Anticoagulant Factor Concentrates in Disseminated Intravascular Coagulation: Rationale for Use and Clinical Experience

Evert de Jonge; Tom van der Poll; Jozef Kesecioglu; Marcel Levi

doi:10.1055/s-2001-18871

Seminars in Thrombosis and Hemostasis, Table of Contents

Semin Thromb Hemost 2001; 27(6): 667-674
DOI: 10.1055/s-2001-18871

Anticoagulant Factor Concentrates in Disseminated Intravascular Coagulation: Rationale for Use and Clinical Experience

Evert de Jonge¹ , Tom van der Poll² , Jozef Kesecioglu¹ , Marcel Levi³

¹Department of Intensive Care, Academic Medical Center, Amsterdam, The Netherlands
²Laboratory of Experimental Internal Medicine, Academic Medical Center, Amsterdam, The Netherlands
³Department of Internal Medicine, Academic Medical Center, Amsterdam, The Netherlands

Abstract

ABSTRACT

Natural inhibitors of coagulation, in other words, antithrombin (AT), the protein C system, and tissue factor pathway inhibitor (TFPI), play an important role in controlling the activation of coagulation during disseminated intravascular coagulation (DIC). Furthermore, they may not only influence coagulation but also attenuate inflammatory responses during sepsis. Low circulating levels of AT and protein C have been associated with poor outcome. Replacement therapy with AT, activated protein C (APC), and TFPI has been shown to attenuate thrombin generation and to reduce mortality in experimental sepsis models. Experience with AT and APC in patients is promising. Data from large phase III trials of AT and APC as treatment of patients with severe sepsis will soon be available. Recombinant TFPI is currently in phase II clinical trials for severe sepsis.

KEYWORD

Sepsis - antithrombin - protein C - tissue factor pathway inhibitor - TFPI - inflammation

