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Factor XIIIa inhibitors as potential novel drugs for venous thromboembolism.

ABSTRACT: Human factor XIIIa (FXIIIa) is a multifunctional transglutaminase with a significant role in hemostasis. FXIIIa catalyzes the last step in the coagulation process. It stabilizes the blood clot by cross-linking the α- and γ-chains of fibrin. It also protects the newly formed clot from plasmin-mediated fibrinolysis, primarily by cross-linking α₂-antiplasmin to fibrin. Furthermore, FXIIIa is a major determinant of clot size and clot's red blood cells content. Therefore, inhibitors targeting FXIIIa have been considered to develop a new generation of anticoagulants to prevent and/or treat venous thromboembolism. Several inhibitors of FXIIIa have been discovered or designed including active site and allosteric site small molecule inhibitors as well as natural and modified polypeptides. This work reviews the structural, biochemical, and pharmacological aspects of FXIIIa inhibitors so as to advance their molecular design to become more clinically relevant.

SUBMITTER: Al-Horani RA

PROVIDER: S-EPMC7513741 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Factor XIIIa inhibitors as potential novel drugs for venous thromboembolism.

Al-Horani Rami A RA Kar Srabani S

European journal of medicinal chemistry 20200518

Human factor XIIIa (FXIIIa) is a multifunctional transglutaminase with a significant role in hemostasis. FXIIIa catalyzes the last step in the coagulation process. It stabilizes the blood clot by cross-linking the α- and γ-chains of fibrin. It also protects the newly formed clot from plasmin-mediated fibrinolysis, primarily by cross-linking α<sub>2</sub>-antiplasmin to fibrin. Furthermore, FXIIIa is a major determinant of clot size and clot's red blood cells content. Therefore, inhibitors target ...[more]

PMID: 32502864

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Project description:BackgroundThere is considerable debate regarding the ideal agent for venous thromboembolism (VTE) prophylaxis after TKA. Numerous studies and meta-analyses have yet to provide a clear answer and often omit one or more of the commonly used agents such as aspirin, warfarin, enoxaparin, and factor Xa inhibitors.Questions/purposesUsing a large database analysis, we asked: (1) What are the differences in VTE incidence in primary TKA after administration of aspirin, warfarin, enoxaparin, or factor Xa inhibitors? (2) What are the differences in bleeding risk among these four agents? (3) How has use of these agents changed with time?MethodsWe queried a combined Humana and Medicare database between 2007 and Quarter 1 of 2016, and identified all primary TKAs performed using ICD-9 and Current Procedural Terminology codes. All patients who had any form of antiplatelet or anticoagulation prescribed within 1 year before TKA were excluded from our study cohort. We then identified patients who had either aspirin, warfarin, enoxaparin, or factor Xa inhibitors prescribed within 2 weeks of primary TKA. Each cohort was matched by age and sex. Elixhauser comorbidities and Charlson Comorbidity Index for each group were calculated. We identified 1016 patients with aspirin, and age- and sex-matched 6096 patients with enoxaparin, 6096 patients with warfarin, and 5080 patients with factor Xa inhibitors. Using ICD-9 codes, with the understanding that patients at greater risk may have had more-attentive surveillance, the incidence of postoperative deep venous thrombosis (DVT), pulmonary embolism (PE), bleeding-related complications (bleeding requiring surgical intervention, hemorrhage, hematoma, hemarthrosis), postoperative anemia, and transfusion were identified at 2 weeks, 30 days, 6 weeks, and 90 days postoperatively. A four-way chi-squared test was used to determine statistical significance. Utilization was calculated using compound annual growth rate.ResultsThere was a difference in the incidence of DVT at 90 days (p < 0.01). Factor Xa inhibitors (2.9%) had the lowest incidence of DVT followed by aspirin (3.0%) and enoxaparin (3.5%), and warfarin (4.8%). There was a difference in the incidence of PE at 90 days (p < 0.01). Factor Xa inhibitors (0.9%) had the lowest incidence of PE followed by enoxaparin (1.1%), aspirin (1.2%), and warfarin (1.6%). There was a difference in the incidence of postoperative anemia at 90 days (p < 0.01). Aspirin (19%) had the lowest incidence of postoperative anemia followed by warfarin (22%), enoxaparin (23%), and factor Xa inhibitors (23%). There was a difference in the incidence of a blood transfusion at 90 days (p < 0.01). Aspirin (7%) had the lowest incidence of a blood transfusion followed by factor Xa inhibitors (9%), warfarin (12%), and enoxaparin (13%). There were no differences in bleeding-related complications (p = 0.81) between the groups. Aspirin use increased at a compound annual growth rate of 30%, enoxaparin at 3%, and factor Xa inhibitors at 43%, while warfarin use decreased at a compound annual growth rate of -3%.ConclusionsFactor Xa inhibitors had the highest growth in utilization during our study period, followed by aspirin, when compared with enoxaparin and warfarin. When selected for the right patient, factor Xa inhibitors provided improved VTE prophylaxis compared with enoxaparin and warfarin, with a lower rate of blood transfusion. Aspirin provided comparable VTE prophylaxis compared with factor Xa inhibitors with improved VTE prophylaxis compared with enoxaparin and warfarin with the lowest risk of bleeding.Level of evidenceLevel III, therapeutic study.

