Coagulation

Hereditary bleeding disorders

Hereditary bleeding disorders - general


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Zaher K. Otrock, M.D.

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PubMed Search: Hereditary bleeding disorders

Zaher K. Otrock, M.D.
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Cite this page: Otrock ZK. Hereditary bleeding disorders - general. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/coagulationhereditarybleedinggeneral.html. Accessed July 3rd, 2022.
Definition / general
  • Hereditary bleeding disorders are a diverse group of diseases that occur due to platelet dysfunction or absence / deficiency of specific clotting proteins, resulting 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 which 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 primary hemostasis abnormalities are more likely to manifest mucocutaneous bleeding, while those with secondary hemostasis abnormalities 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 formation of a weak platelet plug, where damaged endothelium exposes the procoagulant subendothelial matrix, leading to platelet adhesion by and 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 2 December 2021])
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 2 December 2021])
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 2 December 2021])


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 2 December 2021])
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 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) and 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)
Differential diagnosis
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

Comment Here

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 and activated partial thromboplastin time
Board review style answer #2
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