Complement activation: the missing link between ADAMTS-13 deficiency and microvascular thrombosis of thrombotic microangiopathies

 

 Buy Article Permissions and Reprints

Summary

Endothelial injury is the central factor in the events leading to thrombotic microangiopathy (TMA); however, the mechanisms involved are not fully understood. Here we investigate the role of neutrophils (PMNs) and of complement activation in inducing microvascular damage and loss of thromboresistance in TMA associated with ADAMTS-13 deficiency. PMNs isolated during the acute phase of the disease released excessive amounts of reactive-oxygen species (ROS), N-derived oxidants and proteinases and induced damage and thromboresistance loss in human microvascular endothelial cell line (HMEC-1) ex vivo. Endothelial cytotoxicity and thromboresistance loss was also induced by TMA serum. Complement-derived products were responsible for the above effects: in fact, TMA serum caused C3 and Membrane Attack Complex (MAC) deposition on HMEC-1 and its cytotoxic effect was abolished by complement inhibition. TMA serum caused surface expression of P-selectin on HMEC-1 which may promote PMN adhesion and resulted in increased PMN cytotoxicity, indicating that complement may have a role in PMN activation. In addition, TMA serum stimulated control PMNs to release ROS and proteinases, and to cause endothelial cell cytotoxicity. All of the above effects were abrogated by complement inactivation. These data document for the first time that complement-initiated PMN activation and endothelial injury may have a crucial role in microvascular thrombosis of TMA associated with ADAMTS-13 deficiency.

