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DOI: 10.1055/s-0044-1786754
Heparins May Not Be the Optimal Anticoagulants for Sepsis and Sepsis-Associated Disseminated Intravascular Coagulation
Funding This work was supported in part by a Grant-in-Aid for Special Research in Subsidies for ordinary expenses of private schools from The Promotion and Mutual Aid Corporation for Private Schools of Japan.![](https://www.thieme-connect.de/media/sth/EFirst/lookinside/thumbnails/10-1055-s-0044-1786754_03224-1.jpg)
Abstract
Historically, heparin has had the longest historical use as an anticoagulant and continues this day to be the primary therapeutic option for preventing thrombosis and thromboembolism in critically ill hospitalized patients. Heparin is also used to treat sepsis and sepsis-associated disseminated intravascular coagulation (DIC) in various countries. However, the efficacy and safety of heparin for this indication remains controversial, as adequately powered randomized clinical studies have not demonstrated as yet a survival benefit in sepsis and sepsis-associated DIC, despite meta-analyses and propensity analyses reporting improved outcomes without increasing bleeding risk. Further, activated protein C and recombinant thrombomodulin showed greater improvements in outcomes compared with heparin, although these effects were inconclusive. In summary, further research is warranted, despite the ongoing clinical use of heparin for sepsis and sepsis-associated DIC. Based on Japanese guidelines, antithrombin or recombinant thrombomodulin may be a preferable choice if they are accessible.
Keywords
heparin - low-molecular-weight heparin - anticoagulants - sepsis - disseminated intravascular coagulationAuthors Contributions
All authors met authorship criteria and participated significantly in the study. T.I. and T.T. wrote the draft. J.H. and J.H.L. reviewed and revised the manuscript. All authors read and approved the final manuscript.
Publikationsverlauf
Artikel online veröffentlicht:
11. Mai 2024
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References
- 1 Gando S, Shiraishi A, Yamakawa K. et al; Japanese Association for Acute Medicine (JAAM) Focused Outcomes Research in Emergency Care in Acute Respiratory Distress Syndrome, Sepsis and Trauma (FORECAST) Study Group. Role of disseminated intravascular coagulation in severe sepsis. Thromb Res 2019; 178: 182-188
- 2 Iba T, Helms J, Levi M, Levy JH. Thromboinflammation in acute injury: infections, heatstroke, and trauma. J Thromb Haemost 2024; 22 (01) 7-22
- 3 Adelborg K, Larsen JB, Hvas AM. Disseminated intravascular coagulation: epidemiology, biomarkers, and management. Br J Haematol 2021; 192 (05) 803-818
- 4 Qi W, Liu J, Li A. Effect of anticoagulant versus non-anticoagulant therapy on mortality of sepsis-induced disseminated intravascular coagulation: a systematic review and meta-analysis. Clin Appl Thromb Hemost 2023 ;29:10760296231157766
- 5 Hirish J. Heparin. N Engl J Med 1991; 324 (22) 1565-1574
- 6 Li X, Ma X. The role of heparin in sepsis: much more than just an anticoagulant. Br J Haematol 2017; 179 (03) 389-398
- 7 Derhaschnig U, Pernerstorfer T, Knechtelsdorfer M, Hollenstein U, Panzer S, Jilma B. Evaluation of antiinflammatory and antiadhesive effects of heparins in human endotoxemia. Crit Care Med 2003; 31 (04) 1108-1112
- 8 Levi M, Levy M, Williams MD. et al; Xigris and Prophylactic HepaRin Evaluation in Severe Sepsis (XPRESS) Study Group. Prophylactic heparin in patients with severe sepsis treated with drotrecogin alfa (activated). Am J Respir Crit Care Med 2007; 176 (05) 483-490
- 9 Jaimes F, De La Rosa G, Morales C. et al. Unfractioned heparin for treatment of sepsis: a randomized clinical trial (The HETRASE Study). Crit Care Med 2009; 37 (04) 1185-1196
- 10 Wang C, Chi C, Guo L. et al. Heparin therapy reduces 28-day mortality in adult severe sepsis patients: a systematic review and meta-analysis. Crit Care 2014; 18 (05) 563
