The role of heparin and allied compounds in the treatment of sepsis

Thrombosis and Haemostasis

Volumn 98, Issue 3, 2007, Pages 579-586

  Cornet, Alexander D ^a   Smit, Ellen G M ^a   Beishuizen, Albertus ^a   Groeneveld, A B Johan ^a  

^a VU UNIVERSITY MEDICAL CENTER   (Netherlands)

Author keywords

aPC; Cytokines; Disseminated intravascular coagulation; Heparin; Host defence; Inflammation; Sepsis; Survival

Indexed keywords

ANTITHROMBIN; DROTRECOGIN; HEPARIN; HEPARIN DERIVATIVE; HIRUDIN; LOW MOLECULAR WEIGHT HEPARIN; PLACEBO; PROTEIN C;

ANTICOAGULATION; ANTIINFLAMMATORY ACTIVITY; BLEEDING; BLOOD CLOTTING; CLINICAL TRIAL; CONTINUOUS INFUSION; DRUG MEGADOSE; DRUG POTENTIATION; HEPARIN INDUCED THROMBOCYTOPENIA; HUMAN; INFLAMMATION; MEDLINE; MENINGOCOCCEMIA; MONOTHERAPY; NONHUMAN; PRIORITY JOURNAL; REVIEW; SEPSIS; SHOCK; THROMBOEMBOLISM; TISSUE OXYGENATION;

ANIMALS; ANTI-INFLAMMATORY AGENTS; ANTICOAGULANTS; BLOOD COAGULATION; DISEASE MODELS, ANIMAL; DISSEMINATED INTRAVASCULAR COAGULATION; HEPARIN; HUMANS; PROTEIN C; RECOMBINANT PROTEINS; SEPSIS; TREATMENT OUTCOME;

EID: 34548703128     PISSN: 03406245     EISSN: None     Source Type: Journal    
DOI: 10.1160/TH07-01-0006     Document Type: Review

References (125)

