Coagulopathy of sepsis

Carl-Erik Dempfle

doi:10.1160/TH03-03-0182

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2004; 91(02): 213-224
DOI: 10.1160/TH03-03-0182

Review Article

Schattauer GmbH

Coagulopathy of sepsis

Carl-Erik Dempfle

¹University Hospital of Mannheim, I. Department of Medicine, Mannheim, Germany

› Author Affiliations

Abstract

Summary

Disseminated intravascular coagulation (DIC) is a common phenomenon in patients with sepsis, but the clinical implications of this condition are not clear. Clinical trials with coagulation inhibitors have failed to show a significant benefit concerning survival. DIC is primarily a laboratory diagnosis, based on the combination of elevated fibrin-related markers (FRM), with decreased procoagulant factors and platelets. Non-overt DIC is observed in most patients with sepsis, whereas overt DIC is less frequent. Patients with overt DIC may display consumption coagulopathy and purpura fulminans. Consumption coagulopathy is a bleeding disorder caused by low levels of platelets and procoagulant factors associated with massive coagulation activation. Purpura fulminans is caused by widespread microvascular thrombosis, resulting in tissue necrosis. Treatment with drotrecogin alfa (activated) improves survival and other outcome parameters in severe sepsis, including a subgroup of patients fulfilling the laboratory criteria of overt DIC. No randomized trials demonstrating effective therapies in consumption coagulopathy have been published. Bleeding patients with consumption coagulopathy are most frequently treated with platelet transfusions and various plasma products including fresh frozen plasma and coagulation factor concentrates. Based on case reports, treatment with drotrecogin alfa (activated) or substitution of protein C have been recommended for adjuvant treatment of sepsis-related purpura fulminans.

Keywords

Sepsis - disseminated intravascular coagulation (DIC) - purpura fulminans - drotrecogin alfa (activated) - antithrombin

