Deficiency of ADAMTS-13 in thrombotic and thrombocytopenic purpura.

Abstract

Tsai [1] and Remuzzi [2] agree that the clinical features do not satisfactorily discriminate between thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS). The characteristic pentad of symptoms, attributed to TTP, may be quite inconsistent in TTP patients while many HUS patients show neurological signs that should only be observed in TTP. Since siblings of patients with TTP were diagnosed to have HUS and since acute episodes of TTP and HUS were reported to occur sequentially even in the same patient, it has been occasionally thought that the two disorders may be different manifestations of the same pathophysiological process. The observation that patients with TTP had a deficiency of von Willebrand factor (VWF)-cleaving protease (cp), (ADAMTS-13), whereas the protease was normal in HUS [3], promised to offer a better differential diagnosis in patients with TTP/HUS, using the assay of ADAMTS-13 as a laboratory tool to tell apart two serious microangiopathic disorders requiring quite different therapeutic strategies. The interpretation of ADAMTS-13 activities has, unfortunately, some important limits. It is noteworthy that the titles of the above two papers are slightly, but significantly, different: ‘severe’ has been inserted into the title by Tsai [1], because only TTP patients have severe protease deficiency while moderately decreased activities of ADAMTS-13 have also been found in healthy and pathological conditions other than TTP [4]. Thus far, the best agreement between ADAMTS-13 deficiency and diagnosis of TTP was observed in retrospective studies, i.e. in cases with a well-characterized history. However, a laboratory assay should offer immediate assistance in diagnosing a disorder rather than confirm the diagnosis after an extended time period. The presently available procedures for estimation of plasma VWF-cp activity are quite intricate and not suitable for rapid diagnostic use in the clinic. Some of them require as long as 3 days for completion. Because TTP is usually an emergency, it is impossible to wait several days for the therapy until the results of the assay are known. Therefore, what is needed is a simple and rapid procedure for measuring protease activity of ADAMTS-13. Acquired ADAMTS-13 deficiency must be treated differently than congenital protease deficiency, and both should again be dealt with in a different way from most other forms of thrombotic microangiopathy (TMA), such as the epidemic form of the diarrhoea-positive HUS, or the malignancy-associated TMA. In addition, the treatment has to be initiated as soon as possible. Amar et al. [5] have recently reported on a new rapid endothelial cell-based assay of ADAMTS-13 activity. This assay is performed under flowing conditions, may be analogous to physiological processes in vivo, and can be completed within minutes. It uses a parallel-plate flow chamber and a microscope to quantify the cleavage of ultra-large VWF multimers secreted from histamine-stimulated human umbilical vein endothelial cells. Further work on this assay should lead to development of a less demanding assay, appropriate for rapid detection of severe VWF-cp deficiency in the clinical laboratory. When we know that the patient has a severe ADAMTS-13 deficiency, it is not important whether we call this disorder TTP or HUS. The deficient protease activity must be readily replenished by plasma therapy, whereas in plasma refractory patients the plasma exchange should be exercised with supportive measures such as immune suppression, removal of autoantibodies, treatment with vincristine or splenectomy. Furthermore, it is important to examine all siblings of patients with hereditary protease deficiency, since it is possible that they will in the future develop acute episode(s) of TMA. A few of them may never have an event of severe TMA, because ADAMTS-13 deficiency alone is not sufficient to cause acute TTP. A recent study showed that about one-half of patients with congenital deficiency of ADAMTS-13 remained apparently asymptomatic until the age of 20 years and roughly 5% of individuals with hereditary ADAMTS-13 deficiency may never have an acute event of TTP [6]. ADAMTS-13 deficiency is a very strong risk factor for TTP, but the development of an acute episode requires a trigger, such as pregnancy, autoimmune disease, drug abuse, viral or bacterial infection. There is an agreement between Tsai [1] and Remuzzi [2] that a new classification of thrombotic microangiopathies should be established. This classification should not be based upon clinical features alone, but should primarily recognize different pathophysiological mechanisms involved in intravascular platelet clumping [1, 2, 6], such as ADAMTS-13 deficiency, complement factor H deficiency, Shiga toxins, bone marrow transplantation, malignancy, drugs and autoimmune disease. All these disorders seem to have similar symptoms and signs, but show different clinical course, prognosis and outcome, require different therapy, and should not be simply denoted as TTP/HUS.