• References

• 1 Ruggenenti P, Noris M, Remuzzi G. Thrombotic microangiopathy, hemolytic uremic syndrome, and thrombotic thrombocytopenic purpura. Kidney Int 2001; 60: 831-46.
  CrossrefPubMedGoogle Scholar
• 2 Caprioli J, Bettinaglio P, Zipfel PF. et al. The molecular basis of familial hemolytic uremic syndrome: mutation analysis of factor H gene reveals a hot spot in short consensus repeat 20. J Am Soc Nephrol 2000; 12: 297-307.
  PubMedGoogle Scholar
• 3 Noris M, Brioschi S, Caprioli J. et al. for the International Registry of Recurrent and Familial HUS/TTP. Familial haemolytic uraemic syndrome and MCP mutation. Lancet 2003; 362: 1542-7.
  CrossrefPubMedGoogle Scholar
• 4 Levy GG, Nichols WC, Lian EC. et al. Mutations in a member of the ADAMTS gene family cause thrombotic thrombocytopenic purpura. Nature 2001; 413: 475-6.
  CrossrefPubMedGoogle Scholar
• 5 Kokame K, Matsumoto M, Soejima K. et al. Mutations and common polymorphisms in ADAMTS13 gene responsible for von Willebrand factor-cleaving protease activity. Proc Natl Acad Sci USA 2002; 99: 11902-7.
  CrossrefPubMedGoogle Scholar
• 6 Remuzzi G, Galbusera M, Noris M. et al. von Willebrand factor cleaving protease (ADAMTS13) is deficient in recurrent and familial thrombotic thrombocytopenic purpura and hemolytic uremic syndrome. Blood 2002; 100: 778-85.
  CrossrefPubMedGoogle Scholar
• 7 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.
  CrossrefPubMedGoogle Scholar
• 8 Tsai HM, Lian EC. Antibodies to von Willebrand factor-cleaving protease in acute thrombotic thrombocytopenic purpura. N Engl J Med 1998; 339: 1585-94.
  CrossrefPubMedGoogle Scholar
• 9 Forsyrth KD, Simpson AC, Fitzpatrick MM. et al. Neuthrophil-mediated endothelial injury in haemolytic uraemic syndrome. Lancet 1989; 2: 411-4.
  PubMedGoogle Scholar
• 10 Noris M, Ruggenenti P, Todeschini M. et al. Increased nitric oxide formation in recurrent thrombotic microangiopathies: a possible mediator of microvascular injury. Am J Kidney Dis 1996; 27: 790-6.
  CrossrefPubMedGoogle Scholar
• 11 Stoncek DF, Vercellotti GM, Ammerschmidt DE. et al. Characterization of multiple quinine-dependent antibodies in a patient with episodic hemolytic uremic syndrome and immune agranulocytosis. Blood 1992; 80: 241-8.
  PubMedGoogle Scholar
• 12 Mitra D, Jaffe EA, Weksler B. et al. Thrombotic thrombocytopenic purpura and sporadic hemolyticuremic syndrome plasmas induce apoptosis in restricted lineages of human microvascular endothelial cells. Blood 1997; 89: 1224-34.
  PubMedGoogle Scholar
• 13 Alvarez- Larràn A, Petriz J, Martìnez A. et al. Plasma from patients with thrombotic thrombocytopenic purpura induces activaction of human monocytes and polymorphonuclear neutrophils. Br J Haematol 2003; 120: 129-34.
  CrossrefPubMedGoogle Scholar
• 14 Valant PA, Jy W, Horstman LL. et al. Thrombotic thrombocytopenic purpura plasma enhances platelet- leukocyte interaction in vitro. Br J Haematol 1998; 100: 24-32.
  CrossrefPubMedGoogle Scholar
• 15 Eiserich JP, Haristova M, Cross CE. et al. Formation of nitric oxide-derived inflammatory oxidants by myeloperoxidase in neutrophils. Nature 1998; 301: 393-7.
  PubMedGoogle Scholar
• 16 Morigi M, Galbusera M, Binda E. et al. Verotoxin- 1-induced up-regulation of adhesive molecules renders microvascular endothelial cells thrombogenic at high shear stress. Blood 2001; 98: 1828-35.
  CrossrefPubMedGoogle Scholar
• 17 Ribeiro MJA, Philiphs DJ, Benson JM. et al. Hemostatic properties of the SV-40 transfected human microvascular endothelial cell line (HMEC-1). A representative in vitro model for microvascular endothelium. Thromb Res 1995; 79: 153-61.
  CrossrefPubMedGoogle Scholar
• 18 Situnayake RD, Crump BJ, Thurman I D. et al. Further evidence of lipid peroxidation in post-enteropathic haemolytic-uraemic syndrome. Pediatr Nephrol 1991; 5: 387-92.
  CrossrefPubMedGoogle Scholar
• 19 Milford DV, Staten J, McGrecor I. et al. Prognostic markers in diarrhea-associated haemolytic-uraemic syndrome: intial neuthrophil count, human neuthrophil elastase and von Willebrand factor antigen. Nephrol Dial Transplant 1991; 6: 232-7.
  CrossrefPubMedGoogle Scholar
• 20 Fitzpatrick MM, Shah V, Trompeter RS. et al. Interleukin- 8 and polymorphoneuthrophil leukocyte activation in hemolytic uremic syndrome of childhood. Kidney Int 1992; 42: 951-6.
  CrossrefPubMedGoogle Scholar
• 21 Kilgore KS, Ward PA, Warren JS. Neuthrophil adhesion to human endothelial cells is induced by the membrane attack complex: the roles of P-selectin and platelet activating factor. Inflammation 1998; 22: 583-98.
  CrossrefPubMedGoogle Scholar
• 22 Foreman KE, Vaporciyan AA, Bonish BK. et al. C5a-induced expression of P-selectin in endothelial cells. J Clin Invest 1994; 94: 1147-55.
  CrossrefPubMedGoogle Scholar
• 23 McEver RP. Adhesive interaction of leukocytes, platelets, and the vessel wall during hemostasis and inflammation. Thromb Haemost 2001; 86: 746-56.
  Article in Thieme ConnectPubMedGoogle Scholar
• 24 van Epps DE, Chenoweth DE. Analysis of the binding of fluorescent C5a and C3a to human peripheral blood leukocytes. J Immunol 1984; 132: 2862-7.
  PubMedGoogle Scholar
• 25 Elsner J, Opperman M, Czech W. et al. C3a activates the respiratory burst in human polymorphonuclear neuthrophilic leukocytes via pertussis toxin sensitive G-protein. Blood 1994; 83: 3324-31.
  PubMedGoogle Scholar
• 26 Hardy MM, Flickinger AG, Riley DP. et al. Superoxide dismutase mimetics inhibit neuthrophil-mediated human aortic endothelial cell injury in vitro. J Biol Chem 1994; 269: 18535-40.
  PubMedGoogle Scholar
• 27 Noris M, Ruggenenti P, Perna A. et al. Hypocomplementemia discoloses genetic predisposition to hemolytic uremic syndrome and thrombotic thrombocytopenic purpura: role of factor H abnormalities. Italian registry of familial and recurrent hemolytic uremic syndrome/thrombotic thrombocytopenic purpura. J Am Soc Nephrol 1999; 10: 281-93.
  PubMedGoogle Scholar
• 28 Wright JF, Wang H, Horsnstein A. et al. Characterization of platelet glycoproteins and platelet/endothelial cell antibodies in patients with thrombotic thrombocytopenic purpura. Br J Haematol 1999; 107: 546-55.
  CrossrefPubMedGoogle Scholar
• 29 Weisenburger DR, O'Connor ML, Hart MN. Thrombotic thrombocytopenic purpura with C3 vascular deposits: report of a case. Am J Clin Pathol 1977; 67: 61-3.
  CrossrefPubMedGoogle Scholar
• 30 Dong JF, 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.
  CrossrefPubMedGoogle Scholar
• 31 Polley MJ, Nachman R. The human complement system in thrombin-mediated platelet function. J Exp Med 1978; 147: 1713-26.
  CrossrefPubMedGoogle Scholar
• 32 Cheung AK, Faeizi-Jenkin B, Leypoldt JK. Effect of thrombosis on complement activation and neuthrophil degranulation during in vitro hemodialysis. J Am Soc Nephrol 1994; 5: 110-5.
  PubMedGoogle Scholar
• 33 Ekdahl KN, Nilsson B. Phosphorilation of plasma proteins with emphasis on complement component C3. Mol Immunol 1999; 36: 233-9.
  CrossrefPubMedGoogle Scholar
• 34 Ekdahl KN, Nilsson B. Phosphorilation of complement component C3 and C3 fragments by a human platelet protein kinase. Inhibition of factor I-medited cleavage of C3b. J Immunol 1995; 154: 6502-10.
  PubMedGoogle Scholar
• 35 Ekdahl KN, Nilsson B. Alteration in C3 activation and binding caused by phosphorilation by a casein kinase released from activated human platelets. J Immunol 1999; 162: 7426-33.
  PubMedGoogle Scholar
• 36 Ekdahl KN, Ronnblom L, Sturfelt G. et al. Increased phosphate content in complement component C3, fibrinogen, vitronectin, and other plasma proteins in systemic lupus erythematosus: covariation with platelet activation and possible role association with thrombosis. Arthritis Rheum 1997; 40: 2178-86.
  CrossrefPubMedGoogle Scholar
• 37 Smith RA. Targeting anticomplement agents. Biochem Soc Trans 2001; 30: 1037-41.
  PubMedGoogle Scholar