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Coagulation

Hereditary bleeding disorders

Hereditary bleeding disorders - general


Reviewers: Kendall Crookston, M.D., Ph.D., University of New Mexico; Lizabeth Rosenbaum, MD, University of New Mexico; Julie Gober-Wilcox, M.D., Resident, University of New Mexico (see Reviewers page)
Revised: 9 April 2013, last major update September 2010
Copyright: (c) 2002-2013, PathologyOutlines.com, Inc.

Definition
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● 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
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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
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● 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
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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
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● 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
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● 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
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● 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

Additional references
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Consultative Hemostasis and Thrombosis: Elsevier, 2007

End of Coagulation > Hereditary bleeding disorders > Hereditary bleeding disorders - general


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