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Introduction: The 2021 Surviving Sepsis Campaign guidelines recommend low-molecular-weight heparin for the prevention of venous thromboembolism in sepsis. However, observational studies suggest that anticoagulants as a whole may benefit severely ill sepsis patients with coagulopathy, but the optimal targets of unfractionated heparin remain unclear. This study investigated which sepsis patients could most benefit from unfractionated heparin., Materials and Methods: In this retrospective observational study, we identified adult sepsis patients requiring urgent hospitalization from 2006 to 2019 using a large-scale Japanese medical database. Patients were divided into two groups: those receiving unfractionated heparin within 72 h of admission and those who did not. We compared in-hospital mortality, major bleeding complications, and thromboembolic events between these groups using a multivariate logistic regression model adjusted for patient and treatment variables. Additionally, we assessed the association between heparin administration and in-hospital mortality across various subgroups., Results: Among 30,342 sepsis patients, 2520 received early heparin administration, and 27,822 did not. Multivariate logistic regression revealed a significant association between heparin and reduced in-hospital mortality (adjusted OR: 0.735, 95 % CI: 0.596-0.903) but no significant association with major bleeding and thromboembolic risk (adjusted OR: 1.137, 1.243; 95 % CI: 0.926-1.391, 0.853-1.788, respectively). Subgroup analyses suggested significant survival benefits associated with heparin only in the sepsis patients with moderate coagulopathy and sepsis-induced coagulopathy scores of 3 or 4 (adjusted OR: 0.452, 0.625; 95 % CI: 0.265-0.751, 0.410-0.940, respectively)., Conclusions: Early heparin administration upon admission is associated with lower in-hospital mortality, especially in moderate sepsis-induced coagulopathy, and no significant increase in complications., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Kazuma Yamakawa reported receiving research grants from Asahi Kasei Pharma and Japan Blood Products Organization. All other authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Coagulation disorders are common in Kawasaki disease (KD). The main objectives of the present study were to probe the associations of coagulation profiles with clinical classification, IVIG responsiveness, coronary artery abnormalities (CAAs) in the acute episode of KD. A total of 313 KD children were recruited and divided into six subgroups, including complete KD (n = 217), incomplete KD (n = 96), IVIG-responsive KD (n = 293), IVIG-nonresponsive KD (n = 20), coronary artery noninvolvement KD (n = 284) and coronary artery involvement KD (n = 29). Blood samples were collected within 24-h pre-IVIG therapy and 48-h post-IVIG therapy. Coagulation profiles, conventional inflammatory mediators and blood cell counts were detected. Echocardiography was performed during the period from 2- to 14-day post-IVIG infusion. In addition, 315 sex- and age-matched healthy children were enrolled as the controls. (1) Before IVIG therapy, coagulation disorders were more prone to appear in KD patients than in healthy controls, and could be overcome by IVIG therapy. FIB and DD significantly increased in the acute phase of KD, whereas reduced to normal levels after IVIG therapy. (2) PT and APTT were significantly longer in patients with complete KD when compared with their incomplete counterparts after IVIG therapy. (3) The larger δDD, δFDP and the smaller δPT, δINR predicted IVIG nonresponsiveness. (4) The higher δDD and δFDP correlated with a higher risk for CAAs (DD: r = -0.72, FDP: r = -0.54). Coagulation disorders are correlated with complete phenotype, IVIG nonresponsiveness and CAA occurrence in the acute episode of KD, and can be rectified by synergistic effects of IVIG and aspirin., (© 2024. The Author(s).)

Background: The objective of this study was to explore the correlation between statin administration in the intensive care unit (ICU) setting and the in-hospital mortality risk of patients suffering from sepsis-induced coagulopathy (SIC)., Methods: Utilizing a retrospective cohort study design, this investigation collected data from the Medical Information Mart for Intensive Care (MIMIC)-IV spanning 2008 to 2019. The diagnosis of SIC was established based on a SIC score of 4 or above. Statin usage during the ICU period was extracted from the prescription records based on the keywords of statin medications. The primary endpoint analyzed was the in-hospital mortality within the ICU, characterized by any death occurring during the ICU admission., Results: During the follow-up, which had a median duration of approximately 7.28 days, 18.19% of the 4,777 SIC patients died in the ICU. Statin was linked with a decrease in the risk of in-hospital mortality for SIC patients in the ICU [hazard ratio (HR): 0.73, 95% confidence interval (CI): 0.60-0.89, P = 0.002]. Relative to rosuvastatin, the use of atorvastatin (HR: 0.54, 95% CI: 0.34-0.85, P = 0.008) or simvastatin (HR: 0.55, 95% CI: 0.33-0.92, P = 0.024), as well as combinations of multiple statins (HR: 0.36, 95% CI: 0.15-0.86, P = 0.022), was associated with a reduction in ICU in-hospital mortality risk. Subgroup analysis also suggested that the use of atorvastatin, simvastatin, or a combination of statins had an advantage over rosuvastatin in reducing ICU in-hospital mortality in SIC patients older than 65 years of age or SIC patients with respiratory failure or cardiogenic shock (all P < 0.05)., Conclusion: The present study supports the potential benefits of statin use in mortality in SIC patients during ICU stays. The study encourages clinicians to consider the benefits of statins and supports the ongoing exploration of statins for enhanced outcomes in critical care settings., (© 2024. The Author(s).)

Background: Desmopressin (1-deamino-8-D-arginine vasopressin [DDAVP]) has demonstrated efficacy as a treatment option for patients with inherited bleeding disorders. Because of individuals' variable response to the medication, it is recommended to complete a challenge to document appropriate hemostatic response to the medication before recommending its use prior to surgical procedures or treatment of bleeding symptoms. The project aimed to reduce the errors in hemostatic response assessments for patients with bleeding disorders undergoing a DDAVP challenge (process outcome), particularly timing and number of blood samples drawn, from an error rate baseline of 36% to 0% by December 2021 and sustained for one year. Method: Plan-Do-Study-Act methodology was employed for this qualitative improvement initiative. Interventions designed and implemented included: an order set with medication doses and corresponding laboratory orders as clinically indicated for the bleeding disorder indication, clinical procedure guidelines for infusion nurses to follow, hemostasis nurse coordination of appointments with patients, and family education. Results: Baseline data on 22 patients who completed a DDAVP challenge demonstrated a 36% error rate not involving doses of medication administered. Errors encountered included improper timing of laboratory draw after DDAVP administration, incomplete laboratory evaluation, laboratory results displayed incorrectly due to testing orders released at once instead of in a sequential manner. These interventions resulted in a reduction of DDAVP challenge errors to 0% that were sustained for one year. Conclusion: Improvement in procedural medication administration and appropriate laboratory evaluation of patients undergoing a DDAVP challenge leads to a complete and reliable assessment of hemostatic response following medication administration., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Cefoperazone (CPZ) is an antibiotic widely used for moderate to severe infections, especially in countries where resources are difficult to access. This case report aimed to draw attention to coagulopathy, a potential side effect of CPZ. This side effect can cause high mortality and morbidity in patients. In the mechanism of CPZ causing coagulopathy, it is reported that effects such as binding to vitamin K, disrupting vitamin K metabolism, and preventing platelet aggregation are responsible. In this presentation, a case who came to the emergency department with the complaint of hematuria caused by coagulopathy after the use of CPZ-containing antibiotics (CPZ + sulbactam) is presented., (Copyright © 2024 Emergency Nurses Association. Published by Elsevier Inc. All rights reserved.)

Abstract: Objective : The aim of the study is to investigate the efficacy of intravenous immunoglobulin (IVIg) in treating sepsis-induced coagulopathy ( SIC ). Methods : A retrospective controlled analysis was conducted on 230 patients with SIC at Ganzhou People's Hospital from January 2016 to December 2022. All patients were screened using propensity score matching and treated according to the SSC2016 guidelines. Compared with the control group (n = 115), patients in the test group (n = 115) received IVIg (200 mg/kg.d) for 3 consecutive days after admission. The rating scales, coagulation function, survival, and treatment duration were evaluated. Results : On day 3 of treatment, both groups exhibited reduced platelet and thromboelastogram (TEG) maximum amplitude (MA) levels, with the control group showing a more significant decrease ( P < 0.05). By the fifth day, these levels had recovered in both groups. However, the test group experienced a significant increase by day 7 ( P < 0.05). Coagulation factors II and X began to increase on day 3, and normalization was significantly faster in the test group on day 5 ( P < 0.05). The levels of prothrombin time, international normalized ratio, activated partial thromboplastin time, d -dimer, fibrinogen, fibrin degradation products, TEG-R, and TEG-K exhibited a notable decline on day 3 and demonstrated significantly faster recovery on day 5 in the test group ( P < 0.05). In addition, both groups showed a reduction in Acute Physiology and Chronic Health Evaluation II, Sequential Organ Failure Assessment, disseminated intravascular coagulation, and lactate (LAC) levels on day 3, but the test group's scores decreased significantly more by day 7 ( P < 0.05). Within the test group, white blood cell count, C-reactive protein, procalcitonin, IL-6, and Tmax levels were lower ( P < 0.05). Furthermore, the test group demonstrated shorter duration for intensive care unit stay, mechanical ventilation, and continuous renal replacement therapy ( P < 0.05). No significant differences were observed in the duration of fever or vasoactive drug use between the groups. However, the log-rank method indicated a higher 28-day survival rate in the test group ( P < 0.05). Conclusion : IVIg can successfully increase platelet count and coagulation factors, correct coagulation disorders, enhance organ function, and reduce 28-day mortality in patients with SIC ., Competing Interests: The authors report no conflicts of interest., (Copyright © 2024 by the Shock Society.)

