Changes in ADAMTS13 (von-Willebrand-factor-cleaving protease) activity after induced release of von Willebrand factor during acute systemic inflammation

Summary

Von Willebrand factor (VWF) is synthesized in endothelial cells, stored in the form of high molecular weight multimers and released after stimulation. After release, the multimers are cleaved by ADAMTS13 (von-Willebrand-factor-cleaving protease). We studied healthy volunteers in a double-blind, placebo controlled inflammation model. Ten male volunteers received 2 ng/kg endotoxin intravenously, and 5 volunteers placebo. Endotoxin infusion induced systemic inflammation and coagulation activation. After 4 hours the observed increase in neutrophils reached a maximum (273±34 % of baseline; mean ± SEM) and the platelet count dropped (81±2 %). These parameters returned to baseline values after 24 hours. VWF antigen increased to 259±16 % of baseline after 4 hours, remained elevated (192±15 %) after 24 hours and returned to baseline after 7 days. Unusually large VWF multimers occurred in the plasma 4 hours after endotoxin infusion. ADAMTS13 activity (measured with a collagen-binding assay) decreased to 64±5 % of baseline (P< 0.001) after 4 hours, was still reduced after 24 hours (86±6 %; P=0.008) and returned to normal after 7 days. VWF multimer analysis showed pronounced satellite bands in the 4-hour samples, indicating cleavage of VWF by ADAMTS13. No apparent changes of the analyzed parameters were observed in the placebo group. The reciprocal course of ADAMTS13 and VWF after short-term VWF release induced by systemic inflammation is similar to that observed after induction of VWF release by desmopressin.

Keywords

von Willebrand factor - ADAMTS13 - systemic inflammation - endotoxin

• References

• 1 Furlan M. Von Willebrand factor: molecular size and functional activity. Ann Hematol 1996; 72: 341-448.
• 2 Dong J, Moake JL, Nolasco L. et al. ADAMTS-13 rapidly cleaves newly secreted ultralarge von Willebrand factor multimers on the endothelial surface under flowing conditions. Blood 2002; 100: 4033-9.
• 3 Sadler JE. Biochemistry and genetics of von Willebrand factor. Annu Rev Biochem 1998; 67: 395-424.
• 4 Reiter RA. et al. Changes in von Willebrand factor- cleaving protease (ADAMTS13) activity after infusion of desmopressin. Blood 2003; 1101: 946-8.
• 5 Moake JL, Turner NA, Stathopoulos NA. et al. Involvement of large plasma von Willebrand factor (vWF) multimers and unusually large VWF forms derived from endothelial cells in shear stress-induced platelet aggregation. J Clin Invest 1986; 78: 1456-61.
• 6 Furlan M, Robles R, Galbusera M. et al. Von Willebrand factor cleaving protease in thrombotic thrombocytopenic purpura and the hemolytic–uremic syndrome. N Engl J Med 1998; 339: 1578-84.
• 7 Levi M, Ten Cate H. Disseminated intravascular coagulation. N Engl J Med 1999; 341: 586-92.
• 8 Martich GD. et al. Response of man to endotoxin. Immunobiology 1993; 187: 403-16.
• 9 Homoncik M, Blann AD, Hollenstein U. et al. Systemic inflammation increases shear stress-induced platelet plug formation measured by the PFA-100. Br J Haematol 2000; 111: 1250-2.
• 10 Gralnick HR, McKeown LP, Wilson OM. et al. Von Willebrand factor release induced by endotoxin. J Lab Clin Med 1989; 113: 118-22.
• 11 Hollenstein U, Homoncik M, Knöbl P. et al. Acenocoumarol decreases tissue factor-dependent coagulation during systemic inflammation in humans. Clin Pharmacol Ther 2002; 71: 368-74.
• 12 Pernerstorfer T, Hollenstein U, Hansen JB. et al. Lepirudin blunts endotoxin-induced coagulation activation. Blood 2000; 95: 1729-34.
• 13 Gerritsen A, Turecek PL, Schwarz HP. et al. Assay of von Willebrand factor (VWF)-cleaving protease based on decreased collagen binding affinity of degraded VWF. Thromb Haemost 1999; 82: 1386-9.
• 14 Turecek PL. et al. In vivo characterization of recombinant von Willebrand factor in dogs with von Willebrand disease. Blood 1997; 90: 3555-67.
• 15 Siekmann J, Turecek PL, Schwarz HP. The determination of von Willebrand factor activity by collagen binding assay. Haemophilia 1998; 4: 15-24.
• 16 Turecek PL, Pichler L, Auer W. et al. Evidence for extracellular processing of pro-von Willebrand factor after infusion in animals with and without severe von Willebrand disease. Blood 1999; 94: 1637-47.
• 17 Suffredini AF. et al. Dose-related inflammatory effects of intravenous endotoxin in humans: evaluation of a new clinical lot of Escherichia coli O:113 endotoxin. J Infect Dis 1999; 179: 1278-82.
• 18 Levi M, van der Poll T, ten Cate H. et al. The cytokine- mediated imbalance between coagulant and anticoagulant mechanisms in sepsis and endotoxaemia. Eur J Clin Invest 1997; 27: 3-9.
• 19 Derhaschnig U, Reiter R, Knöbl P. et al. Recombinant human activated protein C (rhAPC, drotrecogin alfa [activated]) has minimal effect on markers of coagulation, fibrinolysis, and inflammation in acute human endotoxemia. Blood 2003; 102: 2093-8.
• 20 Pottinger BE, Read RC, Paleolog EM. et al. Von Willebrand factor is an acute phase reactant in man. Thromb Res 1989; 53: 387-94.
• 21 Reiter R, Derhaschnig U, Spiel A. et al. Regulation of protease-activated receptor 1 (PAR1) on platelets and responsiveness to thrombin receptor activating peptide (TRAP) during systemic inflammation in humans. Thromb Haemost 2003; 90: 898-903.
• 22 Derhaschnig U, Pachinger C, Jilma B. Variable inhibition of high-shear-induced platelet plug formation by eptifibatide and tirofiban under conditions of platelet activation and high von Willebrand release: a randomized, placebo-controlled, clinical trial. Am Heart J 2004; 147: 697-703.
• 23 Mannucci PM. et al. Changes in health and disease of the metalloprotease that cleaves von Willebrand factor. Blood 2002; 98: 2730-5.
• 24 Mannucci PM. et al. Plasma levels of von Willebrand factor regulate ADAMTS-13, its major cleaving protease. Br J Haematol 2004; 126: 213-8.
• 25 Crawley JTB, Lam JK, Rance JB. et al. Proteiolytic inactivation of ADAMTS13 by thrombin and plasmin. Blood 2005; 105: 1085-93.
• 26 Bernardo A, Ball C, Nolasco L. et al. Effects of inflammatory cytokines on the release and cleavage of the endothelial cell-derived ultralarge von Willebrand factor multimers under flow. Blood 2004; 104: 100-6.
• 27 Newby DE. et al. Local and systemic effects of intra-arterial desmopressin in healthy volunteers and patients with type 3 von Willebrand disease role of interleukin- 6. Thromb Haemost 1999; 81: 613-7.
• 28 Stohlawetz P, Folman CC, von dem Borne AEGK. et al. Effects of endotoxemia on thrombopoiesis in men. Thromb Haemost 1999; 81: 613-7.
• 29 Knöbl P, Haas M, Laczika K. et al. Immunoadsorption for the treatment of a patient with severe thrombotic thrombocytopenic purpura resistant to plasma exchange: Kinetics of an inhibitor of ADAMTS13. J Thromb Haemost 2003; 1: 187-9.