The Pathophysiology of Disseminated Intravascular Coagulation

Introduction

Disseminated intravascular coagulation (DIC) can be defined as “an acquired syndrome characterized by the activation of intravascular coagulation up to intravascular fibrin formation. The process may be accompanied by secondary fibrinolysis or inhibited fibrinolysis.”¹ Being an acquired disorder, DIC occurs in a wide range of underlying disease states, including sepsis (both by Gram positive and Gram negative bacteria), burns, preeclampsia, malignancy, and polytrauma.¹ In the majority of conditions, the pathogenesis of DIC remains only partly understood, an exception is Gram negative septicemia. In the following chapter, we will discuss the presumed mechanism by which DIC is elicited in different pathological states. The initiation of DIC follows the presentation of the glycoprotein tissue factor (TF) at a cellular surface, being either an intact or perturbed cell, or a cell membrane remnant.² The extracellular TF molecules may interact with circulating factor VIIa to form a catalytic complex. The complex binds the coagulation zymogen factors IX and X. This leads to proteolytic cleavage of these molecules, yielding enzymatically active factors IXa and Xa and promoting the activation of prothrombin to thrombin (Fig. 1).

• References

• 1 Muller-Berghaus G, ten Cate H, Levi M. Disseminated intravascular coagulation. In: Verstraete M, Fuster V, Topol EJ. eds Cardiovascular Thrombosis: Thrombocardiology and Thromboneurology. 2nd Edition. Lippincott-Raven Publishers; New York: 1998: 781-799.
• 2 Edgington TS, Mackman N, Fan ST, Ruf W. Cellular immune and cytokine pathways resulting in tissue factor expression and relevance to septic shock. Nouv Rev Fr Hematol 1992; 34: S15-S27.
• 3 ten Cate H, Bauer KA, Levi M, Edgington TS, Sublett RD, Barzegar S, Kass BL, Rosenberg RD. The activation of factor X and prothrombin by recombinant factor VIIa in vivo is mediated by tissue factor. J Clin Invest 1993; 92: 1207-1212.
• 4 Oeth P, Parry GCN, Mackman N. Regulation of the tissue factor gene in human monocytic cells. Arterioscler Thromb Vasc Biol 1997; 17: 365-374.
• 5 Dean RT, Prydz H. Inflammatory particles stimulate thromboplastin production by human monocytes. Thromb Res 1983; 30: 357-367.
• 6 Koyama T, Nishida K, Ohdama S, Sawada M, Murakami N, Hirosawa S, Kuriyama R, Matzusawa K, Hasegawa R, Aoki N. Determination of plasma tissue factor antigen and its clinical significance. Br J Haematol 1994; 87: 343-347.
• 7 Osterud B, Flaegstad T. Increased tissue thromboplastin activity in monocytes from patients with meningococcal infection: related to an unfavorable prognosis. Thromb Haemost 1983; 49: 5-7.
• 8 Jude B, Agraou B, McFadden EP, Susen S, Bauters C, Lepelley P, Vanhaesbroucke C, Devos P, Cosson A, Asseman P. Evidence for a time-dependent activation of monocytes in the systemic circulation in unstable angina but not in acute myocardial infarction or in stable angina. Circulation 1994; 90: 1662-1668.
• 9 Solovey A, Gui L, Key NS, Hebbel RP. Tissue factor expression by endothelial cells in sickle cell anemia. N Engl J Med 1998; 101: 1899-1904.
• 10 Nieuwland R, Berckmans RJ, Rotteveel-Eijkman RC, Maquelin KN, Roozendaal KJ, Jansen PGM, ten Have K, Eijsman L, Hack CE, Sturk A. Cell-derived microparticles generated in patients during cardiopulmonary bypass are highly procoagulant. Circulation 1997; 96: 3534-3541.
• 11 Contrino J, Hair G, Kreutzer DL, Rickles FR. In situ detection of tissue factor in vascular endothelial cells: correlation with the malignant phenotype of human breast disease. Nat Med 1996; 2: 209-215.
• 12 Bromberg ME, Konigsberg WH, Madison JF, Pawashe A, Garen A. Tissue factor promotes melanoma metastasis by a pathway independent of blood coagulation. Proc Natl Acad Sci USA 1995; 92: 8205-8209.
• 13 Donati BM. Cancer and thrombosis: from phlegmasia alba dolens to transgenic mice. Thromb Haemost 1995; 74: 278-281.
• 14 Nicholson AC, Hajjar DP. Viral induction of endothelial cell procoagulant activity. In: Van Hinsbergh VWM. ed Vascular Control of Hemostasis. Harwood Academic Publishers; New York: 1996: 299-308.
• 15 Taylor Jr. FB. Role of tissue factor in the coagulant and inflammatory response to LD100 E. coli sepsis and in the early diagnosis of DIC in the baboon. In: Muller-Berghaus G, Madlener K, Blomback M, ten Cate JW. eds DIC: Pathogenesis, Diagnosis and Therapy of Disseminated Intravascular Fibrin Formation. Excerpta Medica; New York: 1993: 19-32.
• 16 Levi M, van der Poll T, ten Cate H, van Deventer SJH. The cytokine-mediated imbalance between coagulant and anticoagulant mechanisms in sepsis and endotoxemia. Eur J Clin Invest 1997; 27: 3-9.