This is an animal model study to investigate changes in hemostasis during endotoxemic shock and to determine whether the combination of inhaled nitric oxide (iNO) + intravenous hydrocortisone had an effect on clot formation and fibrinolysis. iNO selectively decreases pulmonary artery pressure, without affecting cardiac index or systemic vascular resistance; however, the results of studies on the possible consequences of iNO administration on coagulation are inconsistent and require further research. Thirty-four piglets were included. Administering endotoxin caused severe hypodynamic shock. Half of the animals received iNO (30 ppm) + hydrocortisone, starting 3 h after endotoxin infusion and continuing to the end of the study. All animals developed coagulation disorders, manifested by a tendency to hypocoagulation; at the same time, fibrinolysis was impaired. Coagulation and fibrinolysis disorders persisted after endotoxin infusion was discontinued, with worse severity in the animals that died before the study was terminated. Administering iNO + hydrocortisone did not cause further changes in coagulation and fibrinolysis parameters, either during or after the endotoxin challenge, suggesting that potential therapeutic interventions with iNO to lower pulmonary arterial pressure will not affect hemostasis., (© 2024 Barbara Adamik et al., published by Sciendo.)

Background: The Western diamondback rattlesnake ( Crotalus atrox ) is a medically important venomous snake in the Southwestern United States, injuring humans, and their companion animals. The goals of this investigation were to utilize a rabbit model of subcutaneous envenomation to assess Crotalus atrox venom coagulopathy and determine the efficacy of a ruthenium-containing antivenom (RA) in attenuating it., Methods: Sedated New Zealand White rabbits had viscoelastic measurements of whole blood coagulation kinetics obtained from ear artery samples. Crotalus atrox venom (4 mg/kg) was injected subcutaneously and changes in coagulation determined over three hours and compared to samples obtained prior to envenomation. Other rabbits had site-directed RA injected 5 min after venom injection., Results: A significant decrease in the velocity of clot growth and thrombus strength was observed in animals injected with venom alone. Site-directed administration of RA resulted in no change in coagulation over the 3 h following venom injection. The interaction of antivenom administration and time was significantly different in the cases of clot growth velocity and strength., Conclusions: A novel rabbit model was used to define the toxicodynamic profile of coagulopathy of Crotalus atrox venom and demonstrate the efficacy of RA. Future investigation is planned involving other medically important venoms and RA administration., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Ε-Aminocaproic acid oral solution (EACA OS) is the only commercially available antifibrinolytic for patients who cannot swallow tablets. Insurance denials and high costs remain barriers to its use., Objectives: To determine the safety and efficacy of crushed tranexamic acid tablets in water (cTXAw) for children with bleeding disorders., Methods: We retrospectively reviewed records of children (<10 years) with bleeding disorders who received cTXAw or EACA OS from 1 December 2018, through 31 July 2022, at Mayo Clinic (Rochester, Minnesota). Bleeding outcomes were defined according to ISTH criteria., Results: Thirty-two patients were included (median age, 3 years; male, n = 23). Diagnoses were VWD (n = 17), haemophilia (n = 5), FVII deficiency (n = 3), inherited platelet disorder (n = 4), ITP (n = 2), and combined FV and FVII deficiencies (n = 1). Thirty-two courses of cTXAw (monotherapy 24/32; mean duration 6 days) and fifteen courses of EACA (monotherapy 12/15; mean duration 5 days) were administered. No surgical procedures (n = 28) were complicated by bleeding. Of the 19 bleeding events, 16 had effective haemostasis, two had no reported outcome, and one had no response. cTXAw and EACA were equally effective in preventing and treating bleeding (p value > .1). No patients had adverse effects. Eight of 19 patients (42%) who were initially prescribed EACA OS did not receive it because of cost or insurance denial. The estimated average wholesale price of one treatment was $94 for cTXAw and $905 for EACA OS., Conclusions: CTXAw appears to be an effective, safe, and low-cost alternative option to EACA OS for young children with bleeding disorders., (© 2024 John Wiley & Sons Ltd.)

Background: Traumatic injury with subsequent hemorrhage is one of the leading causes of mortality among military personnel and civilians alike. Posttraumatic hemorrhage accounts for 40% to 50% of deaths in severe trauma patients occurring secondary to direct vessel injury or the development of trauma-induced coagulopathy (TIC). Hyperfibrinolysis plays a major role in TIC and its presence increases a patient's risk of mortality. Early therapeutic intervention with intravenous (IV) tranexamic acid (TXA) prevents development of hyperfibrinolysis and subsequent TIC leading to decreased mortality. However, obtaining IV access in an austere environment can be challenging. In this study, we evaluated the efficacy of intramuscular (IM) versus IV TXA at preventing hyperfibrinolysis in a hemorrhaged swine., Methods: Yorkshire cross swine were randomized on the day of study to receive IM or IV TXA or no treatment. Swine were sedated, intubated, and determined to be hemodynamically stable before experimentation. Controlled hemorrhaged was induced by the removal of 30% total blood volume. After hemorrhage, swine were treated with 1,000 mg of IM or IV TXA. Control animals received no treatment. Thirty minutes post-TXA treatment, fibrinolysis was induced with a 50-mg bolus of tissue plasminogen activator. Blood samples were collected to evaluate blood TXA concentrations, blood gases, blood chemistry, and fibrinolysis., Results: Blood TXA concentrations were significantly different between administration routes at the early time points but were equivalent by 20 minutes after injection, remaining consistently elevated for up to 3 hours postadministration. Induction of fibrinolysis resulted in 87.18 ± 4.63% lysis in control animals, compared with swine treated with IM TXA, 1.96 ± 2.66% and 1.5 ± 0.42% lysis in the IV TXA group., Conclusion: In the large swine model of hemorrhage with hyperfibrinolysis, IM TXA is bioequivalent and equally efficacious in preventing hyperfibrinolysis as IV TXA administration., (Copyright © 2023 Written work prepared by employees of the Federal Government as part of their official duties is, under the U.S. Copyright Act, a “work of the United States Government” for which copyright protection under Title 17 of the United States Code is not available. As such, copyright does not extend to the contributions of employees of the Federal Government.)

Inherited factor coagulation deficiencies and vascular bleeding disorders, associated with bleeding of various severity, are often classified as rare bleeding disorders (RBDs). These include inherited fibrinogen disorders, inherited platelet function disorders (IPFD) and hereditary haemorrhagic telangiectasia (HHT). In the last decades, there have been large increases in knowledge on the epidemiology, genetics, physiopathology, clinical features, and diagnosis of RBDs, but improvements in management have been more limited and remain challenging. The treatment mainstay of RBDs is based only on replacement of a few available coagulation factor concentrates or cryoprecipitates. There is growing interest in therapeutic agents that enhance coagulation or inhibiting anticoagulant pathways in RBDs. In severe IPFD, the optimal platelet transfusion strategy is not yet established. Moreover, data is scarce on the effectiveness and safety of desmopressin and/or antifibrinolytic drugs often used for milder IPFD treatment. The best fibrinogen replacement strategy (prophylaxis vs. on demand) in afibrinogenemia is still debated. Similarly, the optimal trough fibrinogen target level for treatment of acute bleeding, and the role of fibrinogen replacement during pregnancy in mild hypofibrinogenemia and dysfibrinogenemia, have not been properly evaluated. The therapeutic arsenal in HHT includes antifibrinolytics and a series of antiangiogenic agents whose potential efficacy has been tested in small studies or are under investigation for treatment of bleeding. However, there is need to address several issues, including the optimal dosing strategies, the potential emergent toxicity of longer-term use, and the impact of systemic antiangiogenic treatment on visceral arteriovenous malformations., (© 2024 John Wiley & Sons Ltd.)