Project description:Venous thromboembolism (VTE) is a common cause of mortality and disability in hospitalized patients, and anticoagulation is an essential therapeutic option. Despite the increasing use of direct oral anticoagulants, complications and adverse drug reactions still occur in patients with VTE. Within 5 years, 20% of patients with VTE experience recurrence, and 50% of patients with deep vein thrombosis develop post-thrombotic syndrome. Furthermore, bleeding due to anticoagulants is a side effect that must be addressed. Therefore, safer and more effective anticoagulant strategies with higher patient compliance are urgently needed. Available epidemiological evidence and animal studies have shown that factor XI (FXI) inhibitors can reduce thrombus size and loosen the thrombus structure with a relatively low risk of bleeding, suggesting that FXI has an important role in thrombus stabilization and is a safer target for anticoagulation. Recent clinical trial data have also shown that FXI inhibitors are as effective as enoxaparin and apixaban in preventing VTE, but with a significantly lower incidence of bleeding. Furthermore, FXI inhibitors can be administered daily or monthly; therefore, the monitoring interval can be longer. Additionally, FXI inhibitors can prolong the activated partial thromboplastin time without affecting prothrombin time, which is an easy and common test used in clinical testing, providing a cost-effective monitoring routine for patients. Consequently, the inhibition of FXI may be an effective strategy for the prevention and treatment of VTE. Enormous progress has been made in the research strategies for FXI inhibitors, with abelacimab already in phase III clinical trials and most other inhibitors in phase I or II trials. In this review, we discuss the challenges of VTE therapy, briefly describe the structure and function of FXI, summarize the latest FXI/activated FXI (FXIa) inhibitor strategies, and summarize the latest developments in clinical trials of FXI/FXIa inhibitors.

Project description:Factor XIIIa (FXIIIa) is a cysteine transglutaminase that catalyzes the last step in the coagulation process. An anion-binding site inhibition of FXIIIa is a paradigm-shifting strategy that may offer key advantages of controlled inhibition. Such an approach is likely to lead to novel FXIIIa inhibitors that do not carry bleeding risks. We previously reported a flavonoid trimer-based allosteric inhibitor of FXIIIa with moderate potency and selectivity. To further advance this approach, we evaluated a series of 27 variably sulfonated heparin mimetics against human FXIIIa. Only 13 molecules exhibited inhibitory activity at the highest concentration tested with IC50 values of 2-286 μM. Specifically, inhibitor 16 demonstrated an IC50 value of 2.4 ± 0.5 μM in a bisubstrate, fluorescence-based trans-glutamination assay. It also demonstrated a significant selectivity over other clotting factors including thrombin, factor Xa, and factor XIa as well as other cysteine enzymes including papain and tissue transglutaminase 2. Inhibitor 16 did not affect the viability of three human cell lines at a concentration that is 5-fold its FXIIIa-IC50. The molecule had a very weak effect on the activated partial thromboplastin time of human plasma at a concentration of >700 μM, further supporting its functional selectivity. Importantly, molecule 16 inhibited FXIIIa-mediated polymerization of fibrin(ogen) in a concentration-dependent manner as shown by the gel electrophoresis experiment. Michaelis-Menten kinetics revealed that the molecule competes with the Gln-donor protein substrate, i.e., dimethylcasein, but not with the Lys-donor small substrate, i.e., dansylcadaverine. Molecular modeling studies revealed that this type of molecule likely binds to an anion-binding site comprising the basic amino acids of Lys54, Lys61, Lys73, Lys156, and Arg244 among others. Overall, our work puts forward a new anion-binding site, selective, nontoxic, sulfonated heparin mimetic FXIIIa inhibitor 16 for further development as an effective and safer anticoagulant.

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Factor XIIIa inhibitors as potential novel drugs for venous thromboembolism.

Publications

Factor XIIIa inhibitors as potential novel drugs for venous thromboembolism.

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