NDT Plus Advance Access originally published online on February 13, 2008
NDT Plus 2008 1(2):132-133; doi:10.1093/ndtplus/sfn010
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The difficult distinction between haemolytic uraemic syndrome and thrombotic thrombocytopenic purpura
Department of Haematology, Royal Liverpool University Hospital, Prescot Road, Liverpool, UK
Correspondence: E-mail: jeckothachil{at}yahoo.co.uk
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.
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 Top References |
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- Dragon-Durey MA, Frémeaux-Bacchi V. Atypical haemolytic uraemic syndrome and mutations in complement regulator genes. Springer Semin Immunopathol (2005) 27:359–374.[CrossRef][Web of Science][Medline]
- Furlan M, Robles R, Galbusera M, et al. Von Willebrand factor cleaving proteasein thrombotic thrombocytopenic purpura and haemolytic uremic syndrome. N Engl J Med (1998) 339:1578–1584.
[Abstract/Free Full Text] - Tsai HM, Lian EC-Y. Antibodies of Von Willebrand factor-cleaving protease in acute thrombotic thrombocytopenic purpura. N Engl J Med (1998) 339:1585–1594.
[Abstract/Free Full Text] - Fakhouri F, Frémeaux-Bacchi V. Does hemolytic uremic syndrome differ from thrombotic thrombocytopenic purpura. Nat Clin Pract Nephrol (2007) 3:679–687.[CrossRef][Web of Science][Medline]
- Aird WC. Vascular bed-specific thrombosis. J Thromb Haemost (2007) 5(Suppl):283–291.[CrossRef][Web of Science][Medline]
- Cappellini MD. Coagulation in the pathophysiology of hemolytic anemias. Hematology Am Soc Hematol Educ Program (2007) 2007:74–78.[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] - Ataga KI, Cappellini MD, Rachmilewitz EA. Beta-thalassaemia and sickle cell anaemia as paradigms of hypercoagulability. Br J Haematol (2007) 139:3–13.[CrossRef][Web of Science][Medline]
- Thachil J. Thrombotic thrombocytopenic purpura: is there more than ADAMTS-13. J Thromb Haemost (2007) 5:634–635.[CrossRef][Web of Science][Medline]
- Dran GI, Fernández GC, Rubel CJ, et al. Protective role of nitric oxide in mice with Shiga toxin-induced hemolytic uremic syndrome. Kidney Int (2002) 62:1338–1348.[CrossRef][Web of Science][Medline]
- Noris M, Ruggenenti P, Todeschini M, et al. Increased nitric oxide formation in recurrent thrombotic microangiopathies: a possible mediator of microvascular injury. Am J Kidney Dis (1996) 27:790–796.[Web of Science][Medline]
- Herlitz H, Petersson A, Sigstrom L, et al. The arginine-nitric oxide pathway in thrombotic microangiopathy. Scand J Urol Nephrol (1997) 31:477–479.[Web of Science][Medline]
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