Background: Activated protein C (APC) is one of the mechanisms contributing to coagulopathy, which is associated with high mortality. The counteraction of the APC pathway could help ameliorate bleeding. However, patients also transform frequently from a hemorrhagic state to a prothrombotic state at a later time. Therefore, a prohemostatic therapeutic intervention should take this thrombotic risk into consideration., Objectives: CT-001 is a novel factor VIIa (FVIIa) with enhanced activity and desialylated N-glycans for rapid clearance. We assessed CT-001 clearance in multiple species and its ability to reverse APC-mediated coagulopathic blood loss., Methods: The N-glycans on CT-001 were characterized by liquid chromatography-mass spectrometry. Three species were used to evaluate the pharmacokinetics of the molecule. The potency and efficacy of CT-001 under APC pathway-induced coagulopathic conditions were assessed by coagulation assays and bleeding models., Results: The N-glycosylation sites of CT-001 had high occupancy of desialylated N-glycans. CT-001 exhibited 5 to 16 times higher plasma clearance in human tissue factor knockin mice, rats, and cynomolgus monkeys than wildtype FVIIa. CT-001 corrected the activated partial thromboplastin time and thrombin generation of coagulopathic plasma to normal in in vitro studies. In an APC-mediated saphenous vein bleeding model, 3 mg/kg of CT-001 reduced bleeding time in comparison with wildtype FVIIa. The correction of bleeding by CT-001 was also observed in a coagulopathic tail amputation severe hemorrhage mouse model. The efficacy of CT-001 is independent of the presence of tranexamic acid, and the combination of CT-001 and tranexamic acid does not lead to increased thrombogenicity., Conclusion: CT-001 corrected APC pathway-mediated coagulopathic conditions in preclinical studies and could be a potentially safe and effective procoagulant agent for addressing APC-mediated bleeding., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Current guideline recommendations for primary prophylaxis of venous thromboembolism (VTE) are based on randomized clinical trials that usually exclude subjects at a potentially high risk of bleeding complications. For this reason, no specific guideline is available for thromboprophylaxis in hospitalized patients with thrombocytopenia and/or platelet dysfunction. However, except in patients with absolute contraindications to anticoagulant drugs, antithrombotic prophylaxis should always be considered, for example, in hospitalized cancer patients with thrombocytopenia, especially in those with multiple VTE risk factors. Low platelet number, platelet dysfunction, and clotting abnormalities are also very common in patients with liver cirrhosis, but these patients have a high incidence of portal venous thrombosis, implying that cirrhotic coagulopathy does not fully protect against thrombosis. These patients may benefit from antithrombotic prophylaxis during hospitalization. Patients hospitalized for COVID-19 need prophylaxis, but frequently experience thrombocytopenia or coagulopathy. In patients with antiphospholipid antibodies, a high thrombotic risk is usually present, even in the presence of thrombocytopenia. VTE prophylaxis in high-risk conditions is thus suggested in these patients. At variance with severe thrombocytopenia (< 50,000/mm 3 ), mild/moderate thrombocytopenia (≥ 50,000/mm 3 ) should not interfere with VTE prevention decisions. In patients with severe thrombocytopenia, pharmacological prophylaxis should be considered on an individual basis. Aspirin is not as effective as heparins in lowering the risk of VTE. Studies in patients with ischemic stroke demonstrated that thromboprophylaxis with heparins is safe in these patients also during antiplatelet treatment. The use of direct oral anticoagulants in the prophylaxis of VTE in internal medicine patients has been recently evaluated, but no specific recommendation exists for patients with thrombocytopenia. The need for VTE prophylaxis in patients on chronic treatment with antiplatelet agents should be evaluated after assessing the individual risk of bleeding complications. Finally, the selection of patients who require post-discharge pharmacological prophylaxis remains debated. New molecules currently under development (such as the inhibitors of factor XI) may contribute to improve the risk/benefit ratio of VTE primary prevention in this setting of patients., Competing Interests: None declared., (Thieme. All rights reserved.)

Background: Disseminated intravascular coagulation (DIC) occurs in 30-50% of septic patients and contributes to high mortality in the intensive care unit (ICU). However, there are few proven interventions for coagulation disorder management in sepsis. Experimental and clinical data have demonstrated that sepsis could benefit from unfractionated heparin (UFH) treatment. To date, there are no large multicenter trials to determine the safety and efficacy of UFH in septic patients with suspected DIC., Methods: A multicenter, double-blinded, placebo-controlled randomized trial is designed to recruit 600 patients who met sepsis 3.0 criteria and suspected DIC. Participants will be randomized (1:1) to receive UFH or saline via continuous intravenous administration for 7 days within 6 h of enrolment. The primary outcome is ICU mortality. The secondary outcome includes 28-day all-cause mortality, the improvement of Sequential Organ Failure Assessment scores, and the incidence of major hemorrhage. Investigators, participants, and statisticians will be blinded to the allocation., Discussion: The HepSIC trial is to evaluate the efficacy and safety of UFH on sepsis-related DIC across different areas of China. The small dosage of UFH administration would offer a new potential approach for treating sepsis-related coagulation disorders., Ethics and Dissemination: Ethical approval was granted by all the ethics committees of 20 participant centers. Results will be disseminated via peer-reviewed publications and presented at conferences., Trial Registration: ClinicalTrials.gov NCT02654561. Registered on 13 January 2016., (© 2023. The Author(s).)

Background: Coagulation profiles following major trauma vary depending on injury pattern and degree of shock. The physiologic mechanisms involved in coagulation function at any given time are varied and remain poorly understood. Thromboelastography (TEG) has been used evaluate coagulation profiles in the trauma population with some reports demonstrating a spectrum of fibrinolysis to fibrinolytic shutdown on initial presentation. The objective of this study was to evaluate the fibrinolytic profile of patients with TBI using thromboelastography (TEG). We hypothesized that patients with TBI would demonstrate low fibrinolytic activity., Methods: All trauma activations at an ACS-verified level 1 trauma center received a TEG analysis upon arrival from December 2019 to June 2021. A retrospective review of the results and outcomes was conducted, and TBI patients were compared to patients without TBI. Linear regression was used to evaluate the effect of patient and injury factors on fibrinolysis. Hyperfibrinolysis was defined as LY30 ​> ​7.7%, physiologic fibrinolysis as LY30 0.6-7.7%, and fibrinolytic shutdown as LY30 ​< ​0.6%., Results: A total of 1369 patients received an admission TEG analysis. Patients with TBI had a significantly higher median ISS (16 vs. 8, p ​< ​0.001), lower median admission Glasgow Coma Scale (14 vs. 15, p ​< ​0.001), longer intensive care unit length of stay (3 vs. 2 days, p ​< ​0.0001), increased ventilator days (216 vs. 183, p ​< ​0.001), higher mortality (14.6% vs. 5.1%, p ​< ​0.001), but lower shock index (0.6 vs. 0.7, p ​< ​0.0001) compared to those without TBI. Median LY30 was found to be decreased in the TBI group (0.1 vs. 0.2, p ​= ​0.0006). Patients with TBI were found to have a higher rate of fibrinolytic shutdown compared those without TBI (68.7% vs. 63.5%, p ​= ​0.054). ISS, sex, and shock index were found to be predictive of LY30 on linear regression, but TBI was not (Β: 0.09, SE: 0.277, p ​= ​0.745). The rate of DVT/PE did not appear to be elevated in patients with TBI (0.8%) and without TBI (1.2%)., Conclusions: Trauma patients with and without TBI were found to have high rates of fibrinolytic shutdown. Although there was a high incidence of fibrinolytic shutdown, it did not appear to have an impact on the rate of thrombotic complications. The clinical significance of these results is unclear and differs significantly from recent reports which demonstrated that TBI is associated with a 25% rate of fibrinolytic shutdown. Further investigation is needed to better define the fibrinolytic pathway in patients with trauma and TBI to develop optimal treatment algorithms., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objectives: Coagulopathy is associated with increased mortality in children in the intensive care unit (ICU). Recommended management of vitamin K-deficient coagulopathy is vitamin K administration. The goal of this study was to evaluate vitamin K administration for coagulopathy in critically ill children and determine a relationship between vitamin K dose and change in prothrombin time (PT) and international normalized ratio (INR)., Methods: This retrospective cohort study reviewed electronic medical records of patients ≤17 years who received vitamin K for acute coagulopathy in the pediatric ICU from January 2013 to January 2021. Patients receiving vitamin K antagonists were excluded. Effectiveness data included change in PT/INR after vitamin K administration. Safety data included incidence of hypersensitivity or anaphylaxis., Results: A total of 310 patients (median age 6.8 years, range 22 days-17.7 years) received vitamin K. A median of three doses (range 1-8) and 0.14 mg/kg per dose (range 0.09-0.22 mg/kg) were given, most frequently intravenously (892/949, 94%). Most patients (304/310, 98%) had at least one risk factor for vitamin K deficiency. Mean PT/INR was 21.5/2.1 prior to vitamin K administration, which decreased by 4.4 (SD = 9.0, 95% CI 16.011 to 18.015, p  < 0.001) and 0.5 (SD = 1.0, 95% CI 1.490 to 1.705, p  < 0.001) to means of 17.0 and 1.6, respectively, after the first vitamin K dose. No linear relationship was found between vitamin K dose and change in PT/INR. No hypersensitivity or anaphylaxis occurred following vitamin K administration; 27% (84/310) of patients died., Conclusions: Administration of vitamin K is effective and safe for the management of vitamin K-deficient coagulopathy in critically ill pediatric patients. Further study is needed to determine a relationship between vitamin K dose and change in PT/INR.

