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DOI: 10.1160/TH07-01-0006
The role of heparin and allied compounds in the treatment of sepsis
Publication History
Received
04 January 2007
Accepted after major revision:
17 May 2007
Publication Date:
28 November 2017 (online)
![](https://www.thieme-connect.de/media/10.1055-s-00035024/200703/lookinside/thumbnails/10-1160-th07-01-0006-1.jpg)
Summary
The crosstalk between coagulation and inflammation and the propensity for microthromboembolic disease during sepsis calls for anticoagulant measures to prevent tissue hypoxygenation and to attenuate organ damage and dysfunction. Only one anticoagulant, recombinant human activated protein C (aPC, drotrecogin-α) has a proven survival benefit when used as an adjunctive therapy for human sepsis, partly because of its anti-inflammatory effect. However, heparin (-like compounds) may exert similar beneficial anti-inflammatory actions as aPC, in spite of the relatively narrow therapeutic window for anticoagulation. This narrative review is based on a Medline search of relevant basic and clinical studies published in English and discusses the potential role of heparin in modulating inflammatory responses in the treatment of animal models and human sepsis and its harmful sequelae. In any case, the results of a metaanalysis based on animal data suggest a potentially life-saving effect of heparin (-like compounds) in the treatment of sepsis.Therefore, a prospective randomized clinical trial is called upon to study effects in human sepsis.
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References
- 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 Jr FB, 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 nonanticoagulant 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 weightheparins 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 postoperative 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 bloodbiomaterial 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. Ciruclation 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. Heparinreleased 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 I224-I228.
- 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.