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Hereditary bleeding disorders

Hereditary bleeding disorders - general


Editorial Board Members: Kyle Annen, D.O., Melissa R. George, D.O.
Deputy Editor-in-Chief: Patricia Tsang, M.D., M.B.A.
Zaher K. Otrock, M.D., Ph.D.

Last author update: 7 January 2025
Last staff update: 8 January 2025

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PubMed Search: Hereditary bleeding disorders

Zaher K. Otrock, M.D., Ph.D.
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Table of Contents
Definition / general | Essential features | Overview | Epidemiology | Clinical features | Laboratory | Treatment | Hereditary thrombocytopenia | Differential diagnosis | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2
Cite this page: Otrock ZK. Hereditary bleeding disorders - general. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/coagulationhereditarybleedinggeneral.html. Accessed April 1st, 2025.
Definition / general
  • Hereditary bleeding disorders are a diverse group of diseases that occur due to platelet dysfunction or absence / deficiency of specific clotting proteins and result in abnormalities of primary or secondary hemostasis
  • Most common hereditary bleeding disorders
    • Von Willebrand disease
    • Hemophilia A (factor VIII deficiency)
    • Hemophilia B (factor IX deficiency)
  • Less common hereditary bleeding disorders
    • Factor I (fibrinogen) deficiency / dysfunction
    • Factor II (prothrombin) deficiency
    • Factor V deficiency
    • Factor VII deficiency
    • Factor X deficiency
    • Factor XI deficiency (also known as hemophilia C)
    • Factor XIII deficiency
  • Rare disorders
    • α2 antiplasmin deficiency
    • Combined factor deficiencies: combined factor V and VIII, combined vitamin K dependent clotting factors deficiency
    • Glanzmann thrombasthenia
    • Bernard-Soulier syndrome
    • Gray platelet syndrome
Essential features
  • Hereditary bleeding disorders could occur due to platelet dysfunction (i.e., primary hemostasis disorder) or absence / deficiency of specific clotting proteins (i.e., secondary hemostasis disorder)
  • Primary hemostasis: formation of a platelet plug that involves the endothelium, platelets and von Willebrand factor (vWF)
  • Secondary hemostasis: formation of fibrin plug by activated coagulation factors
  • Von Willebrand disease is the most common hereditary bleeding disorder (M = F), followed by hemophilia A and B (M > F)
  • Patients with abnormalities in primary hemostasis are more likely to manifest mucocutaneous bleeding, while those with abnormalities in secondary hemostasis tend to have muscle and joint bleeds
Overview
  • Hemostasis means stopping bleeding
  • Vasoconstriction is the initial response following vessel injury (Ann Med 2012;44:405)
  • Primary hemostasis involves the formation of a weak platelet plug, where damaged endothelium exposes the procoagulant subendothelial matrix, leading to platelet adhesion by von Willebrand factor (Ann Med 2012;44:405)
  • Normal platelet function can be summarized with the triple A mnemonic: adhesion, activation and aggregation (Hematol Oncol Clin North Am 2021;35:1069)
  • Secondary hemostasis involves the formation of cross linked fibrin by activated coagulation factors (Ann Med 2012;44:405)
  • Inheritance pattern can be autosomal dominant, recessive or X linked
  • In many patients, there is a family history of bleeding (Int J Lab Hematol 2018;40:6)
Epidemiology

Disorders of primary hemostasis
Bleeding disorder Prevalence Inheritance pattern / genetic mutation
Von Willebrand disease (vWD)

  • Type I

  • Type II (A, B, M and N subtypes)

  • Type III
1 in 100 (based on abnormal laboratory results); 1 in 1,000 (symptomatic patients) (Hematol Oncol Clin North Am 2021;35:1085) Chr 12p, VWF gene, multiple mutations identified

  • Autosomal dominant

  • Autosomal dominant (type 2N is autosomal recessive)

  • Autosomal recessive
Glanzmann thrombasthenia 1 in 1,000,000 Autosomal recessive / chr 17q21, ITGA2B or ITGB3 genes (StatPearls: Glanzmann Thrombasthenia [Accessed 1 November 2024])
Bernard-Soulier syndrome < 1 in 1,000,000 Autosomal recessive; rare cases of autosomal dominant inheritance / GPIbα, GPIbβ or GPIX genes on chromosomes 17p12, 22q11.2 and 3q21, respectively (Orphanet J Rare Dis 2006;1:46)
Gray platelet syndrome Rare (< 100 reported cases) Autosomal dominant, recessive or X linked recessive / chr 3p21.31, NBEAL2 gene (J Blood Med 2021;12:719)
Quebec platelet disorder 1 in 300,000 in Quebec, Canada Autosomal dominant / chr 10q22, PLAU gene (Expert Rev Hematol 2011;4:137)
Wiskott-Aldrich syndrome 1 - 10 in 1,000,000 X linked recessive / Xp 11.22-23, WAS gene (StatPearls: Wiskott-Aldrich Syndrome [Accessed 1 November 2024])
Congenital amegakaryocytic thrombocytopenia Rare (< 100 reported cases) Autosomal recessive / chr 1p34.2, MPL gene (Haematologica 2021;106:2439)
Hermansky-Pudlak syndrome 1 - 9 in 1,000,000; 1 in 1,800 in Puerto Rico (Semin Respir Crit Care Med 2020;41:238) Autosomal recessive / mutations in 1 of 10 genes (HPS1, AP3B1, HPS3, HPS4, HPS5, HPS6, DTNBP1, BLOC1S3, PLDN and AP3D1)
Chédiak-Higashi syndrome Rare (< 500 reported cases) Autosomal recessive / chr 1q42.1-q42.2, LYST gene (StatPearls: Chediak-Higashi Syndrome [Accessed 1 November 2024])


