Understanding therapeutic targets in thrombotic thrombocytopenic purpura

Excerpt

Thrombotic thrombocytopenic purpura (TTP) is a rare thrombotic microangiopathy specifically related to a severe functional deficiency of the von Willebrand factor (VWF) cleaving protease, ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 repeats, member 13) [1, 2]. VWF is a multimeric plasma glycoprotein of which the monomers, containing multiple functional domains, are connected by disulfide bonds [3]. In cases of vascular injury, VWF contributes to the initial recruitment of platelets to the injured vessel wall and to the formation of platelet-rich thrombi under conditions of high shear stress. The VWF A1 domain contains the binding site for platelet glycoprotein Ibα (GPIbα) and the VWF A3 domain, the binding site for collagen [3]. The ultra-large and high molecular weight multimers are the hemostatically most potent ones. Under high shear stress conditions, ADAMTS13 regulates the size distribution and consequently the hemostatic power of these VWF multimers by specifically cleaving a peptide bond within the unfolded VWF A2 domain [1‐3] (see Fig. 1). Moreover, human neutrophil peptides can block VWF-ADAMTS13 interactions and inhibit proteolytic cleavage of VWF by ADAMTS13 [4].

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