Thrombotic Thrombocytopenic Purpura and the Hemolytic Uremic Syndrome

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Chapter 59 Thrombotic Thrombocytopenic Purpura and the Hemolytic Uremic Syndrome

Keith R. McCrae, J. Evan Sadler, Douglas B. Cines

Table 59-1 Proposed Classification Scheme for Thrombotic Microangiopathies

Adapted from Taylor CM, Machin S, Wigmore SJ, et al: Clinical Practice Guidelines for the management of atypical haemolytic uraemic syndrome in the United Kingdom. Br J Haematol 148:37, 2009.

Figure 59-1 PATHOGENESIS OF IDIOPATHIC THROMBOTIC THROMBOCYTOPENIC PURPURA CAUSED BY ADAMTS13 DEFICIENCY.

Multimeric vWF adheres to endothelial cells or to connective tissue exposed in the vessel wall. Platelets adhere to vWF through platelet membrane GP1b. In flowing blood, vWF in the platelet-rich thrombus is stretched to form extended linear polymers and cleaved by ADAMTS13, limiting thrombus growth. If ADAMTS13 is absent, vWF-dependent platelet accumulation continues, eventually causing microvascular thrombosis and TTP.

(Reproduced from Sadler JE: von Willebrand factor, ADAMTS13, and thrombotic thrombocytopenic purpura. Blood 112:11, 2008, with permission.)

ADAMTS13 in the Management of TTP

A role for vWF in the pathogenesis of TTP was suspected in the early 1980s, when reports describing the presence of ultralarge vWF multimers in the plasma of affected patients first appeared. This finding led to the hypothesis that TTP might result from deficiency of a protease responsible for vWF cleavage, and almost 20 years later, the vWF cleaving protease was isolated and found to be deficient in most patients with TTP. This protease was subsequently cloned, found to be a member of the ADAMTS metalloprotease family, and denoted ADAMTS13. This advance raised expectations that a simple and accurate diagnostic test would soon be available for the diagnosis of TTP. However, the utility of ADAMTS13 testing remains undefined, due in part to issues such as a lack of assay standardization and the use of different inclusion criteria in studies that have assessed the relevance of ADAMTS13 measurements. Despite these obstacles, areas where this assay may be useful have begun to emerge. First, for patients with thrombotic microangiopathy, severe ADAMTS13 deficiency is specific for idiopathic TTP but may also occur, albeit uncommonly, in other disorders such as sepsis-induced DIC or severe liver failure. Thus although severe ADAMTS13 deficiency is consistent with TTP, it is not diagnostic in the absence of other clinical information. Moreover, normal or moderately reduced ADAMTS13 levels (20% to 40%) do not exclude the diagnosis of TTP. Second, severe ADAMTS13 deficiency at presentation correlates with an increased risk for relapsing TTP, approximately 30% during 2 years of follow-up. Conversely, patients without severe ADAMTS13 deficiency at presentation rarely relapse. Third, persistence or recurrence of severe ADAMTS13 deficiency further increases the risk for relapse, suggesting that monitoring ADAMTS13 activity may prove useful to select patients for additional intensive therapy. However, because these relationships are based on relatively small case series, they require validation in larger, prospective studies.

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Chapter 59 Thrombotic Thrombocytopenic Purpura and the Hemolytic Uremic Syndrome

Keith R. McCrae, J. Evan Sadler, Douglas B. Cines

Table 59-1 Proposed Classification Scheme for Thrombotic Microangiopathies

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