Introduction: Snakebite envenomation is a major public health issue in Sub-Saharan Africa (SSA). Antivenoms are the only etiological treatment. However, the dose recommended by the manufacturer (2 vials renewed every 2 hours in case of persistent bleeding) is usually not applied due to the high cost which is borne only by the patient. Based on clinical presentation, we evaluated the administration of a single vial on admission (instead of 2 vials), which corresponds to the therapeutic protocol used in current practice in most health centers in Benin and beyond in SSA. Renewal of antivenom followed manufacturer's recommendation., Material and Method: The study took place in a first referral hospital in Tanguiéta, North Benin. All envenomed patients received a slow intravenous vial of Inoserp ® Pan-Africa (IPA) upon arrival. A clinical assessment identical to that of inclusion was carried out 2, 4, 6, 12 and 24 hours later to assess the tolerance and efficacy of the IPA, as well as the need to readminister the antivenom. The occurrence, persistence or worsening of clinical hemorrhages or neurological disorders, the latter reflecting envenomation by elapids, systematically led to the injection of 2 or 4 vials of IPA, respectively. Signs of intolerance were sought before and after each administration of antivenom, then 2 weeks to 1 month after treatment, in order to estimate the incidence of adverse effects attributable to the antivenom. Efficacy of IPA was assessed by cessation of bleeding and/or normalization of whole blood coagulation test (WBCT) within 24 hours of initial administration., Results: The study took place from July 31 to October 31, 2019. We received 53 cases of snakebites of which 43 were included. The median age was 21 [IQR: 18-31] years and the sex ratio (M/F) was 1.5. Farmers were the majority (48%). The median time to admission was 1 [IQR: 0-2] day. On admission, 32 patients (74%) presented hemostasis disorders marked by bleeding and/or abnormal WBCT. None of the patients showed neurological symptoms. The median time to normalization of WBCT was 24 [IQR: 4-72] hours. The median time to stop bleeding was 6 [IQR: 4-12] hours. In 3 of the 11 patients whose bleeding had stopped at H2, a recurrence occurred within the following 24 hours. In addition, 3 patients presented with late bleeding 24 hours after admission. Two patients (5%) died as a result of envenomation., Discussion/conclusion: The simplified protocol represents a significant saving in the number of vials used, i.e. 1.8±0.4 vials per patient instead of the 2.4±0.2 which would have been necessary in these same patients treated according to the standard protocol (p = 2.6·10 -4 ). However, in comparison with the results obtained during the previous clinical study, the cessation of bleeding is delayed, as is the normalization of the WBCT at the different follow-up times. In addition, the number of re-administrations of antivenom after H2 is higher in the light protocol than in the standard one, respectively 13 patients out of 43 treated versus 4 patients out of 59 (p = 0.006). There was no significant difference between the incidence of signs of early antivenom intolerance in this study compared to the previous one (16% and 11%, respectively; p = 0.79). This delay can put up to a third of patients at risk of complications. Despite its effectiveness and the antivenom savings made, it does not seem reasonable to recommend it., (Copyright © 2023 SFMTSI.)

The expression "developmental hemostasis" indicates the age-related physiological changes occurring during the maturational process of the hemostatic system. Despite the quantitative and qualitative alterations, the neonatal hemostatic system is competent and well-balanced. Conventional coagulation tests do not provide reliable information as they only explore the procoagulants during the neonatal period. In contrast, viscoelastic coagulation tests (VCTs), such as viscoelastic coagulation monitoring (VCM), thromboelastography (TEG or ClotPro), and rotational thromboelastometry (ROTEM), are point-of-care assays that provide a quick, dynamic and global view of the hemostatic process, allowing prompt and individualized therapeutic intervention when necessary. Their use in neonatal care is on the increase and they could help monitor patients at risk of hemostatic derangement. In addition, they are crucial for anticoagulation monitoring during extracorporeal membrane oxygenation. Moreover, implementing VCT-based monitoring could optimize blood product use.

Background: Trauma-induced coagulopathy (TIC) is common in trauma patients with major hemorrhage. Prothrombin complex concentrate (PCC) is used as a potential treatment for the correction of TIC, but the efficacy, timing, and evidence to support its use in injured patients with hemorrhage are unclear., Methods: A systematic search of published studies was performed on MEDLINE and EMBASE databases using standardized search equations. Ongoing studies were identified using clinicaltrials.gov. Studies investigating the use of PCC to treat TIC (on its own or in combination with other treatments) in adult major trauma patients were included. Studies involving pediatric patients, studies of only traumatic brain injury (TBI), and studies involving only anticoagulated patients were excluded. Primary outcomes were in-hospital mortality and venous thromboembolism (VTE). Pooled effects of PCC use were reported using random-effects model meta-analyses. Risk of bias was assessed for each study, and we used the Grading of Recommendations Assessment, Development, and Evaluation to assess the quality of evidence., Results: After removing duplicates, 1745 reports were screened and nine observational studies and one randomized controlled trial (RCT) were included, with a total of 1150 patients receiving PCC. Most studies used 4-factor-PCC with a dose of 20-30U/Kg. Among observational studies, co-interventions included whole blood (n = 1), fibrinogen concentrate (n = 2), or fresh frozen plasma (n = 4). Outcomes were inconsistently reported across studies with wide variation in both measurements and time points. The eight observational studies included reported mortality with a pooled odds ratio of 0.97 [95% CI 0.56-1.69], and five reported deep venous thrombosis (DVT) with a pooled OR of 0.83 [95% CI 0.44-1.57]. When pooling the observational studies and the RCT, the OR for mortality and DVT was 0.94 [95% CI 0.60-1.45] and 1.00 [95% CI 0.64-1.55] respectively., Conclusions: Among published studies of TIC, PCCs did not significantly reduce mortality, nor did they increase the risk of VTE. However, the potential thrombotic risk remains a concern that should be addressed in future studies. Several RCTs are currently ongoing to further explore the efficacy and safety of PCC., (© 2023. The Author(s).)

Abstract: The interaction between the kidney and the coagulation system greatly affects each other because of the abundant vessel distribution and blood perfusion in the kidney. Clinically, the risks of complicated thrombosis and bleeding have become important concerns in the treatment of nephropathies, especially nephrotic syndrome, CKD, ESKD, and patients with nephropathy undergoing RRTs. Adverse effects of anticoagulant or procoagulant therapies in patients with nephropathy, especially anticoagulation-related nephropathy, heparin-induced thrombocytopenia, and bleeding, seriously worsen the prognosis of patients, which have become challenges for clinicians. Over the decades, the interaction between the kidney and the coagulation system has been widely studied. However, the effects of the kidney on the coagulation system have not been systematically investigated. Although some coagulation-related proteins and signaling pathways have been shown to improve coagulation abnormalities while avoiding additional kidney damage in certain kidney diseases, their potential as anticoagulation targets in nephropathy requires further investigation. Here, we review the progression of research on the crosstalk between the coagulation system and kidney diseases and systematically analyze the significance and shortcomings of previous studies to provide new sight into future research. In addition, we highlight the status of clinical treatment for coagulation disorder and nephropathy caused by each other, indicating guidance for the formulation of therapeutic strategies or drug development., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Society of Nephrology.)

