The Potential Therapeutic Benefit of Targeting ADAMTS13 Activity

Abstract

Platelet–vessel wall interaction is mediated by von Willebrand factor (VWF), which thereby plays a major role in physiological hemostasis and thrombotic disease. VWF is released as ultralarge multimers from endothelial cells, whereupon it is cleaved by ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin type I repeats-13). The prohemostatic properties of VWF are dependent of its multimeric size; hence, ADAMTS13 activity is an important determinant in platelet–vessel wall interaction. Deficiency of ADAMTS13 in its most classical form in thrombotic thrombocytopenic purpura can lead to severe thrombotic microangiopathy. However, there is a growing variety of diseases in which ADAMTS13 levels have been found to be decreased and in which reduced cleavage of VWF may play a role. Hence, targeting of VWF cleavage by pharmacological modulation of ADAMTS13 levels is an interesting approach in some of these conditions. This review discusses the available evidence for a role of ADAMTS13 in various disease states and the potential therapeutic benefit of restoration of ADAMTS13 levels.

Keywords

ADAMTS13 - von Willebrand factor - thrombotic microangiopathy

• References

• 1 Crawley JT, de Groot R, Xiang Y, Luken BM, Lane DA. Unraveling the scissile bond: how ADAMTS13 recognizes and cleaves von Willebrand factor. Blood 2011; 118 (12) 3212-3221
• 2 Zheng XL. Structure-function and regulation of ADAMTS-13 protease. J Thromb Haemost 2013; 11 (Suppl. 01) 11-23
• 3 Levy GG, Motto DG, Ginsburg D. ADAMTS13 turns 3. Blood 2005; 106 (1) 11-17
• 4 George JN. Clinical practice. Thrombotic thrombocytopenic purpura. N Engl J Med 2006; 354 (18) 1927-1935
• 5 Kremer Hovinga JA, Vesely SK, Terrell DR, Lämmle B, George JN. Survival and relapse in patients with thrombotic thrombocytopenic purpura. Blood 2010; 115 (8) 1500-1511 , quiz 1662
• 6 Schiviz A, Wuersch K, Piskernik C , et al. A new mouse model mimicking thrombotic thrombocytopenic purpura: correction of symptoms by recombinant human ADAMTS13. Blood 2012; 119 (25) 6128-6135
• 7 Klaus C, Plaimauer B, Studt JD , et al. Epitope mapping of ADAMTS13 autoantibodies in acquired thrombotic thrombocytopenic purpura. Blood 2004; 103 (12) 4514-4519
• 8 Tarr PI, Gordon CA, Chandler WL. Shiga-toxin-producing Escherichia coli and haemolytic uraemic syndrome. Lancet 2005; 365 (9464) 1073-1086
• 9 Lenting PJ, Casari C, Christophe OD, Denis CV. von Willebrand factor: the old, the new and the unknown. J Thromb Haemost 2012; 10 (12) 2428-2437
• 10 De Meyer SF, Stoll G, Wagner DD, Kleinschnitz C. von Willebrand factor: an emerging target in stroke therapy. Stroke 2012; 43 (2) 599-606
• 11 Zhao BQ, Chauhan AK, Canault M , et al. von Willebrand factor-cleaving protease ADAMTS13 reduces ischemic brain injury in experimental stroke. Blood 2009; 114 (15) 3329-3334
• 12 Khan MM, Motto DG, Lentz SR, Chauhan AK. ADAMTS13 reduces VWF-mediated acute inflammation following focal cerebral ischemia in mice. J Thromb Haemost 2012; 10 (8) 1665-1671
• 13 Crawley JT, Lane DA, Woodward M, Rumley A, Lowe GD. Evidence that high von Willebrand factor and low ADAMTS-13 levels independently increase the risk of a non-fatal heart attack. J Thromb Haemost 2008; 6 (4) 583-588
• 14 Matsukawa M, Kaikita K, Soejima K , et al. Serial changes in von Willebrand factor-cleaving protease (ADAMTS13) and prognosis after acute myocardial infarction. Am J Cardiol 2007; 100 (5) 758-763
• 15 Doi M, Matsui H, Takeda H , et al. ADAMTS13 safeguards the myocardium in a mouse model of acute myocardial infarction. Thromb Haemost 2012; 108 (6) 1236-1238
• 16 De Meyer SF, Savchenko AS, Haas MS , et al. Protective anti-inflammatory effect of ADAMTS13 on myocardial ischemia/reperfusion injury in mice. Blood 2012; 120 (26) 5217-5223
• 17 Gandhi C, Motto DG, Jensen M, Lentz SR, Chauhan AK. ADAMTS13 deficiency exacerbates VWF-dependent acute myocardial ischemia/reperfusion injury in mice. Blood 2012; 120 (26) 5224-5230
• 18 Chauhan AK, Motto DG, Lamb CB , et al. Systemic antithrombotic effects of ADAMTS13. J Exp Med 2006; 203 (3) 767-776
• 19 Crescente M, Thomas GM, Demers M , et al. ADAMTS13 exerts a thrombolytic effect in microcirculation. Thromb Haemost 2012; 108 (3) 527-532
• 20 Martin Jr JN, Rose CH, Briery CM. Understanding and managing HELLP syndrome: the integral role of aggressive glucocorticoids for mother and child. Am J Obstet Gynecol 2006; 195 (4) 914-934
• 21 Lattuada A, Rossi E, Calzarossa C, Candolfi R, Mannucci PM. Mild to moderate reduction of a von Willebrand factor cleaving protease (ADAMTS-13) in pregnant women with HELLP microangiopathic syndrome. Haematologica 2003; 88 (9) 1029-1034