Disorders of secondary hemostasis
Bleeding disorder Prevalence Inheritance pattern / genetic mutation
Factor I (fibrinogen) deficiency

  • Afibrinogenemia

  • Hypofibrinogenemia


  • Dysfibrinogenemia

  • Hypodysfibrinogenemia


  • 1 in 1,000,000

  • True incidence is unknown; more common than afibrinogenemia

  • > 500 reported cases

  • Unknown
Chr 4, mutations in FGA, FGB or FGG genes (Blood Rev 2021;48:100793)
  • Autosomal recessive

  • Autosomal dominant or recessive


  • Autosomal dominant

  • Autosomal dominant
Factor II (prothrombin) deficiency 1 in 2,000,000 Autosomal recessive / chr 11p11.2, F2 gene (Hematol Oncol Clin North Am 2021;35:1181)
Factor V deficiency 1 in 1,000,000 Autosomal recessive / chr 1q24.2, F5 gene (Hematol Oncol Clin North Am 2021;35:1181)
Factor VII deficiency 1 in 500,000 Autosomal recessive / chr 13q34, F7 gene (Hematol Oncol Clin North Am 2021;35:1181)
Factor VIII deficiency (hemophilia A) 1 in 5,000 male births X linked recessive / chr Xq28 (Haematologica 2019;104:1702)
Factor IX deficiency (hemophilia B) 1 in 30,000 male births X linked recessive / chr Xq27 (Haematologica 2019;104:1702)
Factor X deficiency 1 in 500,000 - 1,000,000 Autosomal recessive / chr 13q34, F10 gene (Hematol Oncol Clin North Am 2021;35:1181)
Factor XI deficiency (hemophilia C) 1 in 1,000,000; 5% in Ashkenazi Jews Autosomal recessive / chr 4q35.2, F11 gene (Expert Rev Hematol 2016;9:629)
Factor XIII deficiency 1 in 2,000,000 - 3,000,000 Autosomal recessive / FXIIA gene (chr 6p25.1) or FXIIIB gene (chr 1q31.3) (StatPearls: Factor XIII Deficiency [Accessed 1 November 2024])
Combined factor deficiencies

  • Factors V and VIII



  • Combined vitamin K dependent clotting factors deficiency (deficiency of factors II, VII, IX, X, protein C and protein S)


