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PFA-ADP-test (p<0.05), while no patient on peritoneal dialysis and no HC offered this modification. Thrombin generating potential was significantly lower in patients on hemodialysis, while clot lysis time revealed a hypofibrinolytic state in patients on hemo- and peritoneal dialysis compared to HC (p<0.001). In conclusion, patients with end-stage renal disease have complex hemostatic changes with both hyper- and hypocoagulable features, which are dependent on use and type of dialysis (...) . Hypercoagulable features include elevated fibrinogen levels and a hypofibrinolytic state, whereas hypocoagulable features include decreased thrombin generating capacity and platelet dysfunction. Our results may contribute to a more rational approach to hemostatic management in these patients.
of calibrated automated thrombin generation (CAT-TG) to predict bleeding in patients on anticoagulant treatment. Methods A systematic search was executed in three databases: Medline, Embase, and Cochrane. Results Seven studies were included; two were of good methodological quality. One study showed that patients on warfarin with INRs in range (2-3) admitted for hemorrhage ( n = 28), had lower CAT-TG levels (endogenous thrombin potential [ETP]: 333 ± 89 nM/min) than patients on warfarin admitted for other (...) < 0.05). From the remaining studies, four suggested that CAT-TG is more sensitive in detecting hemostatic abnormalities than INR and one article found ETP and INR to be equally useful. However, insufficient data were provided to validate these conclusions. Conclusion Studies investigating the direct association between decreased CAT-TG values and hemorrhagic events are rare. Therefore, the clinical consequences of low CAT-TG values remain to be further investigated.
The Reversal of Bleeding Caused by New Oral Anticoagulants (NOACs): A Systematic Review and Meta-Analysis. New oral anticoagulants (NOACs; ie, direct thrombin inhibitor [DTI] and factor Xa [FXa] inhibitors) were used as alternatives to warfarin. Specific antidotes (idarucizumab for dabigatran and andexanet alfa for FXa inhibitors) and hemostatic reversal agents were used for lowering bleeding, but their efficacies were still uncertain. The objectives of this study were to estimate and compare
Novel Insights and New Developments Regarding Coagulation Revealed by Studies of the Anti-Factor IXa (Activated Factor IX)/Factor X Bispecific Antibody, Emicizumab. Emicizumab is a humanized anti-FIXa/FX (factor IXa/X) bispecific monoclonal antibody that mimics FVIIIa (activated factor VIII) cofactor function. The hemostatic efficacy of emicizumab has been confirmed in clinical studies of patients with hemophilia A, irrespective of the presence of FVIII inhibitors. Emicizumab differs in some (...) properties from FVIIIa molecule. Emicizumab requires no activation by thrombin and is not inactivated by activated protein C, but emicizumab-mediated coagulation is regulatable and maintains hemostasis. A small amount of FIXa (activated factor IX) is required to initiate emicizumab-mediated hemostasis, whereas tissue factor/FVIIa (activated factor VII)-mediated FXa (activated factor X) and thrombin activation initiates FVIIIa-mediated hemostasis. Fibrin formation, followed by fibrinolysis, appears
A local and global sensitivity analysis of a mathematical model of coagulation and platelet deposition under flow. The hemostatic response involves blood coagulation and platelet aggregation to stop blood loss from an injured blood vessel. The complexity of these processes make it difficult to intuit the overall hemostatic response without quantitative methods. Mathematical models aim to address this challenge but are often accompanied by numerous parameters choices and thus need to be analyzed (...) for sensitivity to such choices. Here we use local and global sensitivity analyses to study a model of coagulation and platelet deposition under flow. To relate with clinical assays, we measured the sensitivity of three specific thrombin metrics: lag time, maximum relative rate of generation, and final concentration after 20 minutes. In addition, we varied parameters of three different classes: plasma protein levels, kinetic rate constants, and platelet characteristics. In terms of an overall ranking
tests available to date.A total of 296 patients with high risk of venous thromboembolism (deep vein thrombosis (DVT), early postoperative period, hemoblastosis) were enrolled in the study. We used a case-crossover design to evaluate the sensitivity of new thrombodynamics assay (TD) to the hemostatic state before and after unfractionated heparin (UFH) and low-molecular-weight heparin (LMWH) therapy/prophylaxis and to compare it with the activated partial thromboplastin time (APTT), anti-Xa activity (...) test, thrombin generation test (TGT) and thromboelastography (TEG). A receiver operating characteristic (ROC) curve analysis was used to evaluate changes before and after heparin prophylaxis and therapy. Blood was sampled before heparin injection, at the time of maximal blood heparin concentration and before the next injection.Hypercoagulation before the start of heparin treatment was detected by TD, TGT and TEG but not by APTT. The area under the ROC curve (AUC) was maximal for TD and anti-Xa
factor and it is synthesised in the liver. Factor IX is activated by factor XIa in the intrinsic coagulation pathway and by factor VII/tissue factor complex in the extrinsic pathway. Activated factor IX, in combination with activated factor VIII, activates factor X. Activated factor X converts prothrombin into thrombin. Thrombin then converts fibrinogen into fibrin and a clot is formed. The Applicant applied for the following indication which was finally approved: Rixubis is indicated (...) such as the thrombin generation assay, as well as the efficiency of activation by FXIa and FVIIa in the presence of tissue factor and the capacity to bind to phospholipid vesicles sufficiently support primary PD of nonacog gamma as discussed under Quality aspects Secondary pharmacodynamic studies Secondary pharmacodynamic studies have not been submitted. Safety pharmacology programme Three in vivo safety pharmacology studies were conducted in rabbits and monkeys to assess the thrombogenic potential of nonacog