1. Vervloet MG, Thijs LG, Hack CE. Derangements of coagulation and fibrinolysis in critically ill patients with sepsis and septic shock. Semin Thromb Hemost 1998; 24: 33-44.
2. Opal SM, Esmon CT. Bench to bedside review: functional relationships between coagulation and the innate immune response and their respective roles in the pathogenesis of sepsis. Crit Care 2003; 7: 23-38.
3. Levi M, van der Poll T. Two-way interactions between inflammation and coagulation. Trends Cardiovasc Med 2005; 15: 254-259.
4. Zeerleder S, Hack CE, Wuillemin WA. Disseminated intravascular coagulation in sepsis. Chest 2005; 128: 2864-2875.
5. Colburn P, Kobayashi E, Buonassisi V. Depleted level of heparin sulphate proteoglycan in the extracellular matrix of endothelial cell cultures exposed to endotoxin. J Cell Physiol 1994; 159: 121-130.
6. Hermida J, Montes R, Muñoz MC, et al. Effects of low molecular weight heparin, alone or combined with antithrombin III, on mortality, fibrin deposits and hemostatic parameters in endotoxin-induced disseminated intravascular coagulation in rabbits. Am J Hematol 1999; 60: 6-11.
7. Pernerstorfer T, Hollenstein U, Hansen JB, et al. Heparin blunts endotoxin-induced coagulation activation. Circulation 1999; 100: 2485-2490.
8. Pernerstorfer T, Hollenstein U, Hansen J-B, et al. Lepirudin blunts endotoxin-induced coagulation activation. Blood 2000; 95: 1729-1734.
9. Derhaschnig U, Pernerstorfer T, Knechtelsdorfer M, et al. Evaluation of antiinflammatory and antiadhesive effects of heparins in human endotoxemia. Crit Care Med 2003; 31: 1108-1112.
10. Eriksson M, Larsson A, Saldeen T, et al. Melagatran, a low molecular weight thrombin inhibitor counteracts endotoxin-induced haemodynamic and renal dysfunctions in the pig. Thromb Haemost 1998; 80: 1022-1026.
11. Johnson K, Choi Y, DeGroot E, et al. Potential mechanisms for a proinflammatory vascular cytokine response to coagulation activation. J Immunol 1998; 160: 5130-5135.
12. Pneumatikos I, Groeneveld ABJ. The inflammatory effect of coagulation and the anti-inflammatory effect of anticoagulation in sepsis and shock. Chapter 5. In: Fachuebergreifende Aspekte der Haemostaseologie IV Sepsis und Gerinnung. Springer Verlag, 2001: 35-48.
13. Hollenstein UM, Pernerstorfer T, Homoncik M, et al. Effect of factor X inhibition on coagulation activation and cytokine induction in human systemic inflammation. J Infect Dis 2002; 186: 1270-1276.
14. 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.
15. Warren BL, Eid A, Singer P, et al. High dose antithrombin III in severe sepsis. A randomized controlled trial. J Am Med Assoc 2001; 286: 1869-1878.
16. Hoffmann JN, Wiedermann CJ, Juers M, et al. Benefit/risk profile of high-dose antithrombin in patients with severe sepsis treated with and without concomitant heparin. Thromb Haemost 2006; 95: 850-856.
17. Wiedermann CJ, Hoffmann JN, Juers M, et al. High-dose antithrombin III in the treatment of severe sepsis in patients with a high risk of death: efficacy and safety. Crit Care Med 2006; 34: 285-292.
18. Abraham E, Reinhart K, Opal SM, et al. Efficacy and safety of tifacogin (recombinant rissue factor pathway inhibitor) in severe sepsis. A randomized controlled trial. J Am Med Assoc 2003; 290: 238-247.
19. Minneci PC, Deans KJ, Cui X, et al. Antithrombotic therapies for sepsis: a need for more studies. Crit Care Med 2006; 34: 538-541.
20. Tyrrell DJ, Kilfeather S, Page CP. Therapeutic uses of heparin beyond its traditional role as an anticoagulant. Trends Physiol Sci 1995; 16: 198-204.
21. Hirsh J, Warkentin TE, Shaughnessy SG, et al. Heparin and low-molecular-weight-heparin mechanisms of action, pharmacokinetics, dosing, monitoring, efficacy and safety. Chest 2001; 119: 64-94.