  • 1 in 1,000,000



  • < 15 families reported


α2 antiplasmin deficiency Unknown Autosomal recessive / chr 17pter-p12, SERPINF2 gene (Haemophilia 2008;14:1250)
Plasminogen activator inhibitor type 1 (PAI1) deficiency Unknown Autosomal recessive / chr 7q21.3-22, SERPINE1 gene (Hematol Oncol Clin North Am 2021;35:1197)
Clinical features
Laboratory
  • Basic screening tests include complete blood count (CBC), prothrombin time (PT) / activated partial thromboplastin time (aPTT), platelet function assay (e.g., PFA 100 / PFA 200), thrombin time, peripheral blood smear review (for platelet and erythrocyte morphology) and fibrinogen (Int J Lab Hematol 2018;40:6)
  • For suspected platelet disorders: platelet aggregation studies, bone marrow aspirate and biopsy, flow cytometry, electron microscopy, next generation sequencing (Hematol Oncol Clin North Am 2021;35:1069)
  • Testing for von Willebrand disease includes factor VIII activity, vWF antigen and vWF activity (measured by ristocetin cofactor activity or vWF GPIbM activity assay) (Pediatr Clin North Am 2013;60:1419)
  • For suspected coagulation factor abnormalities: mixing studies, factor levels, Bethesda assay (to detect coagulation factor inhibitor titers) (Int J Lab Hematol 2018;40:6)
  • Factor XIII assay if delayed bleeding is present with normal PT and aPTT (measured by factor XIII activity assay or urea clot lysis method) (Hematol Oncol Clin North Am 2021;35:1171)
Treatment
  • Bleeding in patients with hereditary platelet disorders is managed with platelet transfusions, antifibrinolytic agents, DDAVP (desmopressin) or recombinant factor VIIa, depending on the defect (Hematol Oncol Clin North Am 2021;35:1069)
  • Specific treatment recommendations are dependent on the type and severity of bleeding disorder but generally factor replacement therapy for factor deficiencies is the mainstay of treatment, with the exceptions of factor V (which is treated with plasma), factor II and factor X deficiencies (which are treated with prothrombin complex concentrates) (Haemophilia 2008;14:671)
  • For von Willebrand disease, use vWF concentrates, DDAVP (desmopressin; contraindicated in vWD type 2B) or antifibrinolytic agents (Hematology Am Soc Hematol Educ Program 2016;2016:683)
Hereditary thrombocytopenia
  • Hereditary thrombocytopenia (inherited thrombocytopenia) encompasses a group of rare genetic disorders characterized by a bleeding tendency
  • Most individuals with hereditary thrombocytopenia present with mild thrombocytopenia and a minimal or no risk of spontaneous bleeding
  • Diagnosing hereditary thrombocytopenia can be challenging, requiring the exclusion of other causes of low platelet counts, such as infections or immune disorders
  • Over the past decade, the advent of high throughput sequencing technologies, including whole exome and whole genome sequencing, has significantly advanced our understanding of these conditions
  • Currently, more than 40 genes have been implicated in various forms of hereditary thrombocytopenia
  • Recent discoveries have also highlighted that certain genetic mutations associated with hereditary thrombocytopenia may predispose individuals to additional congenital abnormalities, hematological malignancies or bone marrow failure
  • Given that the most common forms of hereditary thrombocytopenia pose little to no risk of spontaneous bleeding, most patients require only regular monitoring and in some cases, intervention during hemostatic challenges
  • Historically, platelet transfusion was the only treatment option for hereditary thrombocytopenia; however, thrombopoietin receptor agonists (TPO RAs) have emerged as a promising therapy, reducing the need for platelet transfusions in preparation for surgical or hemostatic challenges and offering longterm management for patients with significant spontaneous bleeding
  • For the most severe forms, such as Wiskott-Aldrich syndrome and congenital amegakaryocytic thrombocytopenia, hematopoietic stem cell transplantation remains the treatment of choice
Differential diagnosis
  • Antiplatelet medications, such as aspirin, glycoprotein IIB / IIIA inhibitors, clopidogrel, ticlopidine
  • Anticoagulants (heparin, warfarin or other anticoagulants) (Wikipedia: Anticoagulant [Accessed 1 November 2024])
  • Liver disease:
    • Patients with liver disease (e.g., liver dysfunction, acute liver failure, cirrhosis) may have varying degrees of thrombocytopenia
    • Mechanism can be due to impaired platelet production from decreased synthesis of thrombopoietin, platelet sequestration in the spleen in the setting of portal hypertension, bone marrow suppression from infection (e.g., hepatitis C virus), alcohol use or antibiotic and antiviral treatment
  • Disseminated intravascular coagulation (DIC):
    • Can be caused by sepsis, malignancy, trauma, obstetrical complications, among others
    • Complete blood count may show increased white blood cell count and low platelet count
    • Prolonged prothrombin time (PT) and activated partial thromboplastin time (aPTT), low fibrinogen, increased D-dimer
    • Peripheral smear may show evidence of microangiopathic hemolytic anemia (MAHA), with schistocytes and helmet cells
  • Vitamin K deficiency:
    • Results in deficiency in vitamin K dependent coagulation factors: factors II, VII, IX, X, protein C and S
    • Certain patients are at increased risk: on warfarin, taking antibiotics, have fat malabsorption (celiac disease, cystic fibrosis, short bowel syndrome, on a diet lacking in vitamin K)
  • Acquired von Willebrand syndrome:
    • Due to any qualitative, structural or functional disorder of vWF
    • Negative family history
    • Lack of previous bleeding
    • Decreased vWF activity to antigen ratio, normal vWF propeptide antigen, loss of high molecular weight multimers
    • Often associated lymphoproliferative, myeloproliferative, cardiovascular and immunological disorders
Board review style question #1
What is the most common hereditary bleeding disorder?

  1. Fibrinogen deficiency
  2. Glanzmann thrombasthenia
  3. Hemophilia A
  4. Hemophilia B
  5. Von Willebrand disease
Board review style answer #1
E. Von Willebrand disease has a prevalence of 1 in 1,000 - 1 in 100. Answer A is incorrect because fibrinogen deficiency is a rare inherited bleeding disorder with a prevalence of 1 in 1,000,000. Answer B is incorrect because Glanzmann thrombasthenia is a rare disorder with a prevalence of 1 in 1,000,000. Answer C is incorrect because hemophilia A is diagnosed in 1 of 5,000 male births. Answer D is incorrect because hemophilia B is diagnosed in 1 of 30,000 male births.

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Reference: Hereditary bleeding disorders - general
Board review style question #2
Which of the following findings is suggestive of a primary hemostasis disorder?

  1. Bleeding into joints
  2. Mucosal bleeding
  3. Negative family history of bleeding
  4. Prolonged prothrombin time or activated partial thromboplastin time
Board review style answer #2
B. Mucosal bleeding. Patients with primary hemostasis abnormalities are more likely to manifest mucocutaneous bleeding. Answer A is incorrect because bleeding into joints manifests in patients with secondary hemostasis. Answer C is incorrect because primary hemostasis disorders are inherited and can run in families. Answer D is incorrect because prolonged prothrombin time or activated partial thromboplastin time are often seen in secondary hemostasis disorders.

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Reference: Hereditary bleeding disorders - general
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