Platelet factor 4 (PF4) is a natural chemokine that binds to negatively charged glycosaminoglycans (GAGs), including the anticoagulant heparin. The formation of the PF4-heparin complex elicits an immune response that results in platelet activation, leading to serious thrombotic complications. This study explores the structure-activity relationships (SAR) of sulfated pseudo-tetrasaccharide aminoglycoside ligands. The binding interactions of these synthetically designed compounds with heparanase (HPSE) and PF4 were systematically elucidated. Through computational design, a library of sulfated aminoglycoside ligands was synthesized in 10-13 steps from readily available paromomycin and neomycin. The SAR studies revealed that hydroxyl-capped ligands interacted with the fondaparinux-binding domain of PF4, while hydrophobic-capped ligands bound to the heparin-binding domain. Notably, steric hindrance imposed by hydrophobic groups impedes the binding of the ligands to PF4's shallow binding site. In contrast, these hydrophobic-capped ligands demonstrated a strong binding affinity for HPSE. The most selective ligands reduced the viability of HPSE-overexpressing cancer cells, highlighting their potential efficacy in modulating the enzymatic activity of HPSE. This SAR study provides a foundational framework for the design of sulfated aminoglycoside-based therapeutics with minimized adverse effects associated with PF4.

In addition to erythematous plaques, nodules, ulcerations, and necrosis, retiform purpura and livedo racemosa are indications of occlusive cutaneous vasculopathies. In contrast to cutaneous vasculitis, occlusive cutaneous vasculopathies primarily lead to vascular occlusion of the skin and only secondarily to signs of vascular inflammation. The lower legs are typically affected, but especially in the presence of acral skin changes, occlusive cutaneous vasculopathies should also be considered. Various stimuli can trigger occlusive cutaneous vasculopathies, including systemic or vascular coagulopathies, emboli, platelet or erythrocyte aggregates, cold-dependent gelling and agglutination of immunoglobulins, or, less commonly, medications.

Platelet glycoprotein IIB/IIIA antagonists are potent inhibitors of platelet aggregation. Although the incidence of thrombocytopenia following their administration is relatively low, it can sometimes lead to fatal consequences. We report a case of a 57-year-old gentleman presenting with non-ST elevation myocardial infarction complicated with tirofiban-induced profound thrombocytopenia that developed within 12 hours of administration. Given the high risk of acute-onset thrombocytopenia following treatment with glycoprotein IIb/IIIa inhibitors, platelet count monitoring is highly encouraged at frequent intervals. This case highlights the importance of early detection and treatment of thrombocytopenia.

Particles are essential building blocks in nanomedicine and cell engineering. Their administration often involves blood contact, which demands a hemocompatible material profile. Coating particles with isolated cell membranes is a common strategy to improve hemocompatibility, but this solution is nonscalable and potentially immunogenic. Cell membrane-like lipid coatings are a promising alternative, as lipids can be synthesized on a large scale and used to create safe cell membrane-like supported bilayers. However, a method to controllably and scalably lipid-coat a wide range of particles has remained elusive. Here, an on-particle solvent-assisted lipid coating (OPSALC) method is introduced as an innovative technique to endow various types of particles with cell membrane-like coatings. Coating formation efficiency is shown to depend on lipid concentration, buffer addition rate, and solvent:buffer ratio, as these parameters determine lipid assembly and lipid-surface interactions. Four lipid formulations with various levels of erythrocyte membrane mimicry are explored in terms of hemocompatibility, demonstrating a reduced particle-induced hemolysis and plasma coagulation time. Interestingly, formulations with higher mimicry levels show the lowest levels of complement activation and highest colloidal stability. Overall, OPSALC represents a simple yet scalable strategy to endow particles with cell membrane-like lipid coatings to facilitate blood-contact applications.

Despite the widespread use of heparin during and following endovascular procedures in the management of aneurysmal subarachnoid hemorrhage (SAH) patients, limited research has explored the incidence and impact of heparin-induced thrombocytopenia (HIT) on SAH.

Descriptive statistics, multivariate regressions, and propensity score-matching were employed to compare clinical characteristics, comorbidities, interventions, complications, and outcomes of HIT in SAH patients identified within the US National Inpatient Sample database from 2010 to 2019.

Among 76 387 SAH patients from 2010 to 2019, 166 (0.22%) developed HIT. HIT was identified as a significant predictor of prolonged length of stay (OR 6.799, 95% CI 3.985 to 11.6, P<0.01) and poor functional outcomes (OR 2.541, 95% CI 1.628 to 3.966, P<0.01) after adjusting for relevant factors. HIT incidence was higher in patients with elevated SAH severity scores (1.42 vs 1.06, P<0.01), younger patients (58.04 vs 61.39 years, P=0.01), overweight individuals (0.4% vs 0.2%, P<0.01), those on long-term anticoagulants (10.84% vs 5.72%, P<0.01), or with a cerebrospinal fluid drainage device (external ventricular drain, ventriculoperitoneal shunt; P<0.01). HIT patients showed increased rates of endovascular coiling, ventricular drain placement, shunt placement, deep vein thrombosis, urinary tract infection, acute kidney injury, pulmonary embolism, venous sinus thrombosis, pneumonia, and cerebral vasospasm (all P<0.01).

SAH patients with HIT exhibited various comorbidities and increased rates of complications, which may contribute to extended hospital stays. This nationwide study aids clinical suspicion and highlights HIT's impact on SAH patients.

