NDT Advance Access originally published online on April 10, 2008
Nephrology Dialysis Transplantation 2008 23(8):2701-2702; doi:10.1093/ndt/gfn173
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The role for adjunctive treatment to plasma exchange in thrombotic thrombocytopenic purpura
E-mail: jeckothachil{at}yahoo.co.ukSir,
Cardiac involvement in thrombotic thrombocytopenic purpura (TTP) is being increasingly recognized as one of the leading causes of mortality in this condition [1,2]. Physicians have previously rarely reported any symptoms related to the heart during acute episodes of TTP despite cardiac involvement being a persistent feature in autopsy studies, both pre- and post-plasma exchange era. This may be due to several reasons including emphasis on Moschowitz's pentad, the common symptoms of dyspnoea and tiredness thought to be due to anaemia rather than heart failure and the relatively younger population affected by TTP who usually do not have cardiac risk factors [2].
Recently, there has been increasing interest in the understanding of the pathophysiology of TTP where the lack of ultralarge von Willebrand factor (VWF) multimer cleaving enzyme (ADAMTS-13) due to congenital deficiency or inhibition by antibodies has been demonstrated to be the causative factor for acute TTP. However, it is difficult to explain all the different clinical features of TTP only as consequences of ADAMTS13 deficiency or inhibition. The fragmentation of erythrocytes from the haemolysis releases free haemoglobin into the plasma, which overwhelms the protective haemoglobin scavenging mechanisms (like haptoglobin). The cell-free haemoglobin is free to bind to nitric oxide (NO), the endothelial-derived relaxation factor, at intensity much higher compared to non-haemolytic states. This would result in intense vasoconstriction and uninhibited platelet aggregation, two important antithrombotic effects of NO. Gladwin et al. demonstrated this concept in paroxysmal nocturnal haemoglobinuria and in sickle cell disease [3]. A similar mechanism and intense haemolysis may also explain some of the non-cardiac symptoms of TTP including abdominal pain, fever and transient neurological symptoms and renal impairment [4].
An early increase in VWF has been reported to be a risk factor for adverse outcomes in the acute coronary syndrome. The deficiency of ADAMTS-13 in TTP should also theoretically cause platelet aggregation by the ultralarge VWF multimers and contribute to the increased incidence of cardiac events. Matsukawa et al. showed a plasma ADAMTS13 value and the VWF/ADAMTS13 ratio as being useful for monitoring in-hospital outcome events in patients with acute myocardial infarction (MI) and also for the prediction of 1-year adverse cardiovascular events after the infarct [5]. Though they demonstrated that plasma ADAMTS13 antigen levels decreased significantly during the first 3 days of hospitalization, the levels were noted to increase gradually afterwards. This finding could be explained as binding of the ADAMTS13 to the VWF in the lesion responsible for coronary thrombus formation and forming a tight enzyme–substrate complex resulting in the reduction of measured ADAMTS13. Plasma samples obtained more than 6 months after an MI, reveal a positive rather than negative association of ADAMTS13 levels with risk of MI in men and concluded that a detrimental effect of low levels of ADAMTS13 is unlikely [6]. So, the question remains whether ADAMTS-13 deficiency in TTP is responsible for the cardiac dysfunction.
It is interesting to observe that NO, either endogenous or exogenous, represents one of the most important defences against myocardial ischaemia-reperfusion injury. The fundamental molecular explanation for NO-mediated cardio protection is the interaction with components of the electron transport chain and/or the mitochondrial permeability transition pore to limit post-ischaemic myocardial damage. Nitrates, especially long-acting formulations, are also an important part of the treatment of an acute cardiac ischaemic episode. The replenishment of NO with the resulting inhibition of platelet aggregation and vasodilatation would help in preventing coronary ischaemia.
The effectiveness of plasma exchange in patients with TTP has been attributed to the removal of ADAMTS13 autoantibodies and replacement of normal protease activity. However, plasma exchange also seems to be effective for patients who do not have a severe deficiency of ADAMTS13 activity, raising doubts on other factors like NO playing a role in the clinical manifestations. It may be hypothesized that this procedure cleans haemolytic products from the plasma and restores the NO necessary for the platelet antiaggregatory function and the maintenance of vasodilatation. Does this mean a role may exist for nitric oxide suppliers like long-acting nitrate compounds? It would, however, be unethical to replace a very effective treatment like plasma exchange (in spite of its though with its multiple risks) with a tablet formulation but it would be still worthwhile to consider administrating nitrates or novel compounds with similar action to the treatment armamentarium of TTP. This strategy may help reduce the cardiac dysfunction with TTP.
Conflict of interest statement. None declared.
Department of Haematology, University of Liverpool, Liverpool, UK
References
- Patschan D, Witzke O, Duhrsen U, et al. Acute myocardial infarction in thrombotic microangiopathies: clinical characteristics, risk factors and outcome. Nephrol Dial Transplant (2006) 21:1549–1554.
[Abstract/Free Full Text] - Hawkins BM, Abu-Fadel M, Vesely SK, et al. Clinical cardiac involvement in thrombotic thrombocytopenic purpura: a systematic review. Transfusion (2008) 48:382–92.[Web of Science][Medline]
- Rother RP, Bell L, Hillmen P, et al. The clinical sequelae of intravascular hemolysis and extracellular plasma haemoglobin. A novel mechanism of human disease. JAMA (2005) 293:1653–1662.
[Abstract/Free Full Text] - Thachil J. Thrombotic Thrombocytopenic purpura: is there more than ADAMTS-13? Thromb Haemost (2007) 5:634–635.[CrossRef]
- Matsukawa M, Kaikita K, Soejima K, et al. Serial changes in von Willebrand factor-cleaving protease (ADAMTS13) and prognosis after acute myocardial infarction. Am J Cardiol (2007) 100:758–63.[CrossRef][Medline]
- Chion CK, Doggen CJ, Crawley JT, et al. ADAMTS13 and von Willebrand factor and the risk of myocardial infarction in men. Blood (2007) 109:1998–2000.
[Abstract/Free Full Text]
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