Full Text

References

References
1 Bone RC, Balk RA, Cerra FB. et al. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine. Chest 1992; 101 (06) 1644-55.
2 Mavrommatis AC, Theodoridis T, Orfanidou A. et al. Coagulation system and platelets are fully activated in uncomplicated sepsis. Crit Care Med 200; 28 (02) 451-7.
3 Spero JA, Lewis JH, Hasiba U. Disseminated intravascular coagulation. Findings in 346 patients. Thromb Haemost 1980; 43 (01) 28-33.
4 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 (10) 699-709.
5 Osterud B. Tissue factor expression by monocytes: regulation and pathophysiological roles. Blood Coagul Fibrinolysis 1998; 09 (Suppl. 01) S9-14.
6 Todoroki H, Nakamura S, Higure A. et al. Neutrophils express tissue factor in a monkey model of sepsis. Surgery 2000; 127 (02) 209-16.
7 Mattsson E, Herwald H, Bjorck L. et al. Peptidoglycan from Staphylococcus aureus induces tissue factor expression and procoagulant activity in human monocytes. Infect Immun 2002; 70 (06) 3033-9.
8 Mirlashari MR, Hoiby EA, Holst J. et al. Outer membrane vesicles from Neisseria meningitidis: effects on tissue factor and plasminogen activator inhibitor-2 production in human monocytes. Thromb Res 2001; 102 (04) 375-80.
9 Bohrer H, Qiu F, Zimmermann T. et al. Role of NFkappaB in the mortality of sepsis. J Clin Invest 1997; 100 (05) 972-85.
10 Muller I, Klocke A, Alex M. et al. Intravascular tissue factor initiates coagulation via circulating microvesicles and platelets. Faseb J 2003; 17 (03) 476-8.
11 Levi M, ten Cate H, van der Poll T. Endothelium: interface between coagulation and inflammation. Crit Care Med 2002; 30 (Suppl. 05) S220-4.
12 Hotchkiss RS, Tinsley KW, Swanson PE. et al. Endothelial cell apoptosis in sepsis. Crit Care Med 2002; 30 (Suppl. 05) S225-8.
13 Hotchkiss RS, Swanson PE, Freeman BD. et al. Apoptotic cell death in patients with sepsis, shock, and multiple organ dysfunction. Crit Care Med 1999; 27 (07) 1230-51.
14 Kannemeier C, Feussner A, Stohr HA. et al. Factor VII and single-chain plasminogen activator-activating protease: activation and autoactivation of the proenzyme. Eur J Biochem 2001; 268 (13) 3789-96.
15 Romisch J. Factor VII activating protease (FSAP): a novel protease in hemostasis. Biol Chem 2002; 383 (7-8): 1119-24.
16 Nuijens JH, Huijbregts CC, Eerenberg-Belmer AJ. et al. Quantification of plasma factor XIIa- Cl(-)-inhibitor and kallikrein-Cl(-)-inhibitor complexes in sepsis. Blood 1988; 72 (06) 1841-8.
17 Wuillemin WA, Fijnvandraat K, Derkx BH. et al. Activation of the intrinsic pathway of coagulation in children with meningococcal septic shock. Thromb Haemost 1995; 74 (06) 1436-41.
18 Herwald H, Morgelin M, Olsen A. et al. Activation of the contact-phase system on bacterial surfaces—a clue to serious complications in infectious diseases. Nat Med 1998; 04 (03) 298-302.
19 Persson K, Russell W, Morgelin M. et al. The conversion of fibrinogen to fibrin at the surface of curliated E. coli bacteria leads to the generation of proinflammatory fibrinopeptides. J Biol Chem 2003; 278: 31884-90.
20 Pixley RA, De La Cadena R, Page JD. et al. The contact system contributes to hypotension but not disseminated intravascular coagulation in lethal bacteremia. In vivo use of a monoclonal anti-factor XII antibody to block contact activation in baboons. J Clin Invest 1993; 91 (01) 61-8.
21 Dormehl IC, Hugo N, Knoessen O. In vivo assessment of regional microvascular albumin leakage during E. coli septic shock in the baboon model. Am J Physiol Imaging 1991; 06 (02) 81-4.
22 Lush CW, Kvietys PR. Microvascular dysfunction in sepsis. Microcirculation 2000; 07 (02) 83-101.
23 Gailani D, Broze Jr. GJ. Factor XI activation in a revised model of blood coagulation. Science 1991; 253 (5022): 909-12.
24 Aird WC. Vascular bed-specific hemostasis: role of endothelium in sepsis pathogenesis. Crit Care Med 2001; 29 (Suppl. 07) S28-34 discussion S34-5.
25 Alcaraz A, Espana F, Sanchez-Cuenca J. et al. Activation of the protein C pathway in acute sepsis. Thromb Res 1995; 79 (01) 83-93.
26 Giles AR, Nesheim ME, Mann KG. Studies of Factors V and VIII:C in an animal model of disseminated intravascular coagulation. J Clin Invest 1984; 74 (06) 2219-25.
27 Dempfle CE, Argiriou S, Kucher K. et al. Analysis of fibrin formation and proteolysis during intravenous administration of ancrod. Blood 2000; 96 (08) 2793-802.
28 Siebenlist KR, Meh DA, Mosesson MW. Protransglutaminase (factor XIII) mediated crosslinking of fibrinogen and fibrin. Thromb Haemost 2001; 86 (05) 1221-8.