22. Taylor KR, Gallo RL. Glycosaminoglycans and their proteoglycans: host-associated molecular patterns for initiation and modulation of inflammation. FASEB J 2006; 20: 9-22.
23. Mulloy B, Gray E, Barrowcliffe TW. Characterization of unfractionated heparin: comparison of materials from the last 50 years. Thromb Haemost 2000; 84: 1052-1056.
24. Baglin T, Barrowcliffe TW, Cohen A, Greaves M. Guidelines on the use and monitoring of heparin. Br J Haematol 2006; 133: 19-34.
25. Lindahl U, Bäckström G, Höök M, et al. Structure of the antithrombin-binding site in heparin. Proc Nat Acad Sci 1979; 76: 2198-3204.
26. Alban S. From heparins to factor Xa inhibitors and beyond. Eur J Clin Invest 2005; 35 (Suppl I): 12-20.
27. Beguin S, Lindhout T, Hemker HC. The mode of action of heparin in plasma. Thromb Haemost 1988; 60: 457-462.
28. Brodin E, Svensson B, Paulssen RH, et al. Intravascular release and urinary excretion of tissue factor pathway inhibitor during heparin treatment. J Lab Clin Med 2004; 144: 247-253.
29. Cadroy Y, Gaspin D, Dupoy D, et al. Heparin reverses the procoagulant properties of stimulated endothelial cells. Thromb Haemost 1996; 75: 190-195.
30. Corrigan JJ, Jordan CM. Heparin therapy in septicemia with disseminated intravascular coagulation. N Engl J Med 1970; 283: 778-782.
31. Derhaschnig U, Reiter R, Baumgartner M, et al. Recombinant human activated protein C (rhAPC; drotecogin alfa [activated]) has minimal effect on markers of coagulation, fibrinolysis, and inflammation in acute human endotoxemia. Blood 2003; 102: 2093-2098.
32. Hoffmann JN, Vollmar B, Laschke MW, et al. Adverse effects of heparin on antithrombin action during endotoxemia: microhemodynamic and cellular mechanisms. Thromb Haemost 2002; 88: 242-252.
33. Oelschläger C, Römisch J, Staubitz A, et al. Antithrombin III inhibits nuclear factor ?B activation in human monocytes and vascular endothelial cells. Blood 2002; 99: 4015-4020.
34. Opal SM, Kessler CM, Roemisch J, et al. Antithrombin, heparin, and heparan sulfate. Crit Care Med 2002; 30: S325-S331.
35. Wiedermann CJ. Clinical review: molecular mechanisms underlying the role of antithrombin in sepsis. Crit Care 2006; 10: 209-218.
36. Taylor FB Jr, Chang A, Hinshaw LB, et al. A model for thrombin protection against endotoxin. Thromb Res 1984; 36: 177-185.
37. Kirschenbaum LA, Lopez WC, Ohrum P, et al. Effect of recombinant activated protein C and low-dose heparin on neutrophil-endothelial cell interactions in septic shock. Crit Care Med 2006; 34: 2207-2212.
38. Friedrich U, Blom AM, Dahlbäck B, et al. Structural and energetic characteristics of the heparin-binding site in antithrombotic protein C. J Biol Chem 2001; 276: 24122-24128.
39. Nicolaes GAF, Srensen KW, Friedrich U, et al. Altered inactivation pathway of factor Va by activated protein C in the presence of heparin. Eur J Biochem 2004; 271: 2724-2736.
40. Iba T, Kidokoro A, Fukunaga M, et al. Antithrombin ameliorates endotoxin-induced organ dysfunction more efficiently when combined with danaparoid sodium than with unfractionated heparin. Intensive Care Med 2005; 31: 1101-1108.
41. Morrison AM, Wang P, Chaudry IH. A novel non-anticoagulant heparin prevents vascular endothelial cell dysfunction during hyperdynamic sepsis. Shock 1996; 6: 46-51.
42. Wang P, Ba ZF, Creich SS, et al. Effects of nonanticoagulant heparin on cardiovascular and hepatocellular function after hemorrhagic shock. Am J Physiol 1996; 270: H1294-H1302.
43. Lever R, Hoult JRS, Page CP. The effects of heparin and related molecules upon the adhesion of human polymorphonuclear leukocytes to vascular endothelium in vitro. Br J Pharmacol 2000; 129: 533-540.
