFVIIa therapy for AHA. Case presentation Here, we report three AHA cases, in which we adjusted the rFVIIa dosing interval based on the results of thromboelastography (TEG) performed just before the administration of the next dose of rFVIIa. The dosing interval of rFVIIa was prolonged based on the reaction rate time (R) according to TEG, which is correlated with coagulation factor activity. The R-value reference range reported by the manufacturer of the TEG system was used as a threshold for making decisions. In these three cases, there was no rebleeding, and the patients’ ability to perform activities of daily living did not decline. Conclusion Our cases suggest that conducting TEG-based monitoring just before the administration of the next dose of rFVIIa may be useful for guiding increases in the rFVIIa dosing interval without causing rebleeding events. Further investigations are warranted to examine how TEG could be used to determine the most appropriate rFVIIa dosing interval, e.g., through regular TEG-based monitoring, and the optimal TEG-derived threshold for indicating changes to the rFVIIa dosing interval.
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31
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Nishiyama A, Ogiwara K, Nakajima Y, Furukawa S, Matsumoto T, Takeda H, Nogami K. A case of a young boy with hyper-fibrinolysis associated with natural fibrin precipitates suspected to have occurred through a novel coagulation and fibrinolysis mechanism. Int J Hematol 2022; 116:276-287. [PMID: 35416587 DOI: 10.1007/s12185-022-03339-3] [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: 12/01/2021] [Revised: 03/25/2022] [Accepted: 03/27/2022] [Indexed: 10/18/2022]
Abstract
An 8-year-old Japanese boy with no underlying disease presented with severe intramuscular hematoma of the hip, and was admitted for a disseminated intravascular coagulation-like state with fibrinolytic dominance. Laboratory examinations revealed severe hyper-fibrinolysis with elevated markers, markedly shortened euglobulin clot lysis time, mildly decreased prothrombin, and severely decreased fibrinogen and factor XIII. Natural fibrin precipitates rapidly appeared in citrate-treated, ethylene-diamine-tetra-acetic-treated, and heparin-treated samples, but not in argatroban-treated samples, indicating that the mechanism of thrombin and fibrin formation was Ca2+-independent. The precipitates were physically similar to thrombin-triggered plasma fibrin. A global coagulation assay revealed that thrombin generation potentials were normal throughout the clinical course, whereas plasmin generation was already detected before initiation of fibrin formation in the acute phase. This phenomenon disappeared with time. Changes in coagulation abnormalities and nature of fibrinolysis paralleled those seen in specific markers for streptococcal infections. Streptokinase was possibly involved in this disease, as SDS-polyacrylamide gel electrophoresis revealed that plasmin derived from streptokinase-plasminogen complex proteolyzed the prothrombin to approximately 35-kDa α-thrombin consisting of the A-B single chain, which was identified by NH2-terminal sequence analysis. The involvement of streptokinase-plasminogen-prothrombin caused by streptococcal infection may be one mechanism that produces marked hyper-fibrinolysis associated with natural fibrin precipitates.
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Affiliation(s)
- Atsuko Nishiyama
- Department of Pediatrics, Nara Medical University, 840 Shijo-cho, Kashihara, Nara, 634-8522, Japan
| | - Kenichi Ogiwara
- Department of Pediatrics, Nara Medical University, 840 Shijo-cho, Kashihara, Nara, 634-8522, Japan.
| | - Yuto Nakajima
- Department of Pediatrics, Nara Medical University, 840 Shijo-cho, Kashihara, Nara, 634-8522, Japan.,Advanced Medical Science of Thrombosis and Hemostasis, Nara Medical University, Kashihara, Japan
| | - Shoko Furukawa
- Department of Pediatrics, Nara Medical University, 840 Shijo-cho, Kashihara, Nara, 634-8522, Japan
| | - Tomoko Matsumoto
- Department of Pediatrics, Nara Medical University, 840 Shijo-cho, Kashihara, Nara, 634-8522, Japan.,Clinical Laboratory, Tenri Health Care University, Tenri, Japan
| | - Hiroki Takeda
- Division of Pediatric Critical Care, Hyogo Prefectural Kobe Children's Hospital, Kobe, Japan
| | - Keiji Nogami
- Department of Pediatrics, Nara Medical University, 840 Shijo-cho, Kashihara, Nara, 634-8522, Japan
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Ogiwara K, Taki M, Suzuki T, Takedani H, Matsushita T, Amano K, Matsumoto M, Nishio K, Shima M, Kasahara M, Nogami K. Assessment of global coagulation function under treatment with emicizumab concomitantly with bypassing agents in haemophilia A with inhibitor (UNEBI Study): multicentre open-label non-randomised clinical trial. BMJ Open 2022; 12:e056922. [PMID: 35177463 PMCID: PMC8860020 DOI: 10.1136/bmjopen-2021-056922] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/03/2022] Open
Abstract
INTRODUCTION Subcutaneous emicizumab prophylaxis substantially reduces bleeding episodes in patients with haemophilia A (PwHA) and factor VIII inhibitor. However, thrombotic events occurred in some PwHA with inhibitor who had received high cumulative doses of activated prothrombin complex concentrates at their breakthrough bleeds, when they were also given prophylactic emicizumab. After that, although the recommended guidance was proposed for bypassing agents (BPAs) therapy under emicizumab prophylaxis for haemostatic management, detailed investigation(s) is(are) required to elucidate the safe and appropriate dose of BPAs to use concomitantly with emicizumab prophylaxis. METHODS AND ANALYSIS In the UNEBI Study, 60 PwHA with inhibitor will be enrolled for a maximum duration of 3 years, and samples of 20 events following concomitant use of BPAs with emicizumab will be collected. An 'event' is defined as obtaining blood samples before and after administration of BPA when a breakthrough bleed or a surgical procedure occurs. The coagulation potential in the obtained samples will be measured by global coagulation assays. The primary endpoint is the degree of improvement in the maximum coagulation rate by clot waveform analysis (CWA) before and after administration of fixed-dose BPAs. This parameter obtained from CWA, which is triggered with an optimally diluted mixture of prothrombin time/activated partial thromboplastin time-reagents, is reported to be an excellent marker for assessing the degree of improvement in coagulation potential in emicizumab-treated plasma. ETHICS AND DISSEMINATION The UNEBI Study was approved by the Japan Certified Review Board of Nara Medical University. The results of the study will be communicated through publication in international scientific journals and presentations at (inter)national conferences. TRIAL REGISTRATION NUMBER jRCTs051190119.