29 Hesselvik JF, Blomback M, Brodin B. et al. Coagulation, fibrinolysis, and kallikrein systems in sepsis: relation to outcome. Crit Care Med 1989; 17 (08) 724-33.
30 Niessen RW, Lamping RJ, Jansen PM. et al. Antithrombin acts as a negative acute phase protein as established with studies on HepG2 cells and in baboons. Thromb Haemost 1997; 78 (03) 1088-92.
31 Boldt J, Papsdorf M, Rothe A. et al. Changes of the hemostatic network in critically ill patients – is there a difference between sepsis, trauma, and neurosurgery patients?. Crit Care Med 2000; 28 (02) 445-50.
32 Taylor Jr. FB, Wada H, Kinasewitz G. Description of compensated and uncompensated disseminated intravascular coagulation (DIC) responses (non-overt and overt DIC) in baboon models of intravenous and intraperitoneal Escherichia coli sepsis and in the human model of endotoxemia: toward a better definition of DIC. Crit Care Med 2000; 28 (Suppl. 09) S12-9.
33 Wada H, Wakita Y, Nakase T. et al. Diagnosis of pre-disseminated intravascular coagulation stage with hemostatic molecular markers. The Mie DIC Study Group. Pol J Pharmacol 1996; 48 (02) 225-8.
34 Lasch HG. [Clinical aspects and therapy of disseminated intravascular coagulation]. Hamatol Bluttransfus 1970; 09: 121-31.
35 Taylor Jr. FB, Toh CH, Hoots WK. et al. Towards definition, clinical and laboratory criteria, and a scoring system for disseminated intravascular coagulation. Thromb Haemost 2001; 86 (05) 1327-30.
36 Sjobring U, Ringdahl U, Ruggeri ZM. Induction of platelet thrombi by bacteria and antibodies. Blood 2002; 100 (13) 4470-7.
37 Mosesson MW. Antithrombin I. Inhibition of thrombin generation in plasma by fibrin formation. Thromb Haemost 2003; 89 (01) 9-12.
38 Lijnen HR, Soria J, Soria C. et al. Dysfibrinogenemia (fibrinogen Dusard) associated with impaired fibrin-enhanced plasminogen activation. Thromb Haemost 1984; 51 (01) 108-9.
39 Mosesson MW, Siebenlist KR, Voskuilen M. et al. Evaluation of the factors contributing to fibrin-dependent plasminogen activation. Thromb Haemost 1998; 79 (04) 796-801.
40 Yakovlev S, Makogonenko E, Kurochkina N. et al. Conversion of fibrinogen to fibrin: mechanism of exposure of tPA- and plasminogen-binding sites. Biochemistry 2000; 39 (51) 15730-41.
41 Dempfle CE, Argiriou S, Alesci S. etal Fibrin formation and proteolysis during ancrod treatment. Evidence for des-A-profibrin formation and thrombin independent factor XIII activity. Ann N Y Acad Sci 2001; 936: 210-4.
42 Watanabe R, Wada H, Miura Y. et al. Plasma levels of total plasminogen activator inhibitor-I (PAI-I) and tPA/PAI-1 complex in patients with disseminated intravascular coagulation and thrombotic thrombocytopenic purpura. Clin Appl Thromb Hemost 2001; 07 (03) 229-33.
43 Francis Jr. RB, Seyfert U. Tissue plasminogen activator antigen and activity in disseminated intravascular coagulation: clinicopathologic correlations. J Lab Clin Med 1987; 110 (05) 541-7.
44 Mavrommatis AC, Theodoridis T, Economou M. et al. Activation of the fibrinolytic system and utilization of the coagulation inhibitors in sepsis: comparison with severe sepsis and septic shock. Intensive Care Med 2001; 27 (12) 1853-9.
45 Mesters RM, Florke N, Ostermann H. et al. Increase of plasminogen activator inhibitor levels predicts outcome of leukocytopenic patients with sepsis. Thromb Haemost 1996; 75 (06) 902-7.
46 Hermans PW, Hibberd ML, Booy R. et al. 4G/5G promoter polymorphism in the plasminogen-activator-inhibitor-1 gene and outcome of meningococcal disease. Meningococcal Research Group. Lancet 1999; 354 (9178): 556-60.
47 Menges T, Hermans PW, Little SG. et al. Plasminogen-activator-inhibitor-1 4G/5G promoter polymorphism and prognosis of severely injured patients. Lancet 2001; 357 (9262): 1096-7.
48 Wada H, Mori Y, Okabayashi K. et al. High plasma fibrinogen level is associated with poor clinical outcome in DIC patients. Am J Hematol 2003; 72 (01) 1-7.
49 Levi M, Ten Cate H. Disseminated intravascular coagulation. N Engl J Med 1999; 341 (08) 586-92.
50 Welty-Wolf KE, Carraway MS, Miller DL. et al. Coagulation blockade prevents sepsisinduced respiratory and renal failure in baboons. Am J Respir Crit Care Med 2001; 164 (10 Pt 1): 1988-96.
51 Hersch M, Gnidec A, Bersten AD. et al. Histologic and ultrastructural changes in nonpulmonary organs during early hyperdynamic sepsis. Surgery 1990; 107 (04) 397-410.
52 Skjorten F. Hyaline microthrombi in an autopsy material. A quantitative study with discussion of the relationship to small vessel thrombosis. Acta Pathol Microbiol Scand 1969; 76 (03) 361-75.
53 Tanaka K, Imamura T. Incidence and clinicopathological significance of DIC in autopsy cases. Bibl Haematol 1983; (49) 79-93.
