Download PDF
Semin Thromb Hemost 2015; 41(06): 665-672
DOI: 10.1055/s-0035-1556732
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

The Activation of Complement and Its Role in the Pathogenesis of Thromboembolism

Sara Boyce
1   Department of Haematology, University Hospital Southampton, Southampton, United Kingdom
,
Efrem Eren
2   Department of Immunology, University Hospital Southampton, Southampton, United Kingdom
,
Bashir A. Lwaleed
3   Faculty of Health Sciences, University of Southampton, Southampton, United Kingdom
,
Rashid S. Kazmi
1   Department of Haematology, University Hospital Southampton, Southampton, United Kingdom
› Author Affiliations
Further Information

Publication History

Publication Date:
25 August 2015 (online)

    Permissions and Reprints

Abstract

It is well established that inflammation and thrombosis are intricately linked processes, and there is increasing evidence of the importance of their roles in activated complement in the pathogenesis of thromboembolism. The two systems are activated by similar stimuli simultaneously and interact, either directly or through biochemical mediators, to protect the host from microbial invasion. Diseases characterized by complement hyperactivity such as paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome have high rates of thrombosis. This review describes how disease processes where there is excessive complement activation leads to thrombosis, and the specific interactions between the complement and coagulation systems that lead to pathological thrombus formation.