Alzheimer's disease (AD) is the most common form of dementia, marked by progressive brain degeneration and cognitive decline. A major pathological feature of AD is the accumulation of hyperphosphorylated tau (p-tau) in the form of neurofibrillary tangles (NFTs), which leads to neuronal death and neurodegeneration. P-tau also induces endoplasmic reticulum (ER) stress and activates the unfolded protein response, causing inflammation and apoptosis. Additionally, p-tau spreads in the brain through interactions with heparan sulfate (HS) proteoglycans, promoting aggregation and internalization. Targeting the tau-HS interaction offers a potential therapeutic strategy for AD. We present a novel HS mimetic with a lipophilic oleanolic acid linker and a sulfated trisaccharide, which shows strong cytoprotective effects against p-tau. Moreover, this compound alleviates p-tau-induced ER stress and inflammation. Molecular docking studies indicate that the conjugation of oleanolic acid enhances binding between the ligand and tau protofilament cores, facilitating protective interactions. These findings provide a foundation for the development of novel HS mimetics, enabling further investigation of tau-HS interactions in AD and other tauopathies.

Thrombocytopenia frequently occurs in patients before, during, and after admission to Pediatric Intensive Care Units (PICUs). In critically ill children, it is often due to multifactorial causes and can be a sign of significant organ dysfunction. This review summarizes the potential causes/mechanisms of thrombocytopenia in acutely ill children, their identification, and treatments, with special attention paid to septic patients. The mechanisms of thrombocytopenia include decreased production and sequestration, but the most common reason is increased destruction or consumption. This review specifically reviews and compares the presentation, pathogenesis, and treatment of disseminated intravascular coagulation (DIC) and the thrombotic microangiopathic spectrum (TMA), including thrombocytopenia-associated multiorgan failure (TAMOF), hemolytic uremic syndrome, and other diagnoses. The other etiologies discussed include HLH/MAS, immune thrombocytopenia, and dilutional thrombocytopenia. Finally, this review analyzes platelet transfusions, the various thresholds, and complications.

Heparins are sulfated polysaccharides with a heterogeneous mixture derived from animal tissues, subject to supply limitations and the risk of animal virus residues. Patients using heparin also face the risks of spontaneous bleeding and thrombocytopenia. Here we reported an efficient riclinoctaose-based approach for rapid chemical synthesis of a structurally defined heparin-like anticoagulant sulfated octasaccharide (SRO). We used sulfur trioxide-pyridine, sulfur trioxide-trimethylamine, and sulfur trioxide-triethylamine complexes as solvents for one-pot O-sulfation and determined the optimal conditions for synthesizing SRO. Sulfur trioxide-trimethylamine provided reasonable control over the degree of substitution between 1.85 and 1.88, revealing a single molecule with a theoretical molecular weight of 2952.96 g/mol. The structural features of the SRO were carried out by Fourier transform infrared spectroscopy and one- and two- dimensional 1H and 13C NMR analysis, revealing sulfation repeatedly present at the fixed positions of C-6/C-2/C-3 and reducing terminals. The anticoagulant activity of SRO was demonstrated by efficiently blocking coagulation in the blood of mice and human. SRO dose-dependently decreased ferric chloride-induced experimental thrombosis in mice. Like heparin, SRO specifically inhibits coagulation factor Xa, but significantly reduces the risk of bleeding compared to heparin. Therefore, we named it octaparin. These results support that octaparin is expected to replace animal-sourced heparin.

Myocardial infarction (MI) is a significant cardiovascular event caused by the decrease in or complete cessation of blood flow to a portion of the myocardium. It can arise from a variety of etiological factors, including pharmacological triggers. This review aims to explore the diverse drugs and substances that might lead to drug-induced myocardial infarction, focusing on their mechanisms of action and the pathophysiological processes involved. Various established and emerging pharmacological agents that could elevate the risk of myocardial infarction, such as nonsteroidal anti-inflammatory drugs, hormonal therapies, anticoagulants, and antipsychotic medications, are discussed. The role of drug-induced endothelial dysfunction, coronary artery spasm, and thrombosis are presented in order to highlight the underlying mechanisms. This review emphasizes the need for increased awareness among healthcare professionals to mitigate the risks associated with different pharmacological therapies to improve patient outcomes.

Background: Although the risk of serious bleeding following peritoneal dialysis catheter insertion is low, pericannular bleeding can increase the risk of catheter-related infections and reduce catheter survival. We aimed to analyze the risk factors for bleeding complications during peritoneal dialysis catheter insertion and assess whether temporary preemptive hemodialysis before catheterization can reduce bleeding and improve catheter survival. Methods: We retrospectively analyzed bleeding complications and catheter survival in patients who underwent temporary hemodialysis prior to peritoneal dialysis catheter insertion. Cox regression analysis was performed to determine the risk factors for bleeding complications and catheter survival. Results: Among 336 patients, 216 and 120 comprised the non-hemodialysis and hemodialysis groups, respectively. No significant association was found between temporary hemodialysis and bleeding (hazard ratio: 1.6, 95% confidence interval: 0.87-2.95, p < 0.134). Multivariate analysis revealed an inverse association of platelet count (hazard ratio: 0.99, 95% confidence interval: 0.99-0.99, p < 0.048) and hemoglobin level (hazard ratio: 0.78, 95% confidence interval: 0.61-0.99, p < 0.04) with bleeding. A positive association was observed between international normalized ratio (hazard ratio: 2.24, 95% confidence interval: 1.19-4.19, p < 0.012) and bleeding. Conversely, temporary hemodialysis was not associated with catheter survival (hazard ratio: 1.64, 95% confidence interval: 0.63-4.25, p < 0.308). Conclusions: Temporary hemodialysis before peritoneal dialysis catheter insertion did not significantly affect bleeding risk in patients with a high risk of uremic bleeding.

Heparin-induced thrombocytopenia (HIT) is clinically the most relevant non-hemorrhagic complication of heparin, which is associated with the increased risk of thrombosis and mortality. This study was conducted to determine platelet activation in HIT-II in hospitalized patients with surgery or deep vein thrombosis (DVT). The clinical outcomes of the patients was also assayed.

