Rare inherited coagulation disorders and thrombosis

Abstract

The traditional clinical paradigm of rare inherited coagulation disorders (RICDs) implies that reduced levels of coagulation factors increase the bleeding tendency, although the relationship between factor activity and clinical phenotype is often variable and disease-related. However, emerging evidence suggests a more complex coagulation balance in RICD, so that a few inherited factor deficiencies predispose patients to arterial thrombosis and venous thromboembolism (VTE). By synthesizing data from international registries, clinical trials and biochemical studies, this review explores the molecular and clinical mechanisms underlying the thrombotic risk in RICDs, including deficiencies of factors II, V, VII, XI, XII, XIII and fibrinogen disorders. We show how some molecular variants disrupt the interplay between procoagulant, anticoagulant, and fibrinolytic pathways. For instance, while FXII and FXI deficiencies are increasingly viewed as protective against thrombosis, in some dysprothrombinemias and dysfibrinogenemias the impairment of anticoagulant regulatory mechanisms lead to increased thrombin generation. In disorders such as FXIII deficiency and afibrinogenemia, mechanical clot instability and loss of thrombin sequestration are proposed as potential mechanisms contributing to an increased risk of thrombotic events. This increased risk is often triggered or exacerbated by replacement therapies, co-inherited thrombophilia, or acquired factors. Understanding the underlying molecular mechanisms is essential to manage patients at risk for both life-threatening hemorrhage and thrombosis. Ultimately, a personalized approach is required to optimize bleeding prophylaxis and as well as episodic treatment.