Variations in the ratio between von Willebrand factor and its cleaving protease during systemic inflammation and association with severity and prognosis of organ failure

Summary

Von Willebrand factor (VWF) and related parameters as well as the protease activity regulating its biological activity were measured in plasma of healthy controls and patients with different cause and severity of systemic inflammation to examine the efficacy of the measures to detect highly prothrombotic states including thrombotic microangiopathy (TMA), one of the sequelae of sepsis. Plasma levels of VWF increased with increasing severity of systemic inflammation, probably due to activation of the endothelium. In parallel, the proteolytic activity of VWF inactivating protease, ADAMTS13, stepwise declined with the severity of inflammation, emphasizing the role of VWF-triggered platelet aggregation on the endothelium subsequently followed by development of TMA. As a consequence, the ratio of VWF antigen level and ADAMTS13 activity was significantly higher in patients with inflammation and sepsis, suggesting that this ratio might be more useful for the diagnosis of highly prothrombotic states including TMA than VWF multimer analysis alone. These findings suggest that ADAMTS13, VWF and related parameters, even in a combined approach, might be useful for the diagnosis and the therapeutic monitoring of patients with sepsis associated thrombotic microangiopathy.

Keywords

ADAMTS13 - sepsis - systemic inflammation - organ failure - platelets - thrombotic microangiopathy - TMA-index

^* Present address: Institute for Pathology, Hannover Medical School, Germany.