• 22 Pourrat O, Coudroy R, Pierre F. ADAMTS13 deficiency in severe postpartum HELLP syndrome. Br J Haematol 2013; 163 (3) 409-410
• 23 Keiser SD, Boyd KW, Rehberg JF , et al. A high LDH to AST ratio helps to differentiate pregnancy-associated thrombotic thrombocytopenic purpura (TTP) from HELLP syndrome. J Matern Fetal Neonatal Med 2012; 25 (7) 1059-1063
• 24 Katz L, de Amorim MM, Figueiroa JN, Pinto e Silva JL. Postpartum dexamethasone for women with hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome: a double-blind, placebo-controlled, randomized clinical trial. Am J Obstet Gynecol 2008; 198 (3) e1-e8
• 25 van den Born BJ, Koopmans RP, van Montfrans GA. The renin-angiotensin system in malignant hypertension revisited: plasma renin activity, microangiopathic hemolysis, and renal failure in malignant hypertension. Am J Hypertens 2007; 20 (8) 900-906
• 26 Immink RV, van den Born BJ, van Montfrans GA, Koopmans RP, Karemaker JM, van Lieshout JJ. Impaired cerebral autoregulation in patients with malignant hypertension. Circulation 2004; 110 (15) 2241-2245
• 27 van den Born BJ, Beutler JJ, Gaillard CA, de Gooijer A, van den Meiracker AH, Kroon AA. Dutch guideline for the management of hypertensive crisis — 2010 revision. Neth J Med 2011; 69 (5) 248-255
• 28 Patel A, Patel H, Patel A. Thrombotic thrombocytopenic purpura: the masquerader. South Med J 2009; 102 (5) 504-509
• 29 van den Born BJ, van der Hoeven NV, Groot E , et al. Association between thrombotic microangiopathy and reduced ADAMTS13 activity in malignant hypertension. Hypertension 2008; 51 (4) 862-866
• 30 Pappelbaum KI, Gorzelanny C, Grässle S , et al. Ultralarge von Willebrand factor fibers mediate luminal Staphylococcus aureus adhesion to an intact endothelial cell layer under shear stress. Circulation 2013; 128 (1) 50-59
• 31 Chauhan AK, Kisucka J, Brill A, Walsh MT, Scheiflinger F, Wagner DD. ADAMTS13: a new link between thrombosis and inflammation. J Exp Med 2008; 205 (9) 2065-2074
• 32 Ono T, Mimuro J, Madoiwa S , et al. Severe secondary deficiency of von Willebrand factor-cleaving protease (ADAMTS13) in patients with sepsis-induced disseminated intravascular coagulation: its correlation with development of renal failure. Blood 2006; 107 (2) 528-534
• 33 Levi M, van der Poll T, Schultz M. New insights into pathways that determine the link between infection and thrombosis. Neth J Med 2012; 70 (3) 114-120
• 34 Claus RA, Bockmeyer CL, Budde U , et al. Variations in the ratio between von Willebrand factor and its cleaving protease during systemic inflammation and association with severity and prognosis of organ failure. Thromb Haemost 2009; 101 (2) 239-247
• 35 de Mast Q, Groot E, Asih PB , et al. ADAMTS13 deficiency with elevated levels of ultra-large and active von Willebrand factor in P. falciparum and P. vivax malaria. Am J Trop Med Hyg 2009; 80 (3) 492-498
• 36 Larkin D, de Laat B, Jenkins PV , et al. Severe Plasmodium falciparum malaria is associated with circulating ultra-large von Willebrand multimers and ADAMTS13 inhibition. PLoS Pathog 2009; 5 (3) e1000349
• 37 Löwenberg EC, Charunwatthana P, Cohen S , et al. Severe malaria is associated with a deficiency of von Willebrand factor cleaving protease, ADAMTS13. Thromb Haemost 2010; 103 (1) 181-187
• 38 Starke RD, Ferraro F, Paschalaki KE , et al. Endothelial von Willebrand factor regulates angiogenesis. Blood 2011; 117 (3) 1071-1080
• 39 Terraube V, Pendu R, Baruch D , et al. Increased metastatic potential of tumor cells in von Willebrand factor-deficient mice. J Thromb Haemost 2006; 4 (3) 519-526
• 40 Mannucci PM. Abnormal hemostasis tests and bleeding in chronic liver disease: are they related? No. J Thromb Haemost 2006; 4 (4) 721-723
• 41 Lisman T, Leebeek FW. Hemostatic alterations in liver disease: a review on pathophysiology, clinical consequences, and treatment. Dig Surg 2007; 24 (4) 250-258
• 42 Lisman T, Bongers TN, Adelmeijer J , et al. Elevated levels of von Willebrand Factor in cirrhosis support platelet adhesion despite reduced functional capacity. Hepatology 2006; 44 (1) 53-61
• 43 Mannucci PM, Canciani MT, Forza I, Lussana F, Lattuada A, Rossi E. Changes in health and disease of the metalloprotease that cleaves von Willebrand factor. Blood 2001; 98 (9) 2730-2735
• 44 Uemura M, Fujimura Y, Matsumoto M , et al. Comprehensive analysis of ADAMTS13 in patients with liver cirrhosis. Thromb Haemost 2008; 99 (6) 1019-1029
• 45 Walsh KA, Lewis DA, Clifford TM , et al. Risk factors for venous thromboembolism in patients with chronic liver disease. Ann Pharmacother 2013; 47 (3) 333-339
• 46 Chen J, Reheman A, Gushiken FC , et al. N-acetylcysteine reduces the size and activity of von Willebrand factor in human plasma and mice. J Clin Invest 2011; 121 (2) 593-603