Dysfibrinogenemia
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Fibrinogen disorders are rare conditions that are classified as either qualitative (type II) or quantitative (type I). Dysfibrinogenemia is a term used to describe a qualitative (ie, functional) fibrinogen disorder wherein abnormality in the fibrin molecule results in defective fibrin clot formation. The other qualitative fibrinogen disorder, hypodysfibrinogenemia, is characterized by both defective clot formation and reduced fibrinogen antigen levels.
In quantitative fibrinogen disorders, only the amount of fibrinogen in circulation is affected. Hypofibrinogenemia is characterized by low fibrinogen levels, whereas afibrinogenemia, an autosomal recessive disease, is characterized by the complete deficiency of fibrinogen. [1]
Congenital dysfibrinogenemia can be inherited in an autosomal-dominant, codominant, or autosomal-recessive pattern affecting the fibrinogen alpha, fibrinogen beta, or fibrinogen gamma genes. More than 100 mutations that result in the phenotype of abnormal fibrinogen have been identified; over 90% of those are point missense mutations. [2]
Dysfibrinogenemia may also be acquired. Chronic liver disease is the most common cause; up to 50% of patients with severe liver disease secondary to cirrhosis, hepatoma, or hepatitis exhibit bleeding complications. [3] Other causes of acquired dysfibrinogenemia include chronic malignancies and autoimmune diseases. A case of acquired dysfibrinogenemia caused by an autoantibody that inhibited fibrin polymerization in a patient previously diagnosed with MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, strokelike episodes) has also been reported. [4]
Individuals with fibrinogen disorders may be asymptomatic or may experience bleeding or thrombotic events (or, rarely, in congenital dysfibrinogenemias, both simultaneously). Clinical manifestatoins that do occur are generally mild, but may be life threatening in severity. (See Presentation.)
In the clotting cascade, the various blood coagulation factors function in concert to produce a balance between fibrin clot formation and its subsequent degradation. When any factor in the cascade is absent, decreased, or abnormal, the delicate balance is disrupted, possibly leading to bleeding or thrombotic disorders. The clinical manifestations range from no symptoms to life-threatening events, depending on which coagulation factor is affected and the degree to which it is affected.
In normal fibrin clot formation, a fibrin monomer forms after thrombin cleaves fibrinopeptide A and B from the alpha and beta chains of the fibrinogen molecule. The fibrin monomer, which is insoluble, aggregates spontaneously into fibrin polymer. Factor XIIIa then catalyzes the cross-linkage between different fibrin chains, forming a stabilized fibrin polymer or clot. Eventually, plasmin lyses the fibrin clot.
Acquired dysfibrinogenemia occurs most often in patients with severe liver disease. The impairment of fibrinogen, which is synthesized in the liver, is due to a structural defect caused by an increased carbohydrate content that interferes with the polymerization of the fibrin, depending on the degree of abnormality of the fibrinogen molecule. Rarely, dysfibrinogenemia may also be associated with malignancies, most commonly primary or secondary liver tumors, but acquired dysfibrinogenemia has also been reported in patients with renal cell carcinoma.
One of the rarer disorders of coagulation is congenital dysfibrinogenemia, a qualitative abnormality of the fibrin molecule. Multiple variations of these dysfibrinogenemias have been elucidated. Each is named for the city where it was first discovered. With only rare exceptions, the congenital dysfibrinogenemias are inherited in an autosomal dominant or codominant fashion. Depending on the fibrinogen abnormality, defects may occur in one or more of the steps in fibrin clot formation, although the most common defect involves polymerization of the fibrin monomer. [5]
Bleeding may ensue when a fibrin clot forms that cannot be effectively stabilized. Bleeding in patients with congenital dysfibrinogenemia tends to be relatively mild or even absent; it is only a laboratory curiosity and is not life threatening. In contrast to the bleeding experienced by approximately half of the patients with congenital dysfibrinogenemia, one subset of patients (diagnosed with fibrinogen Oslo I) has an abnormal fibrinogen that is associated with thromboembolic complications that are often relatively mild. The abnormal fibrinogen in these patients forms a fibrin clot that is resistant to fibrinolysis by plasmin. [6]
Congenital dysfibrinogenemias are most often inherited in an autosomal dominant or codominant fashion. Several variants are inherited autosomal recessively.