Keywords

inflammation - thrombosis - complement activation
 

  • References

  • 1 Sjöberg AP, Trouw LA, Blom AM. Complement activation and inhibition: a delicate balance. Trends Immunol 2009; 30 (2) 83-90
    CrossrefPubMedSearch in Google Scholar
  • 2 Sun H. The interaction between pathogens and the host coagulation system. Physiology (Bethesda) 2006; 21: 281-288
    CrossrefPubMedSearch in Google Scholar
  • 3 Schroeder B, Boyle MD, Sheerin BR, Asbury AC, Lottenberg R. Species specificity of plasminogen activation and acquisition of surface-associated proteolytic activity by group C streptococci grown in plasma. Infect Immun 1999; 67 (12) 6487-6495
    PubMedSearch in Google Scholar
  • 4 Martin DM, Boys CW, Ruf W. Tissue factor: molecular recognition and cofactor function. FASEB J 1995; 9 (10) 852-859
    PubMedSearch in Google Scholar
  • 5 Krem MM, Di Cera E. Evolution of enzyme cascades from embryonic development to blood coagulation. Trends Biochem Sci 2002; 27 (2) 67-74
    CrossrefPubMedSearch in Google Scholar
  • 6 Delvaeye M, Conway EM. Coagulation and innate immune responses: can we view them separately?. Blood 2009; 114 (12) 2367-2374
    CrossrefPubMedSearch in Google Scholar
  • 7 Iwanaga S. The molecular basis of innate immunity in the horseshoe crab. Curr Opin Immunol 2002; 14 (1) 87-95
    CrossrefPubMedSearch in Google Scholar
  • 8 Zhu Y, Thangamani S, Ho B, Ding JL. The ancient origin of the complement system. EMBO J 2005; 24 (2) 382-394
    CrossrefPubMedSearch in Google Scholar
  • 9 Krem MM, Rose T, Di Cera E. The C-terminal sequence encodes function in serine proteases. J Biol Chem 1999; 274 (40) 28063-28066
    CrossrefPubMedSearch in Google Scholar
  • 10 Delvaeye M, Noris M, De Vriese A , et al. Thrombomodulin mutations in atypical hemolytic-uremic syndrome. N Engl J Med 2009; 361 (4) 345-357
    CrossrefPubMedSearch in Google Scholar
  • 11 Markiewski MM, Nilsson B, Ekdahl KN, Mollnes TE, Lambris JD. Complement and coagulation: strangers or partners in crime?. Trends Immunol 2007; 28 (4) 184-192
    CrossrefPubMedSearch in Google Scholar
  • 12 Luzzatto L, Gianfaldoni G, Notaro R. Management of paroxysmal nocturnal haemoglobinuria: a personal view. Br J Haematol 2011; 153 (6) 709-720
    CrossrefPubMedSearch in Google Scholar
  • 13 Hillmen P, Lewis SM, Bessler M, Luzzatto L, Dacie JV. Natural history of paroxysmal nocturnal hemoglobinuria. N Engl J Med 1995; 333 (19) 1253-1258
    CrossrefPubMedSearch in Google Scholar
  • 14 Hillmen P, Muus P, Dührsen U , et al. Effect of the complement inhibitor eculizumab on thromboembolism in patients with paroxysmal nocturnal hemoglobinuria. Blood 2007; 110 (12) 4123-4128
    CrossrefPubMedSearch in Google Scholar
  • 15 Socié G, Mary JY, de Gramont A , et al; French Society of Haematology. Paroxysmal nocturnal haemoglobinuria: long-term follow-up and prognostic factors. Lancet 1996; 348 (9027) 573-577
    CrossrefPubMedSearch in Google Scholar
  • 16 Takeda J, Miyata T, Kawagoe K , et al. Deficiency of the GPI anchor caused by a somatic mutation of the PIG-A gene in paroxysmal nocturnal hemoglobinuria. Cell 1993; 73 (4) 703-711
    CrossrefPubMedSearch in Google Scholar
  • 17 Takahashi M, Takeda J, Hirose S , et al. Deficient biosynthesis of N-acetylglucosaminyl-phosphatidylinositol, the first intermediate of glycosyl phosphatidylinositol anchor biosynthesis, in cell lines established from patients with paroxysmal nocturnal hemoglobinuria. J Exp Med 1993; 177 (2) 517-521
    CrossrefPubMedSearch in Google Scholar
  • 18 Holguin MH, Fredrick LR, Bernshaw NJ, Wilcox LA, Parker CJ. Isolation and characterization of a membrane protein from normal human erythrocytes that inhibits reactive lysis of the erythrocytes of paroxysmal nocturnal hemoglobinuria. J Clin Invest 1989; 84 (1) 7-17
    CrossrefPubMedSearch in Google Scholar
  • 19 Hill A, Kelly RJ, Hillmen P. Thrombosis in paroxysmal nocturnal hemoglobinuria. Blood 2013; 121 (25) 4985-4996 , quiz 5105
    CrossrefPubMedSearch in Google Scholar
  • 20 Noris M, Remuzzi G. Atypical hemolytic-uremic syndrome. N Engl J Med 2009; 361 (17) 1676-1687