Background: Heavy menstrual bleeding (HMB) is associated with a reduced quality of life and limitations in social and physical functioning. Data on HMB in women with rare bleeding disorders (RBDs), including coagulation factor deficiencies and fibrinolytic disorders, are scarce., Objectives: To analyze the prevalence, severity, and treatment of HMB in Dutch women with an RBD., Methods: The Rare Bleeding Disorders in the Netherlands (RBiN) study included 263 patients with an RBD from all 6 hemophilia treatment centers (October 2017-November 2019). In this analysis, data of 111 women aged ≥16 years were studied. According to the International Society on Thrombosis and Haemostasis bleeding assessment tool, HMB symptoms were scored from 0 (no/trivial) to 4 (severe symptoms requiring medical intervention). HMB was defined as a score ≥1. Age at RBD diagnosis was extracted from patient files., Results: HMB was reported by 80% of women (89/111) and was more prevalent in women with a fibrinolytic disorder (33/35; 94%) than in women with a coagulation factor deficiency (56/76; 74%) (P = .011). Of the 89 women with HMB, 82% (n = 73) ever required treatment. Multiple treatment modalities were frequently used, both in severe and mild deficiencies. Hormonal treatment was mostly used (n = 64; 88%), while antifibrinolytics were prescribed less frequently (n = 18; 25%). In women with HMB since menarche (n = 61; 69%), median age at RBD diagnosis was 28 years (IQR, 14-41)., Conclusion: HMB is common in women with RBDs. Women with mild deficiencies also frequently reported HMB. Only a minority of women were treated with hemostatic agents. A significant diagnostic delay was observed after the onset of HMB symptoms., Competing Interests: Declaration of competing interests K. Meijer reports speaker fees from Bayer and Alexion, participation in trial steering committee for Bayer, consulting fees from Uniqure, participation in data monitoring and endpoint adjudication committee for Octapharma. M.H. Cnossen's institution has received investigator-initiated research and travel grants as well as speaker fees over the years from the Netherlands Organisation for Scientific Research (NWO) and Netherlands National research Agenda (NWA), the Netherlands Organization for Health Research and Development (ZonMw), the Dutch Innovatiefonds Zorgverzekeraars, Stichting Haemophilia, Baxter/Baxalta/Shire/ Takeda, Pfizer, Bayer Schering Pharma, CSL Behring, Sobi Biogen, Novo Nordisk, Novartis, Roche, and Nordic Pharma, and for serving as a steering board member for Roche, Bayer and Novartis. All grants and fees go to the Erasmus MC as an institution. She is coordinator of Erasmus MC as a Health Care Provider within the European Reference Network (ERN) for rare hematological diseases EuroBloodNet and (co)leader of the local Erasmus MC Expert Centers for Rare Bleeding Disorders and Sickle Cell and Thalassemia Comprehensive Care Center. R.E.G. Schutgens reports grants from Bayer, Baxalta, Pfizer, and Novo Nordisk outside the submitted work. M. Peters reports a grant from Pfizer outside the submitted work. W.L. van Heerde reports financial support from Takeda, Bayer, Sobi and CSL Behring, and funding from Takeda and Bayer for Enzyre. The remaining authors declare no competing financial interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Venomous snake bite adversely affects millions of people yearly, but few animal models allow for the determination of toxicodynamic timelines with hemotoxic venoms to characterize the onset and severity of coagulopathy or assess novel, site-directed antivenom strategies. Thus, the goals of this investigation were to create a rabbit model of subcutaneous envenomation to assess venom toxicodynamics and efficacy of ruthenium-based antivenom administration. New Zealand White rabbits were sedated with midazolam via the ear vein and had viscoelastic measurements of whole blood and/or plasmatic coagulation kinetics obtained from ear artery samples. Venoms derived from Crotalus scutulatus scutulatus , Bothrops moojeni , or Calloselasma rhodostoma were injected subcutaneously, and changes in coagulation were determined over three hours and compared to samples obtained prior to envenomation. Other rabbits had ruthenium-based antivenoms injected five minutes after venom injection. Viscoelastic analyses demonstrated diverse toxicodynamic patterns of coagulopathy consistent with the molecular composition of the proteomes of the venoms tested. The antivenoms tested attenuated venom-mediated coagulopathy. A novel rabbit model can be used to characterize the onset and severity of envenomation by diverse proteomes and to assess site-directed antivenoms. Future investigation is planned involving other medically important venoms and antivenom development.

Objective: Hematological consequences of novel antiseizure medications (ASMs) or combined therapies are rarely reported, especially in pediatric patients undergoing surgery for epilepsy. This study aimed to assess the prevalence and risk factors of coagulation dysfunction in this population and evaluate their relationship with intra- and postoperative bleeding., Methods: Three hundred ninety children who underwent surgery for epilepsy and 104 children without epilepsy who underwent nonepilepsy surgery at the authors' center were included in the study. The authors retrospectively collected and analyzed the following clinical data: sex, age, weight, course of epilepsy, antiseizure therapy, first laboratory data after admission, and transfusion-related data., Results: ASMs were responsible for the higher incidence of coagulation dysfunction in pediatric epilepsy surgery patients. Low body weight (OR 0.95, 95% CI 0.92-0.98) and valproic acid (VPA) therapy (OR 5.13, 95% CI 3.25-8.22) were the most relevant factors leading to coagulation dysfunction. The most common hematological side effects of VPA were thrombocytopenia and hypofibrinogenemia, whereas low body weight was only associated with hypofibrinogenemia. Both VPA and low body weight increased the need for intra- or postoperative transfusion (p < 0.001)., Conclusions: Pediatric epilepsy surgery patients often take multiple ASMs, resulting in an increased incidence of coagulopathy. VPA levels and low body weight were found to be the main influential factors associated with an increased risk of coagulation dysfunction. Platelet and fibrinogen levels were the main indices that were affected. Both VPA and low body weight were relevant to additional surgery-related transfusion, necessitating the need for increased awareness of preoperative coagulopathy before pediatric epilepsy surgery. Clinical trial registration no.: NCT05675254 (ClinicalTrials.gov).

The Fourth Maastricht Consensus Conference on Thrombosis included the following themes. Theme 1: The "coagulome" as a critical driver of cardiovascular disease. Blood coagulation proteins also play divergent roles in biology and pathophysiology, related to specific organs, including brain, heart, bone marrow, and kidney. Four investigators shared their views on these organ-specific topics. Theme 2: Novel mechanisms of thrombosis. Mechanisms linking factor XII to fibrin, including their structural and physical properties, contribute to thrombosis, which is also affected by variation in microbiome status. Virus infection-associated coagulopathies perturb the hemostatic balance resulting in thrombosis and/or bleeding. Theme 3: How to limit bleeding risks: insights from translational studies. This theme included state-of-the-art methodology for exploring the contribution of genetic determinants of a bleeding diathesis; determination of polymorphisms in genes that control the rate of metabolism by the liver of P2Y12 inhibitors, to improve safety of antithrombotic therapy. Novel reversal agents for direct oral anticoagulants are discussed. Theme 4: Hemostasis in extracorporeal systems: the value and limitations of ex vivo models. Perfusion flow chamber and nanotechnology developments are developed for studying bleeding and thrombosis tendencies. Vascularized organoids are utilized for disease modeling and drug development studies. Strategies for tackling extracorporeal membrane oxygenation-associated coagulopathy are discussed. Theme 5: Clinical dilemmas in thrombosis and antithrombotic management. Plenary presentations addressed controversial areas, i.e., thrombophilia testing, thrombosis risk assessment in hemophilia, novel antiplatelet strategies, and clinically tested factor XI(a) inhibitors, both possibly with reduced bleeding risk. Finally, COVID-19-associated coagulopathy is revisited., Competing Interests: None declared., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/).)

Bleeding events in patients under direct oral anticoagulation (DOAC) can be life-threating but are commonly not related to drug overdose. However, a relevant DOAC plasma concentration impairs the hemostasis and should therefore be ruled out immediately after hospital admission. The effect of DOAC is typically not visible in standard coagulation tests such as activated partial thrombin time or thromboplastin time. Specific anti-Xa or anti-IIa assays allow a specific drug monitoring, but they are too time-consuming in critical bleeding events and typically not available 24 h/7 d in routine care. Recent advantages in point-of-care (POC) testing might improve patient care by early exclusion of relevant DOAC levels, but sufficient validation is still lacking. POC urine analysis help to exclude DOAC in emergency patients, but does not provide a quantitative information about plasma concentration. POC viscoelastic testing (VET) can determine the DOAC effect on clotting time and helps further to reveal other concomitant bleeding disorders in emergency, e.g., factor deficiency or hyperfibrinolysis. If a relevant plasma concentration of the DOAC is assumed or was proven by either laboratory assays or POC testing, restoration of factor IIa or factor IIa activity is key for effective hemostasis. Limited evidence suggests that specific reversals for DOAC, e.g., idarucizumab for dabigatran and andexanet alfa for apixaban or rivaroxaban, might be superior to increasing thrombin generation by administration of prothrombin complex concentrates. To determinate, if DOAC reversal is indicated or not, time from last intake, anti-Xa/dTT values or results from POC tests can be considered. This experts' opinion provides a feasible decision algorithm for clinical practice.

The medical records of 95 pit viper envenomations in client-owned dogs presented to an academic emergency hospital in the Southeastern United States during the period spanning 2018 and 2020 were retrospectively examined. This study's primary objectives were to record the clinical abnormalities and treatment responses associated with envenomation and their relation to outcome. Approximately 80% of the bites involved the head region associated with varying degrees of hemorrhagic lymphedema. Some of the most common additional symptoms observed were; hypotension (10%), cardiac dysrhythmias (17%), and coagulopathy (21%). Treatment in most cases consisted of intravenous fluids, antivenom, and analgesic drugs. Blood products were used as indicated for anemia and persistent bleeding. The average dose of the F('ab') 2 was 1-2 vials. Additional vials (3-22) were administered as needed to counteract persistent or recurrent coagulopathy and hemolysis. Only 3% of the dogs had mild clinical signs of Type 1 hypersensitivity during their treatment period. Antihistamine use at the tertiary hospital was restricted to the three dogs showing signs of a suspected allergic reaction in response to antivenom administration; these patients received diphenhydramine intramuscularly. A glucocorticoid drug was used in only one dog prior to referral but not subsequently. Ninety dogs had a good outcome, while five died. Historically, pit viper envenomation in dogs in the southeastern United States has been a potentially life-threatening problem. Most dogs will survive if treated promptly and appropriately with adequate amounts of intravenous fluids, and antivenom titrated on severity of clinical presentation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper, (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Introduction: Damage to endothelial glycocalyx (EGCX) can lead to coagulation disorders in sepsis. Heat stroke (HS) resembles sepsis in many aspects; however, it is unclear whether EGCX injury is involved in its pathophysiology. The purpose of this study was to examine the relationship between the damage of EGCX and the development of coagulation disorders during HS., Methods: We retrospectively collected 159 HS patients and analyzed coagulation characteristics and prognosis of HS patients with or without disseminated intravascular coagulation (DIC). We also replicated a rat HS model and measured coagulation indexes, pulmonary capillary EGCX injury in HS rats. Finally, we evaluated the effect of the antioxidant N-acetylcysteine (NAC) on HS-initiated EGCX injury and coagulation disorders., Results: Clinical data showed that HS patients complicated with DIC had a higher risk of death than HS patients without DIC. In a rat HS model, we found that rats subjected to heat stress developed hypercoagulability and platelet activation at the core body temperature of 43°C, just before the onset of HS. At 24 h of HS, the rats showed a consumptive hypo-coagulation state. The pulmonary capillary EGCX started to shed at 0 h of HS and became more severe at 24 h of HS. Importantly, pretreatment with NAC substantially alleviated EGCX damage and reversed the hypo-coagulation state in HS rats. Mechanically, HS initiated reactive oxidative species (ROS) generation, while ROS could directly cause EGCX damage. Critically, NAC protected against EGCX injury by attenuating ROS production in heat-stressed or hydrogen peroxide (H 2 O 2 )-stimulated endothelial cells., Discussion: Our results indicate that the poor prognosis of HS patients correlates with severe coagulation disorders, coagulation abnormalities in HS rats are associated with the damage of EGCX, and NAC improves HS-induced coagulopathy, probably through its protection against EGCX injury by preventing ROS generation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Peng, Geng, Ouyang, Liu, Yuan, Wan, Chen, Yu, Tang, Su, Liang, Wang and Liu.)

