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Hereditary thrombophilia / hypercoagulopathies


Reviewer: Jeremy Parsons, M.D. (see Reviewers page)
Revised: 20 June 2012, last major update June 2012
Copyright: (c) 2002-2012, PathologyOutlines.com, Inc.


● Disorders of fibrinogen structure (over 350 described)
● Have variable effects on function (25% associated with bleeding, 20% associated with thrombosis, 55% have no symptoms or prolonged thrombin time)
● Bleeding due to defective fibrin clot formation (impaired release of fibrinopeptides A or B and impaired fibrin monomer polymerization)
● Thrombosis due to:
      (a) defective thrombin binding to fibrin, causing increased thrombin in circulation and more thrombosis
      (b) defective binding of tPA or plasminogen to fibrin or fibrin resistance to plasmin; includes Dusart (Paris V) and Chappel Hill III dysfibrinogens that are resistant to degradation by plasmin
● Congenital (hereditary) dysfibrinogenemia is a rare cause of hypercoagulability (350 reported cases, 0.8% of patients with venous thrombosis); usually due to single amino acid substitutions in fibrinogen Aalpha, Bbeta or gamma genes
● Recommended to use only as a second-line test in patients with thrombosis since dysfibrinogenemia is so rare
● Autosomal dominant inheritance, but higher incidence in women due to pregnancy related thrombosis, particularly post-partum and in venous lower extremities, at mean age 27 years
● Also associated with spontaneous abortions

Laboratory testing

● Primary screening test is thrombin time (prolonged except for fibrinogens Oslo I and Valhalla - shortened)
● Prolongation may also be due to heparin, heparin-like inhibitors, fibrin degradation products, hypofibrinogenemia, excess fibrinogen, paraproteins, excess protamine, anti-fibrinogen antibodies, anti-bovine thrombin antibodies, systemic amyloidosis, acquired dysfibrinogenemia
● The sensitivity of thrombin time assays varies for dysfibrinogenemia because many assays are designed primarily to detect heparin contamination
● Some labs use the reptilase time, which is not affected by heparin

Confirmatory test (if thrombin time or reptilase time is prolonged):
● Fibrinogen activity-antigen ratio below reference range
● Activity measured by Clauss method (rate of clot formation after adding high concentration of thrombin to citrated plasma
● Use standard curve relating clotting time to plasma of known fibrinogen activity)
● Antigen concentration determined by ELISA, radial immunodiffusion, precipitation or thrombin clotting methods
● Perform both tests on same sample in same laboratory and using method-specific reference ranges

● Similar laboratory test abnormalities in family members
● If necessary, demonstrate abnormal structure or function of fibrinogen

Diagnosis of acquired dysfibrinogenemia:
● Abnormal liver function tests, no dysfibrinogenemia in family members

Additional references

Arch Pathol Lab Med 2002;126:1387, Arch Pathol Lab Med 2002;126:499
McDonagh, J. (2001). Dysfibrinogenemia and other disorders of fibrinogen structure or function. In R. Colman, J. Hirsh, V. Marder, A. Clowes, J. George, Hemostasis and Thrombosis (4th ed.) (pp.855892). Philadelphia, PA: Lippincott Williams & Wilkins.

End of Coagulation > Hereditary thrombophilia / hypercoagulopathies > Dysfibrinogenemia

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