• References

• 1 Aird WC. The role of the endothelium in severe sepsis and multiple organ dysfunction syndrome. Blood 2003; 101: 3765-3777.
• 2 Aird WC. Endothelium as a therapeutic target in sepsis. Curr Drug Targets 2007; 8: 501-507.
• 3 Hotchkiss RS, Karl IE. The pathophysiology and treatment of sepsis. N Engl J Med 2003; 348: 138-150.
• 4 Russell JA. Management of sepsis. N Engl J Med 2006; 355: 1699-1713.
• 5 Angus DC, Linde-Zwirble WT, Lidicker J. et al. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med 2001; 29: 1303-1310.
• 6 Angus DC, Pereira CA, Silva E. Epidemiology of severe sepsis around the world. Endocr Metab Immune Disord Drug Targets 2006; 6: 207-212.
• 7 Annane D, Aegerter P, Jars-Guincestre MC. et al. Current epidemiology of septic shock: the CUB-Rea Network. Am J Respir Crit Care Med 2003; 168: 165-172.
• 8 Ware LB, Eisner MD, Thompson BT. et al. Significance of von Willebrand factor in septic and nonseptic patients with acute lung injury. Am J Respir Crit Care Med 2004; 170: 766-772.
• 9 Kayal S, Jais JP, Aguini N. et al. Elevated circulating E-selectin, intercellular adhesion molecule 1, and von Willebrand factor in patients with severe infection. Am J Respir Crit Care Med 1998; 157: 776-784.
• 10 Sadler JE. Biochemistry and genetics of von Wille-brand factor. Annu Rev Biochem 1998; 67: 395-424.
• 11 Arya M, Anvari B, Romo GM. et al. Ultralarge multimers of von Willebrand factor form spontaneous high-strength bonds with the platelet glycoprotein IbIX complex: studies using optical tweezers. Blood 2002; 99: 3971-3977.
• 12 Turner N, Nolasco L, Tao Z. et al. Human endothelial cells synthesize and release ADAMTS-13. J Thromb Haemost 2006; 4: 1396-1404.
• 13 Uemura M, Tatsumi K, Matsumoto M. et al. Localization of ADAMTS13 to the stellate cells of human liver. Blood 2005; 106: 922-924.
• 14 Levy GG, Nichols WC, Lian EC. et al. Mutations in a member of the ADAMTS gene family cause thrombotic thrombocytopenic purpura. Nature 2001; 413: 488-494.
• 15 Ruggeri ZM. Von Willebrand factor, platelets and endothelial cell interactions. J Thromb Haemost 2003; 1: 1335-1342.
• 16 George JN. Clinical insights from observations on ADAMTS13 deficiency in liver cirrhosis. Thromb Haemost 2008; 99: 987-988.
• 17 Uemura M, Fujimura Y, Matsumoto M. et al. Comprehensive analysis of ADAMTS13 in patients with liver cirrhosis. Thromb Haemost 2008; 99: 1019-1029.
• 18 Claus RA, Bockmeyer CL, Sossdorf M. et al. Physical stress as a model to study variations in ADAMTS-13 activity, von Willebrand factor level and platelet activation. J Thromb Haemost 2006; 4: 902-905.
• 19 Mannucci PM, Parolari A, Canciani MT. et al. Opposite changes of ADAMTS-13 and von Willebrand factor after cardiac surgery. J Thromb Haemost 2005; 3: 397-399.
• 20 Bockmeyer CL, Claus RA, Budde U. et al. Inflammation-associated ADAMTS13 deficiency promotes formation of ultra-large von Willebrand factor. Haematologica 2008; 93: 137-140.
• 21 Kremer Hovinga JA, Zeerleder S, Kessler P. et al. ADAMTS-13, von Willebrand factor and related parameters in severe sepsis and septic shock. J Thromb Haemost 2007; 5: 2284-2290.
• 22 Martin K, Borgel D, Lerolle N. et al. Decreased ADAMTS-13 (A disintegrin-like and metalloprotease with thrombospondin type 1 repeats) is associated with a poor prognosis in sepsis-induced organ failure. Crit Care Med 2007; 35: 2375-2382.
• 23 Tsai HM. Molecular mechanisms in thrombotic thrombocytopenic purpura. Semin Thromb Hemost 2004; 30: 549-557.
• 24 Xie L, Chesterman CN, Hogg PJ. Control of von Willebrand factor multimer size by thrombospondin-1. J Exp Med 2001; 193: 1341-1349.
• 25 Ruggeri ZM, Zimmerman TS. The complex multimeric composition of factor VIII/von Willebrand factor. Blood 1981; 57: 1140-1143.
• 26 Budde U, Schneppenheim R, Plendl H. et al. Luminographic detection of von Willebrand factor multimers in agarose gels and on nitrocellulose membranes. Thromb Haemost 1990; 63: 312-315.
• 27 Schneppenheim R, Plendl H, Budde U. Luminography--an alternative assay for detection of von Willebrand factor multimers. Thromb Haemost 1988; 60: 133-136.
• 28 Adcock DM, Bethel M, Valcour A. Diagnosing von Willebrand disease: a large reference laboratory’s perspective. Semin Thromb Hemost 2006; 32: 472-479.
• 29 Franchini M, Montagnana M, Targher G. et al. Reduced von Willebrand factor-cleaving protease levels in secondary thrombotic microangiopathies and other diseases. Semin Thromb Hemost 2007; 33: 787-797.
• 30 Roques F, Michel P, Goldstone AR. et al. The logistic EuroSCORE. Eur Heart J 2003; 24: 881-882.
• 31 American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference: definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Crit Care Med 1992; 20: 864-874.
• 32 Schneppenheim R, Budde U, Oyen F. et al. von Willebrand factor cleaving protease and ADAMTS13 mutations in childhood TTP. Blood 2003; 101: 1845-1850.
