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Rheumatology Advance Access originally published online on April 2, 2007
Rheumatology 2007 46(6):907-910; doi:10.1093/rheumatology/kem040
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© The Author 2007. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

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Vasculopathy and arterial stenotic lesions in the antiphospholipid syndrome

C. Christodoulou, S. Sangle and D. P. D'Cruz

The Lupus Research Unit, The Rayne Institute, St Thomas’ Hospital, London, UK.

Correspondence to: David D’Cruz, The Lupus Research Unit, The Rayne Institute, St Thomas’ Hospital, London, SE1 7EH, UK, E-mail: david.d'cruz{at}kcl.ac.uk


   Abstract
Top
 Abstract
Vasculopathy and arterial...
 Antiphospholipid antibodies and...
 Complement and pregnancy...
 Clinical evidence for a...
 Conclusion
 References
 
The antiphospholipid (Hughes) syndrome (APS) is characterized by recurrent arterial or venous thromboembolism, or pregnancy loss, in association with antiphospholipid antibodies. These antibodies may be associated with premature or accelerated atherosclerosis and emerging evidence supports the concept of a vasculopathy in the APS that may lead to arterial stenotic lesions, possibly contributing to vascular occlusions and pregnancy morbidity.

KEY WORDS: Antiphospholipid syndrome, Vasculopathy, Atherosclerosis, Stenotic lesions, Intima media thickness


   Vasculopathy and arterial stenotic lesions in the antiphospholipid syndrome
Top
 Abstract
 Vasculopathy and arterial...
Antiphospholipid antibodies and...
 Complement and pregnancy...
 Clinical evidence for a...
 Conclusion
 References
 
The antiphospholipid (Hughes) syndrome (APS) is characterized by recurrent arterial or venous thromboembolism, or pregnancy loss, in association with antiphospholipid antibodies (aPL) [1]. It is known that premature or accelerated atherosclerosis is a major cause of death in systemic lupus erythematosus (SLE) patients [2, 3]. Emerging evidence supports the concept of a vasculopathy in the APS that may lead to arterial stenotic lesions, possibly contributing to vascular occlusions and pregnancy morbidity.


   Antiphospholipid antibodies and atherosclerosis
Top
 Abstract
 Vasculopathy and arterial...
 Antiphospholipid antibodies and...
Complement and pregnancy...
 Clinical evidence for a...
 Conclusion
 References
 
Recent studies have suggested that antiphospholipid antibodies may be associated with accelerated atherosclerosis in patients with APS [4–6]. It has been shown that anticardiolipin (aCL) and anti-ß2-glycoprotein-I (ß2GPI) antibodies are elevated in patients with coronary artery disease compared with controls [7]. In the subgroup of patients who underwent coronary angiography, those who had significant coronary artery stenosis had elevated levels of aCL compared with those without significant coronary artery stenosis. In a prospective study, the presence of high aCL level was associated with myocardial infarction and cardiac death [8]. Inflammatory and immunogenic mechanisms may be involved in the initiation and progression of atherosclerotic lesions. Experimental evidence seems to indicate that oxidation of low-density lipoproteins (LDL) plays a central role in early atherogenic events that promote the formation of macrophage-derived foam cells [9–11]. Oxidized LDL (oxLDL) is the principal lipoprotein found in atherosclerotic lesions, and it co-localizes with ß2GPI and immunoreactive lymphocytes [12]. OxLDL binds ß2GPI and these complexes can be found in the plasma of patients with various autoimmune and chronic inflammatory diseases such as SLE, APS, chronic renal disease, diabetes mellitus and a few patients with acute myocardial infarction [13]. Immunoglobulin G (IgG) autoantibodies to oxLDL/ß2GPI were detected only in SLE and APS patients, and were strongly associated with arterial thrombosis. Moreover, immune complexes containing oxLDL, ß2GPI and IgG anti-ß2GPI antibodies have also been detected in SLE and APS patients [13]. In vitro experiments showed that oxLDL/ß2GPI complexes were internalized by macrophages via an anti-ß2GPI antibody-mediated phagocytosis [14–16]. The participation of macrophage Fc{gamma} receptors in the uptake of oxLDL-containing complexes is particularly important in the development of foam cells and atherosclerotic plaques. Moreover, IgG anti-high density lipoprotein (HDL) and IgG anti-ß2GPI antibodies are associated with reduced paraoxonase activity in patients with SLE and primary APS [17]. Since the physiological role of paraoxonase is to prevent low-density lipoprotein oxidation with its atherogenic effects, these interactions may be relevant in the development of atherosclerosis in SLE and primary APS. A recent study has proposed a beneficial role for some aPL in atherosclerosis [18].