Acquired dysfibrinogenemias occur in severe liver disease. The fibrinogen molecule produced by the impaired liver is not functional or able to form a stable fibrin clot.
Congenital dysfibrinogenemia has been reported in only 200-300 families. Transmission is autosomal dominant or codominant, except in a few cases that appear to be transmitted recessively. Acquired abnormalities of fibrinogen may complicate liver disease: approximately 50% of patients with severe liver disease exhibit bleeding secondary to abnormal fibrinogen molecules.
Dysfibinogenemia has no known predilection for race or sex.
Prognosis is good for patients with congenital dysfibrinogenemias. Events of bleeding or thrombosis are usually relatively mild. Acquired dysfibrinogenemia carries a worse prognosis because it is due to a severely damaged liver.
While many patients with congenital dysfibrinogenemias are asymptomatic, those who experience symptoms commonly have only mild bleeding or thrombotic events, although these are extremely rare. Severe hemorrhagic episodes may characterize a few abnormal fibrinogen variants (eg, Imperate, Dettori, Detroit).
Patients with dysfibrinogenemia of liver disease often have a more severe bleeding disorder than patients with an inherited disorder. The condition tends to worsen as the liver disease worsens.
A multicenter study of 101 patients with congenital dysfibrinogenemia found that, over a mean 8.8 year follow-up period after diagnosis, the incidence of major bleeding and of thrombotic events was 2.5 and 18.7 per 1000 patient-years, respectively. By age 50 years, those cumulative incidences were estimated at 19.2% and 30.1%. In addition, of 111 pregnancies identified, the incidence of spontaneous abortions and postpartum hemorrhage were 19.8% and 21.4%, respectively. Abnormal bleeding was a complication in nine of 137 surgical procedures analyzed. [7]
Neerman-Arbez M, Casini A. Clinical Consequences and Molecular Bases of Low Fibrinogen Levels. Int J Mol Sci. 2018 Jan 8. 19 (1):[Medline]. [Full Text].
Keinath K, Church T, Sadowski B, Perkins J. Acute renal artery infarction secondary to dysfibrinogenemia. BMJ Case Rep. 2017 Nov 8. 2017:[Medline]. [Full Text].
Acharya SS, Dimichele DM. Rare inherited disorders of fibrinogen. Haemophilia. 2008 Nov. 14(6):1151-8. [Medline].
Lee N, Kim JE, Yoo HJ, Gu J, Kim H, Chung J, et al. Acquired Dysfibrinogenemia Caused by Autoantibody Inhibiting Fibrin Polymerization in a Patient with MELAS Syndrome and Bleeding Tendency. Ann Clin Lab Sci. 2016 Dec. 46 (6):696-700. [Medline].
Kotlin R, Reicheltova Z, Maly M, et al. Two cases of congenital dysfibrinogenemia associated with thrombosis – Fibrinogen Praha III and Fibrinogen Plzen. Thromb Haemost. 2009 Sep. 102(3):479-86. [Medline].
Morris TA, Marsh JJ, Chiles PG, et al. High prevalence of dysfibrinogenemia among patients with chronic thromboembolic pulmonary hypertension. Blood. 2009 Aug 27. 114(9):1929-36. [Medline]. [Full Text].
Casini A, Blondon M, Lebreton A, Koegel J, Tintillier V, de Maistre E, et al. Natural history of patients with congenital dysfibrinogenemia. Blood. 2015 Jan 15. 125 (3):553-61. [Medline]. [Full Text].
Casini A, de Moerloose P, Neerman-Arbez M. Clinical Features and Management of Congenital Fibrinogen Deficiencies. Semin Thromb Hemost. 2016 Jun. 42 (4):366-74. [Medline].
