Molecular biology of ADAMTS13 and diagnostic utility of ADAMTS13 proteolytic activity and inhibitor assays

Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Filadelfia, Pennsylvania, United States
Seminars in Thrombosis and Hemostasis (Impact Factor: 3.69). 01/2006; 31(6):659-72. DOI: 10.1055/s-2005-925472
Source: PubMed

ABSTRACT ADAMTS13, a reprolysin-like metalloprotease, limits platelet-rich thrombus formation in the small arteries by cleaving von Willebrand factor (vWF) at the Tyr1605-Met1606 peptide bond. Deficiency of plasma ADAMTS13 activity, due to either an inherited or an acquired etiology, may lead to a potentially lethal syndrome, thrombotic thrombocytopenic purpura (TTP). Molecular cloning and characterization of the ADAMTS13 gene have provided further insight into the structure-function relationships, biosynthesis, and regulation of the ADAMTS13 protease, in addition to understanding the pathogenesis of TTP and perhaps other thrombotic disorders. ADAMTS13 consists of a short propeptide, a typical reprolysin-like metalloprotease domain, followed by a disintegrin-like domain, first thrombospondin type 1 (TSP1) repeat, Cys-rich domain, and spacer domain. The carboxyl terminus of ADAMTS13 has seven more TSP1 repeats and two CUB domains. ADAMTS13 is synthesized mainly in hepatic stellate cells, but also in vascular endothelial cells. Recognition and cleavage of vWF require the proximal carboxyl terminal domains, but not the middle and distal carboxyl terminal domains. Cleavage of vWF appears to be modulated by shear force, binding to platelet or platelet glycoprotein-1balpha, heparin, inflammatory cytokine (interleukin-6), and chloride ion. At the site of thrombus formation, the ADAMTS13 may be inactivated by thrombin, plasmin, and factor Xa. Having a sensitive and specific assay for ADAMTS13 activity is not only critical to understand the basic biology of ADAMTS13 protease, but also to facilitate a more timely and accurate clinical diagnosis of TTP, and to initiate potentially life-saving plasma exchange therapy. Although many assays have been developed and tested for clinical applications, the fluorescent resonance energy transfer-vWF73 assay appears to be the simplest and most promising assay to date.


Available from: X. Long Zheng, Jun 02, 2015
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Thrombotic thrombocytopenic purpura (TTP) starts abruptly and is characterized by diffuse occlusion of microcirculation arterioles and capillaries, leading to ischemia of tissues. Occlusion is caused by microscopic clots primarily composed of platelets and von Willebrand factor (VWF). VWF is a multimeric glycoprotein synthesized exclusively by endothelial cells and megakaryocytes. This factor promotes adhesion of platelets to injured endothelium, participates in the process of platelet aggregation and is the carrier protein of factor VIII in the circulation. In physiological conditions, large VWF multimers are present in endothelial cells and platelets and are not present in plasma. As soon as these large multimers are released from the endothelial cell, they are cleaved and removed from circulation by the ADAMTS13 enzyme. A quantitative or functional deficiency of ADAMTS13 results in the accumulation of large VWF multimers in the plasma and may result in the aggregation of platelets and diffuse occlusion of arterioles and capillaries. Most cases of PTT are associated with ADAMTS13 deficiency. The levels of antigens, activity and antibodies of MTS13 can be evaluated using internationally manufactured kits. The laboratory evaluation of ADAMTS13 appears to be a useful tool for the early diagnosis of PTT. However, interpretation of the results requires caution, as well as knowledge of the principles of the method and the steps of the reactions involved.
    Revista Brasileira de Hematologia e Hemoterapia 12/2009; 32(2):155-161.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: We consider the propagation of few-cycle pulses (FCPs) in cubic nonlinear media exhibiting a “crystal-like” structure, beyond the slowly varying envelope approximation, taking into account the wave polarization. By using the reductive perturbation method we derive from the Maxwell–Bloch–Heisenberg equations, in the long-wave-approximation regime, a non-integrable complex modified Korteweg-de Vries equation describing the propagation of circularly polarized (CP) FCPs. By direct numerical simulations of the governing nonlinear partial differential equation we get robust CP FCPs and we show that the unstable ones decays into linearly polarized half-cycle pulses, whose polarization direction slowly rotates around the propagation axis.
    Optics Communications 02/2012; DOI:10.1016/j.optcom.2011.09.051 · 1.54 Impact Factor