    CrossrefPubMedSearch in Google Scholar
  • 21 Roumenina LT, Loirat C, Dragon-Durey MA, Halbwachs-Mecarelli L, Sautes-Fridman C, Fremeaux-Bacchi V. Alternative complement pathway assessment in patients with atypical HUS. J Immunol Methods 2011; 365 (1-2) 8-26
    CrossrefPubMedSearch in Google Scholar
  • 22 Goicoechea de Jorge E, Harris CL, Esparza-Gordillo J , et al. Gain-of-function mutations in complement factor B are associated with atypical hemolytic uremic syndrome. Proc Natl Acad Sci U S A 2007; 104 (1) 240-245
    CrossrefPubMedSearch in Google Scholar
  • 23 de Córdoba SR, de Jorge EG. Translational mini-review series on complement factor H: genetics and disease associations of human complement factor H. Clin Exp Immunol 2008; 151 (1) 1-13
    PubMedSearch in Google Scholar
  • 24 Ruiz-Torres MP, Casiraghi F, Galbusera M , et al. Complement activation: the missing link between ADAMTS-13 deficiency and microvascular thrombosis of thrombotic microangiopathies. Thromb Haemost 2005; 93 (3) 443-452
    PubMedSearch in Google Scholar
  • 25 Wright JF, Wang H, Hornstein A , et al. Characterization of platelet glycoproteins and platelet/endothelial cell antibodies in patients with thrombotic thrombocytopenic purpura. Br J Haematol 1999; 107 (3) 546-555
    CrossrefPubMedSearch in Google Scholar
  • 26 Réti M, Farkas P, Csuka D , et al. Complement activation in thrombotic thrombocytopenic purpura. J Thromb Haemost 2012; 10 (5) 791-798
    CrossrefPubMedSearch in Google Scholar
  • 27 Schraufstatter IU, Trieu K, Sikora L, Sriramarao P, DiScipio R. Complement c3a and c5a induce different signal transduction cascades in endothelial cells. J Immunol 2002; 169 (4) 2102-2110
    CrossrefPubMedSearch in Google Scholar
  • 28 Pierangeli SS, Girardi G, Vega-Ostertag M, Liu X, Espinola RG, Salmon J. Requirement of activation of complement C3 and C5 for antiphospholipid antibody-mediated thrombophilia. Arthritis Rheum 2005; 52 (7) 2120-2124
    CrossrefPubMedSearch in Google Scholar
  • 29 McNeil HP, Simpson RJ, Chesterman CN, Krilis SA. Anti-phospholipid antibodies are directed against a complex antigen that includes a lipid-binding inhibitor of coagulation: beta 2-glycoprotein I (apolipoprotein H). Proc Natl Acad Sci U S A 1990; 87 (11) 4120-4124
    CrossrefPubMedSearch in Google Scholar
  • 30 Bevers EM, Galli M, Barbui T, Comfurius P, Zwaal RF. Lupus anticoagulant IgG's (LA) are not directed to phospholipids only, but to a complex of lipid-bound human prothrombin. Thromb Haemost 1991; 66 (6) 629-632
    PubMedSearch in Google Scholar
  • 31 Giannakopoulos B, Passam F, Rahgozar S, Krilis SA. Current concepts on the pathogenesis of the antiphospholipid syndrome. Blood 2007; 109 (2) 422-430
    CrossrefPubMedSearch in Google Scholar
  • 32 Levine JS, Branch DW, Rauch J. The antiphospholipid syndrome. N Engl J Med 2002; 346 (10) 752-763
    CrossrefPubMedSearch in Google Scholar
  • 33 Pennings MT, Derksen RH, van Lummel M , et al. Platelet adhesion to dimeric beta-glycoprotein I under conditions of flow is mediated by at least two receptors: glycoprotein Ibalpha and apolipoprotein E receptor 2′. J Thromb Haemost 2007; 5 (2) 369-377
    CrossrefPubMedSearch in Google Scholar
  • 34 Machin SJ. Platelets and antiphospholipid antibodies. Lupus 1996; 5 (5) 386-387
    PubMedSearch in Google Scholar
  • 35 Pierangeli SS, Colden-Stanfield M, Liu X, Barker JH, Anderson GL, Harris EN. Antiphospholipid antibodies from antiphospholipid syndrome patients activate endothelial cells in vitro and in vivo. Circulation 1999; 99 (15) 1997-2002
    CrossrefPubMedSearch in Google Scholar
  • 36 Piona A, La Rosa L, Tincani A , et al. Placental thrombosis and fetal loss after passive transfer of mouse lupus monoclonal or human polyclonal anti-cardiolipin antibodies in pregnant naive BALB/c mice. Scand J Immunol 1995; 41 (5) 427-432
    CrossrefPubMedSearch in Google Scholar
  • 37 Shi W, Chong BH, Chesterman CN. Beta 2-glycoprotein I is a requirement for anticardiolipin antibodies binding to activated platelets: differences with lupus anticoagulants. Blood 1993; 81 (5) 1255-1262
    PubMedSearch in Google Scholar