Full Text

References

REFERENCES

1 Fourrier F, Chopin C, Goudemand J. Septic shock, multiple organ failure, and disseminated intravascular coagulation. Compared patterns of antithrombin III, protein C, and protein S deficiencies. Chest . 1992; 101 816-823
2 de Jonge E, Levi M, Stoutenbeek C P, van Deventer J S. Current drug treatment strategies for disseminated intravascular coagulation. Drugs . 1998; 55 767 Review-777 Review
3 Levi M, ten Cate H. Disseminated intravascular coagulation. N Engl J Med . 1999; 341 586-592
4 Ryan J, Brett J, Tijburg P. Tumor necrosis factor-induced endothelial tissue factor is associated with subendothelial matrix vesicles but is not expressed on the apical surface. Blood . 1992; 80 966-974
5 Key N S, Slungaard A, Dandelet L. Whole blood tissue factor procoagulant activity is elevated in patients with sickle cell disease. Blood . 1998; 91 4216-4223
6 Wilcox J N, Smith K M, Schwartz S M, Gordon D. Localization of tissue factor in the normal vessel wall and in the atherosclerotic plaque. Proc Natl Acad Sci USA . 1989; 86 2839-2843
7 Østerud B, Flaegstad T. Increased tissue thromboplastin activity in monocytes of patients with meningococcal infection: related to an unfavourable prognosis. Thromb Haemost . 1983; 49 5-7
8 Rivers R P, Hathaway W E, Weston W L. The endotoxin-induced coagulant activity of human monocytes. Br J Haematol . 1975; 30 311-316
9 Moldow C F, Bach R R, Staskus K, Rick P D. Induction of endothelial tissue factor by endotoxin and its precursors. Thromb Haemost . 1993; 70 702-706
10 Francis J L, Biggerstaff J, Amirkhosravi A. Hemostasis and malignancy. Semin Thromb Hemost . 1998; 24 93-109
11 Lawson C A, Yan S D, Yan S F. Monocytes and tissue factor promote thrombosis in a murine model of oxygen deprivation. J Clin Invest . 1997; 99 1729-1738
12 Bach R R, Moldow C F. Mechanism of tissue factor activation on HL-60 cells. Blood . 1997; 89 3270-3276
13 Levi M, ten Cate H, Bauer K A. Inhibition of endotoxin-induced activation of coagulation and fibrinolysis by pentoxifylline or by a monoclonal anti-tissue factor antibody in chimpanzees. J Clin Invest . 1994; 93 114-120
14 Nuijens J H, Huijbregts C C, Eerenberg-Belmer A J. Quantification of plasma factor XIIa-Cl(-)-inhibitor and kallikrein-Cl(-)-inhibitor complexes in sepsis. Blood . 1988; 72 1841-1848
15 Taylor F BJ, Chang A, Ruf W. Lethal E. coli septic shock is prevented by blocking tissue factor with monoclonal antibody. Circulatory Shock . 1991; 33 127-134
16 Taylor F B, Chang A C, Peer G. Active site inhibited factor VIIa (DEGR VIIa) attenuates the coagulant and interleukin-6 and -8, but not tumor necrosis factor, responses of the baboon to LD100 Escherichia coli Blood . 1998; 91 1609-1615
17 Creasey A A, Chang A C, Feigen L. Tissue factor pathway inhibitor reduces mortality from Escherichia coli septic shock. J Clin Invest . 1993; 91 2850-2856
18 Rao L V, Nordfang O, Hoang A D, Pendurthi U R. Mechanism of antithrombin III inhibition of factor VIIa/tissue factor activity on cell surfaces. Comparison with tissue factor pathway inhibitor/factor Xa-induced inhibition of factor VIIa/tissue factor activity. Blood . 1995; 85 121-129
19 Mammen E F. Antithrombin: Its physiological importance and role in DIC. Semin Thromb Hemost . 1998; 24 19-25
20 Opal S M, Thijs L G. New potential therapeutic modalities: Antithrombin III. Sepsis . 1999; 3 153-159
21 Mammen E F. Clinical relevance of antithrombin deficiencies. Semin Hematol . 1995; 32 2-6
22 Büller H R, ten Cate W J. Acquired antithrombin III deficiency: Laboratory diagnosis, incidence, clinical implications, and treatment with antithrombin III concentrate. Am J Med . 1989; 87 44S Review-48S Review
23 Seitz R, Wolf M, Egbring R, Havemann K. The disturbance of hemostasis in septic shock: Role of neutrophil elastase and thrombin, effects of antithrombin III and plasma substitution. Eur J Haematol . 1989; 43 22-28