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Affiliation(s)
| | - Masashi Taki
- Pediatrics, Sei Marianna University School of Medicine Yokohama Seibu Hospital, Yokohama, Japan
| | - Takashi Suzuki
- Blood Coagulation, Medical Corporation Foundation Ogikubo Hospital, Suginami-ku, Japan
| | | | | | - Kagehiro Amano
- Laboratory Medicine, Tokyo Medical University, Shinjuku-ku, Japan
| | | | - Kenji Nishio
- General Medicine, Nara Medical University, Kashihara, Japan
| | - Midori Shima
- Pediatrics, Nara Medical University, Kashihara, Japan
| | - Masato Kasahara
- Institute for Clinical and Translational Science, Nara Medical University, Kashihara, Japan
| | - Keiji Nogami
- Pediatrics, Nara Medical University, Kashihara, Japan
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Darbandi AD, Saadat GH, Butler BA, Bokhari F. Clinical Outcomes and Surgical Complications Among Patients with Bleeding Disorders After Acute Hip Fracture Surgery. J Orthop Trauma 2022; 36:104-110. [PMID: 35061653 DOI: 10.1097/bot.0000000000002212] [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] [Accepted: 06/11/2021] [Indexed: 02/02/2023]
Abstract
OBJECTIVE To compare short-term (≤30 days) outcomes of hip fracture between patients with and without bleeding disorders. DESIGN Retrospective database review. SETTING The study setting included hospitals participating in the American College of Surgeons National Surgical Quality Improvement Program database. PATIENTS Patients with acute hip fractures were identified from the National Surgical Quality Improvement Program database between 2016 and 2019. INTERVENTION Open reduction internal fixation or hemiarthroplasty. MAIN OUTCOME MEASUREMENTS Mortality, readmission, reoperation, length of stay, and complication were main outcome measurements. RESULTS There were 63,718 patients undergoing hip surgery, and 16.0% had a bleeding disorder. After adjusting for confounders, multivariable regression models showed that cases with bleeding disorders were associated with higher rates of transfusion [odds ratio (OR) 1.404; confidence interval (CI), 1.335-1.479], myocardial infarction (OR 1.367; CI, 1.190-1.572), pneumonia (OR 1.193; CI, 1.078-1.321), renal failure (OR 1.843; CI, 1.363-2.491), surgical site infections (OR 1.429; CI, 1.185-1.175), sepsis (OR 1.25; CI, 1.034-1.511), and readmission (OR 1.314; CI, 1.224-1.408). However, bleeding disorders were not associated with mortality (OR 0.947; CI, 0.866-1.036) or reoperation (OR 1.061; CI, 0.925-1.220). CONCLUSIONS Hip fracture surgery in patients with bleeding disorders is not associated with higher risks of short-term mortality or reoperation. However, special consideration should be taken when calculating preoperative risks of complications among bleeding disorder patients. LEVEL OF EVIDENCE Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.
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Affiliation(s)
| | - Ghulam H Saadat
- Department of Trauma and Burns, John H Stroger Hospital of Cook County, Chicago, IL; and
| | - Bennet A Butler
- Department of Orthopedic Surgery, Northwestern Memorial Hospital, Chicago, IL
| | - Faran Bokhari
- Department of Trauma and Burns, John H Stroger Hospital of Cook County, Chicago, IL; and
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Guo WJ, Chen WY, Yu XR, Shen L, Huang YG. Intraoperative thromboelastography-guided transfusion in a patient with factor XI deficiency: A case report. World J Clin Cases 2022; 10:242-248. [PMID: 35071523 PMCID: PMC8727276 DOI: 10.12998/wjcc.v10.i1.242] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2020] [Revised: 07/12/2021] [Accepted: 11/25/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Factor XI (FXI) deficiency, also known as hemophilia C, is a rare bleeding disorder of unpredictable severity that correlates poorly with FXI coagulation activity. This often poses great challenges in perioperative hemostatic management. Thromboelastography (TEG) is a method for testing blood coagulation using a viscoelastic hemostatic assay of whole blood to assess the overall coagulation status. Here, we present the successful application of intraoperative TEG monitoring in an FXI-deficient patient as an individualized blood transfusion strategy.
CASE SUMMARY A 21-year-old male patient with FXI deficiency was scheduled to undergo reconstructive surgery for macrodactyly of the left foot under general anesthesia. To minimize his bleeding risk, he was scheduled to receive fresh frozen plasma (FFP) as an empirical prophylactic FXI replacement at a dose of 15-20 mL/kg body weight (900-1200 mL) before surgery. Subsequent FFP transfusion was to be adjusted according to surgical need. Instead, TEG assessment was used at the beginning and toward the end of his surgery. According to intraoperative TEG results, the normalization of coagulation function was achieved with an infusion of only 800 mL FFP, and blood loss was minimal. The patient showed an uneventful postoperative course and was discharged on postoperative day 8.
CONCLUSION TEG can be readily applied in the intraoperative period to individualize transfusion needs in patients with rare inherited coagulopathy.
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Affiliation(s)
- Wen-Juan Guo
- Department of Anesthesiology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China
| | - Wei-Yun Chen
- Department of Anesthesiology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China
| | - Xue-Rong Yu
- Department of Anesthesiology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China
| | - Le Shen
- Department of Anesthesiology, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China
| | - Yu-Guang Huang
- Department of Anesthesiology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China
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Aoki H, Ogiwara K, Hasegawa M, Nogami K. Hemostatic rebalance in neonatal intrahepatic cholestasis with citrin deficiency. Pediatr Int 2022; 64:e14741. [PMID: 33851467 DOI: 10.1111/ped.14741] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2021] [Revised: 03/16/2021] [Accepted: 04/09/2021] [Indexed: 01/10/2023]
Abstract
BACKGROUND Neonatal intrahepatic cholestasis with citrin deficiency (NICCD) results in coagulopathy due to decreased levels of vitamin (V)K-dependent clotting factors, similar to biliary atresia (BA). However, the involvement of VK-independent coagulant and anticoagulant factor(s) remains unknown. We examined relationships between coagulant and anticoagulant potential before and after nutritional treatment in NICCD. METHODS Three cases (aged 12, 21, and 45 days) with NICCD-associated coagulopathy were evaluated with standard coagulation/anticoagulation tests and comprehensive coagulation assays, rotational thromboelastometry, and protein C/protein S (PC/PS) pathway function assay (ThromboPath® ), before and after nutritional treatment. RESULTS In all cases, activated partial thromboplastin time and prothrombin time were significantly prolonged, which is associated with very low levels of VK-independent fibrinogen and antithrombin. The initiation of nutritional treatment of medium-chain triglycerides oil improved these levels within the normal range, although low levels of other clotting factors were modestly increased. Whole blood- rotational thromboelastometry analysis revealed near-normal coagulation potential, even before treatment, comparable to healthy adults, and supportive of their non-bleeding symptoms. The introduction of nutritional treatment had further improved comprehensive coagulation potential. The global PC/PS-pathway function assay demonstrated the absence of the features of this function associated with the pathogenesis of NICCD. Compared to BA, the plasma levels of fibrinogen and antithrombin in all cases were markedly low, whilst those after treatment improved, especially to similar level of BA. CONCLUSIONS Neonatal intrahepatic cholestasis with citrin deficiency has the characteristic of rebalancing hemostatic mechanisms associated with coagulant and anticoagulant potential involving low levels of fibrinogen and antithrombin, suggesting a pathophysiological coagulopathy distinct from BA.