In this descriptive/cross-sectional study, 754 heparin-receiving-hospitalized patients with surgery or DVT were evaluated for the incidence of thrombocytopenia 7 days after heparin therapy. Clinical assessment 4Ts and ELISA for heparin-platelet factor 4 (HPF4) antibodies were performed to diagnose HIT-II. Production of platelet microparticles (PMPs), soluble P-selectin (sP-selectin), IL-1, IL-6, and tumor necrosing factor-α (TNF-α) were evaluated in the HIT suspected patients.

The frequency of HIT-II was 4.50%. More HIT-II was diagnosed in the elder patients (P = 0.008) and female (P = 0.005). Thrombosis rate was higher in the HIT-II (P = 0.0001). More PMPs, sP-selectin, IL-1, IL-6, and TNF-α was detected in the HIT-II patients. The length of hospital stay was significantly different in HIT-II (P = 0.015). Mortality rate of the HIT-II patients was higher than non-HIT ones (P = 0.0007).

Platelet activation in the HIT-II patients mediated more thrombosis formation. It was associated with the increased length of hospital stay and mortality.

Endothelium, the lining in this blood vessel, orchestrates three main critical functions such as protecting blood components, modulating of hemostasis by secreting various inhibitors, and directing clot digestion (fibrinolysis) by activating tissue plasminogen activator. No other surface can perform these tasks; thus, the contact of blood and blood-contacting medical devices inevitably leads to the activation of coagulation, often causing device failure, and thromboembolic complications. This perspective, first, discusses the biological mechanisms of activation of coagulation and highlights the efforts of advanced coatings to recapitulate one characteristic of endothelium, hereafter single functions of endothelium and noting necessity of the synergistic integration of its three main functions. Subsequently, it is emphasized that to overcome the challenges of blood compatibility an endothelium-mimicking system is needed, proposing a synergy of bottom-up synthetic biology, particularly synthetic cells, with passive- and bioactive surface coatings. Such integration holds promise for developing advanced biomaterials capable of recapitulating endothelial functions, thereby enhancing the hemocompatibility and performance of blood-contacting medical devices.

Heparin-induced thrombocytopenia is the most clinically relevant non-hemorrhagic complication of heparin and is characterized by the presence of anti-platelet factor 4 (PF4)/heparinimmunoglobulin G (IgG) antibodies. The circulating PF4/heparinIgG immune complex binds to platelets via their FcyIIa receptors, activating them and promoting their aggregation, with consequent platelet consumption, thrombocytopenia, and thrombotic phenomena. Despite thrombocytopenia, this condition is not typically associated with bleeding complications. Instead, thrombosis is the most serious complication of heparin-induced thrombocytopenia, contributing to increased morbidity and mortality. Thrombotic events can be venous and arterial, such as deep vein thrombosis, pulmonary embolism, myocardial infarction, and thrombotic stroke. Skin necrosis at the site of heparin injections is a rare but well-described manifestation of heparin-induced thrombocytopenia. We report a case of heparin-induced thrombocytopenia presented as skin necrosis, highlighting the importance of recognizing this potentially fatal condition and the need for an immediate cessation of all sources of heparin and its replacement by other anticoagulants.

Vascular graft thrombosis is a long-standing clinical problem. A myriad of efforts have been devoted to reducing thrombus formation following bypass surgery. Researchers have primarily taken a chemical approach to engineer and modify surfaces, seeking to make them more suitable for blood contacting applications. Using mechanical forces and surface topology to prevent thrombus formation has recently gained more attention. In this study, we have designed a bilayered porous vascular graft capable of repelling platelets and destabilizing absorbed protein layers from the luminal surface. During systole, fluid penetrates through the graft wall and is subsequently ejected from the wall into the luminal space (Luminal Reversal Flow - LRF), pushing platelets away from the surface during diastole. In-vitro hemocompatibility tests were conducted to compare platelet deposition in high LRF grafts with low LRF grafts. Graft material properties were determined and utilized in a porohyperelastic (PHE) finite element model to computationally predict the LRF generation in each graft type. Hemocompatibility testing showed significantly lower platelet deposition values in high versus low LRF generating grafts (median±IQR = 5,708 ± 987 and 23,039 ± 3,310 platelets per mm2, respectively, p=0.032). SEM imaging of the luminal surface of both graft types confirmed the quantitative blood test results. The computational simulations of high and low LRF generating grafts resulted in LRF values of -10.06 μm/s and -2.87 μm/s, respectively. These analyses show that a 250% increase in LRF is associated with a 75.2% decrease in platelet deposition. PHE vascular grafts with high LRF have the potential to improve anti-thrombogenicity and reduce thrombus-related post-procedure complications. Additional research is required to overcome the limitations of current graft fabrication technologies that further enhance LRF generation.

Laboratories face the challenge of providing quality patient care while managing costs and turnaround times (TATs). To this end, we brought the heparin-induced thrombocytopenia (HIT) antibody test in-house with the goal of reducing costs and the time to diagnosis.

To determine the cost-effectiveness and return on investment of our in-house HIT antibody test by comparing it to send-out assays with TATs of 2, 3, or 4 days.

We performed a retrospective chart review of all patients with a HIT antibody assay and analysis of laboratory financial records. Analysis included the percentage of patients receiving alternative treatment, cost of treatment, startup costs of bringing the test in-house, and average TAT of the in-house test.

We found significant reductions in the cost of treatment for patients and the overall cost to the health care system. The in-house assay became cost-effective at between 8 and 20 tests, with a return on investment of up to 298%.

Bringing the HIT antibody assay in-house becomes cost-effective at a very low test volume with excellent return on investment. This novel analysis can provide a framework for other laboratory medicine professionals to analyze the benefits of bringing this and other assays in-house.

Unfractionated heparin is a widely used anticoagulant in critically ill patients. It has a well-established safety profile and remains an attractive option for clinicians due to its short half-life and reversibility. Heparin has a unique pharmacokinetic profile, which contributes to significant inter-patient and intra-patient variability in effect. The variability in anticoagulant effect combined with heparin's short half-life mean close monitoring is required for clinical efficacy and preventing adverse effects. To optimize heparin use in critically ill patients, effective monitoring assays and dose adjustment strategies are needed.

