Inherited Abnormalities of Fibrinogen Workup

Updated: Apr 20, 2023
  • Author: Suchitra S Acharya, MD, MBBS; Chief Editor: Cameron K Tebbi, MD  more...
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Laboratory Studies

The prevalence of fibrinogen disorders is uncertain, and some fibrinogen deficiencies and dysfunction are not detected by standard anticoagulation screening tests; the prothrombin time (PT) and activated partial thromboplastin time (aPTT) are normal provided some fibrinogen is available for clot formation. Even in fully specialized coagulation laboratories, the diagnosis of some fibrinogen disorders can be quite challenging. Precise detection of one or more molecular defects in some cases can provide a more accurate prenatal or postnatal diagnosis and identify patients at risk for thrombosis rather than bleeding. [18]

Screening tests

PT and aPTT are prolonged in afibrinogenemia and may be prolonged in hypofibrinogenemia and dysfibrinogenemia. However, these tests have a poor sensitivity to mild fibrinogen deficiency or dysfunction.

In testing for thrombin time, a reagent containing thrombin is added to citrated plasma and the time to clot formation is measured. The thrombin time is prolonged by fibrin degradation products (FDPs), afibrinogenemia, hypofibrinogenemia, dysfibrinogenemia, thrombin inhibitors, bovine thrombin antibodies from previous exposure to bovine thrombin, and high concentrations of serum proteins (multiple myeloma). This test is more sensitive than PT or aPTT for quantitative and qualitative defects in fibrinogen. However, the specificity is poor because a prolonged thrombin time can occur in the presence of heparin, high concentration of FDPs, and direct thrombin inhibitors. Furthermore, results can significantly vary between laboratories as the test is not standardized.

A study by Jacquemin et al indicated that qualitative fibrinogen abnormalities can be distinguished from quantitative ones by analyzing the amplitude of coagulation curves derived from thrombin time tests. The investigators found that in patients with dysfibrinogenemia caused by a p.Arg301(275)Cys substitution (resulting from a heterozygous point mutation in the fibrinogen molecule’s γ polypeptide chain), the coagulation curve amplitudes were similar to those associated with persons with no fibrinogen disorder. In patients with acquired hypofibrinogenemia, however, the amplitudes were lower than in the rest of the cohort. [19]

A snake venom that directly activates fibrinogen by cleaving fibrinopeptide A is used as a reagent in the reptilase time test. The advantage over the thrombin time is that this test is not affected by heparin. A prolonged reptilase time, in the presence of a normal fibrinogen concentration, provides strong evidence of a dysfibrinogenemia. However, this test does not detect all forms of dysfibrinogenemia. Elevated fibrinogen levels due to an acute phase reaction can be associated with prolonged reptilase times, possibly due to increased sialyation and/or phosphorylation. [20]

Clottable fibrinogen

A functional assay by the Clauss method is one of the most common tests used to measure fibrinogen activity. In this method, a reagent containing a high concentration of thrombin that triggers clot formation when added to citrated plasma is used. The time to clot formation is recorded and is read off of a reference curve for tests performed with known concentrations of fibrinogen. Most laboratories these days perform this test on instruments with a photo-optical endpoint analyzer, and lipemia and/or hyperbilirubinemia may interfere with this assay.

Fibrinogen antigen

Various immunoassays are commercially available for the quantitative measurement of fibrinogen assay. These assays do not assess fibrinogen function. In afibrinogenemia, fibrinogen concentrations are low using the clottable or quantitative antigen method, usually less than 0.1 g/L, and often undetectable in symptomatic individuals. In dysfibrinogenemia, a discrepancy may be found between fibrinogen measured in a functional assay (low) and fibrinogen measured immunologically (normal); however, in some dysfibrinogenemias, a concordant decrease in the 2 assays is observed. A fibrinogen antigen–to–clottable fibrinogen ratio may help to distinguish dysfibrinogenemia (high ratio) from hypofibrinogenemia (ratio close to 1). [21]


Genotyping identification of the specific molecular defect may be useful in both afibrinogenemia and dysfibrinogenemia. Mutation analysis has not identified any correlation with phenotype or ethnic background. However, it can be useful in diagnosis confirmation, screening of relatives for carrier status, family counseling, and prenatal diagnosis. A review of all available clinical and genetic data from 50 homozygous afibrinogenemic patients demonstrated no clear genotype/phenotype correlations. [6] One possible explanation for this variability is the existence of modifier genes or alleles. Some variants may increase the severity of bleeding whereas others may ameliorate the phenotype. Such modifiers have yet to be identified; however, common variants predisposing to thrombophilia may have a role in decreasing the severity of bleeding. [22]

Thrombophilia evaluation

Because dysfibrinogenemia is a rare cause of thrombosis (< 1%), patients in whom dysfibrinogenemia is diagnosed in the setting of thrombosis should have a complete investigation for other risk factors, inherited and acquired, that may have contributed to the thrombotic event.


Imaging Studies

In the investigation of suspected bleeding, appropriate imaging studies (eg, brain CT scanning or MRI) may reveal the presence of suspected central nervous system (CNS) hemorrhage.