44. Harada N, Okajima K, Uchiba M. Dalteparin, a low molecular weight heparin, attenuates inflammatory responses and reduces ischemia-reperfusion-induced liver injury in rats. Crit Care Med 2006; 34: 1883-1891.
45. Thourani VH, Brar SS, Kennedy TP, et al. Nonanticoagulant heparin inhibits NF-κB activation and attenuates myocardial reperfusion injury. Am J Physiol Heart Circ Physiol 2000; 48: H2084-H2093.
46. Cervera A, Justicia C, Reverter JC, et al. Steady plasma concentration of unfractionated heparin reduces infarct volume an prevents inflammatory damage after transient focal cerebral ischemia in the rat. J Neurosci Res 2004; 77: 565-572.
47. Baldus S, Rudoph V, Roiss M, et al. Heparins increase endothelial nitric oxide bioavailability by liberating vessel-immobilized myeloperoxidase. Circulation 2006; 13: 1871-1878.
48. Myrvang-Hogasen AK, Abrahamsen TG. Heparin suppresses lipopolysaccharide induced monocyte production of several cytokines, but simultaneously stimulates C3 production. Thromb Res 1995; 80: 179-184.
49. Engstad CS, Gutteberg TJ, Osterud B. Modulation of blood cell activation by four commonly used anticoagulants. Thromb Haemost 1997; 77: 690-696.
50. Attanasio M, Gori AM, Giusti B, et al. Cytokine gene expression in human LPS- and IFNgamma stimulated mononuclear cells is inhibited by heparin. Thromb Haemost 1998; 79: 959-962.
51. Gori AM, Attanasio M, Gazzini A, et al. Cytokine gene expression and production by human LPS-stimulated mononuclear cells are inhibited by sulphated heparin-like semi-synthetic derivatives. J Thromb Haemost 2004; 2: 1657-1662.
52. Hochart H, Jenkins PV, Smith OP, White B. Low molecular weight and unfractionated heparin induce a downregulation of inflammation: decreased levels of proinflammatory cytokines and nuclear factor-?B in LPS-stimulated human monocytes. Br J Haematol 2006; 133: 62-67.
53. Matzner Y, Marx G, Drexler R, et al. The inhibitory effect of heparin and related glycosaminoglycans on neutrophil chemotaxis. Thromb Haemost 1984; 52: 134-137.
54. Freischlag JA, Colburn MD, Quiñones-Baldrich WJ, et al. Alteration of neutrophil (PMN) function by heparin, dexamethasone, and enalapril. J Surg Res 1992; 52: 523-529.
55. Moore FD, Warner KG, Assousa S, et al. The effects of complement activation during cardiopulmonary bypass, attenuation by hypothermia, heparin and hemodilution. Ann Surg 1988; 208: 95-103.
56. Weiler JM, Edens RE, Linhardt RJ, et al. Heparin and modified heparin inhibit complement activation in vivo. J Immunol 1992; 148: 3210-3215.
57. Wuillemin WA, Eldering E, Citarella F, et al. Modulation of contact system proteases by glycosaminoglycans. J Biol Chem 1996; 271: 12913-12918.
58. Wuillemin WA, te Velthuis H, Lubbers YTP, et al. Potentiation of C1 inhibitors by glycosaminoglycans. J Immunol 1997; 159: 1953-1960.
59. Webb LMC, Ehrengruber MU, Clark-Lewis I, et al. Binding to heparan sulfate or heparin enhances neutrophil responses to interleukin 8. Proc Natl Acad Sci USA 1993; 90: 7158-7162.
60. Wang L, Fuster M, Sriramarao P, et al. Endothelial heparan sulfate deficiency impairs L-selectin and chemokine-mediated neutrophil trafficking during inflammatory responses. Nat Immunol 2005; 6: 902-910.
61. Taylor KR, Gallo RL. Glycosaminoglycans and their proteoglycans: host-associated molecular patterns for initiation and modulation of inflammation. FASEB J 2006; 20: 9-22.
62. Gautam N, Olofsson AM, Herwald H, et al. Heparin-binding protein (HBP/ CAP37): A missing link in neutrophil-evoked alteration of vascular permeability. Nat Med 2001; 7: 1123-1127.
63. Bannon PG, Kim M-J, Dean RT, et al. Augmentation by vascular endothelial barrier function by heparin and low molecular weight heparin. Thromb Haemost 1995; 73: 706-712.