This paper explores the use of heparin as an anticoagulant and optimal approaches to monitoring in critically ill patients.

Conventional monitoring assays for heparin dosing have significant limitations. Emerging data appear to favor using anti-Xa assay monitoring for heparin anticoagulation, which many centers have successfully adopted as the standard. The anti-Xa assay appears have important benefits relative to the aPTT for heparin monitoring in critically ill patients, and should be considered for broader use.

Heparin, being a widely employed anticoagulant in numerus clinical complications, requires strict quantification and qualitative screening to ensure the safety of patients from potential threat of thrombocytopenia. However, the intricacy of heparin's chemical structures and low abundance hinders the precise monitoring of its level and quality in clinical settings. Conventional laboratory assays have limitations in sensitivity and specificity, necessitating the development of innovative approaches. In this context, nanosensors emerged as a promising solution due to enhanced sensitivity, selectivity, and ability to detect heparin even at low concentrations. This review delves into a range of sensing approaches including colorimetric, fluorometric, surface-enhanced Raman spectroscopy, and electrochemical techniques using different types of nanomaterials, thus providing insights of its principles, capabilities, and limitations. Moreover, integration of smart-phone with nanosensors for point of care diagnostics has also been explored. Additionally, recent advances in nanopore technologies, artificial intelligence (AI) and machine learning (ML) have been discussed offering specificity against contaminants present in heparin to ensure its quality. By consolidating current knowledge and highlighting the potential of nanosensors, this review aims to contribute to the advancement of efficient, reliable, and economical heparin detection methods providing improved patient care.

The extensive use of therapeutic doses of heparin to prevent thrombosis in critically ill patients with COVID-19 during the pandemic has led to an increased incidence of bleeding and heparin-induced thrombocytopenia (HIT). In addition, the introduction of the AstraZeneca and Johnson&Johnson vaccines against COVID-19 into clinical practice was associated with the development of a rare but very severe, adverse thrombotic complication, vaccine-induced immune thrombotic thrombocytopenia (VITT). Thrombotic complications of VITT turned out to be similar to HIT both clinically and pathophysiologically. HIT is a potentially fatal immune-mediated adverse drug response that results in emergence of antibodies that activate platelets in the presence of heparin. HIT is characterized by a high incidence of venous and arterial thromboses, often with fatal outcomes. Currently, there are clearly defined international guidelines for the diagnosis, treatment and prevention of HIT. In case of thrombotic complications, non-heparin anticoagulants should be used.

Kidney replacement therapies (KRTs) including hemodialysis (HD) are one of the treatment options for most of the patients with end-stage kidney disease. Although HD is vital for these patients, it is not hundred percent physiological, and various adverse events including hypersensitivity reactions may occur. Fortunately, these reactions are rare in total and less when compared to previous decades, but it is still very important for at least two reasons: First, the number of patients receiving kidney replacement treatment is increasing globally; and the cumulative number of these reactions may be substantial. Second, although most of these reactions are mild, some of them may be very severe and even lead to mortality. Thus, it is very important to have basic knowledge and skills to diagnose and treat these reactions. Hypersensitivity reactions can occur at any component of dialysis machinery (access, extracorporeal circuit, medications, etc.). The most important preventive measure is to avoid the allergen. However, even with very specific test, sometimes the allergen cannot be found. In mild conditions, HD can be contained with non-specific treatment (topical creams, antihistaminics, corticosteroids). In more severe conditions, treatment must be stopped immediately, blood should not be returned to patient, drugs must be stopped, and rules of general emergency treatment must be followed.

To describe the intraoperative use of bivalirudin during lower extremity revascularization in the setting of heparin-induced thrombocytopenia (HIT).

A 65 year-old man presented with left common iliac, external iliac, and femoral artery occlusion necessitating revascularization with left femoral endarterectomy and common and external iliac stent angioplasty. Three months before the femoral endarterectomy, the patient was hospitalized for a coronary artery bypass procedure. During this admission, the patient tested positive for the presence of heparin-PF4 antibody complexes. With the patient's recent history of HIT, bivalirudin was selected as the optimal agent for intraoperative anticoagulation. Bivalirudin was administered as a 50 mg bolus, followed by a continuous infusion initiated at 1.75 mg/kg/hr. Repeated bivalirudin boluses were necessary to maintain an activated clotting time (ACT) necessary for the revascularization procedures and recurrent subacute thrombi despite appropriate ACT values.

Bivalirudin has been utilized for cardiopulmonary bypass and carotid endarterectomy (CEA), but data for dosing in lower extremity revascularization are lacking. As the risk for thrombosis with HIT continues for months after diagnosis, it is important to elucidate optimal dosing of non-heparin anticoagulant options, such as the direct thrombin inhibitor, bivalirudin. The absence of validated dosing strategies for bivalirudin can result in prolonged operative times, increased risk of bleeding, and inadequate anticoagulation.

Bivalirudin is an appropriate agent for intraoperative anticoagulation in lower extremity revascularization. However, further investigation into the optimal intraoperative bivalirudin dosing regimen is necessary.

Heparin-induced thrombocytopenia (HIT) is a rare and life-threatening autoimmune-mediated adverse drug reaction seen in patients who are exposed to various forms of pharmacological heparin, including unfractionated heparin (UFH) and low molecular weight heparin (LMWH). Despite the presence of thrombocytopenia, these patients face the risk of clot formation and bleeding simultaneously. Prompt cessation of heparin and the initiation of non-heparin anticoagulants are important for the patient's survival. Typically, clinical diagnosis of HIT is necessary, and waiting for lab test results, which can take days, may not be always feasible. Here, we present a case of an unusual presentation of type II HIT, complicated by significant thrombocytopenia, pulmonary hemorrhage, and cardiac arrest after receiving intravenous (IV) heparin bolus during an elective cardiac ablation procedure for paroxysmal atrial fibrillation.