54 Watanabe T, Imamura T, Nakagaki K. et al. Disseminated intravascular coagulation in autopsy cases. Its incidence and clinicopathologic significance. Pathol Res Pract 1979; 165 (03) 311-22.
55 Ely EW, Laterre PF, Angus DC. et al. Drotrecogin alfa (activated) administration across clinically important subgroups of patients with severe sepsis. Crit Care Med 2003; 31 (01) 12-9.
56 Wada H, Wakita Y, Nakase T. et al. Outcome of disseminated intravascular coagulation in relation to the score when treatment was begun. Mie DIC Study Group. Thromb Haemost 1995; 74 (03) 848-52.
57 Gando S, Nanzaki S, Kemmotsu O. Disseminated intravascular coagulation and sustained systemic inflammatory response syndrome predict organ dysfunctions after trauma: application of clinical decision analysis. Ann Surg 1999; 229 (01) 121-7.
58 Bredbacka S, Blomback M, Wiman B. et al. Laboratory methods for detecting disseminated intravascular coagulation (DIC): new aspects. Acta Anaesthesiol Scand 1993; 37 (02) 125-30.
59 Regan DH, Lackner H. Defibrination syndrome: changing concepts and recognition of the low grade form. Am J Med Sci 1973; 266 (02) 84-91.
60 Haslund R. Waterhouse Friderichsen syndrome. Endotoxin shock treated with massive doses of cortisol. J Oslo City Hosp 1973; 23 (03) 49-64.
61 Auburtin M, Porcher R, Bruneel F. et al. Pneumococcal meningitis in the intensive care unit: prognostic factors of clinical outcome in a series of 80 cases. Am J Respir Crit Care Med 2002; 165 (05) 713-7.
62 Lineaweaver W, Branzini D, Dragonetti D. et al. Hemophilus influenzae meningitis and Waterhouse-Friderichsen syndrome in an adult. South Med J 1986; 79 (08) 1034-6.
63 Canpolat C, Bakir M. A case of purpura fulminans secondary to transient protein C deficiency as a complication of chickenpox infection. Turk J Pediatr 2002; 44 (02) 148-51.
64 Karakousis PC, Page KR, Varello MA. et al. Waterhouse-Friderichsen syndrome after infection with group A streptococcus. Mayo Clin Proc 2001; 76 (11) 1167-70.
65 Fox B. Disseminated intravascular coagulation and the Waterhouse-Friderichsen syndrome. Arch Dis Child 1971; 46 (249) 680-5.
66 Waterhouse R. A case of suprarenal apoplexy. Lancet 1911; 01: 577-8.
67 Friedrichsen C. Waterhouse-Friedrichsen’s syndrome. Acta Endocrin 1955; 18: 482-92.
68 Adcock DM, Hicks MJ. Dermatopathology of skin necrosis associated with purpura fulminans. Semin Thromb Hemost 1990; 16 (04) 283-92.
69 Johansen K, Hansen Jr. ST. Symmetrical peripheral gangrene (purpura fulminans) complicating pneumococcal sepsis. Am J Surg 1993; 165 (05) 642-5.
70 Parmar MS. Symmetrical peripheral gangrene: a rare but dreadful complication of sepsis. Cmaj 2002; 167 (09) 1037-8.
71 Cohen JR, Lackner R, Keller A. et al. The surgical implications of purpura fulminans. Ann Vasc Surg 1990; 04 (03) 276-9.
72 Silbart S, Oppenheim W. Purpura fulminans. Medical, surgical, and rehabilitative considerations. Clin Orthop 1985; (193) 206-13.
73 Brozna JP. Shwartzman reaction. Semin Thromb Hemost 1990; 16 (04) 326-32.
74 Muller FM, Ehrenthal W, Hafner G. et al. Purpura fulminans in severe congenital protein C deficiency: monitoring of treatment with protein C concentrate. Eur J Pediatr 1996; 155 (01) 20-5.
75 Nakayama T, Matsushita T, Fidano H. et al. A case of purpura fulminans is caused by homozygous delta8857 mutation (protein Cnagoya) and successfully treated with activated protein C concentrate. Br J Haematol 2000; 110 (03) 727-30.
76 Soria JM, Morell M, Jimenez-Astorga C. et al. Severe type I protein C deficiency in a compound heterozygote for Y124C and Q132X mutations in exon 6 of the PROC gene. Thromb Haemost 1995; 74 (05) 1215-20.
77 Churchwell KB, McManus ML, Kent P. et al. Intensive blood and plasma exchange for treatment of coagulopathy in meningococcemia. J Clin Apheresis 1995; 10 (04) 171-7.
78 Ettingshausen CE, Veldmann A, Beeg T. et al. Replacement therapy with protein C concentrate in infants and adolescents with meningococcal sepsis and purpura fulminans. Semin Thromb Hemost 1999; 25 (06) 537-41.
79 Brandtzaeg P, Sirnes K, Folsland B. et al. Plasmapheresis in the treatment of severe meningococcal or pneumococcal septicaemia with DIC and fibrinolysis. Preliminary data on eight patients. Scand J Clin Lab Invest Suppl 1985; 178: 53-5.
80 Fourrier F, Chopin C, Huart JJ. et al. Doubleblind, placebo-controlled trial of antithrombin III concentrates in septic shock with disseminated intravascular coagulation. Chest 1993; 104 (03) 882-8.