64. Leculier C, Benzerara O, Couprie N, et al. Specific binding between human neutrophils and heparin. Br J Haematol 1992; 81: 81-85.
65. Nelson RM, Cecconi O, Roberts WG, et al. Heparin oligosaccharides bind L- and P-Selectin and inhibit acute inflammation. Blood 1993; 82: 3253-3258.
66. Wang L, Brown JR, Varki A, et al. Heparin's anti-inflammatory effects require glucosamine 6-O-sulfation and are mediated by blockade of L- and P-selectins. J Clin Invest 2002; 110: 127-136.
67. Wang L, Fuster M, Sriramarao P, et al. Endothelial heparan sulfate deficiency impairs L-selectin and chemokine-mediated neutrophil trafficking during inflammatory responses. Nat Immunol 2005; 6: 902-910.
68. El Habbal M, Smith L, Elliott MJ, et al. Effect of heparin anticoagulation on neutrophil adhesion molecules and release of IL-8: C3 is not essential. Cardiovasc Res 1995; 30: 676-681.
69. Koenig A, Norgard-Sumnicht K, Linhardt R, et al. Differential interactions of heparin and heparan sulfate glycosaminooglycans with the selectins. J Clin Invest 1998; 101: 877-889
70. Miller SJ, Hoggatt AM, Faulk WP. Heparin regulates ICAM-1 expression in human endothelial cells: an example of non-cytokine-mediated endothelial activation. Thromb Haemost 1998; 80: 481-487.
71. Peter K, Schwarz M, Conradt C, Nordt T, Moser M, Kübler W, Bode C. Heparin inhibits ligand binding to the leukocyte integrin Mac-1 (CD11b/ CD18). Circulation 1999; 100: 1533-1539.
72. Bazzoni G, Nuñez AB, Mascellani G, et al. Effect of heparin, dermatan sulfate, and related oligo-derivatives on human polymorphonuclear leukocyte functions. J Lab Clin Med 1993; 121: 268-275.
73. Léculier C, Couprie N, Adeleine P et al. The effects of high molecular weight- and low molecular weight-heparins on superoxide ion production and degranulation by human polymorphonuclear leukocytes. Thromb Res 1993; 69: 519-531.
74. Sissi C, Lucatello L, Naggi A, et al. Interactions of low-molecular-weight semi-synthetic sulfated heparins with human leukocyte elastase and human Cathepsin G. Biochem Pharmacol 2006; 71: 287-293.
75. Spencer JL, Stone PJ, Nugent MA. New insights into the inhibition of human neutrophil elastase by heparin. Biochem 2006; 45: 9104-9120.
76. Steinberg BM, Grossi EA, Schwartz DS, et al. Heparin bonding of bypass circuits reduces cytokine release during cardiopulmonary bypass. Ann Thorac Surg 1995; 60: 525-529.
77. Yamada H, Kudo I, Hirose Y, et al. Heparin coated ciruits reduce the formation of TNF alpha during cardiopulmonary bypass. Acta Anaesthesiol Scand 1996; 40: 311-317.
78. Lappegård KT, Fung M, Bergseth G, et al. Artificial surface-induced cytokine synthesis: effect on heparin coating and complement inhibition. Ann Thorac Surg 2004; 78: 38-45.
79. Plotz FB, van Oeveren W, Hultquist KA, et al. A heparin-coated circuit reduces complement activation and the release of leukocyte inflammatory mediators during extracorporeal circulation in a rabbit. Artif Organs 1992; 16: 366-370.
80. Jansen PGM, te Velthuis H, Huybregts RAJM, et al. Reduced complement activation and improved post-operative performance after cardiopulmonary bypass with heparin-coated circuits. J Thorac Cardovasc Surg 1995; 110: 829-834.
81. Hgevold HE, Moen O, Fosse E, et al. Effects of heparin coating on the expression of CD11b, CD11c and CD26L by leukocytes in extracorporeal circulation in vitro. Perfusion 1997; 12: 9-20.
82. Kopp R, Mottaghy K, Kirschfink M. Mechanism of complement activation during extracorporeal blood-biomaterial interaction: effects of heparin coated and uncoated surfaces. ASAIO J 2002; 48: 598-605.