For more than 60 years, anticoagulation drugs have served as a mainstay in preserving and improving the cardiovascular health of patients across the globe. Functioning to reduce a patient's ability to produce blood clots, prescription rates for anticoagulants have been steadily rising year-over-year both in the United States and abroad. Despite decades of clinical usage, modern-day anticoagulants have been shown to predispose an individual to pathological bleeding. Even in seemingly benign instances of bleeding, patients on anticoagulation therapy might require intensive and expensive medical procedures or monitoring. Understanding the clinical implications of pathological bleeding, research and development of future anticoagulants seeking to minimize these effects. One emerging category of anticoagulant drugs are Factor XI/XIa (FXI) inhibitors. Targeting the coagulation cascade, clinical trials of Factor XIa inhibitors have shown promising results in preventing blood clot formation without increasing the instances of spontaneous and/or pathological bleeding events. While still in phase II and III clinical trials, and potentially years away from being implemented as standard of care, these novel drugs might have the potential to improve the safety and quality of life of patients taking anticoagulants. In this review, we discuss a brief history of anticoagulation therapy, followed by an analysis of the potential risks, benefits, and implications of Factor XI/XIa inhibitors across elements of patient care.

Cholesterol embolization syndrome is an increasing but underestimated problem after endovascular intervention or after the start of thrombolytic therapies. Embolies from the aortic wall involves abdominal organs and the skin of the lower extremities or buttocks. In our case a progressive ulceration and necroses occurs spontaneously. Endovascular treatment of the lower extremities was successful for a short period. Due to the progression of necrosis, both legs were amputated. Biopsies were taken from the skin were initially no directions to the diagnosis of Cholesterol embolization syndrome. After a second elliptical excision biopsy the diagnosis of cholesterol embolization syndrome was confirmed. Because the rapid progression of skin necroses despite the treatment of prednisone, patient died due to sepsis and renal failure. This case shows when arterial revascularization is performed and progression in skin necrosis occurs despite optimal arterial vascular status the diagnosis CES should be considered and treated in an early state of disease.

Heparin is the most common anticoagulant used in clinical practice but shows some downsides such as short half-life (for the high molecular weight heparin) and secondary effects. On the other hand, its low molecular weight analogue cannot be neutralized with protamine, and therefore cannot be used in some treatments. To address these issues, we conjugated polyethylene glycol (PEG) to heparin reducing end (end-on) via oxime ligation and studied the interactions of the conjugate (Hep-b-PEG) with antithrombin III (AT) and protamine. Isothermal titration calorimetry showed that Hep-b-PEG maintains the affinity to AT. Dynamic light scattering demonstrated that the Hep-b-PEG formed colloidal stable nanocomplexes with protamine instead of large multi-molecular aggregates, associated with heparin side effects. The in vitro (human plasma) and in vivo experiments (Sprague Dawley rats) evidenced an extended half-life and higher anticoagulant activity of the conjugate when compared to unmodified heparin.

Heparin-induced thrombocytopenia (HIT) is a life-threatening, immune-mediated complication following heparin exposure and is considered to be the most severe adverse reaction to heparin treatment that is not associated with bleeding. Development of autoantibodies against platelet factor 4 (PF4) - heparin complex constitutes the basis of the pathophysiological changes in patients suffering from HIT, which then binds to the surface of platelets and monocytes, thus provoking their activation and subsequent aggregation, ultimately leading to the formation of thrombosis. Formation of arterial and venous thrombosis is aggravated by the simultaneous activation of platelets and monocytes with a substantial mortality rate. The incidence of HIT is reported to be significantly lower in pediatric patients compared with adults. Diagnosis of HIT in pediatric population remains a clinical entity supplemented by laboratory evaluation. The positive predictive value of laboratory evaluation is further elevated by the use of scoring systems and predictive models used for hastening the diagnosis of HIT. Use of alternative anticoagulants like direct thrombin inhibitors and factor Xa inhibitors form the mainstay of treatment in cases of HIT, however, more prospective studies would be required in the pediatric population to delineate definitive guidelines for proper management of patients in this age-group. This article delivers diagnostic and treatment approach in case of patients with HIT, wherein the pathophysiology, clinical manifestations, diagnostic approach and the management of patients with HIT has been described.

Heparin induced thrombocytopenia Type II (HIT-II) is a dangerous thromboembolic complication of heparin therapy. The current literature on incidence and outcomes of HIT-II in aneurysmal subarachnoid hemorrhage (aSAH) patients remains sparse.

We report our institution's incidence and outcomes of HIT-II in aSAH patients.

We performed a retrospective cohort study at an academic medical center between June 2014 and July 2018. All patients had aSAH confirmed by digital subtraction angiography. Diagnosis of HIT-II was determined by positive results on both heparin PF4-platelet antibody ELISA (anti-PF4) and serotonin release assay (SRA).

204 patients met inclusion criteria. Seven patients (7/204, 3.5%) underwent laboratory testing, three of whom met clinical criteria. HIT-II incidence was confirmed in two of these seven patients (2/204, 0.98%), who had high BMI and T4 scores.

Our institution's report of HIT-II incidence in aSAH patients is lower than previously reported in this population and more closely parallels HIT-II incidence in the general and surgical ICU setting. Widely-accepted American College of Chest Physicians (ACCP) clinical diagnostic criteria in conjunction with anti-PF4 and SRA testing is the gold standard of clinical diagnosis of HIT-II in aSAH patients.

We report a case of new-onset thrombocytopenia following administration of a loading dose of ticagrelor.

