Coagulation
Hereditary bleeding disorders
Hereditary bleeding disorders - general

Authors: Kendall Crookston, M.D., Ph.D., Lizabeth Rosenbaum, M.D. and Julie Gober-Wilcox, M.D. (see Authors page)

Revised: 25 April 2016, last major update September 2010

Copyright: (c) 2002-2016, PathologyOutlines.com, Inc.

PubMed Search: Hereditary bleeding disorders - general

Definition / General
  • Hereditary bleeding disorders are a diverse group of diseases that include abnormalities of primary and secondary hemostasis

  • The most common congenital bleeding disorders include:
    • von Willebrand disease
    • Hemophilia A (factor VIII deficiency)
    • Hemophilia B (factor IX deficiency)

  • Less common congenital bleeding disorders include:
    • Factor I (fibrinogen) deficiency
    • Factor II (prothrombin) deficiency
    • Factor V deficiency
    • Factor VII deficiency
    • Factor X deficiency
    • Factor XI deficiency
    • Factor XIII deficiency
    • Platelet disorders

  • Extremely rare disorders include:
    • α2-antiplasmin deficiency
    • α1-antitrypsin Pittsburgh (Antithrombin III Pittsburgh) deficiency (Haematologica 2009;94:881)
    • Combined factor deficiencies: combined factor V and VIII (autosomal recessive, due to mutation in endoplasmic reticulum-Golgi gene ERGIC 53 on #18 that transports these factors), combined factors II, VII, IX and X deficiency (due to mutation in gamma-glutamyl carboxylase gene, whose protein carboxylates glutamate residues in vitamin K-dependent coagulation factors)
Epidemiology
Bleeding disorder Prevalence Inheritance pattern
Factor I (fibrinogen) deficiency
  • Afibrinogenemia
  • Hypofibrinogenemia
  • Dysfibrinogenemia
  • More than 200 cases reported
    Autosomal recessive
    Autosomal dominant or recessive
    Autosomal dominant or recessive
    Factor II (prothrombin) deficiency Less than 100 cases reported Autosomal recessive
    Factor V deficiency Less than 1 in 1,000,000 Autosomal recessive
    Factor VII deficiency 1 in 500,000 Autosomal recessive
    Factor VIII deficiency 1 in 5000 male births X-linked recessive
    Factor IX deficiency 1 in 30,000 male births X-linked recessive
    Factor X deficiency 1 in 500,000 Autosomal recessive
    Factor XI deficiency 4% in Ashkenazi Jews, otherwise rare Autosomal recessive
    Factor XIII deficiency More than 200 cases reported Autosomal recessive
    Combined factor deficiencies
  • Factor V-Factor VIII
  • Factor II, VII, IX, X
  • > 30 families reported < 15 families reported
    Autosomal recessive
    Autosomal recessive
    a2-antiplasmin deficiency > 10 families reported Autosomal recessive
    a1-antitrypsin Pittsburgh deficiency Only 3 cases reported Autosomal dominant
    von Willebrand Disease (VWD)
  • Type I
  • Type II
  • Type III
  • 1 in 100
    Autosomal dominant
    Autosomal dominant
    Autosomal recessive
    Glanzmann thrombasthenia 1 in 1,000,000 Autosomal recessive
    Bernard-Soulier syndrome < 1 in 1,000,000 Autosomal recessive
    Gray platelet syndrome Rare Autosomal dominant, recessive or X-linked recessive
    Wiskott-Aldrich syndrome 1 in 1,000,000 X-linked recessive
    Etiology
  • Primary hemostasis involves formation of the platelet plug which involves platelets, the blood vessel wall and von Willebrand factor; abnormalities can include problems in platelet number, adhesion or aggregation
  • Secondary hemostasis involves the formation of fibrin through the humoral coagulation cascade; abnormalities include deficiencies of coagulation factors or contact factors, deficiencies or abnormalities of fibrinogen or connective tissue diseases
  • Mutations can be inherited in an autosomal dominant, recessive or X-linked pattern

    Disorders of Primary Hemostasis
    von Willebrand disease
    Glanzmann thrombasthenia
    Bernard-Soulier syndrome
    Platelet storage pool disease
    Gray platelet syndrome
    Wiskott-Aldrich syndrome

    Disorders of Secondary Hemostasis
    Factor I (fibrinogen) abnormalities
  • Afibrinogenemia
  • Hypofibrinogenemia
  • Dysfibrinogenemia
  • Factor II (prothrombin) deficiency
    Factor V deficiency
    Factor VII deficiency
    Factor VIII deficiency (Hemophilia A)
    Factor IX deficiency (Hemophilia B)
    Factor X deficiency
    Factor XI deficiency
    Factor XIII deficiency
    Combined factor deficiencies
    a2-antiplasmin deficiency
    a1-antitrypsin deficiency
    Ehlers-Danlos syndrome
    Osler-Weber-Rendu syndrome
    Scurvy (vitamin C deficiency)
  • Clinical Features
  • Symptoms: bleeding associated with surgery, trauma, dental extractions, postpartum, circumcision or umbilical stumps, GI bleeding, intracranial hemorrhage, hemarthrosis or soft tissue hematomas, easy bruising, epistaxis, menorrhagia, hematuria

  • Heterozygous patients have 30 - 60% of normal values of affected factors, usually with no or minor bleeding disorder
  • However, factor I (hypofibrinogenemia or dysfibrinogenemia), X, XI or XIII deficient heterozygotes may have bleeding symptoms
  • Homozygous deficient patients have < 30% of normal values of affected factors
  • In hemophilia A and B, small differences in factor levels (i.e. 1% vs. 3% vs. 10%) may markedly affect the clinical presentation and course
  • Laboratory
  • Basic screening tests include CBC, PT/PTT, bleeding time or platelet function assay (e.g. PFA-100), thrombin time, peripheral blood smear review (for platelet and erythrocyte morphology), fibrinogen
  • Testing for vWD includes Factor VIII activity, vWF antigen, vWF activity (often done by the "ristocetin cofactor" method)
  • These results may lead to obtaining vWF multimer assays and blood type (type O patients have reduced vWF activity)
  • For suspected coagulation factor abnormalities: mixing studies, factor levels, Bethesda assay (to detect coagulation factor inhibitors); can confirm hereditary deficiency by determining factor levels in relatives
  • For suspected platelet disorders: platelet aggregation studies, bone marrow aspirate and biopsy, platelet-associated immunoglobulin levels
  • Factor XIII assay if delayed bleeding is present (often done by "urea clot lysis" method)
  • More esoteric assays include PAI-1 activity and antiplasmin
  • Treatment
  • Specific treatment recommendations are dependent on type and severity of bleeding disorder, but generally factor replacement therapy for factor deficiencies is the mainstay of treatment with the exception of factor II, factor V and factor X deficiencies, which are treated with FFP and cryoprecipitate (Haemophilia 2008;14:671)
  • For vVWD, use DDAVP (desmopressin), vWF concentrates and antifibrinolytic agents
  • For platelet-related bleeding disorders, use platelet transfusions and recombinant factor VIIa
  • Differential Diagnosis
  • Acquired factor deficiencies: due to liver disease, DIC, lupus anticoagulants, heparin, warfarin or other anticoagulants are more common than hereditary factor deficiencies, and should be ruled out first
  • Acquired platelet defects due to anti-platelet medications: aspirin, glycoprotein IIB/IIIA inhibitors, clopidogrel, ticlopidine are much more common than inherited platelet abnormalities