Elsevier

The Lancet Neurology

Volume 8, Issue 11, November 2009, Pages 998-1005
The Lancet Neurology

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Antiphospholipid antibodies and risk of myocardial infarction and ischaemic stroke in young women in the RATIO study: a case-control study

https://doi.org/10.1016/S1474-4422(09)70239-XGet rights and content

Summary

Background

Arterial thrombosis is a major clinical manifestation of the antiphospholipid syndrome, which is an autoimmune disease found mostly in young women. Although the presence of circulating antiphospholipid antibodies in individuals who have a thrombotic event is a prerequisite for the diagnosis of the antiphospholipid syndrome, the risk of arterial thrombosis associated with antiphospholipid antibodies in the general population is unclear.

Methods

In RATIO (Risk of Arterial Thrombosis In relation to Oral contraceptives), a large multicentre population-based case-control study, we enrolled women aged under 50 years who were admitted to hospital at 16 centres with first ischaemic stroke or myocardial infarction between January, 1990, and October, 1995. An additional 59 women who presented with ischaemic stroke at the University Medical Centre Utrecht between 1996 and 2001 were also enrolled. Information on cardiovascular risk factors (such as oral contraceptive use, smoking, and hypertension) were assessed with a standard questionnaire. During the second phase (1998–2002), blood samples were taken to measure antiphospholipid antibody profiles (lupus anticoagulant, anticardiolipin IgG, anti-β2-glycoprotein I IgG, and antiprothrombin IgG) and to determine genetic prothrombotic risk factors (factor V G1691A variant, prothrombin G20210A variant, and factor XIII 204Phe allele).

Findings

175 patients with ischaemic stroke, 203 patients with myocardial infarction, and 628 healthy controls were included. Patients were frequency matched with controls for age, residence area, and index year. Lupus anticoagulant was found in 30 (17%) patients with ischaemic stroke, six (3%) patients with myocardial infarction, and four (0·7%) in the control group. The odds ratio for myocardial infarction was 5·3 (95% CI 1·4–20·8), which increased to 21·6 (1·9–242·0) in women who used oral contraceptives and 33·7 (6·0–189·0) in those who smoked. The odds ratio for ischaemic stroke was 43·1 (12·2–152·0), which increased to 201·0 (22·1–1828·0) in women who used oral contraceptives and 87·0 (14·5–523·0) in those who smoked. In women who had anti-β2-glycoprotein I antibodies, the risk of ischaemic stroke was 2·3 (1·4–3·7), but the risk of myocardial infarction was not increased (0·9, 0·5–1·6). Neither anticardiolipin nor antiprothrombin antibodies affected the risk of myocardial infarction or ischaemic stroke.

Interpretation

Our results suggest that lupus anticoagulant is a major risk factor for arterial thrombotic events in young women, and the presence of other cardiovascular risk factors increases the risk even further.

Funding

Netherlands Heart Foundation and Leducq Foundation.

Introduction

Arterial thrombosis is the second most common cause of death in developed countries. Although the incidence of arterial thrombosis in individuals younger than 50 years is low, the burden of disease in young people is large. Arterial thrombosis is usually associated with several risk factors for cardiovascular disease, such as smoking, hypertension, diabetes, obesity, hyperlipidaemia, or a family history of cardiovascular disease. The antiphospholipid syndrome is an acquired risk factor for arterial thrombosis. The antiphospholipid syndrome is more prevalent in young women than in the general population.1 It is characterised by vascular thrombosis or complications during pregnancy and a repeatedly positive test for antiphospholipid antibodies.2 There are several subpopulations of antiphospholipid antibodies; the coagulation inhibitor lupus anticoagulant and antibodies against the phospholipid cardiolipin or the plasma proteins β2-glycoprotein I and prothrombin are the antibody subpopulations most commonly tested for.

Owing to its non-specific clinical symptoms, diagnosis of the antiphospholipid syndrome is dependent on the detection of antiphospholipid antibodies. Data on the risk of a first thrombotic event in the presence of antiphospholipid antibodies are inconclusive3 because most studies are done in selected populations of patients. Several studies have been done to assess the thrombotic risk associated with antiphospholipid antibodies in the general population.4, 5, 6, 7, 8, 9, 10 Although there is a general consensus from the results of these studies that the presence of antiphospholipid antibodies is independently associated with increased risk of arterial thrombosis, there is still debate on the value of measuring the concentrations of different antiphospholipid antibody subpopulations in the general population.11

We investigated whether the presence of specific antiphospholipid antibody subpopulations (lupus anticoagulant, anticardiolipin, or anti-β2-glycoprotein I and antiprothrombin antibodies) affects the risk of myocardial infarction or ischaemic stroke in young women. Furthermore, we studied the effect of smoking, hyperlipidaemia, diabetes, use of oral contraceptives,12, 13 the factor V G1691A mutation (factor V Leiden),14, 15 the prothrombin G20210A mutation,15, 16, 17 and the factor XIII 204Phe allele18 on the relation between antiphospholipid antibodies and arterial thrombosis.

Section snippets

Participants

Eligible patients were women aged 18–49 years who were admitted to hospital for a first myocardial infarction or ischaemic stroke at 16 centres (eight academic centres and eight large, non-academic hospitals) between January, 1990, and October, 1995. Exclusion criteria were transient ischaemic attack that lasted less than 24 h, haemorrhagic stroke, cerebral sinus venous thrombosis, carotid artery dissection, history of cardiovascular or cerebrovascular disease, aphasia or cognitive impairment

Results

During the first phase (1990–95), 248 patients with myocardial infarction, 203 patients with ischaemic stroke, and 925 controls were enrolled (figure 1). 218 of 248 patients with myocardial infarction included during the first phase of the study agreed to participate in the second phase. Samples of venous blood were collected from 203 women with myocardial infarction and buccal swabs were taken from 15 women. Blood samples were collected from 638 of the 925 controls included during the first

Discussion

We found that lupus anticoagulants were associated with an increased risk of myocardial infarction (OR 5·3) and ischaemic stroke (OR 43·1) in women younger than 50 years. Increased concentrations of anti-β2-glycoprotein I antibodies were associated with an increased risk of ischaemic stroke (OR 2·3). Neither anticardiolipin nor antiprothrombin antibodies alone increased the risk of myocardial infarction or ischaemic stroke. There were no indications that the presence of more than one

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