A 66-year-old male known to have diabetes mellitus type II, chronic obstructive airway disease, and hypertension presented to the emergency department with retrosternal chest pain and dyspnea. Work-up on presentation showed Hb 14.7 g/dL, platelet 229 × 10⁹/L, and troponin 309 ng/mL. The electrocardiogram showed ST elevation in the anterior-lateral leads. The patient underwent balloon angioplasty, and a drug-eluting stent was deployed. During the procedure, intravenous unfractionated heparin and a 180 mg loading dose of ticagrelor were given. Six hours post procedure, the platelet count was 70 × 10⁹/L without active bleeding. Blood smear was unremarkable, and no schistocytes could be seen. So, ticagrelor was stopped, and the patient's platelet count completely recovered four days after discontinuation.

Ticagrelor-induced thrombocytopenia is a rare but increasingly recognized entity. Therefore, post-treatment monitoring and early recognition are crucial parts of management.

SAR107375E is a direct dual inhibitor of both Factor Xa and Factor IIa and has shown potent anticoagulation activity in vitro and animals. This study evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of single ascending intravenous doses of SAR107375E in healthy Chinese adult subjects.

In this randomized, double-blind, placebo-controlled trial, 60 healthy Chinese adult subjects were administered intravenously single ascending doses (0.5, 1.5, 3.0, 5.0, 7.5, 10.0, 15.0, or 20.0 mg) of SAR107375E (N = 44) or placebo (N = 16). Plasma and urine concentrations of SAR107375E were measured and used to calculate pharmacokinetic parameters. Coagulation functions were measured and compared with baseline values. Treatment-emergent adverse events were recorded to evaluate safety.

In plasma, from the 0.5 to 20.0 mg dose group, t1/2 is 1.51-4.00 h, Cmax is 59.05-1360 ug/L, and AUC0-t is 25.01-528.45 h*ug/L. And it shows dose proportionality in the 5.0-20.0 mg range. Activated partial thromboplastin time and Ecarin clotting time correlated linearly with drug plasma concentration. No serious adverse events were reported during the study.

SAR107375E exhibits good safety and tolerability, predictable pharmacokinetics and pharmacodynamics.

www.chinadrugtrials.org.cn, identifier is CTR20211082.

Heparin-induced thrombocytopenia (HIT) is categorized into type 1 and type 2. It causes a decrease in platelet count during or shortly after exposure to heparin. Type 1 is mild and has a non-immune mechanism. Type 2 is a hypercoagulable state resulting from anti-heparin platelet factor 4 (PF4) IgG antibodies. These antibodies cause the activation of endothelium and thrombin generation. Type 2 HIT is complicated by life-threatening thromboembolic events such as deep venous thrombosis, pulmonary embolism, and myocardial infarction. HIT remains an under-recognized cause of dialysis catheter dysfunction and thrombosis. We present a case of a 66-year-old male with recurrent dialysis catheter thrombosis secondary to Type 2 HIT. Avoiding heparin-based dialysis or switching to non-heparin-based anticoagulation or peritoneal dialysis are the possible management strategies for such patients.

Due to the mortality associated with thrombosis and its high recurrence rate, there is a need to investigate antithrombotic approaches. Noninvasive site-specific thrombolysis is a current approach being used; however, its usage is characterized by the following limitations: low targeting efficiency, poor ability to penetrate clots, rapid half-life, lack of vascular restoration mechanisms, and risk of thrombus recurrence that is comparable to that of traditional pharmacological thrombolysis agents. Therefore, it is vital to develop an alternative technique that can overcome the aforementioned limitations. To this end, a cotton-ball-shaped platelet (PLT)-mimetic self-assembly framework engineered with a phototherapeutic poly(3,4-ethylenedioxythiophene) (PEDOT) platform has been developed. This platform is capable of delivering a synthetic peptide derived from hirudin P6 (P6) to thrombus lesions, forming P6@PEDOT@PLT nanomotors for noninvasive site-specific thrombolysis, effective anticoagulation, and vascular restoration. Regulated by P-selectin mediation, the P6@PEDOT@PLT nanomotors target the thrombus site and subsequently rupture under near-infrared (NIR) irradiation, achieving desirable sequential drug delivery. Furthermore, the movement ability of the P6@PEDOT@PLT nanomotors under NIR irradiation enables effective penetration deep into thrombus lesions, enhancing bioavailability. Biodistribution analyses have shown that the administered P6@PEDOT@PLT nanomotors exhibit extended circulation time and metabolic capabilities. In addition, the photothermal therapy/photoelectric therapy combination can significantly augment the effectiveness (ca. 72%) of thrombolysis. Consequently, the precisely delivered drug and the resultant phototherapeutic-driven heat-shock protein, immunomodulatory, anti-inflammatory, and inhibitory plasminogen activator inhibitor-1 (PAI-1) activities can restore vessels and effectively prevent rethrombosis. The described biomimetic P6@PEDOT@PLT nanomotors represent a promising option for improving the efficacy of antithrombotic therapy in thrombus-related illnesses.

Heparin-induced thrombocytopenia type II (HIT II), as stated in the literature, occurs in about 3% of all patients and in 0.1-5% of surgical patients. Thrombosis develops in 20-64% of patients with HIT. The mortality rate in HIT II has not decreased using non-heparin treatment with anticoagulants such as argatroban and lepirudin. An improved understanding of the pathophysiology of HIT may help identify targeted therapies to prevent thrombosis without subjecting patients to the risk of intense anticoagulation. The review will summarize the current knowledge about the pathogenesis of HIT II, potential new therapeutic targets related to it, and new treatments being developed. HIT II pathogenesis involves multi-step immune-mediated pathways dependent on the ratio of PF4/heparin and platelet, monocyte, neutrophil, and endothelium activation. For years, only platelets were known to take part in HIT II development. A few years ago, specific receptors and signal-induced pathways in monocytes, neutrophils and endothelium were revealed. It had been shown that the cells that had become active realised different newly formed compounds (platelet-released TF, TNFα, NAP2, CXCL-7, ENA-78, platelet-derived microparticles; monocytes-TF-MPs; neutrophils-NETs), leading to additional cell activation and consequently thrombin generation, resulting in thrombosis. Knowledge about FcγIIa receptors on platelets, monocytes, neutrophils and FcγIIIa on endothelium, chemokine (CXCR-2), and PSGL-1 receptors on neutrophils could allow for the development of a new non-anticoagulant treatment for HIT II. IgG degradation, Syk kinase and NETosis inhibition are in the field of developing new treatment possibilities too. Accordingly, IdeS and DNases-related pathways should be investigated for better understanding of HIT pathogenesis and the possibilities of being the HIT II treatment targets.

