Thrombophilia

Published on 03/04/2015 by admin

Filed under Hematology, Oncology and Palliative Medicine

Last modified 22/04/2025

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39

Thrombophilia

Patients who are predisposed to thrombosis generally either have a disorder of the blood or an abnormality of the vessel wall. Where enhanced coagulation is the major mechanism, the disorder is referred to as ‘thrombophilia’. Patients with thrombophilia either tend to have thrombosis at an unusually early age or to develop recurrent thrombotic problems. Venous thrombosis predominates with the chance of thrombosis increased by the coexistence of other risk factors. Thrombophilia can be inherited or acquired.

Which patients should be investigated for thrombophilia?

Testing for heritable thrombophilia is not indicted in unselected patients presenting with venous thrombosis. Table 39.1 summarises factors which should prompt consideration of thrombophilia. Accurate history taking is essential; particular attention should be given to the nature of the recent thrombotic event, the presence of known risk factors (Table 39.2), a previous history of thrombosis and the family history. Definition of a ‘positive’ family history of thrombosis is problematic. If we use the simple definition of a history of deep vein thrombosis (DVT) or pulmonary embolus (PE) in a first or second degree relative, then approximately 25% of all patients will have a positive family history. Even among those with a strong family history only a small minority will have a cause of inherited thrombophilia identified.

Table 39.2

Major risk factors for thrombosis

Venous Arterial
Increasing age Increasing age
Immobility Smoking
Obesity Male sex
Oral contraceptive pill Hypertension
Trauma/surgery Strong family history
Thrombophilia (see text) Hyperlipidaemia
Pregnancy Diabetes mellitus
Malignancy Raised fibrinogen

Basic investigations of thrombophilia should include a blood count (to exclude polycythaemia and other myeloproliferative disorders) and a coagulation screen. Further laboratory testing is dictated by the possible causes of familial and acquired thrombophilia detailed below. Testing for thrombophilia should not be undertaken during an acute episode of venous thromboembolism when low levels of coagulation inhibitors are routinely found. Systemic disorders such as liver disease or disseminated intravascular coagulation (DIC) can depress the levels of coagulation inhibitors and thus simulate the laboratory abnormalities found in familial thrombophilia.

Familial thrombophilia

In theory, familial thrombophilia could be caused by any genetically determined defect of the coagulation or fibrinolytic systems that causes accelerated thrombin formation or impaired fibrin dissolution. In practice, the well-defined causes are associated with accelerated thrombin formation either due to a shortage or failure of activation of one of a number of circulating inhibitors of coagulation (Fig 39.1). Inherited thrombophilia defects are only important in venous thrombosis.

Factor V Leiden (FVR506Q)

The anticoagulant property of activated protein C (APC) lies in its capacity to inactivate the activated cofactors Va and VIIIa by limited proteolysis. Inherited resistance to the anticoagulant action of APC (APCR) is an important cause of thrombophilia. In most cases resistance is caused by a single point mutation in the factor V gene (factor V Leiden) with replacement of Arg506 with Gln. Arg506 is located at one of the APC cleavage sites in factor Va and the mutated Va is less sensitive than normal Va to APC-mediated inactivation.

APCR has an autosomal dominant mode of inheritance and is the most common known cause of familial thrombophilia. The increased risk of venous thrombosis in APCR has been estimated as 4–8-fold in heterozygotes and 50–100-fold in homozygotes. The prevalence of the disorder in Western Europe is 3–7% with an incidence of around 15% in unselected cases of venous thrombosis. The risk of venous thrombosis is highest in patients homozygous for the mutation or in heterozygotes with other risk factors.

Protein C and S deficiencies

Hereditary deficiency of protein C is an autosomal dominant disorder found in 2–5% of patients with thromboembolic disease. An acquired deficiency of protein C can occur in liver disease, DIC and warfarin treatment. Familial protein C deficiency manifests as an increased incidence of venous thromboembolism. Thrombotic events vary from a superficial thrombophlebitis to DVT and PE. They may be spontaneous or triggered by other factors such as surgery or pregnancy. In the rare homozygous form, the infant can be born with undetectable levels of protein C and quickly develop DIC and skin necrosis due to microvascular thrombosis of subcutaneous vessels (purpura fulminans). Protein S is the non-enzymatic cofactor of protein C. Hereditary deficiency has similar clinical features to protein C deficiency.

Management of familial thrombophilia

The precise role of laboratory thrombophilia testing in clinical decision making remains unclear.

Acquired forms of thrombophilia

Antiphospholipid antibody syndrome

Diagnosis of this syndrome requires either venous and/or arterial thromboembolism or adverse outcomes in pregnancy in the presence of a persisting antiphospholipid antibody (Table 39.3). The syndrome can be ‘primary’, where the patient has no obvious autoimmune disease, or ‘secondary’ if the patient also has systemic lupus erythematosus (SLE) or a lupus-like disease. About half of all patients have the primary form of the disorder. Up to 2% of the general population have detectable antiphospholipid antibodies – the probability of clinical problems is greatest where the antibody titre is high.

The cause of thrombophilia in antiphospholipid antibody syndrome is not entirely understood. Antiphospholipid antibodies have been shown to play a direct role in the development of thrombosis in experimental animal models. Management must be individualised. Where there has been an episode of major thrombosis, warfarin appears to offer the best protection against recurrent thrombosis. Aspirin may give additional benefit in arterial thrombosis. Women with a history of morbidity in pregnancy are best treated in future pregnancies with a combination of aspirin and heparin.

Other acquired forms of thrombophilia

Myeloproliferative disorders are discussed elsewhere (pp. 64–67). Increased levels of plasma fibrinogen, and D-dimers may be predictors for coronary artery disease. Whether these and other haemostatic abnormalities are constitutional changes predisposing to coronary atherosclerosis and thrombosis or whether they are markers of pre-existing inflammation and endothelial dysfunction is unclear.

Thrombophilia

image The term ‘thrombophilia’ describes a predisposition to thrombosis caused by abnormally enhanced coagulation. Patients often have venous thrombosis at an early age or develop recurrent thrombotic problems.

image Classic familial thrombophilia disorders are deficiencies of the naturally occurring inhibitors of coagulation, protein C, protein S and antithrombin.

image Factor V Leiden is a thrombophilia disorder caused by an inherited mutation in the factor V gene. Heterozygosity is common (3–7% in Western European population).

image The clinical role of laboratory thrombophilia testing is not well defined.

image Antiphospholipid antibody syndrome is an acquired disorder characterised by laboratory identification of antiphospholipid antibodies and clinical features including thrombophilia and morbidity in pregnancy.

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