acid), (3) topical hemostatics ( i.e. , fibrin glue, thrombin gel), (4) PCCs, (5) coagulation factor concentrates (recombinant factor VIIa), and (6) treatments for hypofibrinogenemia (cryoprecipitate, fibrinogen concentrate). Desmopressin: Literature Findings: Meta-analysis of placebo-controlled RCTs indicate that desmopressin is effective in reducing the volume of postoperative blood loss (Category A1-B evidence). Survey Findings: Both the consultants and ASA members agree that, in patients (...) : The consultants and ASA members both agree that, in patients with excessive bleeding, consider the use of antifibrinolytics ( i.e. , ε-aminocaproic acid, tranexamic acid), if not already being used. Topical Hemostatics: Literature Findings: Meta-analysis of RCTs indicates that fibrin glue is effective in reducing the volume of perioperative blood loss and the number of patients transfused when compared with no fibrin glue (Category A1-B evidence ). RCTs indicate that thrombin gel is effective in reducing
). (Unchanged from the previous guideline) Medical Treatment for ICH Hemostasis and Coagulopathy, Antiplatelets, and Deep Vein Thrombosis Prophylaxis Underlying hemostatic abnormalities can contribute to ICH. Patients at risk include those taking oral anticoagulant drugs (OACs), antiplatelet agents, those with acquired or congenital coagulation factor deficiencies, and those with inherited or acquired qualitative or quantitative platelet abnormalities. Patients taking OACs constitute 12% to 20% of patients (...) to <1.5. rFVIIa, licensed to treat hemophilia patients with high titer inhibitors or congenital factor VII deficiency, has garnered attention as a potential treatment for spontaneous and OAC-associated ICH. Although rFVIIa can rapidly normalize INR in the setting of VKA-associated ICH, it does not replenish all of the vitamin K–dependent factors and may not restore thrombin generation as effectively as PCCs. Thus, rFVIIa is not currently recommended for routine use in warfarin reversal. New
effects, including dose-dependent inhibition of platelet function, suppression of plasma coagulation, and enhancement of fibrinolysis. Secondary hemostasis and thrombus stability is also impaired, due to aspirin’s acetylation of fibrinogen and its enhancement of fibrinolysis. Aspirin, unlike non–aspirin NSAIDs, decreases thrombin formation in clotting blood. Aspirin at higher doses prevents endothelial cell prostacyclin production by inhibiting COX-2. Prostacyclin inhibits platelet coagulation
and function of PEVs generated following traumatic injury.PEV content and quantity in circulation following trauma in humans and mice was measured using flow cytometry, size exclusion chromatography, and nanoparticle tracking analysis. PEVs were isolated from circulation and the effects on thrombin generation, bleeding time, hemorrhage control, and thrombus formation were determined. Finally, the effect of hydroxychloroquine (HCQ) on PEV release and thrombosis were examined.Human and murine trauma results (...) in a significant release of PEVs into circulation compared with healthy controls. These PEVs result in abundant thrombin generation, increased platelet aggregation, decreased bleeding times, and decreased hemorrhage in uncontrolled bleeding. Conversely, PEVs contributed to enhanced venous thrombus formation and were recruited to the developing thrombus site. Interestingly, HCQ treatment resulted in decreased platelet aggregation, decreased PEV release, and reduced deep vein thrombosis burden in mice.These data
All-Trans Retinoic Acid Impairs Platelet Function and Thrombus Formation and Inhibits Protein Kinase CßI/δ Phosphorylation. All-trans retinoic acid (ATRA) is widely used for induction of complete remission in patients with acute promyelocytic leukemia (APL). ATRA also regulates protein kinase C (PKC) activity. Therapeutic use of ATRA reportedly interferes with hemostatic function in APL patients, including effects on coagulation or other vascular cells, although effects of ATRA on platelets (...) and adenosine triphosphate release induced by collagen (5 μg/mL) or thrombin (0.05 U/mL) in a dose-dependent manner without affecting P-selectin expression or surface levels of glycoprotein (GP) Ibα, GPVI, or αIIbβ3. ATRA-treated platelets demonstrated reduced spreading on immobilized fibrinogen or collagen and reduced thrombin-induced clot retraction together with reduced phosphorylation of Syk and PLCγ2. In addition, ATRA-treated mice displayed significantly impaired hemostasis and arterial thrombus
Hemostasis stimulates lymphangiogenesis through release and activation of VEGFC. Hemostasis associated with tissue injury is followed by wound healing, a complex process by which damaged cellular material is removed and tissue repaired. Angiogenic responses are a central aspect of wound healing, including the growth of new lymphatic vessels by which immune cells, protein and fluid are transported out of the wound area. The concept that hemostatic responses might be linked to wound healing (...) responses is an old one, but demonstrating such a link in vivo and defining specific molecular mechanisms by which the two processes are connected has been difficult. In the present study we demonstrate that the lymphangiogenic factors VEGFC and VEGFD are cleaved by thrombin and plasmin, serine proteases generated during hemostasis and wound healing. Using a new tail wounding assay to test the relationship between clot formation and lymphangiogenesis in mice, we find that platelets accelerate lymphatic