ABSTRACT
A state-of-the-art lecture titled "Factor V variants in bleeding and thrombosis" was presented at the International Society on Thrombosis and Haemostasis (ISTH) congress in 2023. Blood coagulation is a finely regulated cascade of enzymatic reactions culminating in thrombin formation and fibrin deposition at the site of injury. Factor V (FV) plays a central role in this process, as its activated form is an essential procoagulant cofactor in prothrombin activation. However, other molecular forms of FV act as anticoagulant cofactors of activated protein C and tissue factor pathway inhibitor α, respectively, thereby contributing to the regulation of coagulation. This dual procoagulant and anticoagulant character makes FV a central regulator of the hemostatic balance, and quantitative and qualitative alterations of FV may be associated with an increased risk of bleeding or venous thrombosis. Here, we review the procoagulant and anticoagulant functions of FV and the manifold mechanisms by which F5 gene mutations may affect the balance between these opposite functions and thereby predispose individuals to bleeding or venous thrombosis. In particular, we discuss our current understanding of the 3 main pathological conditions related to FV, namely FV deficiency, activated protein C resistance, and the overexpression of FV-short, a minor splicing isoform of FV with tissue factor pathway inhibitor α-dependent anticoagulant properties and an emerging role as a key regulator of the initiation of coagulation. Finally, we summarize relevant new data on this topic presented during the 2023 ISTH Congress.
ABSTRACT
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.