Background: Coagulopathy is often observed in severe traumatic brain injury (sTBI), and hyperfibrinolysis (HF) is associated with a poor prognosis. Although the efficacy of fibrinogen concentrate (FC) in multiple trauma has been reported, its efficacy in sTBI is unclear. Therefore, we delineated severe HF risk factors despite fresh frozen plasma transfusion. Using these risk factors, we defined high-risk patients and determined whether FC administration to this group improved fibrinogen level., Methods: In the first part of this study, successive adults with sTBI treated at our hospital between April 2016 and March 2019 were reviewed. Patients underwent transfusion as per our conventional protocol and were divided into two groups based on whether fibrinogen levels of ≥ 150 mg/dL were maintained 3-6 h after arrival to delineate the risk factors of severe HF. In the second part of the study, we conducted a before-and-after study in patients with sTBI who were at a higher risk for severe HF (presence of at least one of the risk factors identified in the first part of the study), comparing those treated with FC between April 2019 and March 2021 (FC group) with those treated with conventional transfusion before FC between April 2016 and March 2019. The primary outcome was maintenance of fibrinogen levels, and the secondary outcome was 30-day mortality., Results: In the first part of the study, 78 patients were included. Twenty-three patients did not maintain fibrinogen levels ≥ 150 mg/dL. A D-dimer level on arrival > 50 μg/mL, a fibrinogen level on arrival < 200 mg/dL, depressed skull fracture, and multiple trauma were severe HF risk factors. In the second part, compared with 46 patients who were identified as being at high risk for severe HF but were not administered FC (non-FC group), fibrinogen levels ≥ 150 mg/dL 3-6 h after arrival were maintained in 14 of 15 patients in the FC group (odds ratio: 0.07; 95% confidence interval: 0.01-0.59). Although there were significant differences in fibrinogen levels, no significant differences were observed in terms of 30-day mortality between the groups., Conclusions: Coagulation abnormalities on arrival, severe skull fracture, and multiple trauma are severe HF risk factors. FC administration may contribute to rapid correction of developing hypofibrinogenemia., (© 2022. Springer Science+Business Media, LLC, part of Springer Nature and Neurocritical Care Society.)

Introduction: Adulteration of illicit drugs is a well-known phenomenon that may expose consumers to unexpected adverse effects. We report a large outbreak of severe coagulopathy in northern Israel during nine months in 2021-2022 among users of synthetic cannabinoids adulterated with a long-acting anticoagulant, brodifacoum., Methods: We performed a retrospective cohort study based on data extracted from the Israeli National Poison Information Center database and from electronic medical patient records at three participating hospitals. Confiscated drug samples and blood samples obtained at admission in a subgroup of patients were tested for the presence of long-acting anticoagulants., Results: We identified 98 patients affected by the outbreak. All patients had a prolonged international normalized ratio on admission, and in 69%, the blood was non-coagulating. For patients treated in the three participating centers ( n  = 72), the presenting complaint was overt bleeding in 79% of patients, most commonly in the urinary (53%) and gastrointestinal tracts (50%). The most severe complications were intracranial bleeding (4%), hemothorax (3%), pericardial bleeding (1%), and four patients died. Brodifacoum was detected in all available blood samples (median concentration 207 µg/L, interquartile range 112-349 μg/L, range 45-1,118 µg/L), and the drug samples contained both brodifacoum and the synthetic cannabinoid ADB-BUTINACA. All patients were treated with high-dose phytomenadione (vitamin K 1 ) and additionally by packed red blood cell transfusions, fresh frozen plasma, and/or 4-factor prothrombin complex concentrate when indicated. The most frequent phytomenadione (vitamin K 1 ) dose regimen was initially 20 mg intravenously every eight hours, and at discharge, 20 mg orally three times daily., Conclusions: Outbreaks of severe coagulopathies in users of synthetic cannabinoids adulterated with a long-acting anticoagulant continue to erupt in different regions of the world. Rapid recognition of an outbreak requires a high index of suspicion when confronting young, otherwise healthy subjects with otherwise unexplained severe coagulopathy.

Since the first description of COVID-19 infection, among clinical manifestations of the disease, including fever, dyspnea, cough, and fatigue, it was observed a high incidence of thromboembolic events potentially evolving towards acute respiratory distress syndrome (ARDS) and COVID-19-associated-coagulopathy (CAC). The hypercoagulation state is based on an interaction between thrombosis and inflammation. The so-called CAC represents a key aspect in the genesis of organ damage from SARS-CoV-2. The prothrombotic status of COVID-19 can be explained by the increase in coagulation levels of D-dimer, lymphocytes, fibrinogen, interleukin 6 (IL-6), and prothrombin time. Several mechanisms have been hypothesized to explain this hypercoagulable process such as inflammatory cytokine storm, platelet activation, endothelial dysfunction, and stasis for a long time. The purpose of this narrative review is to provide an overview of the current knowledge on the pathogenic mechanisms of coagulopathy that may characterize COVID-19 infection and inform on new areas of research. New vascular therapeutic strategies are also reviewed.

Inherited and acquired coagulopathy are frequently associated with major bleeding in severe trauma, cardiac surgery with cardiopulmonary bypass, and postpartum hemorrhage. Perioperative management is multifactorial and includes preoperative optimization and discontinuation of anticoagulants and antiplatelet therapy in elective procedures. Prophylactic or therapeutic use of antifibrinolytic agents is strongly recommended in guidelines and has been shown to reduce bleeding and need for allogeneic blood administration. In the context of bleeding induced by anticoagulants and/or antiplatelet therapy, reversal strategies should be considered when available. Targeted goal-directed therapy using viscoelastic point-of-care monitoring is increasingly used to guide the administration of coagulation factors and allogenic blood products. In addition, damage control surgery, which includes tamponade of large wound areas, leaving surgical fields open, and other temporary maneuvers, should be considered when bleeding is refractory to hemostatic measures., (Copyright © 2023, the American Society of Anesthesiologists. All Rights Reserved.)

