Hereditary bleeding disorders
Algorithm for workup of hereditary bleeding disorders

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

Revised: 28 April 2016, last major update September 2010

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

PubMed Search: Hereditary bleeding disorders [title]

Cite this page: Algorithm for workup of hereditary bleeding disorders. website. Accessed October 26th, 2016.
Definition / General
  • Hereditary bleeding disorders are a diverse group of diseases that include abnormalities of primary and secondary hemostasis (see etiology)
  • Evaluation of a patient for a hereditary bleeding disorder is a multistep process that involves a complete and accurate history followed by laboratory evaluation
  • Important considerations are whether the bleeding is truly congenital vs. a possible acquired coagulopathy, and whether the clinical symptoms suggest a disorder of primary vs. secondary hemostasis (see clinical features)
  • Causes of acquired bleeding include liver disease, renal disease, vitamin K related factor deficiency (warfarin, prolonged antibiotic use, malabsorption syndromes, nutritional deficiency), DIC and dilutional coagulopathy in massive transfusion

  • A complete history should include:
    • Surgical history: dental procedures, bleeding during surgery vs. postoperative bleeding
    • Nature of bleeding: habitual epistaxis, menorrhagia, hemarthrosis, postpartum hemorrhage, petechiae, purpura, etc.
    • For patients with menorrhagia: history of severe iron deficiency anemia, multiple red blood cell transfusions, procedures such as D&C or hysterectomy for excessive bleeding
    • Family history of bleeding (but a negative family history of bleeding does not rule out a congenital bleeding disorder)
    • Medication use: warfarin, heparin, aspirin or other NSAIDs, antibiotics (affecting vitamin K dependent clotting factors) and herbal medications
    • Medical problems: renal failure, severe liver disease, malabsorption syndromes
  • 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
Diagrams / Tables
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

    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

    • Note: pregnant women with mild to moderate vWD (von Willebrand disease) or hemophilia A carriers typically are asymptomatic due to elevated vWF and Factor VIII during pregnancy

    • Some symptoms are more suggestive of either a primary or secondary hemostatic defect and can help narrow the differential diagnosis:
      • Epistaxis, menorrhagia, melena, intraoperative or immediate postoperative bleeding and petechiae suggest a platelet disorder or vWD
      • Delayed postoperative bleeding is usually due to a coagulation factor deficiency, fibrinogen abnormalities or a collagen disorder
      • Spontaneous hemarthrosis and intramuscular bleeds suggest coagulation factor deficiencies

      • Note: hemarthrosis is common in classic hemophilias but also can occur in acquired hemophilias
    • 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 ordering vWF multimer assays and blood type determination (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
    • Perform Factor XIII assay if delayed bleeding is present (often done by "urea clot lysis" method)
    • More esoteric assays include PAI-1 activity and antiplasmin

    • Note: lupus anticoagulants can cause prolongation of PTT, but are associated with thrombosis, not bleeding
    • Deficiencies of Factor XII, prekallikrein or high molecular weight kininogen do not cause bleeding but cause prolongation of PTT
    Prognostic Factors
    • Heterozygous patients have 30 - 60% of normal values of affected factors, usually with no or minor bleeding disorder
    • 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
    Case Reports
    • Specific treatment recommendations depend on the type and severity of bleeding disorder, but in general, factor replacement therapy for factor deficiencies is the mainstay of treatment, with the exception of factor II, factor V and factor deficiencies; FFP and cryoprecipitate are also common (Haemophilia 2008;14:671)
    • For von Willebrand disease: DDAVP (desmopressin), vWF concentrates, antifibrinolytic agents
    • For platelet-related bleeding disorders: platelet transfusion, recombinant factor VIIa
    Differential Diagnosis