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2156 Part XII: Hemostasis and Thrombosis Chapter 125: Hereditary Fibrinogen Abnormalities 2157

can be reversed upon addition of fibrinogen. Because fibrinogen is one Global assays, such as thromboelastography and thrombin gener-
of the main determinants of erythrocyte sedimentation, it is not surpris- ation test, may provide a complementary and in some cases a better
ing that afibrinogenemic patients have very low erythrocyte sedimenta- evaluation of an individual’s hemostatic state. Such global assays could
tion rates. When skin testing is performed for delayed hypersensitivity, be useful for the design of individual therapeutic strategies. 67
there is no induration because of the lack of fibrin deposition.
Hypofibrinogenemia is defined as a proportional decrease of func-
tional and immunoreactive fibrinogen. Coagulation tests depending on DIFFERENTIAL DIAGNOSIS
the formation of fibrin as well as the assays used are variably prolonged, Inherited afibrinogenemia and hypofibrinogenemia have to be distin-
the most sensitive assay being the TT. guished from acquired disorders. These include disseminated intra-
vascular coagulation, primary fibrinolysis, liver disease, and can be
Genotype Analysis caused by certain drugs (e.g., thrombolytic agents and l-asparaginase).
The large number of mutations identified in patients with afibrinogen- In addition, one should be aware that artifactually low levels of fibrin-
emia allows the design of an efficient flow-chart for mutation detection ogen can be observed with samples that have clotted as a result of
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in new cases. Two common mutations are found in individuals of improper collection. In most cases, the clinical context as well as the
European origin, both in FGA: the c.510+1G→T intron 4 donor splice- association with other laboratory abnormalities will allow differenti-
site mutation and the FGA 11-kb deletion, both found on multiple hap- ation of inherited from acquired disorders. Identification of a caus-
lotypes. In all new patients of European origin, the FGA c.510+1G→ ative mutation in one of the three fibrinogen genes will confirm the
T should be the first mutation to be screened. Southern blot or poly- diagnosis.
merase chain reaction (PCR) analysis of the FGA 11-kb deletion should
also be performed, because it is the second most common mutation in
patients of European origin and because of the risk of diagnostic error: THERAPY
a nonconsanguineous patient who appears to be homozygous for a Available Treatments and Modalities
mutation in FGA exons 2 to 6 may in reality be a heterozygous carrier Replacement therapy is effective in treating bleeding episodes in con-
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of the large 11-kb deletion. Given the high frequency of mutations in genital fibrinogen disorders. Depending on the country of residence,
FGA, the other FGA exons (starting with exon 5) should then be stud- patients receive fresh-frozen plasma (FFP), cryoprecipitate, or fibrino-
ied for mutations before screening FGB (starting with exon 8) and FGG gen concentrates. Fibrinogen concentrate preparations include safety
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(starting with exons 7 and 8). The same strategy can also be applied to steps for inactivation or removal of viruses, which make them safer
afibrinogenemic patients of non-European origin for whom recurrent than cryoprecipitate or FFP. Furthermore, more precise dosing can be
mutations have yet to be identified. If the patient comes from a geo- accomplished with fibrinogen concentrates because their potency is
graphical region or population in which a mutation has already been known, in contrast to FFP or cryoprecipitates.
identified, that mutation should be the first to be screened for. Screen- The conventional treatment is on demand, in which fibrinogen
ing of patients with hypofibrinogenemia can follow the same strategy is administered as soon as possible after onset of bleeding. Another
apart from patients with ER fibrinogen-positive liver inclusions, for approach is primary prophylaxis that includes administration of fibrin-
which four mutations in FGG are known so far to cause hepatic storage ogen concentrates from an early age to prevent bleeding and, in the case
disease. of pregnancy, to prevent miscarriage. Effective long-term secondary
Prenatal diagnosis has been performed in a few cases. This is prophylaxis with administration of fibrinogen every 7 to 14 days (par-
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important for families with afibrinogenemia and access to adequate ticularly after central nervous system bleeds) has been advocated. The
treatment because the prenatal diagnosis of an affected infant allows frequency and dose of fibrinogen concentrates should be adjusted to
initiation of treatment immediately after birth before the first bleeding maintain a level above 0.5 g L .
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manifestation. The United Kingdom guidelines on therapeutic products for coag-
ulation disorders provide recommendations about the best treatment
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Genotype–Phenotype Correlations: Potential Importance options (dosage, management of bleeding, surgery and pregnancy as
of Global Assays well as prophylaxis). According to these guidelines, in case of bleed-
Current diagnostic tests are appropriate for establishing the diagnosis ing fibrinogen levels should be increased to 1.0 g L and maintained
−1
but clearly additional tests are required for a more accurate prediction above this threshold until hemostasis is secured, and above 0.5 g L
−1
of the clinical phenotype of a patient and consequently the appropri- until wound healing is complete. To increase the fibrinogen concentra-
ate treatment. Indeed, although in afibrinogenemia all patients have tion of 1 g L , a dose of approximately 50 mg/kg is required. The doses
−1
unmeasurable functional fibrinogen, the severity of bleeding is highly and duration of treatment also vary depending on the type of injury or
variable amongst patients, even amongst those with the same genotype. operative procedure and on the patient’s personal and familial history of
Similarly, there is no clear relationship between the molecular defect bleeding and thrombosis.
and the risk of thrombosis. Women with congenital afibrinogenemia are able to conceive and
One possible explanation for the observed variability of clinical embryonic implantation is normal, but the pregnancy usually results
manifestations is the existence of modifier genes/alleles: some variants in spontaneous abortion at 5 to 8 weeks of gestation unless fibrinogen
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may increase the severity of bleeding while others may ameliorate the replacement is given. Maintaining the fibrinogen level above 0.6 g L
−1
−1
phenotype. Such modifiers have yet to be identified. However, the com- and if possible higher than 1.0 g L is recommended. Lower fibrinogen
−1
mon thrombophilias (e.g., factor V Leiden) most certainly play a role in concentrations (<0.4 g L ) have proven adequate to maintain pregnancy
decreasing the severity of bleeding. The existence of modifying genes/ but not to avoid hemorrhagic complications. Continuous infusion of
polymorphisms is also strongly suspected in the previously discussed fibrinogen concentrate should be performed during labor to main-
−1
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cases of hypofibrinogenemia associated with fibrinogen inclusion bod- tain fibrinogen higher than 1.5 g L (ideally greater than 2.0 g L ).
ies in hepatocytes. Indeed, all individuals heterozygous for one of the Thromboembolic events can occur, particularly with the use of cryo-
four FGG causative mutations have hypofibrinogenemia, but not all precipitates that contain appreciable quantities of factor VIII and von
have fibrinogen aggregates and associated liver disease. Willebrand factor in addition to fibrinogen.

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