83. De Vroege R, Huybregts R, Van Oeveren W, et al. The impact of heparin-coated circuits on haemodynamics during and after cardiopulmonary bypass. Artif Org 2005; 29: 490-497.
84. Mangoush O, Purkayastha S, Haj-Yahia S, et al. Heparin-bonded circuits versus nonheparin-bonded circuits: an evaluation of their effect on clinical outcomes. Eur J Cardiothorac Surg 2007; In press.
85. Garred P, Mollnes TE. Immobilized heparin inhibits the increase in leukocyte surface expression of adhesion molecules. Artif Organs 1997; 21: 293-299.
86. Upchurch GR, Welch GN, Freedman JE, et al. High-dose heparin decreases nitric oxide production by cultures bovine endothelial cells. Circulation 1997; 95: 2115-2121.
87. McBride WT, Armstrong MA, McMurray TJ. An investigation of the effects of heparin, low molecular weight heparin, protamine, and fentanyl on the balance of pro- and anti-inflammatory cytokines in in-vitro monocyte cultures. Anaesthesia 1996; 51: 634-640.
88. Heinzelmann M, Miller M, Platz A, et al. Heparin and enoxaparin enhance endotoxin-induced tumor necrosis factor-a production in human monocytes. Ann Surg 1999; 229: 542-550.
89. Heinzelmann M, Bosshart H. Heparin binds to lipopolysaccharide (LPS)-binding protein, facilitates the transfer of LPS to CD14, and enhances LPS-induced activation of peripheral blood monocytes. J Immunol 2005; 174: 2280-2287.
90. Call DR, Remick DG. Low molecular weight heparin is associated with greater cytokine production in a stimulated whole blood model. Shock 1998; 10: 192-197.
91. Oyanagui Y, Sato S. Suppression of carrageenan paw oedema in rats and mice by heparin-induced ECSODs. Free Rad Res Comms 1991; 12-13: 229-237
92. Tasaki H, Yamashita K, Tsutsui M, et al. Heparin-released extracellular superoxide dismutase is reduced in patients with coronary artery atherosclerosis. Atherosclerosis 2006; 187: 131-138.
93. Seeburger J, Hoffmann J, Wendel HP, et al. Gene expression changes in leukocytes during cardiopulmonary bypass are dependent on circuit coating. Circulation 2005; 112 (Suppl I): 1224-1228.
94. Defraigne JO, Pincemail J, Larbuisson R, et al. Cytokine release and neutrophil activation are not prevented by heparin-coated circuits and aprotinin administration. Ann Thorac Surg 2000; 69: 1084-1091.
95. Filkins JP, Di Luzio NR. Heparin protection in endotoxin shock. Am J Physiol 1968; 214: 1074-1077.
96. Griffin MP, Gore DC, Zwischenberger JB, et al. Does heparin improve survival in experimental porcine gram-negative septic shock? Circ Shock 1990; 31: 343-349.
97. Sun Y, Williams H, Hardaway RM, et al. The effect of heparinization on intra-abdominal infection and acute pulmonary failure. Int Surg 1997; 82: 367-370.
98. Takahashi Y, Hosaka Y, Imada K, et al. Human urinary soluble thrombomodulin (MR-33) improves disseminated intravasuclar coagulation without affecting bleeding time in rats: comparison with low molecular weight heparin. Thromb Haemost 1997; 77: 789-795.
99. Gaskins RA, Dalldorf FG. Experimental meningococcal septicemia. Effect of heparin therapy. Arch Pathol Lab Med 1976; 100: 318-324.
100. Dunn DL, Mach PA, Cerra FB, et al. The role of heparin in guinea pig Gram negative bacterial sepsis. J Surg Res 1983; 34: 479-485.
101. Tanaka T, Tsujinaka T, Kambayashi J, et al. The effect of heparin on multiple organ failure and disseminated intravascular coagulation in a sepsis model. Thromb Res 1990; 60: 321-330.
102. Fujishima Y, Yokota K, Sukamoto, T. The effect of danaparoid sodium (Danaparoid®) on endotoxin-induced experimental disseminated intravascular coagulation in rats. Thromb Res 1998; 91: 221-227.
103. Slofstra, SH, van 't Veer C, Buurman WA, et al. Low molecular weight heparin attenuates multiple organ failure in a murine model of disseminated intravascular coagulation. Crit Care Med 2005; 33: 1365-1370.
