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
● 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
● 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.855–892). Philadelphia, PA: Lippincott Williams & Wilkins.
End of Coagulation > Hereditary thrombophilia / hypercoagulopathies > Dysfibrinogenemia
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