What "Drives" the Link Between the Renin-Angiotensin-Aldosterone System and the Prothrombotic State in Hypertension?

Hypertension has a direct causal relationship with vascular disease. The vasculature is intimately involved in the pathogenesis of hypertension, yet suffers its consequences. Indeed, the precise mechanism(s) on how the vasculature contributes to high blood pressure and its complications remains unknown. Despite the blood vessels being exposed to high blood pressures, the common complications of hypertension, that is, stroke and myocardial infarction, are thrombotic rather than hemorrhagic—the so-called “thrombotic paradox of hypertension,” first proposed in 1994.1 Since then, substantial interest has been directed toward understanding the “drivers” or stimuli leading to first, the development of high blood pressure; and second, the complications of hypertension, such as thrombosis. Possible mechanisms that have been proposed are inflammation, growth factors (such as vascular endothelial growth factor) and—of course—the renin–angiotensin–aldosterone system (RAAS). The RAAS plays an influential role in cardiac output and systemic arterial pressure. Various components of the RAAS and a prothrombotic state have been shown to be predictors of cardiovascular events in hypertensive patients. A relationship between the RAAS and the coagulation/fibrinolytic systems has been demonstrated, but the clinical relevance in hypertension is unclear, for example, whether greater hypertensive target organ damage is related to greater RAAS abnormalities. In this issue of American Journal of Hypertension, Sechi et al.2 explore the relationship between the RAAS and the prothrombotic state. They report associations between increasing plasma renin activity (PRA) and aldosterone with coagulation and fibrinolysis, whereas plasma angiotensin-converting enzyme was not. Interestingly, both fibrinogen and PAI-1 levels were independent predictors of target-organ damage and when included in a multivariate analysis, they eliminated PRA and aldosterone as independent predictors. Sechi et al.2 conclude that there was a strong and independent association between renin, aldosterone, and markers of a prothrombotic state in essential hypertension. Nonetheless, this is a modest-sized cross-sectional study, which can show associations between RAAS and the prothrombotic state in hypertension, but not causality. Indeed, statistical adjustments cannot account for all biological and pathophysiological variables. Also, all patients in the present study were of white Caucasian origin where some of them were already treated for hypertension—hence, introducing ascertainment bias and raising the issue on generalizability to other ethnic groups. Indeed, treated hypertensives may express differing degrees or severity of hypertensive target-organ damage, when compared to untreated subjects—especially because previously treated and untreated subjects were mixed for the analyses. Also, could these findings be applied to Afro-Caribbeans given that this ethnic group usually has low-renin hypertension and are salt sensitive? Many antihypertensive drugs are known to influence the prothrombotic state in essential hypertension though some drugs may take longer for their effects to “wash out” of the system, especially in relation to the effects of target organ damage. In the study by Sechi et al.2 subjects were apparently withdrawn from drug treatments for a minimum of 3 weeks (up to 5 weeks for RAAS blockers and statins) before measurement of research parameters. However, even after 3–5 weeks, would target-organ damage “revert” to the untreated state? Many modern antihypertensive drugs have effects on the RAAS. Indeed, the ACE inhibitors and ARBs are well recognized to have effects on the vasculature and the prothrombotic state, by promoting vasodilatation, as well as decreasing platelets activation and improving endothelial function. Modern β-blockers, such as nebivolol, result in improvements in endothelial function amongst hypertensives.3 The precise mechanism(s) that drive the prothrombotic state associated with hypertension may still remain uncertain, but the RAAS seems a good possibility. For example, angiotensin II (and aldosterone) can increase free radical generation which in turn can decrease nitric oxide bioavailability, which in turn can increase endothelin/PAI-1 gene expression.5 The RAAS can influence endothelial damage/dysfunction, which is central to the prothrombotic state in hypertension,5 and recent interest has been directed to the link between the endothelium and abnormal fibrinolysis in hypertension.6 Further studies should delineate the underlying pathophysiological processes to predict and enhance therapeutic strategies in targeting hypertensives before the progression of target-organ damage and other complications of uncontrolled hypertension. The authors declared no conflict of interest.