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Affiliation(s)
- Hirosato Aoki
- Department of Pediatrics, Nara Medical University, Kashihara, Nara, Japan
| | - Kenichi Ogiwara
- Department of Pediatrics, Nara Medical University, Kashihara, Nara, Japan
| | - Mari Hasegawa
- Department of Pediatrics, Nara Medical University, Kashihara, Nara, Japan
| | - Keiji Nogami
- Department of Pediatrics, Nara Medical University, Kashihara, Nara, Japan
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Ishikawa T, Nakajima Y, Omae T, Ogiwara K, Nogami K. Comprehensive coagulation and fibrinolytic potential in the acute phase of pediatric patients with idiopathic nephrotic syndrome evaluated by whole blood-based rotational thromboelastometry. Pediatr Nephrol 2022; 37:1605-1614. [PMID: 34997323 PMCID: PMC8741554 DOI: 10.1007/s00467-021-05366-4] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2021] [Revised: 11/09/2021] [Accepted: 11/09/2021] [Indexed: 12/29/2022]
Abstract
BACKGROUND Venous thromboembolism is a rare, serious complication of idiopathic nephrotic syndrome (INS) in childhood. The mechanisms responsible for the hypercoagulable state in the acute phase of INS are poorly understood, however. This study aimed to assess overall coagulation and fibrinolytic function in pediatric patients with INS. METHODS Global coagulation and fibrinolysis were examined in whole blood samples from 22 children with initial onset INS (initial-group), 22 children with relapsed INS (relapse-group), and 15 control pediatric patients using rotational thromboelastometry (ROTEM®). In the initial-group, blood samples were obtained before (week 0) and 1-4 weeks after initiation of corticosteroid therapy. EXTEM and FIBTEM were used to assess coagulation and fibrinolysis, respectively. Clot time (CT), clot formation time (CFT), maximum clot firmness (MCF), and α-angle were determined as coagulation parameters, and lysis index at 30 and 60 min (LI30 and LI60, respectively) were assessed as fibrinolytic parameters. RESULTS CT was significantly shortened, and MCF and α-angle were significantly greater than controls at week 0 and week 1 both in the initial-group and the relapse-group. MCF correlated with serum albumin (r = 0.70, p < 0.001) and fibrinogen level (r = 0.68, p < 0.001). The fibrinolytic parameters (LI30 and LI60) in the initial-group were stable and higher than those in controls at all time points (p < 0.01). CONCLUSIONS We have shown that the hypofibrinolytic defect did not improve with effective NS treatment at the early 4-week time-point. Additionally, a likely pre-thrombotic state was evident in the period before initial onset and 1 week after corticosteroid therapy in pediatric INS.
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Affiliation(s)
- Tomoaki Ishikawa
- Department of Pediatrics, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522 Japan
| | - Yuto Nakajima
- Department of Pediatrics, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522 Japan ,Advanced Medical Science of Thrombosis and Hemostasis, Nara Medical University, Kashihara, Nara Japan
| | - Takashi Omae
- Department of Pediatrics, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522 Japan
| | - Kenichi Ogiwara
- Department of Pediatrics, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522 Japan
| | - Keiji Nogami
- Department of Pediatrics, Nara Medical University, 840 Shijo-cho, Kashihara, Nara, 634-8522, Japan.
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Omae T, Ishikawa T, Nakajima Y, Nogami K. Coagulation potential in pediatric patients with immunoglobulin A nephropathy. Pediatr Int 2022; 64:e15042. [PMID: 34699659 DOI: 10.1111/ped.15042] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2021] [Revised: 09/29/2021] [Accepted: 10/25/2021] [Indexed: 11/29/2022]
Abstract
BACKGROUND Immunoglobulin A nephropathy (IgAN) is the most prevalent primary chronic glomerular disease in children. Understanding the changes in coagulability caused by IgAN is important for clarifying pathophysiology and choice of treatment. The coagulation potential in patients with IgAN remains to be investigated, however. We aimed to assess comprehensive coagulation potential in pediatric patients with IgAN and explore its relationship with pathological disease severity. METHODS Fourteen children with IgAN diagnosed by renal biopsy, who were admitted at Nara Medical University Hospital between 2015 and 2020, were analyzed. Rotational thromboelastometry was used to evaluate coagulation potential. Values of rotational thromboelastometry parameters in patients with IgAN were compared with those in control children. RESULTS In patients with IgAN (aged median 9.5 year), clotting time plus clot formation time (CT + CFT) was shortened (P = 0.003) and α angle was greater (P < 0.001) than those in controls, indicating a hypercoagulable state. The rate of mesangial hypercellularity of glomeruli correlated with CT + CFT, α, and maximum clot firmness (MCF) (rs = -0.79, 0.56, and 0.37). The rate of cellular/fibrocellular crescent of glomeruli correlated with CT + CFT, α, and MCF (rs = -0.41, 0.60, and 0.50). Patients with mesangial hypercellularity ≥80% of glomeruli showed reduced CT + CFT and increased α angle (P = 0.007 and 0.03). Patients with cellular/fibrocellular crescent ≥10% of glomeruli showed decreased CT + CFT and increased α angle (both P = 0.02). CONCLUSIONS The hypercoagulable state in pediatric patients with IgAN may be associated with the pathological severity of their disease.
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Affiliation(s)
- Takashi Omae
- Department of Pediatrics, Nara Medical University, Kashihara, Nara, Japan
| | - Tomoaki Ishikawa
- Department of Pediatrics, Nara Medical University, Kashihara, Nara, Japan
| | - Yuto Nakajima
- Department of Pediatrics, Nara Medical University, Kashihara, Nara, Japan
| | - Keiji Nogami
- Department of Pediatrics, Nara Medical University, Kashihara, Nara, Japan
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Simurda T, Asselta R, Zolkova J, Brunclikova M, Dobrotova M, Kolkova Z, Loderer D, Skornova I, Hudecek J, Lasabova Z, Stasko J, Kubisz P. Congenital Afibrinogenemia and Hypofibrinogenemia: Laboratory and Genetic Testing in Rare Bleeding Disorders with Life-Threatening Clinical Manifestations and Challenging Management. Diagnostics (Basel) 2021; 11:2140. [PMID: 34829490 PMCID: PMC8622093 DOI: 10.3390/diagnostics11112140] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Revised: 11/10/2021] [Accepted: 11/15/2021] [Indexed: 12/19/2022] Open
Abstract
Congenital fibrinogen disorders are rare pathologies of the hemostasis, comprising quantitative (afibrinogenemia, hypofibrinogenemia) and qualitative (dysfibrinogenemia and hypodysfibrinogenemia) disorders. The clinical phenotype is highly heterogeneous, being associated with bleeding, thrombosis, or absence of symptoms. Afibrinogenemia and hypofibrinogenemia are the consequence of mutations in the homozygous, heterozygous, or compound heterozygous state in one of three genes encoding the fibrinogen chains, which can affect the synthesis, assembly, intracellular processing, stability, or secretion of fibrinogen. In addition to standard coagulation tests depending on the formation of fibrin, diagnostics also includes global coagulation assays, which are effective in monitoring the management of replacement therapy. Genetic testing is a key point for confirming the clinical diagnosis. The identification of the precise genetic mutations of congenital fibrinogen disorders is of value to permit early testing of other at risk persons and better understand the correlation between clinical phenotype and genotype. Management of patients with afibrinogenemia is particularly challenging since there are no data from evidence-based medicine studies. Fibrinogen concentrate is used to treat bleeding, whereas for the treatment of thrombotic complications, administered low-molecular-weight heparin is most often. This review deals with updated information about afibrinogenemia and hypofibrinogenemia, contributing to the early diagnosis and effective treatment of these disorders.
