Thromboembolism in patients with congenital afibrinogenaemia

Abstract

Frequent arterial and venous thromboembolism in patients with congenital afibrinogenaemia (CA) is neither understood nor is a safe and effective treatment established. It was our objective to report on the clinical observations and laboratory data contributing to the understanding of the frequency, physiopathology, prognosis and treatment of CA. We observed the long-term clinical course and laboratory data in a cohort of four patients with CA and thromboembolic complications, and conducted a systematic review retrieving all available data. Four patients with CA developed recurrent and extensive arterial and venous thromboembolism (TE) from an age of 25-51 years. In two patients, a treatment strategy targeting at maintaining constantly measurable fibrinogen (Fbg) levels (≥0.5 g/l) either by regular Fbg replacement or by orthotopic liver transplantation resulted in long-term remissions. Radiological imaging documented resolved arterial thrombi after 6-12 months. In contrast, recurrent thromboembolic events were observed in two other patients with infrequent Fbg replacement. A systematic review of the literature revealed 48 reports of TE in patients with CA (median age at first event 31 years), and a favourable outcome in most patients with frequent application of Fbg, aimed at constantly measurable trough levels. Present data suggests that patients with CA are at high risk of arterial and venous thromboembolic events, probably caused by thrombin excess owing to lack of thrombin scavenging by Fbg/fibrin. Regular low-dose Fbg replacement might be a safe and effective treatment option in patients with CA and thromboembolic complications.

Congenital structural and functional fibrinogen disorders: a primer for internists

“…One hypothesis is that the generation of throm bin in a hematoma or during surgery or during pregnancy, without the antithrombin action of fi brin (ie, acting as a trap for circulating thrombin) can lead to strong platelet activation and aggrega tion stimulated by thrombin and endothelial cell injury, which in turn promotes thrombus forma tion and thromboembolic events in both the ve nous and arterial systems. 35 Thrombosis in such patients requires simultaneous supplementation of fibrinogen and administration of anticoagu lants, most often heparins, with close clinical su pervision and laboratory monitoring. Oral direct thrombin inhibitors and antiplatelet agents, in particular vorapaxar, a protease activated recep tor 1 antagonist, might be considered in afibrino genemic patients with recurrent arterial throm boses; however, in most countries, these agents are unavailable and their safety remains contro versial.…”

Clinical Consequences and Molecular Bases of Low Fibrinogen Levels

“…Thrombosis in both venous and arterial sites are a typical complication of afibrinogenemia [ 26 ]. The pathogenesis of thrombus formation has not been elucidated.…”

Human Fibrinogen: Molecular and Genetic Aspects of Congenital Disorders

“…However, it still remains not fully understood how knowledge of the molecular defect may be translated in a clinical event prediction in individuals with fibrinogen disorders. Family and personal history should be taken into account, as well as lifestyle, demographic profile, co-morbidities, and fibrinogen replacement therapy, to attempt to arrange a genotype/phenotype correlation in fibrinogen disorders [ 85 ]. It has been hypothesized that variants in different genes, which are well-established to enhance the risk for thrombosis, e.g., factor V Leiden, could actually modulate the risk for thrombosis or the bleeding phenotype in individuals with congenital fibrinogen disorders.…”