Heparin is an anticoagulant which has been widely used in various clinical settings, from thromboprophylaxis to the treatment of thromboembolism. Heparin-induced thrombocytopenia (HIT) is a rare medical condition with severe complications if unrecognised, and it carries significant risks of co-morbidities and mortality. The incidence of HIT is relatively less common in low molecular weight heparin. HIT is more common in the venous system than the arterial circulatory system, and it is rare to see multi-vessel coronary artery thrombosis due to HIT. We hereby report a case of multi-vessel coronary thrombosis secondary to low molecular weight HIT, presenting as a case of ST-segment elevation myocardial infarction. We learned from the case that low molecular weight heparin can cause thrombosis secondary to HIT and HIT could be one of the differential diagnoses in those presenting with ST-elevation myocardial infarct and recent exposure to low molecular weight heparin.

Unfractionated heparin has multiple pharmacological activities beyond anticoagulation. These anti-inflammatory, anti-microbial, and mucoactive activities are shared in part by low molecular weight and non-anticoagulant heparin derivatives. Anti-inflammatory activities include inhibition of chemokine activity and cytokine synthesis, inhibitory effects on the mechanisms of adhesion and diapedesis involved in neutrophil recruitment, inhibition of heparanase activity, inhibition of the proteases of the coagulation and complement cascades, inhibition of neutrophil elastase activity, neutralisation of toxic basic histones, and inhibition of HMGB1 activity. This review considers the potential for heparin and its derivatives to treat inflammatory lung disease, including COVID-19, ALI, ARDS, cystic fibrosis, asthma, and COPD via the inhaled route.

As virus outbreaks continue to pose a challenge, a nonspecific viral inhibitor can provide significant benefits, especially against respiratory viruses. Polyglycerol sulfates recently emerge as promising agents that mediate interactions between cells and viruses through electrostatics, leading to virus inhibition. Similarly, hydrophobic C₆₀ fullerene can prevent virus infection via interactions with hydrophobic cavities of surface proteins. Here, two strategies are combined to inhibit infection of SARS-CoV-2 variants in vitro. Effective inhibitory concentrations in the millimolar range highlight the significance of bare fullerene's hydrophobic moiety and electrostatic interactions of polysulfates with surface proteins of SARS-CoV-2. Furthermore, microscale thermophoresis measurements support that fullerene linear polyglycerol sulfates interact with the SARS-CoV-2 virus via its spike protein, and highlight importance of electrostatic interactions within it. All-atom molecular dynamics simulations reveal that the fullerene binding site is situated close to the receptor binding domain, within 4 nm of polyglycerol sulfate binding sites, feasibly allowing both portions of the material to interact simultaneously.

Our team is presenting a patient who is a 57-year -old woman with a past medical history of cerebral vascular accident. The patient presented to the emergency department with symptoms of fever, right upper quadrant pain, and emesis. Initial diagnostic studies revealed thrombocytopenia with acute kidney injury, fever, and leukocytosis. After initiation of treatment for sepsis, the patient developed a hemolytic anemia, which resolved with administration of methylprednisolone. Labs subsequently revealed ADAMTS-13 activity of 4% with positive inhibitor, which confirmed the diagnosis of thrombotic thrombocytopenic purpura (TTP) after the patient's discharge. On retrospective analysis, the case represents a unique and rapid clinical recovery from TTP without administration of therapeutic plasma exchange, rituximab, or caplacizumab.

Currently, the world is recovering from the shock of the coronavirus disease 2019 (COVID-19) pandemic; however, this situation is still fragile. Health authorities recommend administering COVID-19 vaccines as the safest and most reliable tool for eliminating COVID-19. Subsequent to the extensive administration of the COVID-19 vaccines, a series of cardiovascular adverse effects have been reported. This comprehensive review aimed to provide an update on the etiology, pathophysiology, clinical features, and management of the cardiovascular adverse events associated with COVID-19 vaccines, including myocarditis, pericarditis, thrombosis with thrombocytopenia syndrome, myocardial infarction, cardiac arrhythmias, hypertension, and stress-induced cardiomyopathy. The benefits of COVID-19 vaccination far outweigh the reported adverse events. It would be clinically important to provide diagnostic scoring systems to differentiate COVID-19-related cardiovascular adverse events from other causes and develop therapeutic approaches for their management. Further evaluation of cardiovascular adverse events of the COVID-19 vaccines is crucial for implementing vaccination programs and developing safer and more reliable vaccines.

The coronavirus disease (COVID-19) breakout had an unimaginable worldwide effect in the 21st century, claiming millions of lives and putting a huge burden on the global economy. The potential developments in vaccine technologies following the determination of the genetic sequence of SARS-CoV-2 and the increasing global efforts to bring potential vaccines and therapeutics into the market for emergency use have provided a small bright spot to this tragic event. Several intriguing vaccine candidates have been developed using recombinant technology, genetic engineering, and other vaccine development technologies. In the last decade, a vast amount of the vaccine development process has diversified towards the usage of viral vector-based vaccines. The immune response elicited by such vaccines is comparatively higher than other approved vaccine candidates that require a booster dose to provide sufficient immune protection. The non-replicating adenoviral vectors are promising vaccine carriers for infectious diseases due to better yield, cGMP-friendly manufacturing processes, safety, better efficacy, manageable shipping, and storage procedures. As of April 2022, the WHO has approved a total of 10 vaccines around the world for COVID-19 (33 vaccines approved by at least one country), among which three candidates are adenoviral vector-based vaccines. This review sheds light on the developmental summary of all the adenoviral vector-based vaccines that are under emergency use authorization (EUA) or in the different stages of development for COVID-19 management.

