The thrombotic paradox in congenital fibrinogen deficiencies: from pathophysiology to practice

Congenital fibrinogen deficiencies (CFDs) comprise rare inherited disorders characterized by quantitative (afibrinogenemia, hypofibrinogenemia) or qualitative (dysfibrinogenemia, hypodysfibrinogenemia) abnormalities of fibrinogen. While CFDs are typically associated with bleeding, a paradoxical risk of both arterial and venous thrombosis is being increasingly recognized. Proposed mechanisms include impaired thrombin clearance due to a lack of fibrin formation and structurally abnormal fibrin clots that promote thrombin release into the circulation or hinder fibrinolysis. In afibrinogenemia, the absence of fibrinogen leads to increased circulating free thrombin, while in dysfibrinogenemia, structurally abnormal fibrinogen enhances thrombotic risk. Intrinsic factors such as specific fibrinogen variants (eg, Dusart, Bordeaux) alter the fibrin structure and impair thrombin or plasmin interactions, thus promoting abnormal clot formation and reduced fibrinolysis. Coinherited prothrombotic mutations may further increase thrombotic risk. Moreover, acquired factors, including fibrinogen replacement therapy, surgery, trauma, pregnancy, and immobilization, are recognized extrinsic risk factors. The pathogenesis of thrombosis in CFDs is multifactorial and not fully elucidated. Managing thrombosis in CFDs is a clinical challenge, requiring careful balance between the risk of bleeding and thrombosis. Anticoagulation alongside fibrinogen replacement may be necessary, but must be individualized. Although fibrinogen replacement primarily carries prothrombotic potential, some studies suggest it may improve thrombin regulation in afibrinogenemia. Notably, current evidence is limited and mostly derived from case reports. This review provides an overview of the existing evidence on the epidemiology, underlying mechanisms, and clinical management of thrombosis in CFDs, highlighting knowledge gaps and the need for additional research to inform clinicians and improve patient outcomes.