81 Baudo F, Caimi TM, de Cataldo F. et al. 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 (04) 336-42.
82 Eisele B, Lamy M, Thijs LG. et al. Antithrombin III in patients with severe sepsis. A randomized, placebo-controlled, doubleblind multicenter trial plus a meta-analysis on all randomized, placebo-controlled, doubleblind trials with antithrombin III in severe sepsis. Intensive Care Med 1998; 24 (07) 663-72.
83 Warren BL, Eid A, Singer P. et al. Caring for the critically ill patient. High-dose antithrombin III in severe sepsis: a randomized controlled trial. Jama 2001; 286 (15) 1869-78.
84 Inthorn D, Hoffmann JN, Hartl WH. et al. Antithrombin III supplementation in severe sepsis: beneficial effects on organ dysfunction. Shock 1997; 08 (05) 328-34.
85 Lasch HG, Heene DH. Heparin therapy of diffuse intravascular coagulation (DIC). Thromb Diath Haemorrh 1975; 33 (01) 105-6.
86 Corrigan Jr. JJ, Jordan CM. Heparin therapy in septicemia with disseminated intravascular coagulation. N Engl J Med 1970; 283 (15) 778-82.
87 Nishiyama T, Matsukawa T, Hanaoka K. Is protease inhibitor a choice for the treatment of pre- or mild disseminated intravascular coagulation?. Crit Care Med 2000; 28 (05) 1419-22.
88 Taenaka N, Shimada Y, Hirata T. et al. Gabexate mesilate (FOY) therapy of disseminated intravascular coagulation due to sepsis. Crit Care Med 1983; 11 (09) 735-8.
89 de Jonge E, Dekkers PE, Creasey AA. et al. Tissue factor pathway inhibitor dose-dependently inhibits coagulation activation without influencing the fibrinolytic and cytokine response during human endotoxemia. Blood 2000; 95 (04) 1124-9.
90 Abraham E, Reinhart K, Svoboda P. et al. Assessment of the safety of recombinant tissue factor pathway inhibitor in patients with severe sepsis: a multicenter, randomized, placebo-controlled, single-blind, dose escalation study. Crit Care Med 2001; 29 (11) 2081-9.
91 Abraham E, Reinhart K, Opal S. et al. Efficacy and safety of tifacogin (recombinant tissue factor pathway inhibitor) in severe sepsis: a randomized controlled trial. Jama 2003; 290 (02) 238-47.
92 Freeman BD, Zehnbauer BA, Buchman TG. A meta-analysis of controlled trials of anticoagulant therapies in patients with sepsis. Shock 2003; 20 (01) 5-9.
93 Vincent JL. Drotrecogin alfa: a new approach in the treatment of severe sepsis. Expert Opin Biol Ther 2002; 02 (06) 659-64.
94 Riewald M, Petrovan RJ, Donner A. et al. Activation of endothelial cell protease activated receptor 1 by the protein C pathway. Science 2002; 296 (5574): 1880-2.
95 Joyce DE, Grinnell BW. Recombinant human activated protein C attenuates the inflammatory response in endothelium and monocytes by modulating nuclear factor-kappaB. Crit Care Med 2002; 30 (Suppl. 05) S288-93.
96 Macias WL, Dhainaut JF, Yan SC. et al. Pharmacokinetic-pharmacodynamic analysis of drotrecogin alfa (activated) in patients with severe sepsis. Clin Pharmacol Ther 2002; 72 (04) 391-402.
97 Manns BJ, Lee H, Doig CJ. et al. An economic evaluation of activated protein C treatment for severe sepsis. N Engl J Med 2002; 347 (13) 993-1000.
98 Angus DC, Linde-Zwirble WT, Clermont G. et al. Cost-effectiveness of drotrecogin alfa (activated) in the treatment of severe sepsis. Crit Care Med 2003; 31 (01) 1-11.
99 Ely EW, Angus DC, Williams MD. et al. Drotrecogin alfa (activated) treatment of older patients with severe sepsis. Clin Infect Dis 2003; 37 (02) 187-95.
100 Opal SM, Garber GE, LaRosa SP. et al. Systemic host responses in severe sepsis analyzed by causative microorganism and treatment effects of drotrecogin alfa (activated). Clin Infect Dis 2003; 37 (01) 50-8.
101 Vincent JL, Angus DC, Artigas A. et al. Effects of drotrecogin alfa (activated) on organ dysfunction in the PROWESS trial. Crit Care Med 2003; 31 (03) 834-40.
102 Pernerstorfer T, Hollenstein U, Hansen J. et al. Heparin blunts endotoxin-induced coagulation activation. Circulation 1999; 100 (25) 2485-90.
103 Pernerstorfer T, Hollenstein U, Hansen JB. et al. Lepirudin blunts endotoxin-induced coagulation activation. Blood 2000; 95 (05) 1729-34.
104 Derhaschnig U, Reiter R, Knobl P. et al. Recombinant human activated protein C (rhAPC, drotrecogin alfa activated) has minimal effect on markers of coagulation, fibrinolysis and inflammation in acute human endotoxemia. Blood 2003; 102: 2093-8.
105 Levi M, Dorffler-Melly J, Reitsma P. et al. Aggravation of endotoxin-induced disseminated intravascular coagulation and cytokine activation in heterozygous protein-C-deficient mice. Blood 2003; 101 (12) 4823-7.