  • 38 Davis WD, Brey RL. Antiphospholipid antibodies and complement activation in patients with cerebral ischemia. Clin Exp Rheumatol 1992; 10 (5) 455-460
    PubMedSearch in Google Scholar
  • 39 Salmon JE, Girardi G. The role of complement in the antiphospholipid syndrome. Curr Dir Autoimmun 2004; 7: 133-148
    PubMedSearch in Google Scholar
  • 40 Gando S, Kameue T, Nanzaki S, Nakanishi Y. Disseminated intravascular coagulation is a frequent complication of systemic inflammatory response syndrome. Thromb Haemost 1996; 75 (2) 224-228
    PubMedSearch in Google Scholar
  • 41 Okusawa S, Yancey KB, van der Meer JW , et al. C5a stimulates secretion of tumor necrosis factor from human mononuclear cells in vitro. Comparison with secretion of interleukin 1 beta and interleukin 1 alpha. J Exp Med 1988; 168 (1) 443-448
    CrossrefPubMedSearch in Google Scholar
  • 42 Scholz W, McClurg MR, Cardenas GJ , et al. C5a-mediated release of interleukin 6 by human monocytes. Clin Immunol Immunopathol 1990; 57 (2) 297-307
    CrossrefPubMedSearch in Google Scholar
  • 43 Zöller B, Li X, Sundquist J, Sundquist K. Autoimmune diseases and venous thromboembolism: a review of the literature. Am J Cardiovasc Dis 2012; 2 (3) 171-183
    PubMedSearch in Google Scholar
  • 44 Zöller B, Li X, Sundquist J, Sundquist K. Risk of pulmonary embolism in patients with autoimmune disorders: a nationwide follow-up study from Sweden. Lancet 2012; b; 379 (9812) 244-249
    CrossrefPubMedSearch in Google Scholar
  • 45 Ballanti E, Perricone C, Greco E , et al. Complement and autoimmunity. Immunol Res 2013; 56 (2-3) 477-491
    CrossrefPubMedSearch in Google Scholar
  • 46 Carter AM. Inflammation, thrombosis and acute coronary syndromes. Diab Vasc Dis Res 2005; 2 (3) 113-121
    CrossrefPubMedSearch in Google Scholar
  • 47 Carter AM. Complement activation: an emerging player in the pathogenesis of cardiovascular disease. Scientifica (Cairo) 2012; 2012: 402783
    PubMedSearch in Google Scholar
  • 48 Niculescu F, Rus H, Cristea A, Vlaicu R. Localization of the terminal C5b-9 complement complex in the human aortic atherosclerotic wall. Immunol Lett 1985; 10 (2) 109-114
    CrossrefPubMedSearch in Google Scholar
  • 49 Yasojima K, Schwab C, McGeer EG, McGeer PL. Complement components, but not complement inhibitors, are upregulated in atherosclerotic plaques. Arterioscler Thromb Vasc Biol 2001; 21 (7) 1214-1219
    CrossrefPubMedSearch in Google Scholar
  • 50 Distelmaier K, Adlbrecht C, Jakowitsch J , et al. Local complement activation triggers neutrophil recruitment to the site of thrombus formation in acute myocardial infarction. Thromb Haemost 2009; 102 (3) 564-572
    PubMedSearch in Google Scholar
  • 51 Speidl WS, Exner M, Amighi J , et al. Complement component C5a predicts future cardiovascular events in patients with advanced atherosclerosis. Eur Heart J 2005; 26 (21) 2294-2299
    CrossrefPubMedSearch in Google Scholar
  • 52 Howes JM, Richardson VR, Smith KA , et al. Complement C3 is a novel plasma clot component with anti-fibrinolytic properties. Diab Vasc Dis Res 2012; 9 (3) 216-225
    CrossrefPubMedSearch in Google Scholar
  • 53 Collet JP, Allali Y, Lesty C , et al. Altered fibrin architecture is associated with hypofibrinolysis and premature coronary atherothrombosis. Arterioscler Thromb Vasc Biol 2006; 26 (11) 2567-2573
    CrossrefPubMedSearch in Google Scholar
  • 54 Polley MJ, Nachman R. The human complement system in thrombin-mediated platelet function. J Exp Med 1978; 147 (6) 1713-1726
    CrossrefPubMedSearch in Google Scholar
  • 55 Polley MJ, Nachman RL. Human platelet activation by C3a and C3a des-arg. J Exp Med 1983; 158 (2) 603-615
    CrossrefPubMedSearch in Google Scholar
  • 56 Shats-Tseytlina EA, Nair CH, Dhall DP. Complement activation: a new participant in the modulation of fibrin gel characteristics and the progression of atherosclerosis?. Blood Coagul Fibrinolysis 1994; 5 (4) 529-535
    PubMedSearch in Google Scholar
  • 57 Zucker MB, Grant RA. Aggregation and release reaction induced in human blood platelets by zymosan. J Immunol 1974; 112 (3) 1219-1230
    PubMedSearch in Google Scholar
