Syndrome
Shirish R. Sangle and David P. D’Cruz
Introduction
In the original description of antiphospholipid syndrome (APS), Hughes described a correlation between hypertension and livedo reticularis [1]. Although hyperten- sion is a recognized and common feature, the literature on hypertension in APS is surprisingly scanty. The information so far aggregated is mainly based on the renal/
reno-vascular pathology and associated hypertension in the patients with APS/antiphospholipid antibody (aPL). Indeed, it was suggested that the hyperten- sion seen in these patients is exclusively renal in origin. Recent studies, however, do not support this concept as the only explanation for hypertension. In this chapter we have outlined the possible mechanisms of hypertension in the patients with aPL.
Prevalence of Hypertension in APS and aPL
APS is classified as a primary disorder, primary APS (PAPS), and secondary APS in association mostly with systemic lupus erythematosus (SLE). Nasssanov et al described a prevalence of hypertension up to 50% in her series of 28 primary APS patients [2]. To our knowledge there are no previous studies on the prevalence of hypertension in primary or secondary APS and /or aPL-positive patients. In our cohort of 600 patients with aPL, 173 (29%) had definite hypertension requiring therapy. The prevalence of hypertension in primary APS or aPL-positive patients was significantly high (44%) as compared to 27 % of secondary APS/aPL-positive patients. Our patients with APS/aPL were relatively young (median age, 46 years) and, in contrast with essential hypertension which is more common in Afro- Caribbean population, most of our patients (greater than 90%) were Caucasian women [3]. Other risk factors like diabetes and obesity/overweight were present in less than 10% of these hypertensive patients.
Aetio-pathogenesis
Renal and reno-vascular pathology remains the major cause of hypertension in APS. Thrombotic microangiopathy (TMA) affecting the kidney has been described
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in both primary and secondary APS [4] and is reviewed in detail in elsewhere in this book. The renal impairment due to TMA ranges from mild to end-stage renal failure and mild-to-nephrotic range proteinuria is also not uncommon. Nochy et al described renal hypertension as a feature of APS in his patients with TMA [5]. The severity of hypertension varies from mild labile to severe accelerated hypertension.
Hughes suggested that the labile hypertension seen in these patients fluctuates with the severity of livedo reticularis [1]. Malignant or accelerated hypertension is also not uncommonly observed in patients with TMA without any evidence of lupus nephritis (see Fig. 10.1) [6]. Previously, anecdotal reports of renal artery stenosis and hypertension in APS/aPL were reported and it is now an established fact that renal artery stenosis is more frequently seen in APS patients with uncontrolled hypertension compared to young aPL-negative hypertensives and healthy controls.
The renal artery stenosis seen in these patients appears to be unique to this syn- drome and is completely different from that seen in atherosclerotic disease and fibro-muscular dysplasia (see Fig. 10.2) [7]. Although the precise mechanisms are not clear, the renal artery occlusion may be secondary to thrombosis or possibly embolization from the cardiac valves. There is also a possibility that endothelin acti- vation leading to smooth muscle hyperplasia and/or accelerated atherosclerosis are also pathogenic in renal artery stenosis. It may lead to renal infarcts and acute renal shut down has also been reported [8–10]. Obviously in patients with SLE, lupus nephritis may be an additional factor in the development of hypertension in patients with secondary APS.
Figure 10.1. Renal thrombotic micro-angiopathy seen in a patient with APS and hypertension.
Interestingly, in our cohort of hypertensive APS patients approximately one third (66/173) had renal involvement either in the form of TMA, renal artery stenosis, and/or lupus nephritis. Other non-renal risk factors like obesity, patients receiving high-dose corticosteroids (prednisolone >7.5 mg/day), diabetes mellitus, and hyperlipidaemia were less than 10% of the patients [3]. This suggests that there are other non-renal factors responsible for developing hypertension in these relatively young patients.
There is an established link between accelerated atherosclerosis and aPL [11]. aPL interacts with oxidized low-density lipoprotein (LDL) and monocytes triggering the atherosclerotic process (12–14). Atsumi et al has demonstrated that endothelin levels are raised in arterial occlusion in patients with APS [15]. Our preliminary studies have shown that inflammatory markers, such as fasting insulin and high sensitivity C-reactive protein, are elevated in hypertensive APS patients in compari- son to non-hypertensive APS and healthy controls. This data supports the idea that accelerated atherosclerosis may be a major factor in the development of hyperten- sion in APS patients [16].
Livedo reticularis is a term used to explain the violaceous discoloration of the skin. Sneddon described the relationship between livedo reticularis and cerebro- vascular accidents [17]. In addition, pregnancy morbidity, arterial and venous occlusions, and low platelets were also noticed in increased frequency in patients with livedo and aPL [18]. In our cohort, 80% of hypertensive patients were found to Figure 10.2. Magnetic resonance angiogram showing renal artery stenosis in a patient with APS and hypertension.
have livedo reticularis. Although the precise mechanisms are not clear, it is likely that the livedo may have a role in the development of hypertension.
Therapy
APS is a pro-thrombotic condition. Thrombotic insult to the kidneys in the form of TMA and renal artery stenosis are important causes of hypertension in patients with APS. This brings up the issue of anticoagulation in the patients with hyperten- sion having renal involvement. Remondino et al described re-canalization of renal arteries in a hypertensive patient with bilateral renal artery stenosis with APS. At the end of 2 years on anticoagulation, she did not require hypotensive drugs to control the blood pressure [19]. Our preliminary studies indicate anticoagulation [target international normalized ratio (INR) 3.0–4.5] in patients with renal artery stenosis gives better control of blood pressure and may improve renal function [20].
Although there are no published data on the effect of anticoagulation in TMA, as with renal artery stenosis, we suggest that anticoagulation may be helpful in these patients.
In summary, hypertension in APS/aPL-positive patients may develop at a rela- tively young age and is more common in Caucasian women. The presence of aPL appears to be a distinct parameter associated with hypertension which may vary from mild labile hypertension to severe malignant hypertension. Hypertension seen in these patients is multi-factorial. Although renal pathology, renal artery stenosis, and/or TMA, are prominent etiological factors, the majority of the patients did not have any obvious renal pathology. The role of livedo reticularis certainly needs to be explored. Preliminary studies suggest anticoagulation may have a role in the man- agement of hypertensive APS patients with renal artery stenosis.
References
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