Investigation and management of heritable thrombophilia

Abstract

There is no internationally accepted definition of thrombophilia. The British Committee for Standards in Haematology (1990) suggested that the term thrombophilia be used to describe ‘disorders of the haemostatic mechanisms which are likely to predispose to thrombosis’. This definition is widely used but has disadvantages. Firstly, as new thrombophilic conditions have been described, it has become evident that many individuals who carry these defects remain asymptomatic. Secondly, even though there is an increase in the number of abnormalities recognized as likely to enhance the risk of thrombosis, detailed laboratory investigations fail to detect any abnormality in at least 50% of patients who present with a history of thrombosis. In North America, the term thrombophilic is frequently used by clinicians to describe patients who have developed venous thrombosis either spontaneously or of a severity out of proportion to any recognized stimulus, patients who have recurrent venous thrombotic events and patients who develop venous thrombosis at an early age. This may be a more clinically useful concept. Individuals who have a thrombophilic defect identified on laboratory testing and who have a family history of proven venous thrombosis are at greater risk of thrombosis than individuals who have a thrombophilic defect but no personal or family history of venous thrombosis (Lensen et al, 1996). Inevitably, with the developing interest in the role of prothrombotic abnormalities in thrombosis risk, haematologists and other clinicians have come under pressure to initiate laboratory tests on an increasing number of patients. Performance of a comprehensive range of laboratory tests for thrombophilia has thus become commonplace in subjects presenting with deep vein thrombosis (DVT) or pulmonary embolism. Detection of a heritable prothrombotic state may also lead to testing of family members in an attempt to identify asymptomatic relatives who may be at increased risk of venous thromboembolism (VTE). There are several important issues relevant to the clinical utility and cost effectiveness of this approach. Clinicians may tend to overestimate the risk of thrombosis associated with thrombophilias and to underestimate the risks associated with anticoagulation. Frequently, this has led to the belief that prophylactic anticoagulation is a safer option than clinical surveillance. As evidence about the risk of venous thrombosis associated with thrombophilias accumulates, it is becoming clear that for most patients this is not the case. Furthermore, there is often a lack of recognition that failure to identify a defect in an individual is not proof that no defect exists, only that the particular defects for which tests have been performed are probably not present. The patient with ‘negative’ test results may well have as yet unidentifiable prothrombotic abnormalities, which increase his or her risk of thrombosis. Reassuring patients with normal test results may constitute false reassurance, which may present a real risk for the patient if negative laboratory results lead to ignoring or underestimating the clinical history. Prothrombotic states may be heritable, acquired or mixed – the result of the environment (e.g. oestrogen use, obesity or other lifestyle factors) interacting with genetic background. To date, a limited number of genetic variants are proven to be independent risk factors for venous thromboembolism. These include mutations in the genes encoding the natural anticoagulants antithrombin, protein C and protein S, and the clotting factors fibrinogen, prothrombin and factor V. Antithrombin deficiency Antithrombin (previously called antithrombin III) is synthesized by the liver. Its inhibitory effect is not confined to thrombin. It also inhibits the activated clotting factors IXa, Xa, XIa, XIIa and tissue factor-bound factor VIIa. Heparins markedly accelerate the rate of complex formation between antithrombin and the serine proteases. Within the last decade, our understanding of the basis of familial antithrombin deficiency has been greatly facilitated by advances made in the molecular biology and functional characterization of this inhibitory glycoprotein. Of particular significance has been the recognition that the antithrombin molecule possesses two important functional regions – a heparin-binding domain and a thrombin-binding domain. Two major types of heritable antithrombin deficiency are recognized. Type I is characterized by a quantitative reduction of qualitatively (functionally) normal antithrombin protein. Type II deficiency is due to the production of a qualitatively abnormal protein. In both types of antithrombin deficiency, antithrombin activity is reduced to a variable extent. Type II deficiency is subclassified according to the site of the molecular defect: (a) Reactive site (RS) – abnormalities residing in the reactive (thrombin binding) site. (b) Heparin binding site (HBS) – abnormalities residing in