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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

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