24 Mann L TJ, Jensenius J C, Simonsen M, Abildgaard U. Antithrombin 3. Protection against death after injection of thromboplastin. Science . 1969; 166 517-518
25 Taylor F BJ, Emerson T EJ, Jordan R, Chang A K, Blick, K E. Antithrombin-III prevents the lethal effects of Escherichia coli infusion in baboons. Circulatory Shock . 1988; 26 227-235
26 Minnema M C, Chang A C, Jansen P M. Recombinant human antithrombin III improves survival and attenuates inflammatory responses in baboons lethally challenged with Escherichia coli Blood . 2000; 95 1117-1123
27 Kessler C M, Tang Z, Jacobs H M, Szymanski L M. 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
28 Dickneite G. Antithrombin III in animal models of sepsis and organ failure. Semin Thromb Hemost . 1998; 24 61-69
29 Giebler R, Schmidt U, Koch S, Peters J, Scherer R. Combined antithrombin III and C1-esterase inhibitor treatment decreases intravascular fibrin deposition and attenuates cardiorespiratory impairment in rabbits exposed to Escherichia coli endotoxin. Crit Care Med . 1999; 27 597-604
30 Blauhut B, Kramar H, Vinazzer H, Bergmann H. Substitution of antithrombin III in shock and DIC: A randomized study. Thromb Res . 1985; 39 81-89
31 Vinazzer H. Therapeutic use of antithrombin III in shock and disseminated intravascular coagulation. Semin Thromb Hemost . 1989; 15 347-352
32 Fourrier F, Chopin C, Huart J J. Double-blind, placebo-controlled trial of antithrombin III concentrates in septic shock with disseminated intravascular coagulation. Chest . 1993; 104 882-888
33 Baudo F, Caimi T M, de Cataldo F. Antithrombin III (ATIII) replacement therapy in patients with sepsis and/or postsurgical complications: A controlled double-blind, randomized, multicenter study. Intensive Care Med . 1998; 24 336-342
34 Eisele B, Lamy M, Thijs L G. Antithrombin III in patients with severe sepsis. A randomized, placebo-controlled, double-blind multicenter trial plus a meta-analysis on all randomized, placebo-controlled, double-blind trials with antithrombin III in severe sepsis. Intensive Care Med . 1998; 24 663-672
35 Inthorn D, Hoffmann J N, Hartl W H, Muhlbayer D, Jochum M. Effect of antithrombin III supplementation on inflammatory response in patients with severe sepsis. Shock . 1998; 10 90-96
36 Inthorn D, Hoffmann J N, Hartl W H, Muhlbayer D, Jochum M. Antithrombin III supplementation in severe sepsis: Beneficial effects on organ dysfunction. Shock . 1997; 8 328-334
37 Levi M, de Jonge E, van der Poll T, ten Cate H. Disseminated intravascular coagulation. Thromb Haemost . 1999; 82 695-705
38 Maki M, Terao T, Ikenoue T. Clinical evaluation of antithrombin III concentrate (BI 6.013) for disseminated intravascular coagulation in obstetrics. Well-controlled multicenter trial. Gynecol Obstet Invest . 1987; 23 230-240
39 Ilias W, List W, Decruyenaere J. Antithrombin III in patients with severe sepsis: A pharmacokinetic study. Intensive Care Med . 2000; 26 704-715
40 Riess H. Antithrombin in severe sepsis-``new'' indication of an ``old'' drug?. Intensive Care Med . 2000; 26 657 (Editorial)-659 (Editorial)
41 Dreyfus M, Magny J F, Bridey F. Treatment of homozygous protein C deficiency and neonatal purpura fulminans with a purified protein C concentrate. N Engl J Med . 1991; 325 1565-1568
42 Esmon C T, Xu J, Gu J M. Endothelial protein C receptor. Thromb Haemost . 1999; 82 251-258
43 Fijnvandraat K, Derkx B, Peters M. Coagulation activation and tissue necrosis in meningococcal septic shock: Severely reduced protein C levels predict a high mortality. Thromb Haemost . 1995; 73 15-20
44 Taylor Jr B F. Protein S, C4b binding protein, and the hypercoagulable state. J Lab Clin Med . 1992; 119 596 Editorial and comment-597 Editorial and comment
