Congenital Afibrinogenemia

An inherited bleeding syndrome resulting from an absence of fibrinogen.

Familial Afibrinogenemia; Familial Dysfibrinogenemia; Familial Hypofibrinogenemia.

Approximately 150 cases have been described in the medical literature. The incidence is estimated to be 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 mutations have been mapped to 4q28.

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 results from a 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.

The homozygous form often is lethal and is 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 troubles. Diagnosed by 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 intracranial hemorrhage. Recurrent spontaneous abortions (most commonly between 6 and 8 weeks of gestation if no fibrinogen replacement therapy is used) and heavy menstrual bleeding have been described in women with congenital afibrinogenemia. During pregnancy where fibrinogen is also involved in maintaining the integrity of placental implantation, fibrinogen levels of at least 0.6 g/liter (better 1.0 g/liter) have been recommended and should be started before 5 weeks of gestation. For delivery (spontaneous or cesarean section), the fibrinogen level should be maintained at 1.5 g/liter (better 2.0 g/liter) with a continuous infusion of fibrinogen.

Obtain bleeding history, serum fibrinogen levels, PT, PTT, bleeding time, and a complete blood count with differentiation. Consider hematology consultation. Since these patients are exposed to recurrent transfusions, they have a higher risk for transfusion related diseases (e.g., hepatitis, HIV).

Patients are at high risk for severe hemorrhage in the perioperative period because of partial or complete incoagulability of the blood. Regional anesthesia in general and central neuraxial blockade in particular should be avoided. Fibrinogen serum levels usually are less than 0.1 g/liter, and increasing it perioperatively to at least 0.5 g/liter (better 1.0 g/liter) is recommended. Either fibrinogen concentrate or cryoprecipitate can be used to achieve this level. Fresh-frozen plasma also can be used, but significant amounts are required to bring the fibrinogen level in the desired range. The half-life of fibrinogen is approximately 4 to 7 days.

Fibrinogen replacement therapy in the form of fresh-frozen plasma, cryoprecipitate, or fibrinogen concentrate prior to surgery usually is required.