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Affiliation(s)
- Tomas Simurda
- National Center of Hemostasis and Thrombosis, Department of Hematology and Transfusiology, Comenius University in Bratislava, Jessenius Faculty of Medicine in Martin and University Hospital in Martin, 03601 Martin, Slovakia; (J.Z.); (M.B.); (M.D.); (I.S.); (J.H.); (J.S.); (P.K.)
| | - Rosanna Asselta
- Department of Biomedical Sciences, Humanitas University, 20072 Pieve Emanuele, Italy;
- Humanitas Clinical and Research Center IRCCS, 20089 Rozzano, Italy
| | - Jana Zolkova
- National Center of Hemostasis and Thrombosis, Department of Hematology and Transfusiology, Comenius University in Bratislava, Jessenius Faculty of Medicine in Martin and University Hospital in Martin, 03601 Martin, Slovakia; (J.Z.); (M.B.); (M.D.); (I.S.); (J.H.); (J.S.); (P.K.)
| | - Monika Brunclikova
- National Center of Hemostasis and Thrombosis, Department of Hematology and Transfusiology, Comenius University in Bratislava, Jessenius Faculty of Medicine in Martin and University Hospital in Martin, 03601 Martin, Slovakia; (J.Z.); (M.B.); (M.D.); (I.S.); (J.H.); (J.S.); (P.K.)
| | - Miroslava Dobrotova
- National Center of Hemostasis and Thrombosis, Department of Hematology and Transfusiology, Comenius University in Bratislava, Jessenius Faculty of Medicine in Martin and University Hospital in Martin, 03601 Martin, Slovakia; (J.Z.); (M.B.); (M.D.); (I.S.); (J.H.); (J.S.); (P.K.)
| | - Zuzana Kolkova
- Biomedical Center Martin, Comenius University in Bratislava, Jessenius Faculty of Medicine in Martin, 03601 Martin, Slovakia; (Z.K.); (D.L.)
| | - Dusan Loderer
- Biomedical Center Martin, Comenius University in Bratislava, Jessenius Faculty of Medicine in Martin, 03601 Martin, Slovakia; (Z.K.); (D.L.)
| | - Ingrid Skornova
- National Center of Hemostasis and Thrombosis, Department of Hematology and Transfusiology, Comenius University in Bratislava, Jessenius Faculty of Medicine in Martin and University Hospital in Martin, 03601 Martin, Slovakia; (J.Z.); (M.B.); (M.D.); (I.S.); (J.H.); (J.S.); (P.K.)
| | - Jan Hudecek
- National Center of Hemostasis and Thrombosis, Department of Hematology and Transfusiology, Comenius University in Bratislava, Jessenius Faculty of Medicine in Martin and University Hospital in Martin, 03601 Martin, Slovakia; (J.Z.); (M.B.); (M.D.); (I.S.); (J.H.); (J.S.); (P.K.)
| | - Zora Lasabova
- Department of Molecular Biology and Genomics, Comenius University in Bratislava, Jessenius Faculty of Medicine in Martin, 03601 Martin, Slovakia;
| | - Jan Stasko
- National Center of Hemostasis and Thrombosis, Department of Hematology and Transfusiology, Comenius University in Bratislava, Jessenius Faculty of Medicine in Martin and University Hospital in Martin, 03601 Martin, Slovakia; (J.Z.); (M.B.); (M.D.); (I.S.); (J.H.); (J.S.); (P.K.)
| | - Peter Kubisz
- National Center of Hemostasis and Thrombosis, Department of Hematology and Transfusiology, Comenius University in Bratislava, Jessenius Faculty of Medicine in Martin and University Hospital in Martin, 03601 Martin, Slovakia; (J.Z.); (M.B.); (M.D.); (I.S.); (J.H.); (J.S.); (P.K.)
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Speybroeck J, Marsee M, Shariff F, Zackariya N, Grisoli A, Lune SV, Larson EE, Hatch J, McCauley R, Shariff F, Aversa JG, Son M, Agostini V, Campello E, Simioni P, Scărlătescu E, Kwaan H, Hartmann J, Fries D, Walsh M. Viscoelastic testing in benign hematologic disorders: Clinical perspectives and future implications of point-of-care testing to assess hemostatic competence. Transfusion 2021; 60 Suppl 6:S101-S121. [PMID: 33089936 DOI: 10.1111/trf.16088] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2020] [Revised: 09/04/2020] [Accepted: 09/05/2020] [Indexed: 01/04/2023]
Abstract
Viscoelastic tests (VETs) have been used routinely for liver transplantation, cardiac surgery, and trauma, but only recently have found clinical utility in benign hematologic disorders. Therefore, guidelines for diagnosis and treatment of these disorders based on viscoelastic variables have been adapted from the existing transplant, cardiothoracic surgery, and trauma resuscitation literature. As a result, diagnostic and therapeutic strategies for benign hematologic disorders utilizing VETs are not uniform. Accordingly, even though there has been a recent increase in the utilization of VET for the diagnosis and treatment of such disorders, the literature is still in its early stages. Analysis of point-of-care viscoelastic tracings from benign hematologic disorders has the potential to allow prompt recognition of disease and to guide patient-specific intervention. Here we present a review describing the application of VETs to benign hematologic disorders.
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Affiliation(s)
- Jacob Speybroeck
- Indiana University School of Medicine, Notre Dame Campus, South Bend, Indiana
| | - Mathew Marsee
- Indiana University School of Medicine, Notre Dame Campus, South Bend, Indiana
| | - Faadil Shariff
- Saint Joseph Regional Medical Center, Mishawaka, Indiana
| | - Nuha Zackariya
- Saint Joseph Regional Medical Center, Mishawaka, Indiana
| | - Anne Grisoli
- Indiana University School of Medicine, Notre Dame Campus, South Bend, Indiana
| | - Stefani Vande Lune
- Indiana University School of Medicine, Notre Dame Campus, South Bend, Indiana
| | - Emilee E Larson
- Indiana University School of Medicine, Notre Dame Campus, South Bend, Indiana
| | - Jordan Hatch
- Indiana University School of Medicine, Notre Dame Campus, South Bend, Indiana
| | - Ross McCauley
- Indiana University School of Medicine, Notre Dame Campus, South Bend, Indiana
| | - Faisal Shariff
- Indiana University School of Medicine, Notre Dame Campus, South Bend, Indiana
| | - John G Aversa
- Department of General Surgery, Indiana University School of Medicine, Indianapolis, Indiana
| | - Michael Son
- Saint Joseph Regional Medical Center, Mishawaka, Indiana
| | - Vanessa Agostini
- Department of Transfusion Medicine, IRCC Polyclinic Hospital San Marino, Genoa, Italy
| | - Elena Campello
- Thrombotic and Hemorrhagic Diseases Unit, Department of Medicine, Padua University Hospital, Padua, Italy
| | - Paolo Simioni
- Thrombotic and Hemorrhagic Diseases Unit, Department of Medicine, Padua University Hospital, Padua, Italy
| | - Escaterina Scărlătescu
- Department of Anaesthesia and Intensive Care, Fundeni Clinical Institute, Bucharest, Romania
| | - Hau Kwaan
- Department of Hematology Oncology, Northwestern University School of Medicine, Chicago, Illinois
| | - Jan Hartmann
- Department of Medical Affairs, Haemonetics Corporation, Boston, Massachusetts
| | - Dietmar Fries
- Department of General and Surgical Critical Care Medicine, Medical University of Innsbruck, Innsbruck, Austria
| | - Mark Walsh
- Indiana University School of Medicine, Notre Dame Campus, South Bend, Indiana.,Saint Joseph Regional Medical Center, Mishawaka, Indiana
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Yeom RS, Wang XA, Elia E, Yoon U. Severe Congenital Factor VII Deficiency with Normal Perioperative Coagulation Profile Based on ROTEM Analysis in a Hepatectomy. AMERICAN JOURNAL OF CASE REPORTS 2021; 22:e930245. [PMID: 34375324 PMCID: PMC8366573 DOI: 10.12659/ajcr.930245] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Revised: 06/29/2021] [Accepted: 06/15/2021] [Indexed: 11/09/2022]
Abstract
BACKGROUND Factor VII (FVII) deficiency is the most common autosomal-recessive bleeding disorder. FVII activity level (FVII: C) of 10-20% is often used as the threshold for administering activated recombinant FVII (rFVIIa) for patients undergoing major surgery. However, rFVIIa is expensive and carries the risk of a thromboembolic event, and thus should only be administered when truly indicated. CASE REPORT A 22-year-old woman with 8% FVII: C underwent a hepatectomy. Although there were no clinical signs of bleeding, peri-operative administration of rFVIIa was recommended by the hematologist (first dose at surgical incision, then 4 h later, then every 12 h until 48 h postoperatively). Intraoperatively, serials of ROTEM analysis were performed to evaluate the effect of rFVIIa administration. No significant effect of rFVIIa was seen on NATEM. Surgery was unremarkable, without any significant blood loss. The patient developed radial artery thrombosis 24 h postoperatively, the arterial line was removed, and rFVIIa was discontinued (PT: 14.6, FVII: C 36%). On POD 3, INR was elevated (3.15, FVII: C 3%). To correct INR, the patient was transfused 8 units of FFP, despite any signs of clinical bleeding. However, INR and FVII: C did not correct and the patient was discharged on POD 7 in a stable condition. CONCLUSIONS Even with FVII: C of 8%, the ROTEM analysis revealed a normal coagulation status. The administration of rFVIIa did not improve the already normal baseline coagulation profile, but rather potentially led to an accelerated coagulation or hypercoagulable state and may have led to the radial artery thrombosis. We endorse the use of viscoelastic testing for hemostasis assessment and factor replacement in congenital FVII deficiency.
