The difficult distinction between haemolytic uraemic syndrome and thrombotic thrombocytopenic purpura.

Sir,

Haemolytic uraemic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP) are thrombotic microangiopathies (TMA) once considered the different ends of a spectrum. The recent discovery of mutations in the gene-encoding factors involved in the alternate complement pathway (factors H, I, B and CD46) in HUS and von Willebrand factor-cleaving protease (or ADAMTS-13) in TTP has prompted a new nomenclature ‘complement-dysregulation-related TMA’ for HUS, ‘ADAMTS13-deficiency-related TMA’ for TTP and an ‘indeterminate TMA’ group for TMA of unknown aetiology [1-4]. However, this classification is likely to be useful only retrospectively as most laboratories are unable to give definite diagnostic results for either condition in a short time. So, clinically there is a trend to call a predominant renal picture as HUS (though renal involvement in TTP is not uncommon) and neurological as TTP.

Why platelet microthrombi, which occur in both these conditions, cause different organ predominance has not yet been identified. It is interesting to note that endothelial heterogeneity is an important factor in determining the clotting nature of different diseases [5]. There is a differential distribution of procoagulants and anticoagulants in the endothelium from different sites of the vascular tree to balance local haemostasis which may be perturbed by different mechanisms like the complement pathway or ADAMTS-13.

Another factor which has been increasingly recognized as determining the clinical characteristics of haemolytic microangiopathy is nitric oxide (NO) [6]. The fragmentation of erythrocytes in haemolysis releases free haemoglobin into the plasma, which overwhelms the protective haemoglobin-scavenging mechanisms like haptoglobin [7]. The free haemoglobin has a high affinity for NO and depletes it, causing clinical effects from vasoconstriction and platelet aggregation. This mechanism has been used to explain symptoms of several haemolytic diseases including paroxysmal nocturnal haemoglobinuria, sickle-cell disease and TTP [7-9].

It is important to note that many of the symptoms related to TTP, like gastrointestinal symptoms, and transient neurological deficits, cannot be explained by ADAMTS deficiency but by the depletion of NO [9]. Since plasma exchange has been shown to be effective for patients with TTP who do not have a severe deficiency of ADAMTS-13 activity, it has been hypothesized that this procedure cleans haemolytic products from the plasma and restores the NO (thus inhibiting platelet aggregation) and improves the symptoms [9]. Plasma exchange is also a treatment strategy for severe HUS and NO has been demonstrated to play a protective role in the early pathogenesis of HUS by maintaining the antithrombogenic properties of the renal endothelium [10]. It is possible that the haemolysis associated with HUS depletes NO and thus contributes to the renal impairment which can be halted by plasma exchange, which provides more NO. It is also possible that the endogenous NO production is increased in less severe forms of HUS which explains studies demonstrating this observation [11,12].

Thus, the distinction between HUS and TTP based on pathophysiology may be helpful in research laboratories and for retrospective studies, but more work on the aspect of haemolysis and NO in both these conditions is required to make the distinction clearer and identify novel treatments.

Conflict of interest statement. None declared.