45 Nawroth P P, Handley D A, Esmon C T, Stern D M. Interleukin 1 induces endothelial cell procoagulant while suppressing cell-surface anticoagulant activity. Proc Natl Acad Sci USA . 1986; 83 3460-3464
46 Nawroth P P, Stern D M. Modulation of endothelial cell hemostatic properties by tumor necrosis factor. J Exp Med . 1986; 163 740-745
47 Fukudome K, Esmon C T. Identification, cloning, and regulation of a novel endothelial cell protein C/activated protein C receptor. J Biol Chem . 1994; 269 26486-26491
48 Boehme M W, Deng Y, Raeth U. Release of thrombomodulin from endothelial cells by concerted action of TNF-alpha and neutrophils: In vivo and in vitro studies. Immunology . 1996; 87 134-140
49 Slungaard A, Vercellotti G M, Tran T, Gleich G J, Key N S. Eosinophil cationic granule proteins impair thrombomodulin function. A potential mechanism for thromboembolism in hypereosinophilic heart disease. J Clin Invest . 1993; 91 1721-1730
50 Hesselvik J F, Malm J, Dahlbäck B, Blombäck M. Protein C, protein S and C4b-binding protein in severe infection and septic shock. Thromb Haemost . 1991; 65 126-129
51 Takahashi Y, Hosaka Y, Imada K. Human urinary soluble thrombomodulin (MR-33) improves disseminated intravascular coagulation without affecting bleeding time in rats: Comparison with low molecular weight heparin. Thromb Haemost . 1997; 77 789-795
52 Uchiba M, Okajima K, Murakami K. Effect of human urinary thrombomodulin on endotoxin-induced intravascular coagulation and pulmonary vascular injury in rats. Am J Hematol . 1997; 54 118-123
53 Mohri M, Gonda Y, Oka M. The antithrombotic effects of recombinant human soluble thrombomodulin (rhsTM) on tissue factor-induced disseminated intravascular coagulation in crab-eating monkeys (Macaca fascicularis). Blood Coagul Fibrinolysis . 1997; 8 274-283
54 Uchiba M, Okajima K, Murakami K. rhs-TM prevents ET-induced increase in pulmonary vascular permeability through protein C activation. Am J Physiol . 1997; 273 L889-L894
55 Nakashima M, Uematsu T, Umemura K, Maruyama I, Tsuruta K. A novel recombinant soluble human thrombomodulin, ART-123, activates the protein C pathway in healthy male volunteers. J Clin Pharmacol . 1998; 38 540-544
56 Nakashima M, Kanamaru M, Umemura K, Tsuruta K. Pharmacokinetics and safety of a novel recombinant soluble human thrombomodulin, ART-123, in healthy male volunteers. J Clin Pharmacol . 1998; 38 40-44
57 Maruyama I. Recombinant thrombomodulin and activated protein C in the treatment of disseminated intravascular coagulation. Thromb Haemost . 1999; 82 718-721
58 Taylor F BJ, Chang A, Esmon C T. Protein C prevents the coagulopathic and lethal effects of Escherichia coli infusion in the baboon. J Clin Invest . 1987; 79 918-925
59 Ettingshausen C E, Veldmann A, Beeg T. Replacement therapy with protein C concentrate in infants and adolescents with meningococcal sepsis and purpura fulminans. Semin Thromb Hemost . 1999; 25 537-541
60 Rintala E, Kauppila M, Seppala O P. Protein C substitution in sepsis-associated purpura fulminans. Crit Care Med . 2000; 28 2373-2378
61 Rivard G E, David M, Farrell C, Schwarz H P. Treatment of purpura fulminans in meningococcemia with protein C concentrate. J Pediatr . 1995; 126 646-652
62 Smith O P, White B, Vaughan D. Use of protein-C concentrate, heparin, and haemodiafiltration in meningococcus-induced purpura fulminans. Lancet . 1997; 350 1590-1593
63 Gerson W T, Dickerman J D, Bovill E G, Golden E. Severe acquired protein C deficiency in purpura fulminans associated with disseminated intravascular coagulation: Treatment with protein C concentrate. Pediatrics . 1993; 91 418-422
64 Bernard G R, Hartman D L, Helterbrand J D, Fisher C J. Recombinant human activated protein C (rhAPC) produces a trend toward improvement in morbidity and 28 day survival in patients with severe sepsis. Crit Care Med . 1998; 27 S4
