Coagulation
Hereditary bleeding disorders
Hereditary bleeding disorders - general
Author: Zaher K. Otrock, M.D., Ph.D.
Editorial Board Member: Kyle Annen, D.O.
Deputy Editor-in-Chief: Patricia Tsang, M.D., M.B.A.
Last author update: 2 May 2022
Last staff update: 2 May 2022
Copyright: 2002-2023, PathologyOutlines.com, Inc.
PubMed Search: Hereditary bleeding disorders
Table of Contents
Definition / general | Essential features | Overview | Epidemiology | Clinical features | Laboratory | Treatment | Differential diagnosis | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2Cite this page: Otrock ZK. Hereditary bleeding disorders - general. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/coagulationhereditarybleedinggeneral.html. Accessed February 8th, 2023.
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)
| 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
|
| 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]) |
Clinical features
- Symptoms: bleeding associated with surgery, trauma, dental extractions, postpartum, circumcision or umbilical stumps, easy bruising, epistaxis, menorrhagia, gastrointestinal bleeding, hemarthrosis, soft tissue hematomas, hematuria, intracranial bleeding
- Patients with primary hemostasis abnormalities are more likely to manifest mucocutaneous bleeding (Eur J Pediatr 2012;171:1)
- Reasons to suspect hereditary platelet disorder (Int J Mol Sci 2021;22:4521):
- Persistence of neonatal thrombocytopenia or onset of bleeding symptoms in childhood
- Family history of thrombocytopenia or mucocutaneous bleeding
- Association with other diseases (check for unique physical characteristics and findings on peripheral blood smear)
- Bleeding out of proportion to the platelet count
- Patients with secondary hemostasis abnormalities tend to have muscle and joint bleeds (Eur J Pediatr 2012;171:207)
- Heterozygous patients have 30 - 60% of normal values of affected factors, usually with no or minor bleeding disorder (UpToDate: Rare Inherited Coagulation Disorders [Accessed 26 October 2021])
- Factor I, X, XI or XIII deficient heterozygotes may have bleeding symptoms (UpToDate: Rare Inherited Coagulation Disorders [Accessed 26 October 2021])
- Homozygous deficient patients have < 30% of normal values of affected factors (UpToDate: Rare Inherited Coagulation Disorders [Accessed 26 October 2021])
- In hemophilia A and B, small differences in factor levels (i.e., < 1% versus 1 - 5% versus > 5%) may markedly affect the clinical presentation, disease course and management (UpToDate: Clinical Manifestations and Diagnosis of Hemophilia [Accessed 26 October 2021])
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)
- These results may lead to obtaining vWF multimer analysis and blood type (group O patients have reduced vWF antigen and activity) (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
- Antiplatelet medications, such as aspirin, glycoprotein IIB / IIIA inhibitors, clopidogrel, ticlopidine
- Anticoagulants (heparin, warfarin or other anticoagulants) (Wikipedia: Anticoagulant [Accessed 19 April 2022])
- Liver disease:
- 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 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?
- Fibrinogen deficiency
- Glanzmann thrombasthenia
- Hemophilia A
- Hemophilia B
- Von Willebrand disease
Board review style answer #1
Board review style question #2
Which of the following findings is suggestive of a primary hemostasis disorder?
- Bleeding into joints
- Mucosal bleeding
- Negative family history of bleeding
- Prolonged prothrombin time and activated partial thromboplastin time
Board review style answer #2