  • 58 Ozge-Anwar AH, Freedman JJ, Senyi AF, Cerskus AL, Blajchman MA. Enhanced prothrombin-converting activity and factor Xa binding of platelets activated by the alternative complement pathway. Br J Haematol 1984; 57 (2) 221-228
    CrossrefPubMedSearch in Google Scholar
  • 59 Muhlfelder TW, Niemetz J, Kreutzer D, Beebe D, Ward PA, Rosenfeld SI. C5 chemotactic fragment induces leukocyte production of tissue factor activity: a link between complement and coagulation. J Clin Invest 1979; 63 (1) 147-150
    CrossrefPubMedSearch in Google Scholar
  • 60 Ikeda K, Nagasawa K, Horiuchi T, Tsuru T, Nishizaka H, Niho Y. C5a induces tissue factor activity on endothelial cells. Thromb Haemost 1997; 77 (2) 394-398
    PubMedSearch in Google Scholar
  • 61 Sims PJ, Faioni EM, Wiedmer T, Shattil SJ. Complement proteins C5b-9 cause release of membrane vesicles from the platelet surface that are enriched in the membrane receptor for coagulation factor Va and express prothrombinase activity. J Biol Chem 1988; 263 (34) 18205-18212
    PubMedSearch in Google Scholar
  • 62 Ritis K, Doumas M, Mastellos D , et al. A novel C5a receptor-tissue factor cross-talk in neutrophils links innate immunity to coagulation pathways. J Immunol 2006; 177 (7) 4794-4802
    CrossrefPubMedSearch in Google Scholar
  • 63 Köhl J. Anaphylatoxins and infectious and non-infectious inflammatory diseases. Mol Immunol 2001; 38 (2-3) 175-187
    CrossrefPubMedSearch in Google Scholar
  • 64 Wiedmer T, Esmon CT, Sims PJ. Complement proteins C5b-9 stimulate procoagulant activity through platelet prothrombinase. Blood 1986; 68 (4) 875-880
    PubMedSearch in Google Scholar
  • 65 Combes V, Simon AC, Grau GE , et al. In vitro generation of endothelial microparticles and possible prothrombotic activity in patients with lupus anticoagulant. J Clin Invest 1999; 104 (1) 93-102
    CrossrefPubMedSearch in Google Scholar
  • 66 Oleksowicz L, Mrowiec Z, Zuckerman D, Isaacs R, Dutcher J, Puszkin E. Platelet activation induced by interleukin-6: evidence for a mechanism involving arachidonic acid metabolism. Thromb Haemost 1994; 72 (2) 302-308
    PubMedSearch in Google Scholar
  • 67 Shebuski RJ, Kilgore KS. Role of inflammatory mediators in thrombogenesis. J Pharmacol Exp Ther 2002; 300 (3) 729-735
    CrossrefPubMedSearch in Google Scholar
  • 68 Wojta J, Kaun C, Zorn G , et al. C5a stimulates production of plasminogen activator inhibitor-1 in human mast cells and basophils. Blood 2002; 100 (2) 517-523
    CrossrefPubMedSearch in Google Scholar
  • 69 Sims PJ, Wiedmer T. The response of human platelets to activated components of the complement system. Immunol Today 1991; 12 (9) 338-342
    CrossrefPubMedSearch in Google Scholar
  • 70 Wiedmer T, Ando B, Sims PJ. Complement C5b-9-stimulated platelet secretion is associated with a Ca2+-initiated activation of cellular protein kinases. J Biol Chem 1987; 262 (28) 13674-13681
    PubMedSearch in Google Scholar
  • 71 Yin W, Ghebrehiwet B, Peerschke EI. Expression of complement components and inhibitors on platelet microparticles. Platelets 2008; 19 (3) 225-233
    CrossrefPubMedSearch in Google Scholar
  • 72 Italiano Jr JE, Mairuhu AT, Flaumenhaft R. Clinical relevance of microparticles from platelets and megakaryocytes. Curr Opin Hematol 2010; 17 (6) 578-584
    CrossrefPubMedSearch in Google Scholar
  • 73 Diamant M, Tushuizen ME, Sturk A, Nieuwland R. Cellular microparticles: new players in the field of vascular disease?. Eur J Clin Invest 2004; 34 (6) 392-401
    CrossrefPubMedSearch in Google Scholar
  • 74 Tans G, Rosing J, Thomassen MC, Heeb MJ, Zwaal RF, Griffin JH. Comparison of anticoagulant and procoagulant activities of stimulated platelets and platelet-derived microparticles. Blood 1991; 77 (12) 2641-2648
    PubMedSearch in Google Scholar
  • 75 Sims PJ, Rollins SA, Wiedmer T. Regulatory control of complement on blood platelets. Modulation of platelet procoagulant responses by a membrane inhibitor of the C5b-9 complex. J Biol Chem 1989; 264 (32) 19228-19235
    PubMedSearch in Google Scholar