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Affiliation(s)
- Richard S. Yeom
- Department of Anesthesiology, Thomas Jefferson University Hospital, Philadelphia, PA, USA
| | - Xuejun A. Wang
- Department of Internal Medicine, Thomas Jefferson University Hospital, Philadelphia, PA, USA
| | - Elia Elia
- Department of Anesthesiology, Thomas Jefferson University Hospital, Philadelphia, PA, USA
| | - Uzung Yoon
- Department of Anesthesiology, Thomas Jefferson University Hospital, Philadelphia, PA, USA
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Mao JY, Unnikrishnan B, Chu HW, Harroun SG, Chen YR, Wu AT, Chang HT, Lin HJ, Huang CC. Thermally driven formation of polyphenolic carbonized nanogels with high anticoagulant activity from polysaccharides. Biomater Sci 2021; 9:4679-4690. [PMID: 34018502 DOI: 10.1039/d1bm00402f] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
We have demonstrated that alginate with negligible anticoagulant activity can be converted into carbonized nanogels with potent anticoagulant activity through a solid-state heating process. The conversion of alginate into graphene-like nanosheet (GNS)-embedded polyphenolic-alginate nanogels (GNS/Alg-NGs) has been carried out through condensation and carbonization processes. The GNS/Alg-NGs exhibit much stronger anticoagulant activity (>520-fold) compared to untreated alginate, mainly because their polyphenolic structures have a high binding affinity [dissociation constant (Kd) = 2.1 × 10-10 M] toward thrombin. In addition, the thrombin clotting time delay caused by the GNS/Alg-NGs is 10-fold longer than that of natural polyphenolic compounds, such as quercetin, catechin, naringenin, caffeic acid, and ferulic acid. The thrombin- or kaolin-activated thromboelastography of whole-blood coagulation reveals that the GNS/Alg-NGs display a much stronger anticoagulant ability than that of untreated alginate and naturally sulfated polysaccharides (fucoidan). The GNS/Alg-NGs exhibit superior biocompatibility and anticoagulant activity, as observed with an in vivo rat model, revealing their potential as a blood thinner for the treatment of thrombotic disorders.
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Affiliation(s)
- Ju-Yi Mao
- Department of Bioscience and Biotechnology, National Taiwan Ocean University, Keelung 20224, Taiwan. and Doctoral Degree Program in Marine Biotechnology, National Taiwan Ocean University, Keelung 20224, Taiwan and Doctoral Degree Program in Marine Biotechnology, Academia Sinica, Taipei 11529, Taiwan
| | - Binesh Unnikrishnan
- Department of Bioscience and Biotechnology, National Taiwan Ocean University, Keelung 20224, Taiwan.
| | - Han-Wei Chu
- Department of Bioscience and Biotechnology, National Taiwan Ocean University, Keelung 20224, Taiwan.
| | - Scott G Harroun
- Department of Chemistry, Université de Montréal, Montréal, Québec H3C 3J7, Canada
| | - Yet-Ran Chen
- Agricultural Biotechnology Research Center, Academia Sinica, Taipei 11529, Taiwan
| | - An-Tai Wu
- Department of Chemistry, National Changhua University of Education, Changhua 50058, Taiwan
| | - Huan-Tsung Chang
- Department of Chemistry, National Taiwan University, Taipei 10617, Taiwan
| | - Han-Jia Lin
- Department of Bioscience and Biotechnology, National Taiwan Ocean University, Keelung 20224, Taiwan. and Center of Excellence for the Oceans, National Taiwan Ocean University, Keelung 20224, Taiwan
| | - Chih-Ching Huang
- Department of Bioscience and Biotechnology, National Taiwan Ocean University, Keelung 20224, Taiwan. and Center of Excellence for the Oceans, National Taiwan Ocean University, Keelung 20224, Taiwan and School of Pharmacy, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan
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42
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Stanciakova L, Dobrotova M, Holly P, Zolkova J, Vadelova L, Skornova I, Ivankova J, Bolek T, Samos M, Grendar M, Danko J, Kubisz P, Stasko J. How Can Rotational Thromboelastometry as a Point-of-Care Method Be Useful for the Management of Secondary Thromboprophylaxis in High-Risk Pregnant Patients? Diagnostics (Basel) 2021; 11:diagnostics11050828. [PMID: 34063712 PMCID: PMC8147835 DOI: 10.3390/diagnostics11050828] [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: 03/04/2021] [Revised: 04/22/2021] [Accepted: 04/28/2021] [Indexed: 11/16/2022] Open
Abstract
Thromboprophylaxis with low-molecular-weight heparin (LMWH) for patients with a history of venous thromboembolism (VTE) is suggested. Rotational thromboelastometry (ROTEM®) represents an innovative point-of-care method enabling the complex and quick evaluation of hemostasis. However, there are only episodic cases of its use for hemostasis assessment and guidance of LMWH in pregnancy. Therefore, we provide the results of unique prospective and longitudinal monitoring of hemostasis in high-risk pregnant women, which we used for the individualized optimalization of secondary thromboprophylaxis. According to the shortening of clot formation time (CFT) in EXTEM (p = 0.0007 from the 26th gestational week vs. controls) and INTEM (p = 0.002 from the 35th gestational week), increase in alpha angle (AA) in EXTEM, INTEM, and HEPTEM, and the persistence of increase in maximum clot firmness (MCF) in EXTEM, INTEM, and HEPTEM (p < 0.001 from the 26th and 35th gestational week vs. controls for EXTEM and INTEM, p = 0.0012 from the 26th gestational week in HEPTEM), LMWH dose was modified. Even after the postpartum period, AA in EXTEM was steeper than in controls (p = 0.0007), indicating that hemostasis is not fully normalized after 6–8 weeks following delivery. Therefore, ROTEM may be a useful tool for the individual evaluation of the termination of anticoagulant thromboprophylaxis.
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Affiliation(s)
- Lucia Stanciakova
- National Center of Hemostasis and Thrombosis, Department of Hematology and Transfusion Medicine, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin University Hospital, 03659 Martin, Slovakia; (M.D.); (P.H.); (J.Z.); (L.V.); (I.S.); (J.I.); (P.K.); (J.S.)