65 Bernhard G R, Vincent J-L, Laterre P-F. Efficacy and safety of recombinanat human activated protein C for severe sepsis. N Engl J Med . 2001; 344 699-709
66 Taylor F, Chang A, Ferrell G. C4b-binding protein exacerbates the host response to Escherichia coli Blood . 1991; 78 357-363
67 Creasey A A. New potential therapeutic modalities: Tissue factor pathway inhibitor. Sepsis . 1999; 3 173-182
68 Carr C, Bild G S, Chang A C. Recombinant E. coli- derived tissue factor pathway inhibitor reduces coagulopathic and lethal effects in the baboon gram-negative model of septic shock. Circulatory Shock . 1994; 44 126-137
69 de Jonge E, Dekkers P E, Creasey A A. Tissue factor pathway inhibitor dose-dependently inhibits coagulation activation without influencing the fibrinolytic and cytokine response during human endotoxemia. Blood . 2000; 95 1124-1129
70 Girard T J, Warren L A, Novotny W F. Functional significance of the Kunitz-type inhibitory domains of lipoprotein-associated coagulation inhibitor. Nature . 1989; 338 518-520
71 Novotny W F, Girard T J, Miletich J P, Broze Jr J G. Purification and characterization of the lipoprotein-associated coagulation inhibitor from human plasma. J Biol Chem . 1989; 264 18832-18837
72 Novotny W F, Girard T J, Miletich J P, Broze Jr J G. Platelets secrete a coagulation inhibitor functionally and antigenically similar to the lipoprotein associated coagulation inhibitor. Blood . 1988; 72 2020-2025
73 Ameri A, Kuppuswamy M N, Basu S, Bajaj S P. Expression of tissue factor pathway inhibitor by cultured endothelial cells in response to inflammatory mediators. Blood . 1992; 79 3219-3226
74 Lindahl A K. Tissue factor pathway inhibitor: From unknown coagulation inhibitor to major antithrombotic principle [see comments]. Cardiovascular Research . 1997; 33 286 Review-291 Review
75 Takahashi H, Sato N, Shibata A. Plasma tissue factor pathway inhibitor in disseminated intravascular coagulation: Comparison of its behavior with plasma tissue factor. Thromb Res . 1995; 80 339-348
76 Novotny W F, Brown S G, Miletich J P, Rader D J, Broze Jr J G. Plasma antigen levels of the lipoprotein-associated coagulation inhibitor in patient samples. Blood . 1991; 78 387-393
77 Sabharwal A K, Bajaj S P, Ameri A. Tissue factor pathway inhibitor and von Willebrand factor antigen levels in adult respiratory distress syndrome and in a primate model of sepsis [published erratum appears in Am J Respir Crit Care Med 1995;151:following 2118]. Am J Respir Crit Care Med . 1995; 151 758-767
78 Day K C, Hoffman L C, Palmier M O. Recombinant lipoprotein-associated coagulation inhibitor inhibits tissue thromboplastin-induced intravascular coagulation in the rabbit. Blood . 1990; 76 1538-1545
79 Bregengard C, Nordfang O, Wildgoose P. The effect of two-domain tissue factor pathway inhibitor on endotoxin-induced disseminated intravascular coagulation in rabbits. Blood Coagul Fibrinolysis . 1993; 4 699-706
80 Randolph M M, White G L, Kosanke S D. Attenuation of tissue thrombosis and hemorrhage by ala-TFPI does not account for its protection against E. coli-a comparative study of treated and untreated non-surviving baboons challenged with LD100 E. coli Thromb Haemost . 1998; 79 1048-1053
81 Camerota A J, Creasey A A, Patla V, Larkin V A, Fink M P. Delayed treatment with recombinant human tissue factor pathway inhibitor improves survival in rabbits with gram-negative peritonitis. J Infect Dis . 1998; 177 668-676
82 Kemme M J, Burggraaf J, Schoemaker R C. The influence of reduced liver blood flow on the pharmacokinetics and pharmacodynamics of recombinant tissue factor pathway inhibitor. Clin Pharmacol Ther . 2000; 67 504-511
83 Esmon C T. Introduction: Are natural anticoagulants candidates for modulating the inflammatory response to endotoxin?. Blood . 2000; 95 1113-1116