   Complement and pregnancy complications in APS
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 Abstract
 Vasculopathy and arterial...
 Antiphospholipid antibodies and...
 Complement and pregnancy...
Clinical evidence for a...
 Conclusion
 References
 
It has been demonstrated that factor B, complement (C) 3, C5 and its receptor C5aR are important players in pregnancy complications triggered by aPL and that neutrophils are critical effector cells in a mouse model of APS [19, 20]. The fact that aPL-IgG can initiate foetal damage in the absence of activating Fc{gamma}Rs but not in the absence of C4, and that F(ab)’2 fragments of aPL-IgG do not mediate such injury, suggest that initiation of the complement cascade occurs via the classical pathway. The observation that factor B is required for foetal death and that its presence is associated with increased C3 deposition shows, however, that the alternative pathway amplifies local complement activation and also plays a critical role in the induction of foetal loss [20].

The same authors showed that heparin prevented complement activation in vivo and in vitro and protected mice from pregnancy complications induced by aPL antibodies [21]. Neither of the two other anticoagulants, fondaparinux nor hirudin, inhibited the generation of complement split products or prevented pregnancy loss, demonstrating that anticoagulation therapy is insufficient protection against APS-associated miscarriage, at least in this mouse model. Their data suggest that heparins prevent obstetric complications in some women with APS because they block activation of complement induced by aPL antibodies targeted to decidual tissues, not because they prevent placental thrombosis. According to the authors, these findings provide a framework for understanding how subanticoagulant doses of heparin exert beneficial effects in antibody-mediated tissue injury and emphasize the importance of developing and testing targeted complement-inhibitory therapy for patients with APS [21]. These animal model data have not yet been confirmed in humans.


   Clinical evidence for a vasculopathy in the antiphospholipid syndrome (Table 1)
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 Abstract
 Vasculopathy and arterial...
 Antiphospholipid antibodies and...
 Complement and pregnancy...
 Clinical evidence for a...
Conclusion
 References
 
Abnormal ankle brachial index
The ankle brachial index (ABI) has been demonstrated as a good predictor for peripheral vascular disease, but also for stroke and cardiovascular events in middle-aged and older populations [22–26]. Hence, the ABI has been used successfully in many studies and in different populations such as diabetics, healthy populations and cardiac patients [5, 27]. It is a simple, inexpensive, non-invasive technique for assessing the risk of developing atherosclerosis, only requiring a blood pressure cuff and a Doppler ultrasound probe and could easily be used in the clinic room. It has been shown that 19% of patients with primary APS (mean age 40 years) and previous thrombosis had an abnormal ABI compared with 4% of healthy controls (P= 0.026) [28]. In another study, 23% of APS patients (mean age 37 years) with pregnancy loss but no previous thrombosis had an abnormal ABI compared with none in the control group (P< 0.02) [29]. These data suggest that a large vessel vasculopathy may be a contributing factor to both thrombosis and pregnancy loss in APS.


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  		TABLE 1. Evidence supporting the presence of a vasculopathy in the antiphospholipid syndrome

 
Increased carotid artery intima media thickness
Intima media thickness (IMT) measurements are strong prognosticators of coronary artery disease risk [30, 31]. Increased IMT and the presence of plaque in carotid or femoral arteries [32] are complementary but distinct risk factors for coronary artery disease events [33]. In one study, 82% of primary APS patients (mean age 40 years) had increased carotid artery IMT (mean 2.6 mm) compared with 25% of controls (mean 1.2 mm) (P= 0.0001) [34]. A decrease in the lumen diameter was also found in 39% of primary APS patients without carotid atherosclerotic plaque and 7% of controls (P= 0.004). Patients with IMT had a 3-fold higher risk for stroke than those without IMT. In another study, aPL positive patients had increased carotid artery IMT as compared to controls (0.75± 0.02 mm vs 0.64± 0.01 mm, P< 0.001) [35]. Several studies have shown that endothelium-dependent flow mediated dilatation was reduced in aPL positive patients [35–37]. It has been shown that 15% of APS patients (mean age 40 years) had atherosclerotic plaques affecting the carotid and/or femoral arteries as compared with 6% of SLE/aCL-positive patients, 12% of SLE/aCL-negative patients and 3% of healthy subjects (P= 0.33) [38]. APS patients had significantly more affected vessels than healthy controls (P= 0.016). There were no significant differences in IMT between the groups. Another study has reported a higher prevalence of carotid plaque in SLE patients than in primary APS patients or controls (29% vs 8% vs 15%, respectively, P< 0.001) [39]. The IMT was similar in the three groups. SLE patients with secondary APS had a higher prevalence of carotid plaque than patients with primary APS (37% vs 8%, P= 0.03).