106 Aoki N, Matsuda T, Saito H. et al. A comparative double-blind randomized trial of activated protein C and unfractionated heparin in the treatment of disseminated intravascular coagulation. Int J Hematol 2002; 75 (05) 540-7.
107 Oelschlager C, Romisch J, Staubitz A. et al. Antithrombin III inhibits nuclear factor kappaB activation in human monocytes and vascular endothelial cells. Blood 2002; 99 (11) 4015-20.
108 Kessler CM, Tang Z, Jacobs HM. et al. The suprapharmacologic dosing of antithrombin concentrate for Staphylococcus aureusinduced disseminated intravascular coagulation in guinea pigs: substantial reduction in mortality and morbidity. Blood 1997; 89 (12) 4393-401.
109 Hoffmann JN, Vollmar B, Inthorn D. et al. Antithrombin reduces leukocyte adhesion during chronic endotoxemia by modulation of the cyclooxygenase pathway. Am J Physiol Cell Physiol 2000; 279 (01) C98-C107.
110 Hoffmann JN, Vollmar B, Romisch J. et al. Antithrombin effects on endotoxin-induced microcirculatory disorders are mediated mainly by its interaction with microvascular endothelium. Crit Care Med 2002; 30 (01) 218-25.
111 Blauhut B, Kramar H, Vinazzer H. et al. Substitution of antithrombin III in shock and DIC: a randomized study. Thromb Res 1985; 39 (01) 81-9.
112 Langley PG, Hughes RD, Forbes A. et al. Controlled trial of antithrombin III supplementation in fulminant hepatic failure. J Hepatol 1993; 17 (03) 326-31.
113 Schipper HG, Jenkins CS, Kahle LH. et al. Antithrombin-III transfusion in disseminated intravascular coagulation. Lancet 1978; 01 (8069): 854-6.
114 Fuse S, Tomita H, Yoshida M. et al. High dose of intravenous antithrombin III without heparin in the treatment of disseminated intravascular coagulation and organ failure in four children. Am J Hematol 1996; 53 (01) 18-21.
115 Blauhut B, Necek S, Vinazzer H. et al. Substitution therapy with an antithrombin III concentrate in shock and DIC. Thromb Res 1982; 27 (03) 271-8.
116 Hellgren M, Javelin L, Hagnevik K. et al. Antithrombin III concentrate as adjuvant in DIC treatment. A pilot study in 9 severely ill patients. Thromb Res 1984; 35 (04) 459-66.
117 Kreuz WD, Schneider W, Nowak-Gottl U. Treatment of consumption coagulopathy with antithrombin concentrate in children with acquired antithrombin deficiency – a feasibility pilot study. Eur J Pediatr 1999; 158 (Suppl. 03) S187-91.
118 Hoffmann JN, Vollmar B, Laschke MW. et al. Adverse effect of heparin on antithrombin action during endotoxemia: microhemodynamic and cellular mechanisms. Thromb Haemost 2002; 88 (02) 242-52.
119 Marik PE, Andrews L, Maini B. 1997; The incidence of deep venous thrombosis in ICU patients. Chest 111 (03) 661-4.
120 Anderson DR, Wells PS, Stiell L. et al. Thrombosis in the emergency department: use of a clinical diagnosis model to safely avoid the need for urgent radiological investigation. Arch Intern Med 1999; 159 (05) 477-82.
121 Attia J, Ray JG, Cook DJ. et al. Deep vein thrombosis and its prevention in critically ill adults. Arch Intern Med 2001; 161 (10) 1268-79.
122 Takada A, Takada Y, Mori T. et al. Prevention of severe bleeding by tranexamic acid in a patient with disseminated intravascular coagulation. Thromb Res 1990; 58 (02) 101-8.
123 Mesters RM, Mannucci PM, Coppola R. et al. Factor VIIa and antithrombin III activity during severe sepsis and septic shock in neutropenic patients. Blood 1996; 88 (03) 881-6.
124 Moscardo F, Perez F, de la Rubia J. et al. Successful treatment of severe intra-abdominal bleeding associated with disseminated intravascular coagulation using recombinant activated factor VII. Br J Haematol 2001; 114 (01) 174-6.
125 Chuansumrit A, Chantarojanasiri T, Isarangkura P. et al. Recombinant activated factor VII in children with acute bleeding resulting from liver failure and disseminated intravascular coagulation. Blood Coagul Fibrinolysis 2000; 11 (Suppl. 01) S101-5.
126 Hesselvik F, Brodin B, Blomback M. et al. Fibronectin and other DIC-related variables in septic ICU patients receiving cryoprecipitate. Scand J Clin Lab Invest Suppl 1985; 178: 67-74.
127 Brodin B, Hesselvik F, Blomback M. et al. Fibronectin and other DIC-related variables in patients with moderately severe infections receiving cryoprecipitate. Scand J Clin Lab Invest Suppl 1985; 178: 57-65.
128 Sugawara T, Okuda M, Yamaguchi Y. et al. Successful treatment with tranexamic acid for severe bleeding in acute promyelocytic leukemia. Acta Haematol 1992; 87 (1-2): 109.
129 Chandler WL, Patel MA, Gravelle L. et al. Factor XIIIA and clot strength after cardiopulmonary bypass. Blood Coagul Fibrinolysis 2001; 12 (02) 101-8.
