Mohsenian Samin, Casini Alessandro, Peyvandi Flora
Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy.
Division of Angiology and Hemostasis, Faculty of Medicine, Geneva University Hospitals, Geneva, Switzerland.
Res Pract Thromb Haemost. 2025 Jul 22;9(5):102979. doi: 10.1016/j.rpth.2025.102979. eCollection 2025 Jul.
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.
先天性纤维蛋白原缺乏症（CFDs）是一类罕见的遗传性疾病，其特征为纤维蛋白原存在数量（无纤维蛋白原血症、低纤维蛋白原血症）或质量（异常纤维蛋白原血症、低异常纤维蛋白原血症）异常。虽然CFDs通常与出血相关，但动脉和静脉血栓形成的矛盾风险正越来越受到认可。提出的机制包括由于缺乏纤维蛋白形成导致凝血酶清除受损，以及结构异常的纤维蛋白凝块促进凝血酶释放到循环中或阻碍纤维蛋白溶解。在无纤维蛋白原血症中，纤维蛋白原的缺乏导致循环中游离凝血酶增加，而在异常纤维蛋白原血症中，结构异常的纤维蛋白原增加血栓形成风险。内在因素如特定的纤维蛋白原变体（如杜萨特、波尔多）会改变纤维蛋白结构并损害凝血酶或纤溶酶相互作用，从而促进异常凝块形成和纤维蛋白溶解减少。共同遗传的促血栓形成突变可能进一步增加血栓形成风险。此外，获得性因素，包括纤维蛋白原替代治疗、手术、创伤、妊娠和制动，是公认的外在风险因素。CFDs中血栓形成的发病机制是多因素的，尚未完全阐明。管理CFDs中的血栓形成是一项临床挑战，需要在出血和血栓形成风险之间仔细权衡。抗凝与纤维蛋白原替代可能是必要的，但必须个体化。虽然纤维蛋白原替代主要具有促血栓形成潜力，但一些研究表明它可能改善无纤维蛋白原血症中的凝血酶调节。值得注意的是，目前的证据有限，大多来自病例报告。本综述概述了关于CFDs中血栓形成的流行病学、潜在机制和临床管理的现有证据，强调了知识空白以及需要更多研究为临床医生提供信息并改善患者结局。