  • 76 Wiedmer T, Hall SE, Ortel TL, Kane WH, Rosse WF, Sims PJ. Complement-induced vesiculation and exposure of membrane prothrombinase sites in platelets of paroxysmal nocturnal hemoglobinuria. Blood 1993; 82 (4) 1192-1196
    PubMedSearch in Google Scholar
  • 77 Tedesco F, Pausa M, Nardon E, Introna M, Mantovani A, Dobrina A. The cytolytically inactive terminal complement complex activates endothelial cells to express adhesion molecules and tissue factor procoagulant activity. J Exp Med 1997; 185 (9) 1619-1627
    CrossrefPubMedSearch in Google Scholar
  • 78 Frenette PS, Johnson RC, Hynes RO, Wagner DD. Platelets roll on stimulated endothelium in vivo: an interaction mediated by endothelial P-selectin. Proc Natl Acad Sci U S A 1995; 92 (16) 7450-7454
    CrossrefPubMedSearch in Google Scholar
  • 79 Del Conde I, Crúz MA, Zhang H, López JA, Afshar-Kharghan V. Platelet activation leads to activation and propagation of the complement system. J Exp Med 2005; 201 (6) 871-879
    CrossrefPubMedSearch in Google Scholar
  • 80 Gralnick HR, Vail M, McKeown LP , et al. Activated platelets in paroxysmal nocturnal haemoglobinuria. Br J Haematol 1995; 91 (3) 697-702
    CrossrefPubMedSearch in Google Scholar
  • 81 Morigi M, Galbusera M, Gastoldi S , et al. Alternative pathway activation of complement by Shiga toxin promotes exuberant C3a formation that triggers microvascular thrombosis. J Immunol 2011; 187 (1) 172-180
    CrossrefPubMedSearch in Google Scholar
  • 82 Levi M, Van Der Poll T. Thrombomodulin in sepsis. Minerva Anestesiol 2013; 79 (3) 294-298
    PubMedSearch in Google Scholar
  • 83 Fang W, Guo ZH, Zhang BQ , et al. [Effect of C5a on expression of thrombomodulin in endothelial cells in vitro]. Zhongguo Wei Zhong Bing Ji Jiu Yi Xue 2009; 21 (3) 168-171
    PubMedSearch in Google Scholar
  • 84 Takano S, Kimura S, Ohdama S, Aoki N. Plasma thrombomodulin in health and diseases. Blood 1990; 76 (10) 2024-2029
    CrossrefPubMedSearch in Google Scholar
  • 85 Peerschke EI, Ghebrehiwet B. Human blood platelets possess specific binding sites for C1q. J Immunol 1987; 138 (5) 1537-1541
    PubMedSearch in Google Scholar
  • 86 Peerschke EI, Reid KB, Ghebrehiwet B. Platelet activation by C1q results in the induction of alpha IIb/beta 3 integrins (GPIIb-IIIa) and the expression of P-selectin and procoagulant activity. J Exp Med 1993; 178 (2) 579-587
    CrossrefPubMedSearch in Google Scholar
  • 87 Lood C, Eriksson S, Gullstrand B , et al. Increased C1q, C4 and C3 deposition on platelets in patients with systemic lupus erythematosus—a possible link to venous thrombosis?. Lupus 2012; 21 (13) 1423-1432
    CrossrefPubMedSearch in Google Scholar
  • 88 Peerschke EI, Yin W, Alpert DR, Roubey RA, Salmon JE, Ghebrehiwet B. Serum complement activation on heterologous platelets is associated with arterial thrombosis in patients with systemic lupus erythematosus and antiphospholipid antibodies. Lupus 2009; 18 (6) 530-538
    CrossrefPubMedSearch in Google Scholar
  • 89 Hesselvik JF, Malm J, Dahlbäck B, Blombäck M. Protein C, protein S and C4b-binding protein in severe infection and septic shock. Thromb Haemost 1991; 65 (2) 126-129
    PubMedSearch in Google Scholar
  • 90 Taylor Jr FB. Studies on the inflammatory-coagulant axis in the baboon response to E. coli: regulatory roles of proteins C, S, C4bBP and of inhibitors of tissue factor. Prog Clin Biol Res 1994; 388: 175-194
    PubMedSearch in Google Scholar
  • 91 García de Frutos P, Alim RI, Härdig Y, Zöller B, Dahlbäck B. Differential regulation of alpha and beta chains of C4b-binding protein during acute-phase response resulting in stable plasma levels of free anticoagulant protein S. Blood 1994; 84 (3) 815-822
    PubMedSearch in Google Scholar
  • 92 Regnault V, Boehlen F, Ozsahin H , et al. Anti-protein S antibodies following a varicella infection: detection, characterization and influence on thrombin generation. J Thromb Haemost 2005; 3 (6) 1243-1249
    CrossrefPubMedSearch in Google Scholar
  • 93 Rezende SM, Simmonds RE, Lane DA. Coagulation, inflammation, and apoptosis: different roles for protein S and the protein S-C4b binding protein complex. Blood 2004; 103 (4) 1192-1201
    PubMedSearch in Google Scholar