130 Lee SY, Chang SK, Lee IH. et al. Depletion of plasma factor XIII prevents disseminated intravascular coagulation-induced organ damage. Thromb Haemost 2001; 85 (03) 464-9.
131 Hunter J. Heparin therapy in meningococcal septicaemia. Arch Dis Child 1973; 48 (03) 233-5.
132 Chu DZ, Blaisdell FW. Purpura fulminans. Am J Surg 1982; 143 (03) 356-62.
133 Wilson FE, Morse SR. Therapy of acute meningococcal infections: early volume expansion and prophylactic low dose heparin. Am J Med Sci 1972; 264 (06) 445-55.
134 Fourrier F, Lestavel P, Chopin C. et al. Meningococcemia and purpura fulminans in adults: acute deficiencies of proteins C and S and early treatment with antithrombin III concentrates. Intensive Care Med 1990; 16 (02) 121-4.
135 Cobcroft R, Henderson A, Solano C. et al. Meningococcal purpura fulminans treated with antithrombin III concentrate: what is the optimal replacement therapy?. Aust N Z J Med 1994; 24 (05) 575-6.
136 Mertens R, Peschgens T, Granzen B. Diagnosis and stage-related treatment of disseminated intravascular coagulation in meningococcal infections. Klin Padiatr 1999; 211 (02) 65-9.
137 White B, Livingstone W, Murphy C. et al. An open-label study of the role of adjuvant hemostatic support with protein C replacement therapy in purpura fulminans-associated meningococcemia. Blood 2000; 96 (12) 3719-24.
138 Brandtzaeg P, Joo GB, Brusletto B. et al. Plasminogen activator inhibitor 1 and 2, alpha-2-antiplasmin, plasminogen, and endotoxin levels in systemic meningococcal disease. Thromb Res 1990; 57 (02) 271-8.
139 Madden RM, Gill JC, Marlar RA. Protein C and protein S levels in two patients with acquired purpura fulminans. Br J Haematol 1990; 75 (01) 112-7.
140 Dreyfus M, Masterson M, David M. et al. Replacement therapy with a monoclonal antibody purified protein C concentrate in newborns with severe congenital protein C deficiency. Semin Thromb Hemost 1995; 21 (04) 371-81.
141 Rivard GE, David M, Farrell C. et al. Treatment of purpura fulminans in meningococcemia with protein C concentrate. J Pediatr 1995; 126 (04) 646-52.
142 Kreuz W, Veldman A, Escuriola-Ettingshausen C. et al. Protein-C concentrate for meningococcal purpura fulminans. Lancet 1998; 351 (9107): 986-7 discussion 988.
143 Rintala E, Seppala O, Kotilainen P. et al. Protein C in the treatment of coagulopathy in meningococcal disease. Lancet 1996; 347 (9017): 1767.
144 Rintala E, Seppiala OP, Kotilainen P. et al. Protein C in the treatment of coagulopathy in meningococcal disease. Crit Care Med 1998; 26 (05) 965-8.
145 Rintala E, Kauppila M, Seppiala OP. et al. Protein C substitution in sepsis-associated purpura fulminans. Crit Care Med 2000; 28 (07) 2373-8.
146 de Kleijn ED, de Groot R, Hack CE. et al. Activation of protein C following infusion of protein C concentrate in children with severe meningococcal sepsis and purpura fulminans: a randomized, double-blinded, placebo-controlled, dose-finding study. Crit Care Med 2003; 31 (06) 1839-47.
147 Hodgson A, Ryan T, Moriarty J. et al. Plasma exchange as a source of protein C for acute onset protein C pathway failure. Br J Haematol 2002; 116 (04) 905-8.
148 Yan SB, Dhainaut JF. Activated protein C versus protein C in severe sepsis. Crit Care Med 2001; 29 (Suppl. 07) S69-74.
149 Faust SN, Levin M, Harrison OB. et al. Dysfunction of endothelial protein C activation in severe meningococcal sepsis. N Engl J Med 2001; 345 (06) 408-16.
150 Weisel G, Joyce D, Gudmundsdottir A. et al. Human recombinant activated protein C in meningococcal sepsis. Chest 2002; 121 (01) 292-5.
151 Bachli EB, Vavricka SR, Walter RB. et al. Drotrecogin alfa (activated) for the treatment of meningococcal purpura fulminans. Intensive Care Med 2003; 29 (02) 337.
152 Aoki Y, Ota M, Katsuura Y. et al. Effect of activated human protein C on disseminated intravascular coagulation induced by lipopolysaccharide in rats. Arzneimittelforschung 2000; 50 (09) 809-15.
153 Zenz W, Muntean W, Zobel G. et al. Treatment of fulminant meningococcemia with recombinant tissue plasminogen activator. Thromb Haemost 1995; 74 (02) 802-3.
154 Zenz W, Muntean W, Gallistl S. et al. Recombinant tissue plasminogen activator treatment in two infants with fulminant meningococcemia. Pediatrics 1995; 96 (1 Pt 1): 44-8.
155 Zenz W, Bodo Z, Zobel G. et al. Recombinant tissue plasminogen activator restores perfusion in meningococcal purpura fulminans. Crit Care Med 1998; 26 (05) 969-71 discussion 972-3.
156 Aiuto LT, Barone SR, Cohen PS. et al. Recombinant tissue plasminogen activator restores perfusion in meningococcal purpura fulminans. Crit Care Med 1997; 25 (06) 1079-82.
