Response to the Malignant Hypertension-Thrombotic Microangiopathy Link
We read with interest the comments by Thachil1 regarding our article on the association between ADAMTS-13 and thrombotic microangiopathy (TMA) in malignant hypertension.2 Thachil1 proposes a role for NO as a link between malignant hypertension and TMA. We believe that the lack of NO may be an important mediator, but believe it is not the “missing link” between malignant hypertension and TMA. Although previous experiments have shown that administration of the endothelial NO synthase inhibitor NG-nitro-l-arginine methyl ester results in more severe tissue injury and end-organ dysfunction in various animal models of TMA,3,4 the effects of NG-nitro-l-arginine methyl ester were only observed on a permissive background for the development of TMA. For example, in the study by Sethi et al,4 administration of NG-nitro-l-arginine methyl ester led to the development of TMA in mice that were transgenic for the human renin and angiotensinogen genes. The same degree of tissue injury was also observed when these mice were placed on a high-salt diet. Administration of NG-nitro-l-arginine methyl ester in control animals did not lead to tissue injury and fibrin thrombi associated with TMA.
We agree that free hemoglobin may be important as an NO scavenger in situations where endothelial damage is associated with severe hemolysis (eg, sickle cell disease). In the TMA of malignant hypertension, hemolysis is usually not a prominent feature, because only a few fragmented red blood cells are present.5 In our study, free hemoglobin levels did not differ between patients with and without TMA, nor was there an association between free hemoglobin and the severity of TMA.
Although the sequence of events that lead to TMA in malignant hypertension are still incompletely understood, a further increase in blood pressure, by whatever mechanism, appears to be necessary to provoke TMA in experimental models.6 Treatment directed at lowering blood pressure, either via NO-dependent or via NO-independent mechanisms, leads to resolution of the TMA associated with malignant hypertension and helps to restore organ function. Therefore, the damage to the endothelium and vascular wall elicited by the high arterial pressures may be the trigger that leads to coagulation activation and TMA. This includes the expression of large amounts of prothrombogenic von Willebrand factor (VWF) multimers in the circulation. As discussed in our article, even low-normal levels of ADAMTS-13 have been associated with the appearance of ultra large VWF multimers in situations of endothelial stimulation, possibly because of a misbalance between the amount of VWF and its cleaving protease. We were unable to detect ultra large VWF multimers, because our technique, which was developed to demonstrate decreases in VWF size, may not have been sensitive enough to detect more subtle increases in VWF size. Other than a role for VWF and ADAMTS-13, we agree with the author that other (coagulation) factors that are released on endothelial damage and injury to the vascular wall may be important in the development of TMA. In addition to lowering blood pressure, therapy aimed at inhibiting vital procoagulant pathways in the acute phase of this condition may assist in further ameliorating the vascular damage and organ dysfunction observed in this condition.
Thachil J. The malignant hypertension-thrombotic microangiopathy link. Hypertension. 2008; 52: e32.
van den Born BJ, van der Hoeven NV, Groot E, Lenting PJ, Meijers JC, Levi M, van Montfrans GA. Association between thrombotic microangiopathy and reduced ADAMTS13 activity in malignant hypertension. Hypertension. 2008; 51: 862–866.
Shao J, Miyata T, Yamada K, Hanafusa N, Wada T, Gordon KL, Inagi R, Kurokawa K, Fujita T, Johnson RJ, Nangaku M. Protective role of nitric oxide in a model of thrombotic microangiopathy in rats. J Am Soc Nephrol. 2001; 12: 2088–2097.
Sethi S, Iida S, Sigmund CD, Heistad DD. Renal thrombotic microangiopathy in a genetic model of hypertension in mice. Exp Biol Med (Maywood). 2006; 231: 196–203.
van den Born BJ, Honnebier UP, Koopmans RP, van Montfrans GA. Microangiopathic hemolysis and renal failure in malignant hypertension. Hypertension. 2005; 45: 246–251.
Gavras H, Brunner HR, Laragh JH, Vaughan ED Jr, Koss M, Cote LJ, Gavras I. Malignant hypertension resulting from deoxycorticosterone acetate and salt excess: role of renin and sodium in vascular changes. Circ Res. 1975; 36: 300–309.