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Review
. 2015:66:211-25.
doi: 10.1146/annurev-med-061813-013241.

ADAMTS13 and von Willebrand factor in thrombotic thrombocytopenic purpura

X Long Zheng  1
Affiliations
Review

ADAMTS13 and von Willebrand factor in thrombotic thrombocytopenic purpura

X Long Zheng. Annu Rev Med. 2015.

Abstract

Pathogenesis of thrombotic thrombocytopenic purpura (TTP) was a mystery for over half a century until the discovery of ADAMTS13. ADAMTS13 is primarily synthesized in the liver, and its main function is to cleave von Willebrand factor (VWF) anchored on the endothelial surface, in circulation, and at the sites of vascular injury. Deficiency of plasma ADAMTS13 activity (<10%) resulting from mutations of the ADAMTS13 gene or autoantibodies against ADAMTS13 causes hereditary or acquired (idiopathic) TTP. ADAMTS13 activity is usually normal or modestly reduced (>20%) in other forms of thrombotic microangiopathy secondary to hematopoietic progenitor cell transplantation, infection, and disseminated malignancy or in hemolytic uremic syndrome. Plasma infusion or exchange remains the initial treatment of choice to date, but novel therapeutics such as recombinant ADAMTS13 and gene therapy are under development. Moreover, ADAMTS13 deficiency has been shown to be a risk factor for the development of myocardial infarction, stroke, cerebral malaria, and preeclampsia.

Keywords: arterial thrombosis; autoantibodies; autoimmune disorder; metalloprotease; mutations; rare hematological disease.

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Figures

Figure 1
Figure 1
Schematic representation of ADAMTS13 domain organization, potential role in substrate recognition, and binding sites of autoantibodies in acquired TTP. S, signal peptide; P, propeptide; M, metalloprotease domain; D, disintegrin domain; 1, the first thrombospondin type 1 (TSP1) repeat; Cys, the cysteine-rich domain; Spa, the spacer domain; 2–8, TSP1 2–8 repeats; C1 and C2, the first and second CUB domain. Other abbreviations: ULVWF, ultralarge von Willebrand factor; VWF, von Willebrand factor; A2, the A2 domain of VWF.
Figure 2
Figure 2
Schematic representation of pro-VWF domain organization, proteins that interact with VWF (von Willebrand factor), and the ADAMTS13 cleavage site. The large propeptide (D1–D2) in pro-VWF is cleaved by furin to generate the mature VWF subunit, which includes FVIII-binding domains (D′-D3), GP1b- (A1) and collagen-binding (A3) domains, and a central A2 domain containing the ADAMTS13 cleavage site, as well as several C-terminal domains (D4-CK) that bind αIIβIII integrin.
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