- Correspondence: ; Tel.: +42-143-420-3696
| | - Miroslava Dobrotova
- National Center of Hemostasis and Thrombosis, Department of Hematology and Transfusion Medicine, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin University Hospital, 03659 Martin, Slovakia; (M.D.); (P.H.); (J.Z.); (L.V.); (I.S.); (J.I.); (P.K.); (J.S.)
| | - Pavol Holly
- National Center of Hemostasis and Thrombosis, Department of Hematology and Transfusion Medicine, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin University Hospital, 03659 Martin, Slovakia; (M.D.); (P.H.); (J.Z.); (L.V.); (I.S.); (J.I.); (P.K.); (J.S.)
| | - Jana Zolkova
- National Center of Hemostasis and Thrombosis, Department of Hematology and Transfusion Medicine, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin University Hospital, 03659 Martin, Slovakia; (M.D.); (P.H.); (J.Z.); (L.V.); (I.S.); (J.I.); (P.K.); (J.S.)
| | - Lubica Vadelova
- National Center of Hemostasis and Thrombosis, Department of Hematology and Transfusion Medicine, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin University Hospital, 03659 Martin, Slovakia; (M.D.); (P.H.); (J.Z.); (L.V.); (I.S.); (J.I.); (P.K.); (J.S.)
- Center of Immunology in Martin, 03601 Martin, Slovakia
| | - Ingrid Skornova
- National Center of Hemostasis and Thrombosis, Department of Hematology and Transfusion Medicine, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin University Hospital, 03659 Martin, Slovakia; (M.D.); (P.H.); (J.Z.); (L.V.); (I.S.); (J.I.); (P.K.); (J.S.)
| | - Jela Ivankova
- National Center of Hemostasis and Thrombosis, Department of Hematology and Transfusion Medicine, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin University Hospital, 03659 Martin, Slovakia; (M.D.); (P.H.); (J.Z.); (L.V.); (I.S.); (J.I.); (P.K.); (J.S.)
| | - Tomas Bolek
- Department of Internal Medicine I., Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin University Hospital, 03659 Martin, Slovakia; (T.B.); (M.S.)
| | - Matej Samos
- Department of Internal Medicine I., Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin University Hospital, 03659 Martin, Slovakia; (T.B.); (M.S.)
| | - Marian Grendar
- Biomedical center Martin, Laboratory of Bioinformatics and Biostatistics, Comenius University in Bratislava, Jessenius Faculty of Medicine in Martin, 03601 Martin, Slovakia;
- Laboratory of Theoretical Methods, Institute of Measurement Science, Slovak Academy of Sciences, 84104 Karlova Ves, Slovakia
| | - Jan Danko
- Department of Gynecology and Obstetrics, Jessenius Faculty of Medicine in Martin and University Hospital in Martin, Comenius University in Bratislava, 03659 Martin, Slovakia;
| | - Peter Kubisz
- National Center of Hemostasis and Thrombosis, Department of Hematology and Transfusion Medicine, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin University Hospital, 03659 Martin, Slovakia; (M.D.); (P.H.); (J.Z.); (L.V.); (I.S.); (J.I.); (P.K.); (J.S.)
| | - Jan Stasko
- National Center of Hemostasis and Thrombosis, Department of Hematology and Transfusion Medicine, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin University Hospital, 03659 Martin, Slovakia; (M.D.); (P.H.); (J.Z.); (L.V.); (I.S.); (J.I.); (P.K.); (J.S.)
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Karuppiah A, Galey JL, Bharadwaj S, Elsamadicy EA, Kodali BS. Peripartum Management in Myelodysplastic Syndrome Guided by Serial Thromboelastography: A Case Report. A A Pract 2021; 15:e01403. [PMID: 33710973 DOI: 10.1213/xaa.0000000000001403] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
Myelodysplastic syndrome with severe thrombocytopenia is a rare disease in women of child-bearing age. The challenging aspect in management of such a patient is maintaining optimal coagulation with minimum platelet transfusion during the peripartum period. Multiple transfusions can result in allo-sensitization which can affect lifesaving bone marrow transplantation in future. Thromboelastography is a useful tool to assess and guide appropriate transfusion requirements.
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Affiliation(s)
| | | | | | - Emad A Elsamadicy
- Obstetrics, Gynecology and Reproductive Sciences, University of Maryland School of Medicine, Baltimore, Maryland
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Takeyama M, Furukawa S, Yada K, Ogiwara K, Shimonishi N, Nakajima Y, Mizumachi K, Noguchi-Sasaki M, Shima M, Nogami K. Ex Vivo Prediction of Comprehensive Coagulation Potential Using Simulated Blood Concentrations of Emicizumab in Patients with Acquired Hemophilia A. Thromb Haemost 2021; 121:1289-1298. [PMID: 33641138 DOI: 10.1055/s-0041-1725009] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
INTRODUCTION Emicizumab prophylaxis improves coagulation function in congenital hemophilia A, regardless of inhibitor presence. We recently reported that emicizumab enhanced the coagulant potentials, ex vivo, in plasmas from patients with acquired hemophilia A (PwAHAs) at diagnosis. However, coagulant effects of emicizumab in PwAHAs during the clinical course remain unclear. AIM To assess ex vivo coagulant effects of emicizumab in PwAHAs during the clinical course. METHODS/RESULTS Blood samples were obtained from 14 PwAHAs on (median) days 0 and 6 during a severe-bleeding phase, and days 27 and 59 during a reduced-bleeding phase with elevated endogenous factor VIII (FVIII) and decreased inhibitor titers. If administered a single dose of 3 or 6 mg/kg, or two doses at 6 mg/kg followed by 3 mg/kg, estimated plasma emicizumab concentrations (10/5/2.5, 20/10/5, and 30/15/7.5 µg/mL on days 0-7/30/60, respectively) could be used to represent potential changes, based on the half-life (T 1/2: ∼30 days). Emicizumab concentrations that covered maximum plasma concentrations of each dosage were used for spiking on day 0. Ex vivo addition of estimated emicizumab to PwAHA's plasma containing endogenous FVIII and/or inhibitor, without and with recombinant (r)FVIIa administration during immunosuppressive therapy, increased the calculated Ad|min1| values, assessed by clot waveform analysis, and their coagulant potentials were below normal levels. Rotational thromboelastometry revealed that ex vivo emicizumab addition resulted in the further improvement of coagulant potentials in whole bloods when combined with rFVIIa administration. CONCLUSION Based on ex vivo and in vitro data, emicizumab has the potential to be effective in clinical situations for PwAHAs.
