An inherited bleeding syndrome resulting from an absence of fibrinogen.
Familial Afibrinogenemia; Familial Hypofibrinogenemia; Familial Dysfibrinogenemia.
Estimated to be in the range of 1-2:1,000,000 live births. No racial or sexual predilection has been reported.
Autosomal recessive. A high rate of consanguinity in the parents of affected children has been reported. The defects are caused by mutations in the Fibrinogen Alpha, Beta, or Gamma Polypeptide genes, which have been mapped to chromosome 4q31.3 (α and β) and 4q32.1 (γ), respectively.
The fibrinogen molecule is a hexamer consisting of three polypeptide chain pairs (α, β, γ). Each chain is controlled by a different gene, with all genes located on chromosome 4. Congenital afibrinogenemia is caused by defective fibrinogen synthesis in the liver. It can be caused by mutations in any of the three genes, but the most common mutation affects the fibrinogen α-gene. The genetic defect leads to errors in the assembly of the hexamer and problems with its secretion from the hepatocytes. Complete (homozygous type) or partial (heterozygous type) absence of fibrinogen results in mild-to-severe bleeding. Conversion of fibrinogen to fibrin by thrombin plays a crucial role in clot formation. It further affects primary hemostasis with platelet aggregation by binding to glycoprotein IIb/IIIa on the surface of activated platelets.
The homozygous form is often lethal and diagnosed at birth secondary to severe bleeding from the umbilical stump. Other common presentations include splenic rupture, osseous hemorrhages, and hepatic hemorrhage. Surprisingly, some affected persons have only minor bleeding complications. Diagnosed by proof of partial or complete afibrinogenemia in blood samples, and prolonged bleeding time, prothrombin time (PT), and activated partial thromboplastin time (PTT).
Bleeding may be mild to severe and affect the gastrointestinal tract, the cranial vault and central nervous system, the joints (hemarthros), the bones (osseous hemorrhages), the liver (hepatic hemorrhage), and the spleen (rupture). Death is most often attributable to postoperative bleeding and/or intracranial hemorrhage. Recurrent spontaneous abortions (most commonly between 6 and 8 weeks of gestation in the absence of fibrinogen replacement therapy) and heavy menstrual bleeding (menorrhagia) have been described in women with congenital afibrinogenemia. Fibrinogen is also involved in maintaining the integrity of placental implantation during pregnancy and fibrinogen levels of at least 0.6 g/L (better 1.0 g/L) have been recommended and treatment should be started before 5 weeks of gestation. For delivery (spontaneous or cesarean section), the fibrinogen level should be maintained at 1.5 g/L (better 2.0 g/L) with continuous infusion of fibrinogen. A higher risk of thromboembolic events has been described in a few patients and is most often associated with fibrinogen replacement therapy. There seems to be a fine balance ...