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Genetic disorders of coagulation 

Genetic disorders of coagulation

Chapter:
Genetic disorders of coagulation
Author(s):

Eleanor S. Pollak

and Katherine A. High

DOI:
10.1093/med/9780199204854.003.220604_update_001

Update:

Updated information on gene transfer as a method of treating haemophilia.

Updated on 30 May 2013. The previous version of this content can be found here.
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date: 28 April 2017

Much of what is understood about specific coagulation proteins has emerged from the careful study of hereditary disorders of blood coagulation.

Haemophilia

Haemophilia is a familial X-linked disorder due to deficiency of either factor VIII (haemophilia A) or factor IX (haemophilia B), components of the intrinsic enzymatic complex that activates factor X. The severity of the disease correlates with predicted concentrations of activated factor protein, and those with activity levels below 1% are defined as having severe disease.

Clinical features and diagnosis—the main manifestations are bleeding into joints and soft tissues, with haemophilic arthropathy and joint deformity being inevitable complications in untreated patients. Other features include pseudotumours, bleeding into the urinary system, and bleeding following clinical procedures (e.g. dental extractions). Laboratory diagnosis is based on a modification of the classic activated partial thromboplastin time (aPTT) assay, with inhibitor screening used to exclude other causes of prolonged aPTT (e.g. lupus anticoagulant).

Treatment—this involves the administration of the deficient factor VIII or factor IX, most commonly ‘on demand’ in response to bleeding, with prophylactic treatment given before surgery. The use of recombinant factors is preferable to preparations derived from pooled human plasma samples, which have led to numerous infectious complications (hepatitis B and C, HIV, and parvovirus. The development of inhibitory antibodies is a significant problem, particularly in patients with haemophilia A. Trials of gene therapy are being performed.

von Willebrand’s disease

von Willebrand’s disease is a common autosomal dominant disorder of platelet function caused by a functional deficiency of von Willebrand factor (VWF). VWF, normally synthesized by megakaryocytes, prevents degradation of factor VIII; VWF, also made by endothelial cells, enhances platelet activation and recruitment at sites of tissue damage. It may be due to quantitative deficiency of VWF (types 1 and 3), or to defect in platelet binding affinity (type 2).

Clinical features and diagnosis—typical presentation is with nosebleeds, menorrhagia, and easy bruising. Laboratory diagnosis involves both an antigenic test and an activity test (ristocetin cofactor), in which formalin-fixed platelet aggregation is induced due to ristocetin-enhanced VWF binding to glycoprotein complex Ib–IX.

Treatment—mild von Willebrand’s disease is treated with desmopressin 1-desamino-8-D-arginine vasopressin (DDAVP), which releases factor VIII and VWF from endothelial cells. Other treatments include ε‎-aminocaproic acid (for patients who require dental surgery, and women with menorrhagia), oestrogens. and factor VIII concentrates.

Other hereditary disorders of coagulation

These include (1) hereditary deficiency of the plasma metalloproteinase ADAMTS13, which predisposes to thrombotic thrombocytopenic purpura; (2) combined deficiency of coagulation factors V and VIII, caused by single-gene defects in the coordinated machinery for protein trafficking and secretion; (3) factor XI deficiency—an autosomal recessive diathesis of variable severity frequently occurring in Ashkenazi Jews; (4) inherited deficiencies of factors II, V, VII, and X—these cause bleeding tendencies of varying severity and are inherited as recessive disorders; (5) deficiency of the contact activating factors, factor XIII, and fibrinogen.

Hypercoagulable diseases due to deficiencies of anticoagulants or propensity to thrombosis

Typical presentations occur with deep venous thrombosis and/or pulmonary embolism, and hypercoagulable states should be considered particularly when there is ‘unusual’ thrombosis, e.g. superficial thrombophlebitis, mesenteric vein thrombosis, and cerebral vein thrombosis.

Antithrombin III deficiency—diagnosis is particularly difficult in the post-thrombotic period when patients frequently have lower levels of antithrombin III due either to consumption of antithrombin III during clot formation or to the decreased function seen with heparin administration. Treatment is typically with therapeutic or prophylactic low molecular weight heparin or warfarin; antithrombin III concentrate may be given during an acute event or as a prophylactic treatment to prevent further disease.

Deficiencies of protein C and protein S—in addition to thrombotic manifestations, protein C deficiency may also manifest as warfarin-induced skin necrosis and dangerously life-threatening purpura fulminans in the homozygous or compound heterozygous protein C deficient neonate.

Factor V Leiden—a single mutation, in the gene encoding the factor Va protein, leads to prolonged factor Va activity and resistance to activated protein C. The factor V Leiden mutation occurs in about 5% of people of European ancestryand may predispose to thrombotic disease.

Prothrombin 20210 mutation—this frequent allelic variant in populations of European ancestry increases the concentration of prothrombin, thus biasing haemostatic balance towards excess thrombin formation.

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