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Coagulation
Hereditary bleeding disorders
Algorithm for workup of hereditary bleeding disorders
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.
General
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● Hereditary bleeding disorders are a diverse group of diseases that include abnormalities of primary and secondary hemostasis (see etiology)
● Evaluation of a patient for a hereditary bleeding disorder is a multistep process that involves a complete and accurate history followed by laboratory evaluation
● Important considerations are whether the bleeding is truly congenital vs. a possible acquired coagulopathy, and whether the clinical symptoms suggest a disorder of primary vs. secondary hemostasis (see clinical features)
● Causes of acquired bleeding include liver disease, renal disease, vitamin K related factor deficiency (warfarin, prolonged antibiotic use, malabsorption syndromes, nutritional deficiency), DIC and dilutional coagulopathy in massive transfusion
A complete history should include:
● Surgical history: dental procedures, bleeding during surgery vs. postoperative bleeding
● Nature of bleeding: habitual epistaxis, menorrhagia, hemarthrosis, postpartum hemorrhage, petechiae, purpura, etc.
● For patients with menorrhagia: history of severe iron deficiency anemia, multiple red blood cell transfusions, procedures such as D&C or hysterectomy for excessive bleeding
● Family history of bleeding (but a negative family history of bleeding does not rule out a congenital bleeding disorder)
● Medication use: warfarin, heparin, aspirin or other NSAIDs, antibiotics (affecting vitamin K dependent clotting factors) and herbal medications
● Medical problems: renal failure, severe liver disease, malabsorption syndromes
Etiology / Pathophysiology
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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
Tables
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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 |
| 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
● Note: Pregnant women with mild to moderate vWD (von Willebrand disease) or Hemophilia A carriers typically are asymptomatic due to elevated vWF and Factor VIII during pregnancy
Some symptoms are more suggestive of either a primary or secondary hemostatic defect and can help narrow the differential diagnosis:
● Epistaxis, menorrhagia, melena, intraoperative or immediate postoperative bleeding and petechiae suggest a platelet disorder or vWD
● Delayed postoperative bleeding is usually due to a coagulation factor deficiency, fibrinogen abnormalities or a collagen disorder
● Spontaneous hemarthrosis and intramuscular bleeds suggest coagulation factor deficiencies
● Note: hemarthrosis is common in classic hemophilias but also can occur in acquired hemophilias
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 ordering vWF multimer assays and blood type determination (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
● Perform Factor XIII assay if delayed bleeding is present (often done by "urea clot lysis" method)
● More esoteric assays include PAI-1 activity and antiplasmin
● Note: lupus anticoagulants can cause prolongation of PTT, but are associated with thrombosis, not bleeding
● Deficiencies of Factor XII, prekallikrein or high molecular weight kininogen do not cause bleeding but cause prolongation of PTT
Prognostic factors
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● Heterozygous patients have 30-60% of normal values of affected factors, usually with no or minor bleeding disorder
● 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
Case reports
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● Bleeding due to familial platelet cyclo-oxygenase deficiency
(Thromb Res 2005;116:483)
Treatment
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● Specific treatment recommendations depend on the type and severity of bleeding disorder, but in general, factor replacement therapy for factor deficiencies is the mainstay of treatment, with the exception of factor II, factor V and factor deficiencies; FFP and cryoprecipitate are also common (Haemophilia 2008;14:671)
● For von Willebrand disease: DDAVP (desmopressin), vWF concentrates, antifibrinolytic agents
● For platelet-related bleeding disorders: platelet transfusion, recombinant factor VIIa
Differential diagnosis
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● Acquired factor deficiencies: are due to liver disease, DIC, lupus anticoagulants, heparin, warfarin or other anticoagulants, inhibitors; 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, Clin Lab Haematol 2000;22 Suppl 1:91
End of Coagulation > Hereditary bleeding disorders > Algorithm for workup of hereditary bleeding disorders
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