84 Coalson J J, Benjamin B, Archer L T. Prolonged shock in the baboon subjected to infusion of E. coli endotoxin. Circulatory Shock . 1978; 5 423-437
85 Taylor F BJ, Chang A C, Peer G T. DEGR-factor Xa blocks disseminated intravascular coagulation initiated by Escherichia coli without preventing shock or organ damage. Blood . 1991; 78 364-368
86 Cirino G, Cicala C, Bucci M. Factor Xa as an interface between coagulation and inflammation. Molecular mimicry of factor Xa association with effector cell protease receptor-1 induces acute inflammation in vivo. J Clin Invest . 1997; 99 2446-2451
87 Senden N H, Jeunhomme T M, Heemskerk J W. Factor Xa induces cytokine production and expression of adhesion molecules by human umbilical vein endothelial cells. J Immunol . 1998; 161 4318-4324
88 Johnson K, Choi Y, DeGroot E. Potential mechanisms for a proinflammatory vascular cytokine response to coagulation activation. J Immunol . 1998; 160 5130-5135
89 Jones A, Geczy C L. Thrombin and factor Xa enhance the production of interleukin-1. Immunology . 1990; 71 236-241
90 Hoffman M, Cooper S T. Thrombin enhances monocyte secretion of tumor necrosis factor and interleukin-1 beta by two distinct mechanisms. Blood Cells Mol Dis . 1995; 21 156-167
91 Kranzhofer R, Clinton S K, Ishii K. Thrombin potently stimulates cytokine production in human vascular smooth muscle cells but not in mononuclear phagocytes. Circ Res . 1996; 79 286-294
92 Ueno A, Murakami K, Yamanouchi K, Watanabe M, Kondo T. Thrombin stimulates production of interleukin-8 in human umbilical vein endothelial cells. Immunology . 1996; 88 76-81
93 Grandaliano G, Valente A J, Abboud H E. A novel biologic activity of thrombin: Stimulation of monocyte chemotactic protein production. J Exp Med . 1994; 179 1737-1741
94 Colotta F, Sciacca F L, Sironi M. Expression of monocyte chemotactic protein-1 by monocytes and endothelial cells exposed to thrombin. Am J Pathol . 1994; 144 975-985
95 Anrather D, Millan M T, Palmetshofer A. Thrombin activates nuclear factor-kappaB and potentiates endothelial cell activation by TNF. J Immunol . 1997; 159 5620-5628
96 Kahn M L, Nakanishi-Matsui M, Shapiro M J, Ishihara H, Coughlin S R. Protease-activated receptors 1 and 4 mediate activation of human platelets by thrombin. J Clin Invest . 1999; 103 879-887
97 Camerer E, Huang W, Coughlin S R. Tissue factor- and factor X-dependent activation of protease-activated receptor 2 by factor VIIa. Proc Natl Acad Sci USA . 2000; 97 5255-5260
98 Grey S T, Tsuchida A, Hau H. Selective inhibitory effects of the anticoagulant activated protein C on the responses of human mononuclear phagocytes to LPS, IFN-gamma, or phorbol ester. J Immunol . 1994; 153 3664-3672
99 Hancock W W, Grey S T, Hau L. Binding of activated protein C to a specific receptor on human mononuclear phagocytes inhibits intracellular calcium signaling and monocyte-dependent proliferative responses. Transplantation . 1995; 60 1525-1532
100 Grinnell B W, Hermann R B, Yan S B. Human protein C inhibits selectin-mediated cell adhesion: Role of unique fucosylated oligosaccharide. Glycobiology . 1994; 4 221-225
101 Taylor F BJ, Chang A, Hinshaw L B. A model for thrombin protection against endotoxin. Thromb Res . 1984; 36 177-185
102 Comp P C, Jacocks R M, Ferrell G L, Esmon C T. Activation of protein C in vivo. J Clin Invest . 1982; 70 127-134
103 Cunningham M A, Romas P, Hutchinson P, Holdsworth S R, Tipping P G. Tissue factor and factor VIIa receptor/ligand interactions induce proinflammatory effects in macrophages. Blood . 1999; 94 3413-3420
104 Randolph G J, Luther T, Albrecht S, Magdolen V, Muller W A. Role of tissue factor in adhesion of mononuclear phagocytes to and trafficking through endothelium in vitro. Blood . 1998; 92 4167-4177