Histopathological findings
Autopsy samples from 14 SLE patients were examined histomorphologically and immunohistologically [40]. Thirteen patients were persistently positive for IgG aCL and had common thrombotic complications and/or other clinical features related to APS. The autopsy samples showed frequent occlusive vascular changes such as thromboses, thrombotic microangiopathy related changes and arterial intimal fibrous hyperplasia. Immune complex related vascular changes were uncommon and present mainly in low aCL positive patients. According to the authors, their findings suggest two pathogenic mechanisms associated with the presence of aCL, one related to abnormal coagulation and the other to endothelial cell injury.

Renal and coeliac artery stenosis
It has been shown that 26% of patients positive for antiphospholipid antibodies and uncontrolled hypertension (mean age 43 years) had evidence of renal artery stenosis (16 unilateral and 4 bilateral) [41, 42]. Eighty percent of the patients with renal artery stenosis had smooth well-defined stenoses in the proximal third of the renal artery. Only 8% of hypertensive patients (mean age 42 years) had renal artery stenosis (P< 0.001) and only 3% of healthy controls (mean age 52 years) had renal artery stenosis (P< 0.0001). All but two patients with renal artery stenosis were treated with anticoagulants with a target international normalized ratio (INR) 3.0–4.0 [41]. Magnetic resonance imaging angiography (MRA)/CT contrast angiography was repeated in five patients for suspected re-stenosis. All five had previously undergone angioplasty of stenosed renal arteries (stents were inserted in three) and were anticoagulated after the angioplasty. Two of the five had evidence of re-stenosis. One of these was not anticoagulated and the other was inadequately anticoagulated with a mean INR< 2.3. The remaining three patients who had an INR> 3.0 showed no evidence of re-stenosis. All other patients who had a mean INR> 3.0 showed good control of blood pressure and stable renal parameters, suggesting that adequate anticoagulation may be important in maintaining the patency of the renal arteries. In another paper, the same authors showed that anticoagulation with an INR> 3.0 helped to control the blood pressure and prevented the progression of renal disease in APS patients with renal artery stenosis [43]. Local treatment may involve percutaneous transluminal balloon angioplasty with or without stenting [44]. Surgery should be reserved for severe lesions not amenable to angioplasty. Local treatment should be followed by anticoagulation in order to prevent re-stenosis [42].

Recently, coeliac artery lesions ranging from narrowing to complete occlusion have been reported in 17 patients (median age 42 years) positive for aPL [45]. Fourteen of these patients fulfilled the Sapporo criteria for APS (12 secondary to SLE, 2 primary APS). Ten patients complained of abdominal angina and weight loss or failure to thrive. Seven patients were asymptomatic. The lesions were at and distal to the ostium and were smooth and regular.

Cardiac manifestations
Cardiac manifestations of APS include valvular abnormalities such as valve thickening, vegetations and dysfunction (including insufficiency), occlusive arterial disease (atherosclerosis and myocardial infarction), intracardiac emboli, ventricular hypertrophy and dysfunction and pulmonary hypertension [46]. The deformed valves of APS patients display deposits of immunoglobulins (consisting of aCL) and complement in subendothelial connective tissue [47]. C1q, C3c and C4 deposits are similar in form and location, but are more granular, suggesting immune complexes. Histopathology demonstrates superficial or intravalvular fibrin deposits and subsequent organisation: vascular proliferation, fibroblast influx, fibrosis and calcification. This results in valve thickening, fusion and rigidity leading to disrupted function. Recurrent pulmonary embolism is assumed to be the cause of pulmonary hypertension in APS.

For valvulopathy patients with evidence of thromboembolic disease, anticoagulation with warfarin/heparin is recommended [47]. For asymptomatic patients, prophylactic aspirin may be appropriate. For patients with coronary occlusion, it is strongly recommended to aggressively treat all atherosclerotic risk factors such as hypertension, hypercholesterolaemia and smoking. According to the authors, the use of folic acid, B vitamins, statins and hydroxychloroquine should be considered [47]. For those who have thrombosis in the absence of atherosclerosis, they recommend warfarin. For patients with intracardiac thrombi, they recommend intensive warfarin anticoagulation and consultation with cardiac surgeons when appropriate. For patients with pulmonary hypertension, intensive anticoagulation with warfarin is also recommended [47].