Background: Snakebite (SB) envenoming is an acute emergency requiring an early care delivery. We aimed to search for the time to reach healthcare facilities in various regions of French Guiana (FG) and to assess the impact of time to antivenom (AV) on the correction of coagulation parameters in these patients., Methodology: This is a prospective observational study conducted in Cayenne General Hospital between January 1st, 2016, and July 31st, 2022. We included all patients hospitalized for SB envenoming less than 48h after the bite, and receiving antivenom (AV). We assessed the time lapse between SB and medical attention and the time needed to return of the coagulation parameters to normal., Principal Findings: Overall, 119 patients were investigated, and 48.7% were from remote areas. The median time from SB to AV therapy was 09:15 h (05:32-17:47). The time was longer in patients from remote rural locations. AV was dispensed within the first six hours after the SB in 45 cases (37.8%). Time from SB to reaching normal plasma fibrinogen concentration was 23:27 h (20:00-27:10) in patients receiving AV≤6h vs. 31:23 h (24:00-45:05) in those receiving AV>6h (p<0.001). Whereas, the time from AV administration to reach normal fibrinogen dosage was similar in the two groups., Conclusions: Patients from rural settings in FG suffer from a delay in AV administration after SB envenoming leading to an extended time in which patients are coagulopathic. Once AV is administered, clotting parameters recover at a similar rate. Supplying remote healthcare facilities with AV and with medical teams trained on its use should be planned., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Houcke et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Heart failure (HF) is a clinical syndrome that is divided into 3 subtypes based on the left ventricular ejection fraction. Every subtype has specific clinical characteristics and concomitant diseases, substantially increasing risk of thromboembolic complications, such as stroke, peripheral embolism and pulmonary embolism. Despite the annual prevalence of 1% and devastating clinical consequences, thromboembolic complications are not typically recognized as the leading problem in patients with HF, representing an underappreciated clinical challenge. Although the currently available data do not support routine anticoagulation in patients with HF and sinus rhythm, initial reports suggest that such strategy might be beneficial in a subset of patients at especially high thromboembolic risk. Considering the existing evidence gap, we aimed to review the currently available data regarding coagulation disorders in acute and chronic HF based on the insight from preclinical and clinical studies, to summarize the evidence regarding anticoagulation in HF in special-case scenarios and to outline future research directions so as to establish the optimal patient-tailored strategies for antiplatelet and anticoagulant therapy in HF. In summary, we highlight the top 10 pearls in the management of patients with HF and no other specific indications for oral anticoagulation therapy. Further studies are urgently needed to shed light on the pathophysiological role of platelet activation in HF and to evaluate whether antiplatelet or antithrombotic therapy could be beneficial in patients with HF. LAY SUMMARY: Heart failure (HF) is a clinical syndrome divided into 3 subtypes on the basis of the left ventricular systolic function. Every subtype has specific clinical characteristics and concomitant diseases, substantially increasing the risk of thromboembolic complications, such as stroke, peripheral embolism and pulmonary embolism. Despite the annual prevalence of 1% and devastating clinical consequences, thromboembolic complications are not typically recognized as the leading problem in patients with HF, representing an underappreciated clinical challenge. Although the currently available data do not support routine anticoagulation in patients with HF and no atrial arrhythmia, initial reports suggest that such a strategy might be beneficial in a subset of patients at especially high risk of thrombotic complications. Considering the existing evidence gap, we aimed to review the currently available data regarding coagulation problems in stable and unstable patients with HF based on the insight from preclinical and clinical studies, to summarize the evidence regarding anticoagulation in HF in specific patient groups and to outline future research directions to establish the optimal strategies for antiplatelet and anticoagulant therapy in HF, tailored to the needs of an individual patient. In summary, we highlight the top 10 pearls in the management of patients with HF and no other specific indications for oral anticoagulation therapy., Competing Interests: Disclosures AS reports research support and consulting fees from Adamed, AstraZeneca, Gedeon Richter; AG reports research support and consulting fees from Adamed and Boehringer Ingelheim; JB reports consulting fees from Boehringer Ingelheim and Novartis; PEP reports consulting fees from Boehringer Ingelheim; WAEP reports research support and consulting fees from AstraZeneca. All other authors have nothing to declare., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Competing Interests: Declaration of competing interest There are no competing interests to disclose.

Multifocal lymphangioendotheliomatosis with thrombocytopenia is a rare disease characterized by progressive multiple vascular lesions and is accompanied by thrombocytopenia. The precise diagnosis of this disease is frequently difficult because of the heterogeneity of the clinical symptoms. We report a case of a male infant who presented with severe thrombocytopenia induced by local inflammation. In addition, enlargement of the extremities with soft tissue and bone involvement without gastrointestinal bleeding was observed. The thrombocytopenia resolved after a combination therapy of sirolimus and prednisolone. Our finding that plasma angiopoietin-2 concentrations reflected the disease status suggests its utility as a biomarker of Multifocal lymphangioendotheliomatosis with thrombocytopenia., Competing Interests: M.O. received research funding from Nobelpharma (Tokyo, Japan). The sirolimus tablets were supplied by Nobelpharma. The remaining authors declare no conflict of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: Three venomous snakes of the Gloydius genus belonging to the Viperidae family cause most snake envenomations in South Korea. Envenomation signs often include local swelling, coagulopathy, and rhabdomyolysis. The benefit of additional antivenom after the initial does is unclear., Methods: This retrospective study divided patients into four groups according to the presence of rhabdomyolysis (creatine kinase ≥1000 IU/L) and coagulopathy, which were defined using the Korean Society on Thrombosis and Hemostasis disseminated intravascular coagulation score (rhabdomyolysis, coagulopathy, combination, and local effects groups). We describe the clinical features of envenomation and the antivenom response., Results: Greater local swelling predicted more severe snakebite pain. Ninety of the 231 enrolled patients (38.9%) developed rhabdomyolysis. The patients with severe rhabdomyolysis in the combination group displayed higher peak creatine kinase activity than the rhabdomyolysis group. Seven patients with rhabdomyolysis, including two patients requiring kidney replacement therapy, developed acute kidney injury, but the incidence of acute kidney injury did not differ between the combination group and rhabdomyolysis group. Bleeding developed in 3.5% of the patients, but its incidence did not differ between the combination and coagulopathy groups. Approximately half of all patients needed repeated antivenom administration, mainly due to the local envenomation effect. Earlier administration of additional antivenom for progressive local swelling did not reduce the hospitalization duration., Conclusion: Rhabdomyolysis is one of the major effects of Gloydius snake envenomation in South Korea, although it is not associated with the same risk of clinical deterioration as coagulopathy. Additionally, the ability of antivenom to ameliorate local swelling should be investigated to prevent unnecessary antivenom administration in South Korea.

Objective: Consumptive coagulopathy treatment and pain management are crucial for patients with venous malformations (VMs). Dabigatran etexilate, a non-vitamin K antagonist oral anticoagulant, has known advantages compared with low-molecular-weight heparin and vitamin K antagonists, including oral administration, a more consistent pharmacokinetics/pharmacodynamics profile, a better safety profile, and no need for coagulation surveillance. In the present study, we tested the efficacy and safety of dabigatran etexilate for consumptive coagulopathy treatment and pain management for patients with VMs., Methods: To investigate the efficacy and safety of dabigatran etexilate in treating localized intravascular coagulation (LIC) associated with VM, we retrospectively collected data for 19 outpatients with VM and LIC, who had been treated with dabigatran etexilate from September 2019 to June 2021. The patients provided oral informed consent and underwent biologic blood testing, routine examinations, and determination of coagulation function before and after treatment. The dosage of dabigatran etexilate was 110 mg twice daily for adults and 55 mg twice daily for children., Results: All 19 patients had benefited from dabigatran etexilate treatment with coagulation improvement and pain relief. Pain had improved in all 16 evaluable patients. The fibrinogen and D-dimer levels had improved in 18 of 19 patients. The fibrin degradation product level had improved in 10 of 14 patients. None of patients reported lesion regression, appearance changes, or improvement in mobility. No significant differences were found in the D-dimer, fibrinogen, and fibrin degradation product levels between the short-term (<10 days) and long-term (≥10 days) use of the medication. Dabigatran etexilate was well tolerated by all patients. No bleeding event had occurred during follow-up., Conclusions: The results of our study have confirmed the efficacy and safety of dabigatran etexilate in treating pain and LIC in patients with VMs. Dabigatran etexilate is a suitable choice preoperatively to modify coagulation function and pain in patients with VMs., (Copyright © 2022. Published by Elsevier Inc.)

Sodium dehydroacetate (S-DHA) is used widely as a preservative in several products, including poultry feed. The anticoagulation effect of 200 mg/kg S-DHA in rats has been reported to accompany a reduction in hepatic expression of vitamin K epoxide reductase complex 1 (VKORC1). Poultry and mammals have different physiology and coagulation systems, and species differences in VKORC1 expression have been found. The effect of S-DHA on blood clotting of poultry has not been studies deeply. S-DHA was given to yellow-plumage broilers (YBs) as single and multiple administrations. Vitamin K3 (VK 3 ) was injected into YBs 2 wk after S-DHA administration. Then, the prothrombin time (PT), partial activated prothrombin time (APTT), plasma levels of vitamin K (VK), factor IX (FIX), and S-DHA, and hepatic expression of VKORC1 were obtained. Chicken hepatocellular carcinoma (LMH) cells were also exposed to S-DHA, and the cell activity, VK level, and FIX level were measured. S-DHA prolonged the PT or APTT significantly, decreased levels of VK and FIX in blood, and inhibited hepatic expression of VKORC1. The maximum changes were 1.15-fold in the PT, 1.42-fold in the APTT, 0.8-fold in the VK level, 0.7-fold in the FIX level, and 0.35-fold in VKORC1 expression compared with controls. The cell activity, VK level, FIX level, and VKORC1/VKORC1L1 expression of LMH cells were reduced significantly at S-DHA doses of 2.0 to 10.0 mM. Prolongation of the PT/APTT and lower levels of VK/FIX in YBs or the lower cell activity and VK/FIX levels in LMH cells induced by S-DHA therapy were resisted significantly by VK 3 treatment. We demonstrated that S-DHA could induce a disorder in coagulation function in YBs or in LMH cells via reduction of VKORC1/VKORC1L1 expression, and that VK could resist this anticoagulation effect., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: Management of coagulopathy in chronic liver disease (CLD) poses a challenge for critical care physicians. Prothrombinex®-VF is a low-volume product with rapid onset of action. Evidence for its efficacy and safety in CLD is limited and cases of acute intravascular coagulation and fibrinolysis (AICF) and/or disseminated intravascular coagulation (DIC) have been reported. Our objective was to evaluate the role of Prothrombinex®-VF in reversal of coagulopathy and the incidence AICF/DIC, thromboembolic events and mortality., Methods: This was a retrospective, multi-centre study of Prothrombinex®-VF use in CLD across 11 hospitals over a 2-year period, excluding those on therapeutic anticoagulation. Patients were subclassified into acute on chronic liver failure (ACLF), acute decompensation (ADC) and compensated cirrhosis. Reversal of coagulopathy was defined as international normalised ratio (INR) <1.5× upper limit normal (ULN), prothrombin time <1.5× ULN, activated partial thromboplastin time <1.5× ULN and fibrinogen >1 g/L. Markers of AICF/DIC were recorded., Results: Thirty CLD patients were included, and the median model for end-stage liver disease score was 23.5. Acute bleeding was the most common indication for Prothrombinex®-VF (60%). All had baseline coagulopathy and the majority did not achieve reversal. Key indicators of AICF/DIC were mainly observed in those with ACLF; bleeding from mucosa or lines (53%), worsening hypofibrinogenaemia (60%), worsening thrombocytopaenia (60%). The ADC and compensated cirrhosis groups were relatively unaffected. Incidence of venous thromboembolism was 6%. Overall mortality was 43% and 70% in ACLF., Conclusion: Prothrombinex®-VF did not lead to meaningful reversal of coagulopathy and should be used with caution in CLD. Patients with ACLF were more likely to develop AICF/DIC following Prothrombinex®-VF, although the association is uncertain. Further studies are needed to evaluate the safety and efficacy of Prothrombinex®-VF use in CLD., (© 2022 The Authors. Emergency Medicine Australasia published by John Wiley & Sons Australia, Ltd on behalf of Australasian College for Emergency Medicine.)

