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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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