157 Hirsch DR, Ingenito EP, Goldhaber SZ. Prevalence of deep venous thrombosis among patients in medical intensive care. Jama 1995; 274 (04) 335-7.
158 Moser KM, LeMoine JR, Nachtwey FJ. et al. Deep venous thrombosis and pulmonary embolism. Frequency in a respiratory intensive care unit. Jama 1981; 246 (13) 1422-4.
159 Samama MM, Cohen AT, Darmon JY. et al. A comparison of enoxaparin with placebo for the prevention of venous thromboembolism in acutely ill medical patients. Prophylaxis in Medical Patients with Enoxaparin Study Group. N Engl J Med 1999; 341 (11) 793-800.
160 Merrer J, De Jonghe B, Golliot F. et al. Complications of femoral and subclavian venous catheterization in critically ill patients: a randomized controlled trial. Jama 2001; 286 (06) 700-7.
161 Timsit JF, Farkas JC, Boyer JM. et al. Central vein catheter-related thrombosis in intensive care patients: incidence, risks factors, and relationship with catheter-related sepsis. Chest 1998; 114 (01) 207-13.
162 Young E, Podor TJ, Venner T. et al. Induction of the acute-phase reaction increases heparinbinding proteins in plasma. Arterioscler Thromb Vasc Biol 1997; 17 (08) 1568-74.
163 Cosmi B, Fredenburgh JC, Rischke J. et al. Effect of nonspecific binding to plasma proteins on the antithrombin activities of unfractionated heparin, low-molecular-weight heparin, and dermatan sulfate. Circulation 1997; 95 (01) 118-24.
164 Manson L, Weitz JI, Podor TJ. et al. The variable anticoagulant response to unfractionated heparin in vivo reflects binding to plasma proteins rather than clearance. J Lab Clin Med 1997; 130 (06) 649-55.
165 Priglinger U, Delle GKarth, Geppert A. et al. Prophylactic anticoagulation with enoxaparin: Is the subcutaneous route appropriate in the critically ill?. Crit Care Med 2003; 31 (05) 1405-9.
166 Dorffler-Melly J, de Jonge E, Pont AC. et al. Bioavailability of subcutaneous low-molecular-weight heparin to patients on vasopressors. Lancet 2002; 359 (9309): 849-50.
167 Fraisse F, Holzapfel L, Couland JM. et al. Nadroparin in the prevention of deep vein thrombosis in acute decompensated COPD. The Association of Non-University Affiliated Intensive Care Specialist Physicians of France. Am J Respir Crit Care Med 2000; 161 (4 Pt 1): 1109-14.
168 Reeves JH, Cumming AR, Gallagher L. et al. A controlled trial of low-molecular-weight heparin (dalteparin) versus unfractionated heparin as anticoagulant during continuous venovenous hemodialysis with filtration. Crit Care Med 1999; 27 (10) 2224-8.
169 De Waele JJ, Van Cauwenberghe S, Hoste E. et al. The use of the activated clotting time for monitoring heparin therapy in critically ill patients. Intensive Care Med 2003; 29 (02) 325-8.
170 de Pont AC, Oudemans-van Straaten HM, Roozendaal KJ. et al. Nadroparin versus dalteparin anticoagulation in high-volume, continuous venovenous hemofiltration: a doubleblind, randomized, crossover study. Crit Care Med 2000; 28 (02) 421-5.
171 De Pont AC, Bouman CS, De Jonge E. et al. Treatment with recombinant human activated protein C obviates additional anticoagulation during continuous venovenous hemofiltration in patients with severe sepsis. Intensive Care Med 2003; 29 (07) 1205.
172 Lemmer Jr. JH, Despotis GJ. Antithrombin III concentrate to treat heparin resistance in patients undergoing cardiac surgery. J Thorac Cardiovasc Surg 2002; 123 (02) 213-7.
173 Williams MR, D’Ambra AB, Beck JR. et al. A randomized trial of antithrombin concentrate for treatment of heparin resistance. Ann Thorac Surg 2000; 70 (03) 873-7.
174 Francois B, Trimoreau F, Vignon P. et al. Thrombocytopenia in the sepsis syndrome: role of hemophagocytosis and macrophage colony-stimulating factor. Am J Med 1997; 103 (02) 114-20.
175 Trimoreau F, Francois B, Desachy A. et al. Platelet-activating factor acetylhydrolase and haemophagocytosis in the sepsis syndrome. Mediators Inflamm 2000; 09 (3-4): 197-200.
176 Hoffman M, Monroe 3rd DM, Roberts HR. Activated factor VII activates factors IX and X on the surface of activated platelets: thoughts on the mechanism of action of highdose activated factor VII. Blood Coagul Fibrinolysis 1998; 09 (Suppl. 01) S61-5.
177 Alberio L, Lammle B, Esmon CT. Protein C replacement in severe meningococcemia: rationale and clinical experience. Clin Infect Dis 2001; 32 (09) 1338-46.
178 Betrosian AP, Balla M, Kofinas G. et al. Protein C in the treatment of coagulopathy in meningococcal sepsis. Crit Care Med 1999; 27 (12) 2849-50.
179 Smith OP, White B, Vaughan D. et al. Use of protein-C concentrate, heparin, and haemodiafiltration in meningococcus-induced purpura fulminans. Lancet 1997; 350 (9091): 1590-3.