Background: Currently, the frequency of coagulation dysfunction associated with chimeric antigen receptor-T cell (Car-T) therapy cannot yet be determined., Objective: We performed a systematic review and meta-analysis to examine the prevalence of abnormal laboratory tests related to coagulation disorders in patients receiving Car-T therapy and provide a reference for future risk assessment mechanisms., Methods: We searched PubMed, Embase, and Web of Science for relevant studies and evaluated their quality using the methodology index of non-random research (MINORS). 2672 quotations were retrieved via systematic searches. After screening of titles, abstracts and full-text, 45 trials involving 2541 patients were ultimately included. 41 studies reported the incidence of thrombocytopenia, 8 studies reported the rate of low fibrin, 4 trials reported the rate of APTT or PT abnormalities and only 3 trials reported the incidence of venous thromboembolism (VTE). We performed a quantitative meta-analysis to explore the incidence of thrombocytopenia following Car-T treatment. The incidence of hypofibrinogenemia, VTE, and abnormal APTT or PT was only qualitatively assessed, as fewer reports were included in this study., Results: The overall incidence of thrombocytopenia associated with Car-T therapy was 45.8% (95%[CI], 0.384-0.533). The highest rates of thrombocytopenia occurred in patients with multiple myeloma (60.1%, 95%[CI], 0.507-0.688) and aged between 18 to 60 (50%, 95%[CI], 0.367-0.633). There was greater prevalence of thrombocytopenia in BCMA-Car-T therapy of 58.7% (95%[CI], 0.482-0.685). Thrombocytopenia occurred most frequently in Car-T patients treated with a dosage of 1 × 105-1 × 106 cell/kg, at a rate of 66.2% (95%[CI], 0.561-0.749)., Conclusion: Overall, 45.8 percent of patients receiving Car-T treatment suffered from thrombocytopenia. Multiple myeloma patients, ages between 18-60, a dose of 1 × 105-1 × 106 cell/kg and BCMA-Car-T therapy are all considered high-risk factors.

The presence of coagulopathy as part of the systemic inflammatory response syndrome is a characteristic feature of severe coronavirus disease 2019 (COVID-19). Hematological changes (increased D-dimer [DD], prolonged activated partial thromboplastin clotting time [APTT] and prothrombin time [PT], high fibrinogen levels) have been observed in hospitalized patients with COVID-19, which characterize the risk of thrombotic events. Against the background of COVID-19 there is endothelial dysfunction, hypoxia and pulmonary congestion, mediated by thrombosis and microvascular occlusion. Up to 71.4% of patients who died from COVID-19 had disseminated intravascular coagulation syndrome, compared with only 0.6% of survivors. The main manifestation of COVID-19-associated coagulopathy is a significant increase in DD without a decrease in platelet count or prolongation of APTT and PT, indicating increased thrombin formation and the development of local fibrinolysis. An increase in DD levels of more than 3-4 times was associated with higher in-hospital mortality. Therefore, COVID-19 requires assessment of the severity of the disease for further tactics of thromboprophylaxis. The need for continued thromboprophylaxis, or therapeutic anticoagulation, in patients after inpatient treatment for two weeks using imaging techniques to assess of thrombosis assessment.

Disseminated intravascular coagulation (DIC) is a life-threatening complication in sepsis and other critical conditions. The International Society on Thrombosis and Haemostasis (ISTH) released the diagnostic criteria for overt DIC in 2001. Since then, ISTH overt DIC has been used as the global standard criterion for a decompensated stage of DIC. Because detecting an earlier stage of DIC would be useful for therapeutic considerations, the scientific standardization committees of the ISTH introduced the sepsis-induced coagulopathy (SIC) scoring system in 2019. The SIC scoring system is specifically designed to detect the compensated phase of DIC in sepsis, which can lead to overt DIC with disease progression. Studies examining the performance of the SIC scoring system have reported its usefulness over the past 5 years. The reported incidence of SIC was approximately 60% in patients with sepsis, which was twice as much as that of overt DIC. Almost all patients with overt DIC were diagnosed with SIC earlier. The reported mortality of SIC was ≥30% and, thus, can be used for patient selection for anticoagulant therapy. Despite the limited data, some continue to suggest the potential efficacy of anticoagulant therapy in patients with SIC. Although heparin, antithrombin, and thrombomodulin are the candidates for anticoagulation, none of them have proven to be effective with robust evidence, and future trials are warranted., Competing Interests: Declaration of competing interest T. Iba participated on the advisory boards of Japan Blood Products Organization, Asahi Kasei Pharmaceuticals, and Toray Medical. M. Levi has received grants and has participated on the advisory boards of Novo Nordisk, Eli Lilly, Asahi Kasei Pharmaceuticals America, and Johnson & Johnson. J. Helms has received honoraria from Diagnostica Stago, Pfizer PFE France, Sanofi Aventis France, MSD, Shionogi, and Inotrem. J. H. Levy serves on the Steering or Advisory Committees for Instrumentation Laboratories, Merck, Octapharma. E. Scarlatescu has received speaker fees from CSL Behring. J. Thachil has no competing interests to disclose., (Copyright © 2022 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)

Abstract: There is strong evidence in adult literature that tranexamic acid (TXA) given within 3 hours from injury is associated with improved outcomes. The evidence for TXA use in injured children is limited to retrospective studies and one prospective observational trial. Two studies in combat settings and one prospective civilian US study have found association with improved mortality. These studies indicate the need for a randomized controlled trial to evaluate the efficacy of TXA in injured children and to clarify appropriate timing, dose and patient selection. Additional research is also necessary to evaluate trauma-induced coagulopathy in children. Recent studies have identified three distinct fibrinolytic phenotypes following trauma (hyperfibrinolysis, physiologic fibrinolysis, and fibrinolytic shutdown), which can be identified with viscohemostatic assays. Whether viscohemostatic assays can appropriately identify children who may benefit or be harmed by TXA is also unknown., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

The administration of 4-factor prothrombin complex concentrate (4F-PCC) has expanded beyond its Food and Drug Administration (FDA)-approved indication for the emergent reversal of vitamin K antagonists (VKAs). Therefore, this study aimed to evaluate the risks and benefits associated with the expanded use of 4F-PCC. We conducted a single-center retrospective review of 4F-PCC administrations at our university hospital. Of the 159 patients who received 4F-PCC, 76% (n = 121) and 24% (n = 38) received it for the FDA-approved indication in the vitamin K-related coagulopathy (VKA) group and for expanded use in the nonvitamin K-related coagulopathy (nVKA) group, respectively. The expanded use of 4F-PCC was associated with a less robust reduction in the international normalized ratio (INR) (INR of -0.7 ± 1.3 vs INR of -1.6 ± 1.8, P  = .002), and fewer patients in the nVKA group achieved a postadministration INR of less than1.5 (11% vs 79%, P  = .001) than those in the VKA group. Furthermore, the 30-day mortality rate was significantly higher in the nVKA cohort than in the VKA cohort (42% vs 20%, P  = .04). Notably, based on our data, underlying differences in the patient's comorbidities, particularly advanced liver disease, may have contributed to the observed outcome variations, including mortality rate. Therefore, factors, including comorbidities and the underlying etiology of coagulopathy, should be considered when deciding on the expanded use of 4F-PCC. Further research is needed to better understand the potential risks and benefits of 4F-PCC in expanded use scenarios, and the clinical decision to use 4F-PCC outside its FDA-approved indication should be made carefully, considering this information.