• 33 Tripodi A, Chantarangkul V, Bohm M. et al. Measurement of von Willebrand factor cleaving protease (ADAMTS-13): results of an international collaborative study involving 11 methods testing the same set of coded plasmas. J Thromb Haemost 2004; 2: 1601-1609.
• 34 Taylor Jr FB, Toh CH, Hoots WK. et al. Towards definition, clinical and laboratory criteria, and a scoring system for disseminated intravascular coagulation. Thromb Haemost 2001; 86: 1327-1330.
• 35 Bernard GR, Vincent JL, Laterre PF. et al. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 2001; 344: 699-709.
• 36 Budde U, Metzner HJ, Muller HG. Comparative analysis and classification of von Willebrand factor/ factor VIII concentrates: impact on treatment of patients with von Willebrand disease. Semin Thromb Hemost 2006; 32: 626-635.
• 37 Mannucci PM, Canciani MT, Forza I. et al. Changes in health and disease of the metalloprotease that cleaves von Willebrand factor. Blood 2001; 98: 2730-2735.
• 38 Moake JL. Thrombotic microangiopathies. N Engl J Med 2002; 347: 589-600.
• 39 Wada H, Mori Y, Shimura M. et al. Poor outcome in disseminated intravascular coagulation or thrombotic thrombocytopenic purpura patients with severe vascular endothelial cell injuries. Am J Hematol 1998; 58: 189-194.
• 40 Lo B, Nierich AP, Kalkman CJ. et al. Relatively increased von Willebrand factor activity after off-pump coronary artery bypass graft surgery. Thromb Haemost 2007; 97: 21-26.
• 41 Tomic V, Russwurm S, Moller E. et al. Transcriptomic and proteomic patterns of systemic inflammation in on-pump and off-pump coronary artery bypass grafting. Circulation 2005; 112: 2912-2920.
• 42 Dong JF. Cleavage of ultra-large von Willebrand factor by ADAMTS-13 under flow conditions. J Thromb Haemost 2005; 3: 1710-1716.
• 43 Kobayashi T, Wada H, Nishioka N. et al. ADAMTS13 related markers and von Willebrand factor in plasma from patients with thrombotic micro-angiopathy (TMA). Thromb Res 2008; 121: 849-854.
• 44 Rondaij MG, Bierings R, Kragt A. et al. Dynamics and plasticity of Weibel-Palade bodies in endothelial cells. Arterioscler Thromb Vasc Biol 2006; 26: 1002-1007.
• 45 Reiter RA, Knobl P, Varadi K. et al. Changes in von Willebrand factor-cleaving protease (ADAMTS13) activity after infusion of desmopressin. Blood 2003; 101: 946-948.
• 46 Reiter RA, Varadi K, Turecek PL. et al. Changes in ADAMTS13 (von-Willebrand-factor-cleaving pro-tease) activity after induced release of von Willebrand factor during acute systemic inflammation. Thromb Haemost 2005; 93: 554-558.
• 47 Zhou W, Inada M, Lee TP. et al. ADAMTS13 is expressed in hepatic stellate cells. Lab Invest 2005; 85: 780-788.
• 48 Schouten M, Wiersinga WJ, Levi M. et al. Inflammation, endothelium, and coagulation in sepsis. J Leukoc Biol 2008; 83: 536-545.
• 49 Jarrar D, Chaudry IH, Wang P. Organ dysfunction following hemorrhage and sepsis: mechanisms and therapeutic approaches (Review). Int J Mol Med 1999; 4: 575-583.
• 50 Kume Y, Ikeda H, Inoue M. et al. Hepatic stellate cell damage may lead to decreased plasma ADAMTS13 activity in rats. FEBS Lett 2007; 581: 1631-1634.
• 51 Cao WJ, Niiya M, Zheng XW. et al. Inflammatory cytokines inhibit ADAMTS13 synthesis in hepatic stellate cells and endothelial cells. J Thromb Haemost 2008; 6: 1233-1235.
• 52 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: 100-106.
• 53 Lam JK, Chion CK, Zanardelli S. et al. Further characterization of ADAMTS-13 inactivation by thrombin. J Thromb Haemost 2007; 5: 1010-1018.
• 54 Crawley JT, Lam JK, Rance JB. et al. Proteolytic inactivation of ADAMTS13 by thrombin and plasmin. Blood 2005; 105: 1085-1093.
• 55 Mannucci PM, Capoferri C, Canciani MT. Plasma levels of von Willebrand factor regulate ADAMTS-13, its major cleaving protease. Br J Haematol 2004; 126: 213-218.
• 56 Amitrano L, Guardascione MA, Brancaccio V. et al. Risk factors and clinical presentation of portal vein thrombosis in patients with liver cirrhosis. J Hepatol 2004; 40: 736-741.
• 57 Vanderschueren S, De Weerdt A, Malbrain M. et al. Thrombocytopenia and prognosis in intensive care. Crit Care Med 2000; 28: 1871-1876.
• 58 Ono T, Mimuro J, Madoiwa S. et al. Severe secondary deficiency of von Willebrand factor-cleaving pro-tease (ADAMTS13) in patients with sepsis-induced disseminated intravascular coagulation: its correlation with development of renal failure. Blood 2006; 107: 528-534.
• 59 Feys HB, Canciani MT, Peyvandi F. et al. ADAMTS13 activity to antigen ratio in physiological and pathological conditions associated with an increased risk of thrombosis. Br J Haematol 2007; 138: 534-540.
• 60 Mannucci PM, Vanoli M, Forza I. et al. Von Wille-brand factor cleaving protease (ADAMTS-13) in 123 patients with connective tissue diseases (systemic lupus erythematosus and systemic sclerosis). Haematologica 2003; 88: 914-918.
• 61 Lattuada A, Rossi E, Calzarossa C. et al. Mild to moderate reduction of a von Willebrand factor cleaving protease (ADAMTS-13) in pregnant women with HELLP microangiopathic syndrome. Haematologica 2003; 88: 1029-1034.