Jacquemin M, Vanlinthout I, Van Horenbeeck I, Debasse M, Toelen J, Schoeters J, et al. The amplitude of coagulation curves from thrombin time tests allows dysfibrinogenemia caused by the common mutation FGG-Arg301 to be distinguished from hypofibrinogenemia. Int J Lab Hematol. 2017 Jun. 39 (3):301-307. [Medline].
Casini A, Neerman-Arbez M, Ariëns RA, de Moerloose P. Dysfibrinogenemia: from molecular anomalies to clinical manifestations and management. J Thromb Haemost. 2015 Jun. 13 (6):909-19. [Medline].
Miesbach W, Schenk J, Alesci S, Lindhoff-Last E. Comparison of the fibrinogen Clauss assay and the fibrinogen PT derived method in patients with dysfibrinogenemia. Thromb Res. 2010 Dec. 126(6):e428-33. [Medline].
Miesbach W, Galanakis D, Scharrer I. Treatment of patients with dysfibrinogenemia and a history of abortions during pregnancy. Blood Coagul Fibrinolysis. 2009 Jul. 20(5):366-70. [Medline].
Bornikova L, Peyvandi F, Allen G, Bernstein J, Manco-Johnson MJ. Fibrinogen replacement therapy for congenital fibrinogen deficiency. J Thromb Haemost. 2011 Sep. 9(9):1687-704. [Medline].
Russell Burgess, MD (Retired) Chief, Division of Hematology/Oncology, Eastern Carolina Internal Medicine, PA
Russell Burgess, MD is a member of the following medical societies: American College of Physicians, American Medical Association
Disclosure: Nothing to disclose.
Guy B Faguet, MD Retired Professor, Department of Medicine, Section of Hematology and Oncology, Georgia Regents University
Guy B Faguet, MD is a member of the following medical societies: American Association of Immunologists, American Society of Hematology, International Society of Hematology, New York Academy of Sciences, Southern Medical Association, Southern Society for Clinical Investigation, American Federation for Clinical Research, Southeastern Cancer Research Association, Polycythemia Vera Study Group
Disclosure: Nothing to disclose.
Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Received salary from Medscape for employment. for: Medscape.
Marcel E Conrad, MD Distinguished Professor of Medicine (Retired), University of South Alabama College of Medicine
Marcel E Conrad, MD is a member of the following medical societies: Alpha Omega Alpha, American Association for the Advancement of Science, American Association of Blood Banks, American Chemical Society, American College of Physicians, American Physiological Society, American Society for Clinical Investigation, American Society of Hematology, Association of American Physicians, Association of Military Surgeons of the US, International Society of Hematology, Society for Experimental Biology and Medicine, SWOG
Disclosure: Partner received none from No financial interests for none.
Perumal Thiagarajan, MD Professor, Department of Pathology and Medicine, Baylor College of Medicine; Director, Transfusion Medicine and Hematology Laboratory, Michael E DeBakey Veterans Affairs Medical Center
Perumal Thiagarajan, MD is a member of the following medical societies: American College of Physicians, American Heart Association, American Society for Biochemistry and Molecular Biology, American Society for Clinical Investigation, American Society of Hematology, Association of American Physicians, Royal College of Physicians
Disclosure: Nothing to disclose.
Karen Seiter, MD Professor, Department of Internal Medicine, Division of Oncology/Hematology, New York Medical College
Karen Seiter, MD is a member of the following medical societies: American Association for Cancer Research, American College of Physicians, American Society of Hematology
Disclosure: Received honoraria from Novartis for speaking and teaching; Received consulting fee from Novartis for speaking and teaching; Received honoraria from Celgene for speaking and teaching.
Wendy Brick, MD Consulting Staff, Department of Internal Medicine, Division of Hematology and Oncology, Mecklenburg Medical Group
Wendy Brick, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, American Medical Association, and American Society of Hematology
Disclosure: Nothing to disclose.
Dysfibrinogenemia
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