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Review
. 2006:57:419-36.
doi: 10.1146/annurev.med.57.061804.084505.

Current concepts in thrombotic thrombocytopenic purpura

Han-Mou Tsai  1
Affiliations
Review

Current concepts in thrombotic thrombocytopenic purpura

Han-Mou Tsai. Annu Rev Med. 2006.

Abstract

Recent advances have demonstrated that thrombotic thrombocytopenic purpura (TTP), characterized by widespread thrombosis in the arterioles and capillaries, is caused by deficiency of a circulating zinc metalloprotease, ADAMTS13. Two types of TTP are recognized: autoimmune TTP, caused by inhibitory antibodies of ADAMTS13, and hereditary TTP, caused by genetic mutations of ADAMTS13. This article reviews the characteristics and function of ADAMTS13, the mechanism by which ADAMTS13 deficiency may lead to thrombosis, and the causes of ADAMTS13 deficiency. It also discusses how the new knowledge may improve the diagnosis and treatment of this previously mysterious disorder.

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Figures

Figure 1
Figure 1
A schematic depiction of the homologous domain structure of ADAMTS13. The sequence of ADAMTS13 consists of a signal peptide, a propeptide that ends with a consensus RQRR sequence, a metalloprotease domain with zinc binding catalytic sequence motif (HExGHxxGxxHD), a disintegrin-like domain, a central thrombospondin type 1 repeat (TSR-1), a cysteine-rich domain, a cysteine-free spacer region, 7 additional TSR-1’s, and two unique CUB (complement, uEGF, and bone morphogenesis) domains. The metalloprotease-disintegrin domain is essential for VWF cleaving activity. The cysteine-rich and spacer domain sequence markedly enhances the potency of the protease.
Figure 2
Figure 2
A schematic depiction of the critical role that shear stress plays in enhancing VWF-platelet aggregation as well as in cleavage of VWF by ADAMTS13. A. At a site of vessel injury, VWF binds to extracellular ligands and quickly becomes unfolded by high levels of shear stress in the arterioles and capillaries. B. In normal circulation, ADAMTS13 cleaves partially unfolded VWF. This process progressively decreases the size of VWF but maintains the VWF molecules in a globular, inactive conformation. C. When ADAMTS13 is missing, VWF becomes unfolded to elongated forms, causing platelet aggregation and intravascular thrombosis characteristic of TTP.
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References

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