Regular articlePatients with primary antiphospholipid antibody syndrome and without associated vascular risk factors present a normal endothelial function
Introduction
Primary antiphospholipid syndrome (PAPS) is an autoimmune condition characterized by the occurrence of venous or arterial thrombosis or of pregnancy complications and by the presence, upon repeated determination, of elevated levels of antiphospholipid antibodies (APLA) in the absence of other known autoimmune conditions [1]. The incidence of thrombotic complications in patients with APS is of around 2.5% patient/years [2]. It is well established that VTE is the main clinical manifestation of APS [3]. Amongst APLA, the LAC is a recognized risk factor for VTE (OR 3.6; 95% CI, 1.2–10.9) in patients with APS [4]. VTE risk increases up to 10 times when LAC is associated with positivity for anti beta2-glycoprotein I (β2-GPI) antibodies (a subgroup of APLA) [5].
It is still discussed whether patients with APS have an increased risk of ischemic cardiovascular events. Some studies suggested early atherosclerosis in patients with APS, as indicated by a lower ankle brachial index (ABI) or by an increased intimal media thickness (IMT) of the carotid artery [6]. The association between APLA and atherosclerosis [7] was strengthened by the identification of anti β2GPI antibodies in atherosclerotic specimens obtained from human carotid endarterectomies [8].
Several studies, over the last few years, have shown that chronic autoimmune rheumatic disorders are characterized by early atherosclerosis and by increased cardiovascular morbidity and mortality [9]. The question of whether early atherosclerosis is a feature of APS or rather a consequence of the chronic inflammation associated with a generalized autoimmune condition remains to be clarified [10].
Endothelial dysfunction (ED) is an early event in the natural history of atherosclerosis and is defined as the loss of the vasodilatory, anti-thrombotic and antiproliferative capacities of the endothelium [11]. ED is a very precocious consequence of the presence of cardiovascular risk factors [12].
Endothelial function can be studied non invasively in humans by the evaluation of the dilation of peripheral arteries induced by pharmacological stimuli or by the increased flow-provoked vessel wall shear stress (Flow Mediated Dilatation = FMD) which release endothelial-derived nitric oxide (NO) [13], [14].
The evaluation of FMD of the brachial artery is a widely applicable method to screen and to repeat the evaluation over time, for ED [11], [13]. FMD is reduced in subjects with atherosclerosis and cardiovascular risk factors. More specifically, smoking [15], high cholesterol levels, arterial hypertension, diabetes and renal failure are associated with NO-related ED [14], [15], [16]. In addition, FMD correlates with coronary vasodilator function and serological markers of endothelial perturbation [17], [18].
Recently, an impaired FMD was shown to be present in patients with spontaneous, unprovoked DVT. This observation supports the hypothesis that also conditions not primarily involving arteries may induce an impairment of endothelial function leading to atherosclerosis [19].
FMD is a useful marker of ED but it may not give a complete information on the damage to and repair of the endothelial monolayer, thus the assessment of some plasma markers of endothelium perturbation may provide additional informations [20]. Moreover, also the measurement of circulating endothelial cells (CEC) and of endothelial progenitor cells (EPC) adds to the assessment of endothelial perturbation in disease conditions [21], [22], [23].
The aim of our study was to evaluate endothelial function in patients with confirmed primary APS and without any associated risk factors for vascular disease, compared with age- and sex-matched controls.
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Patients
Patients with objectively documented APS were included in a case-control study. The following criteria were adopted for objectively documented PAPS: 1) the presence of one or more venous or arterial thromboses or of one or more otherwise unexplained fetal losses; 2) the positivity of at least one APLA test (LAC or anticardiolipin antibodies (ACLA) or anti β2GPI antibodies) in at least two consecutives determinations 12-weeks apart, in accordance with the international consensus statement on the
Patients
Overall, 20 patients (11 females, mean age 42 ± 4.0 years, 80% positive for 3 APL markers and 20% only positive for LAC antibodies) and 39 matched controls (22 females, mean age 41 ± 2.9) were included in the study. Cases and controls were well matched for age, sex and BMI. Twelve patients and three controls (1 affected by atrial fibrillation and 2 with prosthetic heart valves) were on oral anticoagulants (Table 1).
Flow mediated dilation
FMD was 5.7 ± 0.8% in patients (95% CI: 4.1 to 7.3) and 6.8 ± 0.5% (5.7 to 7.9) in
Discussion
Atherosclerosis is a complex, multifactorial disease leading to a variety of clinical manifestations, including peripheral arterial disease, coronary artery disease and stroke. Genetic and environmental factors participate to elicit atherogenesis, like smoking, hypertension, diabetes, repeated injury to vascular tissues and high levels of oxidized LDL-associated cholesterol. Lately, immunological mechanisms have been increasingly implicated in modulating these processes. Several chronic
Acknowledgments
This work was supported in part by a grant to P.G. from the Fondazione Cassa di Risparmio di Perugia (Project n. 2007.0130.020).
References (38)
Antiphospholipid thrombosis syndromes
Hematol Oncol Clin North Am
(2003)- et al.
Comparison of the primary and secondary antiphospholipid syndrome: a European Multicenter Study of 114 patients
Am J Med
(1994) - et al.
Lupus anticoagulants and the risk of a first episode of deep venous thrombosis
J Thromb Haemost
(2005) - et al.
Antiphospholipid antibodies: are they pro-atherogenic or an epiphenomenon of atherosclerosis?
Immunobiology
(2003) - et al.
Close relation of endothelial function in the human coronary and peripheral circulations
J Am Coll Cardiol
(1995) - et al.
Participating Centres of Italian Federation of Thrombosis Centres (FCSA). Survey of lupus anticoagulant diagnosis by central evaluation of positive plasma samples
J Thromb Haemost
(2007) - et al.
Standardization group of the European Forum on Antiphospholipid Antibodies. Proposals for the measurement of anti β2GPI antibodies. Standardization group of the European Forum on Antiphospholipid Antibodies
J Thromb Haemost
(2004) - et al.
Endothelial function is impaired in patients with primary antiphospholipid syndrome
Thromb Res
(2006) - et al.
Inflammatory response and the endothelium
Thromb Res
(2004) - et al.
Peripheral vascular disease in antiphospholipid syndrome
Thromb Res
(2004)