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Affiliation(s)
- Masahiro Takeyama
- Department of Pediatrics, Nara Medical University, Kashihara, Nara, Japan
| | - Shoko Furukawa
- Department of Pediatrics, Nara Medical University, Kashihara, Nara, Japan.,The Course of Thrombosis and Hemostasis Molecular Pathology, Nara Medical University, Kashihara, Nara, Japan
| | - Koji Yada
- Department of Pediatrics, Nara Medical University, Kashihara, Nara, Japan.,The Course of Hemophilia Education, Nara Medical University, Kashihara, Nara, Japan
| | - Kenichi Ogiwara
- Department of Pediatrics, Nara Medical University, Kashihara, Nara, Japan
| | - Naruto Shimonishi
- Department of Pediatrics, Nara Medical University, Kashihara, Nara, Japan
| | - Yuto Nakajima
- Department of Pediatrics, Nara Medical University, Kashihara, Nara, Japan
| | | | | | - Midori Shima
- Department of Pediatrics, Nara Medical University, Kashihara, Nara, Japan
| | - Keiji Nogami
- Department of Pediatrics, Nara Medical University, Kashihara, Nara, Japan
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45
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Nakanishi N, Kaikita K, Ishii M, Kuyama N, Tabata N, Ito M, Yamanaga K, Fujisue K, Hoshiyama T, Kanazawa H, Hanatani S, Sueta D, Takashio S, Arima Y, Araki S, Usuku H, Nakamura T, Suzuki S, Yamamoto E, Soejimaa H, Matsushita K, Tsujita K. Hemodialysis-related low thrombogenicity measured by total thrombus-formation analysis system in patients undergoing percutaneous coronary intervention. Thromb Res 2021; 200:141-148. [PMID: 33610886 DOI: 10.1016/j.thromres.2021.02.004] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2020] [Revised: 01/26/2021] [Accepted: 02/02/2021] [Indexed: 12/14/2022]
Abstract
BACKGROUND Established antithrombotic therapies can increase bleeding risk, especially in hemodialysis (HD) patients. The Total Thrombus-formation Analysis System (T-TAS) is useful for evaluating thrombogenicity. The aim of this study was to examine the relationship between HD and thrombogenicity, or bleeding events in patients undergoing percutaneous coronary intervention (PCI). METHODS In this retrospective cohort study, 300 patients undergoing elective PCI were enrolled between April 2017 and March 2019. Blood samples obtained on the day of PCI were analyzed with T-TAS to compute the thrombus formation area under the curve (AUC; PL18-AUC10 for platelet chip; AR10-AUC30 for atheroma chip). The patients were divided into three groups according to estimated glomerular filtration rate (eGFR): 33 HD patients, 124 non-HD patients with eGFR <60 mL/min/1.73m2, and 143 non-HD patients with eGFR ≥60. We examined the thrombogenicity and spontaneous bleeding events within 1-year post-PCI. RESULTS HD was significantly associated with both low PL18-AUC10 and AR10-AUC30 levels determined by T-TAS. Bleeding events defined by the Bleeding Academic Research Consortium criteria types 2, 3, or 5 occurred during follow-up in 27 patients (9.0%): 7 in HD, 10 in non-HD with eGFR <60, and 10 in non-HD with eGFR ≥60. Both T-TAS parameters in the patients with bleeding were lower compared with those in the patients without bleeding, and HD was significantly associated with 1-year bleeding events. CONCLUSIONS The results suggested that HD patients undergoing PCI might be a predictor for low thrombogenicity measured by T-TAS and 1-year bleeding risk.
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Affiliation(s)
- Nobuhiro Nakanishi
- Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Koichi Kaikita
- Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
| | - Masanobu Ishii
- Department of Cardiovascular Medicine, Miyazaki Prefectural Nobeoka Hospital, Miyazaki, Japan
| | - Naoto Kuyama
- Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Noriaki Tabata
- Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Miwa Ito
- Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Kenshi Yamanaga
- Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Koichiro Fujisue
- Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Tadashi Hoshiyama
- Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Hisanori Kanazawa
- Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Shinsuke Hanatani
- Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Daisuke Sueta
- Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Seiji Takashio
- Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Yuichiro Arima
- Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Satoshi Araki
- Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Hiroki Usuku
- Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Taishi Nakamura
- Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Satoru Suzuki
- Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Eiichiro Yamamoto
- Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Hirofumi Soejimaa
- Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Kenichi Matsushita
- Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Kenichi Tsujita
- Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
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He S, Cao H, Thålin C, Svensson J, Blombäck M, Wallén H. The Clotting Trigger Is an Important Determinant for the Coagulation Pathway In Vivo or In Vitro-Inference from Data Review. Semin Thromb Hemost 2020; 47:63-73. [PMID: 33348413 DOI: 10.1055/s-0040-1718888] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Abstract
Blood coagulation comprises a series of enzymatic reactions leading to thrombin generation and fibrin formation. This process is commonly illustrated in a waterfall-like manner, referred to as the coagulation cascade. In vivo, this "cascade" is initiated through the tissue factor (TF) pathway, once subendothelial TF is exposed and bound to coagulation factor VII (FVII) in blood. In vitro, a diminutive concentration of recombinant TF (rTF) is used as a clotting trigger in various global hemostasis assays such as the calibrated automated thrombogram, methods that assess fibrin turbidity and fibrin viscoelasticity tests such as rotational thromboelastometry. These assays aim to mimic in vivo global coagulation, and are useful in assessing hyper-/hypocoagulable disorders or monitoring therapies with hemostatic agents. An excess of rTF, a sufficient amount of negatively charged surfaces, various concentrations of exogenous thrombin, recombinant activated FVII, or recombinant activated FIXa are also used to initiate activation of specific sub-processes of the coagulation cascade in vitro. These approaches offer important information on certain specific coagulation pathways, while alterations in pro-/anticoagulants not participating in these pathways remain undetectable by these methods. Reviewing available data, we sought to enhance our knowledge of how choice of clotting trigger affects the outcome of hemostasis assays, and address the call for further investigations on this topic.
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Affiliation(s)
- Shu He
- Department of Clinical Sciences, Karolinska Institutet, Danderyd Hospital, Stockholm, Sweden.,Division of Coagulation Research, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
| | - Honglie Cao
- Division of Coagulation Research, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
| | - Charlotte Thålin
- Department of Clinical Sciences, Karolinska Institutet, Danderyd Hospital, Stockholm, Sweden
| | - Jan Svensson
- Department of Clinical Sciences, Karolinska Institutet, Danderyd Hospital, Stockholm, Sweden
| | - Margareta Blombäck
- Department of Clinical Sciences, Karolinska Institutet, Danderyd Hospital, Stockholm, Sweden.,Division of Coagulation Research, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
| | - Håkan Wallén
- Department of Clinical Sciences, Karolinska Institutet, Danderyd Hospital, Stockholm, Sweden
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Fan K, McArthur J, Morrison RR, Ghafoor S. Diffuse Alveolar Hemorrhage After Pediatric Hematopoietic Stem Cell Transplantation. Front Oncol 2020; 10:1757. [PMID: 33014865 PMCID: PMC7509147 DOI: 10.3389/fonc.2020.01757] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2020] [Accepted: 08/05/2020] [Indexed: 12/21/2022] Open
Abstract
Pulmonary complications are common following hematopoietic cell transplantation (HCT) and contribute significantly to its morbidity and mortality. Diffuse alveolar hemorrhage is a devastating non-infectious complication that occurs in up to 5% of patients post-HCT. Historically, it carries a high mortality burden of 60–100%. The etiology remains ill-defined but is thought to be due to lung injury from conditioning regimens, total body irradiation, occult infections, and other comorbidities such as graft vs. host disease, thrombotic microangiopathy, and subsequent cytokine release and inflammation. Clinically, patients present with hypoxemia, dyspnea, and diffuse opacities consistent with an alveolar disease process on chest radiography. Diagnosis is most commonly confirmed with bronchoscopy findings of progressively bloodier bronchoalveolar lavage or the presence of hemosiderin-laden macrophages on microscopy. Treatment with glucocorticoids is common though dosing and duration of therapy remains variable. Other agents, such as aminocaproic acid, tranexamic acid, and activated recombinant factor VIIa have also been tried with mixed results. We present a review of diffuse alveolar hemorrhage with a focus on its pathogenesis and treatment options.
