Elsevier

Thrombosis Research

Volume 123, Issue 3, January 2009, Pages 444-451
Thrombosis Research

Regular article
Patients with primary antiphospholipid antibody syndrome and without associated vascular risk factors present a normal endothelial function

https://doi.org/10.1016/j.thromres.2008.05.015Get rights and content

Abstract

Introduction

Primary antiphospholipid antibody syndrome (PAPS) is characterized by venous or arterial thrombosis and positive antiphospholipid antibodies. It is controversial whether PAPS patients have early atherosclerosis. Endothelial dysfunction is an early event in the natural history of atherosclerosis. Aim of our study was to compare endothelial function of patients with PAPS and no associated risk factors with that of age- and sex-matched controls.

Materials and Methods

Patients with PAPS, carefully selected to exclude all known risk factors for cardiovascular diseases, estrogen therapy, pregnancy, intake of drugs affecting endothelial function, vitamins or antioxidants, were included in a case-control study. Controls were age- (± 5 years) and sex-matched subjects with the same exclusion criteria but without PAPS. Flow-mediated dilation of the brachial artery and some plasmatic markers of endothelial and platelet activation were measured. Measures are expressed as mean±SEM.

Results

Twenty cases (mean age 42 ± 4.0 years, 11 females) and 39 controls (mean age 41 ± 2.9, 22 females) were studied. FMD was 5.7 ± 0.8% in cases (95% CI: 4.1 to 7.3) and 6.8 ± 0.5% (5.7 to 7.9) in controls (p = NS). Plasma von Willebrand factor was 128 ± 11.3% and 134.2 ± 16.1% in cases and controls, respectively (p = NS). Soluble P-selectin and soluble CD40L were 94.1 ± 4.9 ng/ml and 0.7 ± 0.1 ng/ml in cases and 87.7 ± 4.0 ng/ml and 1.0 ± 0.2 in controls, respectively (p = NS). In a substudy, circulating progenitor and mature endothelial cells were comparable between the two groups.

Conclusions

Endothelial function in patients with PAPS and no associated risk factors is similar to that of age- and sex- matched controls. These data suggest that the alterations leading to thrombosis in PAPS concern primarily the clotting system.

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.

Section snippets

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).

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