Thrombosis and intimal hyperplasia have remained the major failure mechanisms of small-diameter vascular grafts used in bypass procedures. While most efforts to reduce thrombogenicity have used a biochemical surface modification approach, the use of local mechanical phenomena to aid in this goal has received somewhat less attention. In this work, the mechanical, fluid transport, and geometrical properties of a layered and porous vascular graft are optimized within a porohyperelastic finite element framework to maximize self-cleaning via luminal reversal fluid velocity (into the lumen). This is expected to repel platelets as well as inhibit the formation of and/or destabilize adsorbed protein layers thereby reducing thrombogenic potential. A particle swarm optimization algorithm was utilized to maximize luminal reversal fluid velocity while also compliance matching our graft to a target artery (rat aorta). The maximum achievable luminal reversal fluid velocity was approximately 246 μm/s without simultaneously optimizing for host compliance. Simultaneous optimization of reversal flow and compliance resulted in a luminal reversal fluid velocity of 59 μm/s. Results indicate that a thick highly permeable compressible inner layer and a thin low permeability incompressible outer layer promote intraluminal reversal fluid velocity. Future research is needed to determine the feasibility of fabricating such a layered and optimized graft and verify its ability to improve hemocompatibility.

As COVID-19 vaccines became widely available, there have been reports of neurovascular complications. In this article, we aim to report a case of cerebral venous sinus thrombosis (CVST) induced by COVID-19 vaccination, with a literature review on similar cases as well as the potential pathophysiological mechanisms. Our case is a healthy male who developed headache, vomiting, photophobia and diplopia after receiving the Ad26.COV2.S vaccine. Fundus examination showed papilledema, and magnetic resonance imaging of the brain and cerebral veins showed CVST involving the superior sagittal sinus and right transverse sinus extending into the right jugular vein. Hypercoagulability workup was unremarkable, and the patient received immunotherapy and anticoagulation. Following this treatment, symptoms resolved, and he had no residual neurologic deficits. Developing neurologic manifestations, especially severe headaches with papilledema, after COVID-19 vaccination should warrant neuroimaging. Early recognition and management of CVST are essential for good clinical outcomes.

Thrombotic events are common in critically ill patients with COVID-19 and have been linked with COVID-19- induced hyperinflammatory state. In addition to anticoagulant effects, heparin and its derivatives have various anti-inflammatory and immunomodulatory properties that may affect patient outcomes. This study compared the effectiveness and safety of prophylactic standard-doses of enoxaparin and unfractionated heparin (UFH) in critically ill patients with COVID-19.  METHODS: A multicenter, retrospective cohort study included critically ill adult patients with COVID-19 admitted to the ICU between March 2020 and July 2021. Patients were categorized into two groups based on the type of pharmacological VTE thromboprophylaxis given in fixed doses (Enoxaparin 40 mg SQ every 24 hours versus UFH 5000 Units SQ every 8 hours) throughout their ICU stay. The primary endpoint was all cases of thrombosis. Other endpoints were considered secondary. Propensity score (PS) matching was used to match patients (1:1 ratio) between the two groups based on the predefined criteria. Multivariable logistic, Cox proportional hazards, and negative binomial regression analysis were used as appropriate.  RESULTS: A total of 306 patients were eligible based on the eligibility criteria; 130 patients were included after PS matching (1:1 ratio). Patients who received UFH compared to enoxaparin had higher all thrombosis events at crude analysis (18.3% vs. 4.6%; p-value = 0.02 as well in logistic regression analysis (OR: 4.10 (1.05, 15.93); p-value = 0.04). Although there were no significant differences in all bleeding cases and major bleeding between the two groups (OR: 0.40 (0.07, 2.29); p-value = 0.31 and OR: 1.10 (0.14, 8.56); p-value = 0.93, respectively); however, blood transfusion requirement was higher in the UFH group but did not reach statistical significance (OR: 2.98 (0.85, 10.39); p-value = 0.09). The 30-day and in-hospital mortality were similar between the two groups at Cox hazards regression analysis. In contrast, hospital LOS was longer in the UFH group; however, it did not reach the statistically significant difference (beta coefficient: 0.22; 95% CI: -0.03, 0.48; p-value = 0.09).

Prophylactic enoxaparin use in critically ill patients with COVID-19 may significantly reduce all thrombosis cases with similar bleeding risk compared to UFH.

Heparin-induced thrombocytopenia (HIT), a severe autoimmune disorder, occurs in patients undergoing heparin therapy. The presence of platelet-activating antibodies against platelet factor 4/Heparin in the blood confirms patients suffering from HIT. The most widely used methods for HIT diagnosis are immunoassays but the results only suit to rule out HIT as the assays provide only around 50% specificity. To confirm HIT, samples with positive results in immunoassays are retested in functional assays (>98% specificity) that track platelet-activating antibodies via platelet aggregation. However, the protocols in functional assays are either time-consuming (due to the requirement of the detection of serotonin release) or require highly trained staff for the visualization of platelets. Here, we applied a cheap and easy-to-use contactless sensor, which employs high-frequency microwaves to detect the changes in the resonant frequency caused by platelet aggregation/activation. Analysis of change in conductivity and permittivity allowed us to distinguish between HIT-like (KKO) and non-HIT-like (RTO) antibodies. KKO caused a stronger reduction of conductivity of platelet samples than RTO. Our results imply that the high-frequency contactless sensor can be a promising approach for the development of a better and easier method for the detection of HIT.