Inherited dysfibrinogenemia: clinical phenotypes associated with five different fibrinogen structure defects

Abstract

Hereditary dysfibrinogenemia is a rare clotting disorder, which results from mutations in at least one of the three fibrinogen genes. We examined the frequency of hemostatic clinical and laboratory anomalies at presentation of 37 probands from 12 unrelated families with five different defects (Aalpha R16C, gamma A357T, gamma318-319 del, gamma M310T, and Aalpha R16S), among. The median age was 51 years (11-86 years). Among 62% who were women three (13%) had experienced one or more spontaneous abortion. More than half of the probands had experienced one or more undue bleeding episode, easy bruising being by far the most common. In 19% of probands (9/37, all above age of 50 years), had experienced at least one episode of arterial or venous thrombosis. Among these, were two (7%) with deep venous thrombosis, seven with arterial thrombosis, and five (14%) had experienced both. We propose that the higher frequency of prolonged PT than aPTT, in ours and in other reported studies, reflects the polymerization delay, which in aPTT is attenuated owing to contact activation prior to calcium addition.

Aetiology of Venous Thrombosis

“…Fibrinogen is encoded by three genes on chromosome 4 (Acharya & Dimichele, 2008;Miesbach et al, 2010). Genetic abnormalities in the fibrinogen genes may lead to lower or no production of fibrinogen (quantitative defects), causing bleeding problems in patients.…”

“…Dysfibrinogenaemia was first reported in 1965 (Beck et al, 1965). Around 60% of cases show no clinical manifestations, while 20% show bleeding problems and 20% show thrombosis (Ehsan & Plumbley, 2002;Miesbach et al, 2010). There are at least 15 different genetic defects affecting the fibrinogen gene that were associated with Dysfibrinogenaemia (Bertina, 1997;Miesbach et al, 2010;).…”

“…Around 60% of cases show no clinical manifestations, while 20% show bleeding problems and 20% show thrombosis (Ehsan & Plumbley, 2002;Miesbach et al, 2010). There are at least 15 different genetic defects affecting the fibrinogen gene that were associated with Dysfibrinogenaemia (Bertina, 1997;Miesbach et al, 2010;). Still, Dysfibrinogenaemia remains a very rare disorder (1% of VTE cases) and more cases should be studied to fully understand the disease (Manucci, 2000;Acharya & Dimichele;2008).…”

Management of Inherited Bleeding Disorders in Pregnancy

“…122,131,189,190 Partial quantitative (hypofibrinogenaemia), with or without qualitative defects (dysfibrinogenaemia), can be autosomal dominant in inheritance and may be asymptomatic or associated with a variable risk of bleeding and/or venous and arterial thrombosis. [191][192][193][194] Poor wound healing and splenic rupture have also been reported with severe and partial fibrinogen deficiency. 193 Laboratory diagnosis of afibrinogenaemia is straightforward, but diagnosis of hypofibrinogenaemia and dysfibrinogenaemia may be unreliable in the neonate, requiring retesting in later life.…”

“…196,200 Case reviews have highlighted that dysfibrinogenaemia is often asymptomatic. 191,192,194 Thrombotic complications are very common in patients with congenital fibrinogen deficiency, with or without fibrinogen replacement therapy. 198 LMWH prophylaxis has been used both antenatally and postpartum.…”