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Affiliation(s)
- Kimberly Fan
- Division of Pediatric Critical Care, University of Tennessee Health Science Center, Memphis, TN, United States
| | - Jennifer McArthur
- Division of Critical Care, St. Jude Children's Research Center, Memphis, TN, United States
| | - R Ray Morrison
- Division of Critical Care, St. Jude Children's Research Center, Memphis, TN, United States
| | - Saad Ghafoor
- Division of Critical Care, St. Jude Children's Research Center, Memphis, TN, United States
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Kwak J, Mazzeffi M, Boggio LN, Simpson ML, Tanaka KA. Hemophilia: A Review of Perioperative Management for Cardiac Surgery. J Cardiothorac Vasc Anesth 2020; 36:246-257. [DOI: 10.1053/j.jvca.2020.09.118] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2020] [Revised: 09/16/2020] [Accepted: 09/18/2020] [Indexed: 02/08/2023]
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49
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Wakui M, Fujimori Y, Nakamura S, Oka S, Ozaki Y, Kondo Y, Nakagawa T, Katagiri H, Murata M. Characterisation of antithrombin-dependent anticoagulants through clot waveform analysis to potentially distinguish them from antithrombin-independent inhibitors targeting activated coagulation factors. J Clin Pathol 2020; 74:251-256. [PMID: 32796051 DOI: 10.1136/jclinpath-2020-206835] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2020] [Revised: 06/26/2020] [Accepted: 06/30/2020] [Indexed: 11/04/2022]
Abstract
AIMS While antithrombin (AT)-independent inhibitors targeting thrombin or activated factor X have been assessed through clot waveform (CWA), there are no reports on assessment with respect to AT-dependent anticoagulants. The present study aims to characterise AT-dependent anticoagulants through CWA to distinguish them from AT-independent inhibitors. METHODS CWA was applied to the activated partial thromboplastin time (APTT) assay of plasma samples spiked with each of AT-dependent drugs (unfractionated heparin, enoxaparin and fondaparinux) and AT-independent drugs (rivaroxaban, apixaban, edoxaban, dabigatran, argatroban, hirudin and bivalirudin), which was performed using the CS-5100 or CN-6000 (Sysmex). The APTT-CWA data were automatically gained by the analyser program. The positive mode of clotting reaction curves was defined as the direction towards fibrin generation. RESULTS Regarding dose-response curves in AT-dependent anticoagulants, the maximum positive values of the first and secondary derivatives (Max1 and Maxp2, respectively) and the maximum negative values of the secondary derivative (Maxn2) seemed to drop to zero without making an asymptotic line, consistent with the irreversibility. Such a feature was observed also in hirudin, as reported previously. Notably, the symmetric property of Max1 peaks in the waveforms was distorted dose dependently in AT independent but not AT-dependent drugs. A plot of Maxp2 logarithm versus Maxn2 logarithm was linear. The slope was about 1 in AT-dependent drugs while that was more than 1 in AT-independent drugs. These features made it possible to distinguish AT-dependent and AT-independent drugs. CONCLUSIONS The results aid in further understanding of the pharmacological aspects of anticoagulation and in screening of candidates for novel anticoagulants.
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Affiliation(s)
- Masatoshi Wakui
- Department of Laboratory Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Yuta Fujimori
- Office of Clinical Laboratory Technology, Keio University Hospital, Tokyo, Japan
| | - Shoko Nakamura
- Clinical Laboratory, Keio University Hospital, Tokyo, Japan
| | - Shusaku Oka
- Clinical Laboratory, Keio University Hospital, Tokyo, Japan
| | - Yuko Ozaki
- Clinical Laboratory, Keio University Hospital, Tokyo, Japan
| | - Yoshino Kondo
- Clinical Laboratory, Keio University Hospital, Tokyo, Japan
| | | | | | - Mitsuru Murata
- Department of Laboratory Medicine, Keio University School of Medicine, Tokyo, Japan
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Erdoes G, Koster A, Ortmann E, Meesters MI, Bolliger D, Baryshnikova E, Martinez Lopez De Arroyabe B, Ahmed A, Lance MD, Ranucci M, von Heymann C, Agarwal S, Ravn HB. A European consensus statement on the use of four-factor prothrombin complex concentrate for cardiac and non-cardiac surgical patients. Anaesthesia 2020; 76:381-392. [PMID: 32681570 DOI: 10.1111/anae.15181] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/12/2020] [Indexed: 02/06/2023]
Abstract
Modern four-factor prothrombin complex concentrate was designed originally for rapid targeted replacement of the coagulation factors II, VII, IX and X. Dosing strategies for the approved indication of vitamin K antagonist-related bleeding vary greatly. They include INR and bodyweight-related protocols as well as fixed dose regimens. Particularly in the massively bleeding trauma and cardiac surgery patient, four-factor prothrombin complex concentrate is used increasingly for haemostatic resuscitation. Members of the Transfusion and Haemostasis Subcommittee of the European Association of Cardiothoracic Anaesthesiology performed a systematic literature review on four-factor prothrombin complex concentrate. The available evidence has been summarised for dosing, efficacy, drug safety and monitoring strategies in different scenarios. Whereas there is evidence for the efficacy of four-factor prothrombin concentrate for a variety of bleeding scenarios, convincing safety data are clearly missing. In the massively bleeding patient with coagulopathy, our group recommends the administration of an initial bolus of 25 IU.kg-1 . This applies for: the acute reversal of vitamin K antagonist therapy; haemostatic resuscitation, particularly in trauma; and the reversal of direct oral anticoagulants when no specific antidote is available. In patients with a high risk for thromboembolic complications, e.g. cardiac surgery, the administration of an initial half-dose bolus (12.5 IU.kg-1 ) should be considered. A second bolus may be indicated if coagulopathy and microvascular bleeding persists and other reasons for bleeding are largely ruled out. Tissue-factor-activated, factor VII-dependent and heparin insensitive point-of-care tests may be used for peri-operative monitoring and guiding of prothrombin complex concentrate therapy.
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Affiliation(s)
- G Erdoes
- Department of Anaesthesiology and Pain Medicine, Inselspital, Bern University Hospital, University of Bern, Switzerland
| | - A Koster
- Institute for Anaesthesiology, Heart and Diabetes Centre NRW, Ruhr-University Bochum, Bad Oeynhausen, Germany
| | - E Ortmann
- Department of Anaesthesia, Kerckhoff Heart and Lung Centre, Bad Nauheim, Germany
| | - M I Meesters
- Department of Anaesthesiology, University Medical Centre Utrecht, The Netherlands
| | - D Bolliger
- Department of Anaesthesia, Prehospital Emergency Medicine, and Pain Therapy, University Hospital Basel, Switzerland
| | - E Baryshnikova
- Department of Cardiovascular Anaesthesia and Intensive Care Unit, IRCCS Policlinico San Donato, San Donato Milanese, Milan, Italy
| | | | - A Ahmed
- Department of Anaesthesia, University Hospitals of Leicester NHS Trust, UK.,Department of Cardiovascular Sciences, University of Leicester, UK
| | - M D Lance
- Hamad Medical Corporation, HMC, Anaesthesiology, ICU and Peri-operative Medicine, Doha, Qatar
| | - M Ranucci
- Department of Cardiovascular Anaesthesia and Intensive Care Unit, IRCCS Policlinico San Donato, San Donato Milanese, Milan, Italy
| | - C von Heymann
- Department of Anaesthesia, Intensive Care Medicine, Emergency Medicine and Pain Therapy, Vivantes Klinikum im Friedrichshain, Berlin, Germany
| | - S Agarwal
- Department of Anaesthesia, Manchester University Hospitals, Manchester, UK
| | - H B Ravn
- Department of Cardiothoracic Anaesthesiology, Rigshospitalet, Copenhagen University, Copenhagen, Denmark
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