104. Uchiba M, Okajima K, Murakami K, et al. Endotoxin-induced pulmonary vascular injury is mainly mediated by activated neutrophils in rats. Thromb Res 1995; 78: 117-125.
105. Darien BJ, Fareed J, Centgraf KS, et al. Low molecular weight heparin prevents the pulmonary hemodynamic and pathomorphologic effects of endotoxin in a porcine acute lung injury model. Shock 1998; 9: 274-281.
106. Murakami K, McGuire R, Cox RA, et al. Heparin nebulization attenuates acute lung injury in sepsis following smoke inhalation in sheep. Shock 2002; 18: 236-241.
107. Murakami K, Enkhbaatar P, Shimoda K, et al. High-dose heparin fails to improve acute lung injury following smoke inhalation in sheep. Clin Sci 2003; 104: 349-356.
108. Leiner KA, Newman D, Li C-M, et al. Heparin and fibroblast growth factors affect surfactant protein gene expression in type II cells. Am J Respir Cell Mol Biol 2006; 35: 611-618.
109. Schiffer ERC, Reber G, de Moerloose P, et al. Evaluation of unfractionated heparin and recombinant hirudin on survival in a sustained ovine endotoxin shock model. Crit Care Med 2002; 30: 2689-2699.
110. Haugen J. Intravascular clearance of endotoxin in warfarin-treated rabbits. Acta Pathol Microbiol Scand 1972; 80: 305-313.
111. Gans H. Mechanism of heparin protection in endotoxin shock. Surgery 1975; 77: 602-606.
112. Meyer J, Cox CS, Herndon DN, et al. Heparin in experimental hyperdynamic sepsis. Crit Care Med 1993; 21: 84-89.
113. Corrigan JJ, Kiernat JF. Effect of heparin in experimental Gram-negative septicaemia. J Infect Dis 1975; 131: 139-143.
114. Gardlund B for the heparin prophylaxis study group. Randomised, controlled trial of low-dose heparin for prevention of fatal pulmonary embolism in patients with infectious diseases. The heparin prophylaxis study group. Lancet 1996; 347: 1357-1361.
115. Geerts W, Selby R. Prevention of venous thromboembolism in the ICU Chest 2003; 124 (Suppl): 357S-363S.
116. Leizorovicz A, Cohen AT, Turpie AGG, et al. (PREVENT medical thromboprophylaxis study group). Randomized, placebo-controlled trial of dalteparin for the prevention of venous thromboembolism in acutely ill medical patients. Circulation 2004; 110: 874-879.
117. Davidson BL, Geerts WH, Lensing AWA. Low dose heparin for severe sepsis. N Engl J Med 2002; 347: 1036-1037.
118. Iba T, Kidokoro A. What can we learn from the three megatrials using anticoagulants in severe sepsis? Shock 2004; 22: 508-512.
119. Polderman KH, Girbes ARJ. Drug intervention trials in sepsis: divergent results. Lancet 2004; 363: 1721-1723.
120. Agarwal R, Gupta D. Anticoagulation in sepsis: is low-dose heparin as effective as activated protein C? Intensive Care Med 2005; 31: 1297-1298.
121. Opal SM. Unintended bias, clinical trial results, and the heparin post hoc crossover fallacy. Crit Care Med 2004; 32: 874-875.
122. Koestenberger M, Gallistl S, Muntean W, et al. Additive effects of anticoagulants: recombinant human activated protein C and heparin or melagatran, in tissue factor-activated umbilical-cord plasma. Thromb Haemost 2005; 94: 69-74.
123. Smith OP, White B, Vaughan D, et al. Use of protein-C concentrate, heparin, and haemodiafiltration in meningococcus-induced purpura fulminans. Lancet 1997; 350: 1590-1593.
124. Jaimes F, De La Rosa G, Arango C, et al. A randomised clinical trial of unfractionated heparin for treatment of sepsis (the HETRASE study): design and rationale. Trials 2006; 7: 19.
125. Dörffler-Melly J, de Jonge E, de Pont AC, et al. Bioavailability of subcutaneous low-molecular-weight heparin to patients on vasopressors. Lancet 2002; 359: 849-850.