An inherited bleeding syndrome resulting from an absence
Familial Afibrinogenemia; Familial Dysfibrinogenemia;
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
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