• 17 Levi M, ten Cate H, Bauer KA, van der Poll T, Edgington TS, Buller HR, van Deventer SJH, Hack CE, Rosenberg RD. Inhibition of endotoxin-induced activation of coagulation and fibrinolysis by pentoxifylline or by a monoclonal anti-tissue factor antibody in a chimpanzee model. J Clin Invest 1994; 93: 114-120.
• 18 Van der Poll T, Levi M, Hack CE, ten Cate H, van Deventer SJH, Eerenberg AJ, de Groot ER, Jansen J, Gallati H, Buller HR, ten Cate JW. Elimination of interleukin-6 attenuates coagulation activation in experimental endotoxemia in chimpanzees. J Exp Med 1994; 179: 1253-1259.
• 19 Taylor Jr FB, Chang ACK, Peer GT, Mather T, Blick K, Catlett R, Lockhart CMS, Esmon CT. DEGR-factor Xa blocks disseminated intravascular coagulation initiated by Escherichia coli without preventing shock or organ damage. Blood 1991; 78: 364-368.
• 20 Taylor Jr FB, Chang A, Esmon CT, D’Angelo A, Vigano-D’Angelo S, Blick KE. Protein C prevents the coagulopathic and lethal effects of Escherichia coli infusion in the baboon. J Clin Invest 1987; 79: 918-925.
• 21 Rintala E, Seppala OP, Kotilainen P, Pettila V, Rasi V. Protein C in the treatment of coagulopathy in meningococcal disease. Crit Care Med 1998; 26: 965-968.
• 22 Fourrier F, Chopin C, Huart J, Runge I, Caron C, Goudemand J. Double blind placebo-controlled trial of antithrombin III concentrates in septic shock with disseminated intravascular coagulation. Chest 1993; 104: 882-888.
• 23 Kessler CM, Tang ZC, Jacobs HM, Szymanski LM. The suprapharmacologic dosing of antithrombin concentrate for Staphylococcus aureus-induced disseminated intravascular coagulation in guinea pigs: substantial reduction in mortality and morbidity. Blood 1997; 89: 4393-4401.
• 24 Malik AE, Horgan MJ. Mechanisms of thrombin-induced lung vascular injury and edema. Am Rev Respir Dis 1987; 136: 467-470.
• 25 Fijnvandraat K, Derkx B, Peters M, Bijlmer R, Sturk A, Prins MH, van Deventer SJH, ten Cate JW. Coagulation activation and tissue necrosis in meningococcal septic shock: severely reduced protein C levels predict a high mortality. Thromb Haemost 1995; 73: 15-20.
• 26 Kobayashi M, Wada H, Wakita Y, Shimura M, Nakase T, Hiyoyama K, Nagaya S, Minami N, Nakano T, Shiku H. Decreased plasma tissue factor pathway inhibitor levels in patients with thrombotic thrombocytopenic purpura. Thromb Haemost 1995; 73: 10-14.
• 27 van der Poll T, ten Cate H, van Deventer SJH, ten Cate JW. Pathogenesis of the altered vascular hemostasis properties in sepsis: in vivo studies. In: Van Hinsbergh VWM. ed Vascular Control of Hemostasis. Harwood Academic Publishers; New York: 1996: 281-297.
• 28 von dem Borne PA, Meijers JC, Bouma BN. Feedback activation of factor XI by thrombin in plasma results in additional formation of thrombin that protects fibrin clots from fibrinolysis. Blood 1995; 86: 3035-3042.
• 29 Comp PC, Jacocks RM, Ferrell GL, Esmon CT. Activation of protein C in vivo. J Clin Invest 1982; 70: 127-134.
• 30 Pixley RA, de la Cadena R, Page JD, Kaufman N, Wyshock EG, Chang A, Taylor Jr FB, Colman RW. The contact system contributes to hypotension but not disseminated intravascular coagulation in lethal bacteremia. J Clin Invest 1993; 91: 61-68.
• 31 Kaufman N, Page JD, Pixley RA, Schein R, Schmaier AH, Colman RW. A2 macroglobulin.kallikrein complexes detect contact system activation in hereditary angioedema and human sepsis. Blood 1991; 77: 2660-2667.
• 32 Wuillemin WA, Fijnvandraat K, Derkx BHF, Peters M, Vreede W, ten Cate H, Hack CE. Activation of the intrinsic pathway of coagulation in children with meningococcal septic shock. Thromb Haemost 1996; 74: 1436-1441.
• 33 Minnema MC, Pajkrt D, Wuillemin WA, Roem D, Bleeker WK, Levi M, van Deventer SJH, Hack CE, ten Cate H. Activation of clotting factor XI without detectable contact activation in experimental human endotoxemia. Blood 1998; 92: 3294-3301.
• 34 Biemond BJ, Levi M, ten Cate H, van der Poll T, Buller HR, Hack CE, ten Cate JW. Plasminogen activator and plasminogen activator inhibitor 1 release during experimental endotoxemia in chimpanzees: effects of interventions in the cytokine and coagulation cascades. Clin Sci (Colch) 1995; 88: 587-594.
• 35 Minnema MC, Friederich PW, Levi M, von dem Borne PAK, Mosnier LO, Meijers JCM, Biemond BJ, Hack CE, Bouma BN, ten Cate H. Enhancement of rabbit jugular vein thrombolysis by neutralization of factor XI. J Clin Invest 1998; 101: 10-14.
• 36 Johnson K, Aarden L, Choi Y, de Groot E, Creasey A. The proinflammatory cytokine response to coagulation and endotoxin in whole blood. Blood 1996; 87: 5051-5060.
• 37 ten Cate H, Brandjes DP, Wolters HJ, van Deventer SJH. Disseminated intravascular coagulation: pathophysiology, diagnosis, and treatment. New Horiz 1993; 1: 312-323.