Peripheral vascular disease
It is reported that the prevalence of APS in patients with peripheral vascular disease ranges from 1.7 to 6%, while the prevalence of aPL reaches 14% [48]. However, about 50% of these patients express other traditional risk factors for atherosclerosis. As early as 1989, Alarcon-Segovia et al. [49] described three relatively young patients who developed arterial occlusions in a limb requiring amputation. Two patients had primary APS and one APS secondary to SLE. Their arterial angiograms showed gradual narrowing of the arterial lumen and histopathology showed striking intimal and medial proliferation and some increase in the thickness of the adventitia. There was little evidence of thrombosis.

Ischaemic stroke
The central nervous system is frequently involved in APS, and ischaemic stroke is a common manifestation. High levels of aCL are associated with a 2-fold risk of ischaemic stroke compared with aCL negative patients [50] and are associated with an increased risk of recurrent stroke [51]. Several studies have reported a strong association between valve lesions and brain infarcts [52–54]. Another paper reported the angiographic results of 23 patients positive for aPL and ischaemic cerebrovascular events [55]. Seventeen of these patients (average age 40 years) had abnormal angiograms (16 arterial abnormalities and 1 dural sinus thrombosis). Intracranial arterial abnormalities included stem or branch occlusions of the cerebral or basilar arteries in six patients and findings suggestive of vasculitis in four patients. However, only one patient had a clinical course that was thought to clearly reflect vasculitis. In the other three patients, a non-inflammatory vasculopathy was considered to be the probable cause of the angiographic findings and not true vasculitis. Four patients had stenoses of two or more great vessels. Two patients had extracranial internal carotid artery stenoses or occlusions that were not typical of atheromatous disease. One patient had stenosis of the origin of the internal carotid artery that appeared typical of atheromatous disease. Infarctions were seen on CT or MRI in 13 of the 17 patients with abnormal angiograms. The authors conclude that infrequent lesions in the general stroke patients were common in patients positive for aPL, and that the aetiology and pathogenesis of stroke in APS is fundamentally different from that in the general population. Interestingly, luminal narrowing caused by concentric intimal hyperplasia, fibrous occlusions and fresh and recanalized thrombi have been noted in small leptomeningeal arteries in patients positive for aPL and ischaemic cerebrovascular events [56, 57].

The American Heart Association/American Stroke Association (AHA/ASA) guidelines of 2006 state that for patients with cryptogenic ischaemic stroke or transient ischaemic attack (TIA) and positive aPL, antiplatelet therapy is reasonable particularly for elderly patients [58]. For patients with ischaemic stroke or TIA, who meet classification criteria for APS with venous and arterial occlusive disease in multiple organs, miscarriages and livedo reticularis, they recommend oral anticoagulation with warfarin and a target INR of 2–3. These recommendations remain controversial for young patients with stroke in the context of APS. For example, other authors advocate that specific therapy must be decided on an individual basis, taking into account the severity of the initial thrombotic event, the concurrent presence of other vascular risk factors or additional thromboses, the presence of lupus anticoagulant and very high titre aCL and the estimated bleeding risk according to age, bleeding history and polypharmacy [59]. According to these authors, high-intensity oral anticoagulation (INR 3.1–4.0) would be justified in a sizeable number of APS patients with stroke.


   Conclusion
Top
 Abstract
 Vasculopathy and arterial...
 Antiphospholipid antibodies and...
 Complement and pregnancy...
 Clinical evidence for a...
 Conclusion
References
 
In conclusion, taken together, the above evidence supports the presence of a vasculopathy in the APS, which may lead in some patients to arterial stenotic lesions as well as vascular occlusions contributing to the typical clinical manifestations of this syndrome. It is therefore important to consider the different possible vascular clinical manifestations with which patients with APS might present (Table 1). These findings remind us yet again of Virchow's triad of abnormalities in blood flow, the blood itself and the vessel wall all being important in the pathogenesis of thrombosis. Future well-designed trials will hopefully help us stratify risks in patients with APS and help us establish the optimal treatment strategy for the management of its various vascular manifestations. It would seem logical in these patients to treat aggressively all other traditional atherosclerotic risk factors.

Formula

The authors have declared no conflicts of interest.


   References
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 Antiphospholipid antibodies and...
 Complement and pregnancy...
 Clinical evidence for a...
 Conclusion
 References
 

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Submitted 2 October 2006; revised version accepted 24 January 2007.
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