Haemolytic uraemic syndrome and thrombotic thrombocytopenic purpura in southern Iran

Abstract

In the first 2006 issue, Karimi et al.1 presented the results of a retrospective analysis conducted in 136 patients from southern Iran affected by thrombotic thrombocytopenic purpura (TTP) or haemolytic uraemic syndrome (HUS). Patients discharged during a 13-year period (April 1991March 2004) from the three main referral hospitals of the area were identified by review of medical records. TTP and HUS are two related disorders recognized more than 50 years ago. The hallmark of these disorders is represented by the concomitant occurrence of microangiopathic haemolytic anaemia, manifested by red-cell fragmentation, and thrombocytopenia. In addition, a wide spectrum of organ involvement with functional failure due to systemic microvascular arterial thrombosis is present in both syndromes, with the central nervous system more frequently and severely affected in TTP and the kidney in HUS. Recently, major advances have been made in the understanding of the pathophysiology of these disorders and in clarifying the basis of their clinical distinctive features2. TTP, once an ominous disease in more than 80-90% of cases, can now be effectively managed with intensive plasma exchange with a cure rate of 90% or more3. This is a heterogeneous disorder including possibly more than a single entity. The prototypical vascular lesions of TTP are characterised by platelet-rich thrombi within or beneath a damaged or swollen endothelium. Microvascular arterial thrombosis of TTP, leading to clamping and consumption of platelets, is triggered by ultra large von Willebrand factor (VWF) multimers released by insulted endothelial cells. Mechanical destruction of the red blood cells occurs when these cells are forced to circulate in small vessels obstructed by thrombi made of platelet, VWF and fibrin in high shear stress strictures. HUS occurs mostly in children, and it is characterised by variably severe renal disease that can lead to end-stage renal failure. In most cases, HUS is triggered by an infection caused by Shiga toxin producing Escherichia coli (O157:H7) usually manifested by watery or bloody diarrhoea. The disorder presents often with an acute onset. The clinical course may be self-limited despite no treatment and efficacy of plasma exchange is not proven. In both diseases an initiating condition is supposed to trigger the illness only in predisposed individuals. Clear examples of the importance of the individual genetic background in TTP are represented by the rare cases of homozygous deficiency of ADAMTS13, a recently discovered matalloprotease that is required to process the ultra large VWF multimers into smaller, less active species. In these patients TTP presents mainly as a familial or chronic relapsing disease. Severe reduction of ADAMTS13 is indeed also observed in a significant proportion (50 to 100%) of acquired idiopathic cases, indicating the critical role of ultra large VWF multimers in the pathogenesis of the disorder. In most, but not all cases with reduced ADAMTS13 activity, neutralizing autoantibodies have been demonstrated. Anyway, the diagnosis remains based on clinical features, and the clinical usefulness of dosing ADAMTS13 activity remains uncertain. Genetic predisposition to HUS is exemplified by the demonstration that an increasing number of non-Shiga toxin-associated cases occurs in patients with mutations in genes encoding complement regulatory proteins. More than 50 different mutations with variable penetrance have been described so far. Recently, among 156 Caucasian cases of familial or sporadic, non-Shiga-associated HUS, mutations have been found in 30 of them, including children and adults4. Triggering conditions were not always identifiable, although infection, pregnancy or drugs (cyclosporine, ticlopidine, clopidogrel, quinine, etc.) could be implicated in a significant proportion. Similar triggering factors have been implicated also in cases of typical TTP. VWF has not a critical role in the pathogenesis of microthrombi found in HUS, which are more rich in fibrin than in platelets and no ultra large VWF multimers are observed. This is in keeping with no or less severe deficiency of ADAMTS13 in HUS. Karimi et al.1 could not investigate the genetic individual predisposing factors in their patients, but they were able to extrapolate from medical records, distinctive cases of TTP or HUS, and to provide reliable relevant epidemiological data on the changing incidence rate of these disorders during the last 13 years. Although based on very simple criteria, the accuracy of differential diagnosis between 101 cases of HUS and the 35 cases of TTP finally identified seems confirmed by the clear-cut differences between the two Clinical letters