- 11 Warren BL, Eid A, Singer P. et al; KyberSept Trial Study Group. Caring for the critically ill patient. High-dose antithrombin III in severe sepsis: a randomized controlled trial. JAMA 2001; 286 (15) 1869-1878
- 12 Bernard GR, Vincent JL, Laterre PF. et al; Recombinant human protein C Worldwide Evaluation in Severe Sepsis (PROWESS) study group. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 2001; 344 (10) 699-709
- 13 Abraham E, Reinhart K, Opal S. et al; OPTIMIST Trial Study Group. Efficacy and safety of tifacogin (recombinant tissue factor pathway inhibitor) in severe sepsis: a randomized controlled trial. JAMA 2003; 290 (02) 238-247
- 14 Davidson BL, Geerts WH, Lensing AW. Low-dose heparin for severe sepsis. N Engl J Med 2002; 347 (13) 1036-1037
- 15 Zarychanski R, Abou-Setta AM, Kanji S. et al; Canadian Critical Care Trials Group. The efficacy and safety of heparin in patients with sepsis: a systematic review and metaanalysis. Crit Care Med 2015; 43 (03) 511-518
- 16 Fan Y, Jiang M, Gong D, Zou C. Efficacy and safety of low-molecular-weight heparin in sepsis patients: a randomized controlled trial meta-analysis of randomized controlled trials. Sci Rep 2016; 6: 25984
- 17 Fu S, Yu S, Wang L, Ma X, Li X. Unfractionated heparin improves the clinical efficacy in adult sepsis patients: a systematic review and meta-analysis. BMC Anesthesiol 2022; 22 (01) 28
- 18 Umemura Y, Yamakawa K, Ogura H, Yuhara H, Fujimi S. Efficacy and safety of anticoagulant therapy in three specific populations with sepsis: a meta-analysis of randomized controlled trials. J Thromb Haemost 2016; 14 (03) 518-530
- 19 Yamakawa K, Yoshimura J, Ito T, Hayakawa M, Hamasaki T, Fujimi S. External validation of the two newly proposed criteria for assessing coagulopathy in sepsis. Thromb Haemost 2019; 119 (02) 203-212
- 20 Pernerstorfer T, Hollenstein U, Hansen J. et al. Heparin blunts endotoxin-induced coagulation activation. Circulation 1999; 100 (25) 2485-2490
- 21 Liu XL, Wang XZ, Liu XX. et al. Low-dose heparin as treatment for early disseminated intravascular coagulation during sepsis: a prospective clinical study. Exp Ther Med 2014; 7 (03) 604-608
- 22 El-Nawawy AA, Elshinawy MI, Khater DM. et al. Outcome of early hemostatic intervention in children with sepsis and nonovert disseminated intravascular coagulation admitted to PICU: a randomized controlled trial. Pediatr Crit Care Med 2021; 22 (03) e168-e177
- 23 Omidkhoda N, Abedi F, Ghavami V. et al. The effect of heparin and its preparations on disseminated intravascular coagulation mortality and hospitalization: a systematic review. Int J Clin Pract 2022; 2022: 2226761
- 24 Peng JC, Nie F, Li YJ. et al. Favorable outcomes of anticoagulation with unfractioned heparin in sepsis-induced coagulopathy: a retrospective analysis of MIMIC-III database. Front Med (Lausanne) 2022; 8: 773339
- 25 Zou ZY, Huang JJ, Luan YY. et al. Early prophylactic anticoagulation with heparin alleviates mortality in critically ill patients with sepsis: a retrospective analysis from the MIMIC-IV database. Burns Trauma 2022; 10: tkac029
- 26 Sun Y, Ding R, Sun H, Liang Y, Ma X. Efficacy and safety of heparin for sepsis-induced disseminated intravascular coagulation (HepSIC): study protocol for a multicenter randomized controlled trial. Trials 2024; 25 (01) 4
- 27 Hoffmann JN, Wiedermann CJ, Juers M. et al; KyberSept investigators. Benefit/risk profile of high-dose antithrombin in patients with severe sepsis treated with and without concomitant heparin. Thromb Haemost 2006; 95 (05) 850-856
- 28 Aoki N, Matsuda T, Saito H. et al; CTC-111-IM Clinical Research Group. 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) 540-547
- 29 Saito H, Maruyama I, Shimazaki S. et al. Efficacy and safety of recombinant human soluble thrombomodulin (ART-123) in disseminated intravascular coagulation: results of a phase III, randomized, double-blind clinical trial. J Thromb Haemost 2007; 5 (01) 31-41
- 30 Aikawa N, Shimazaki S, Yamamoto Y. et al. Thrombomodulin alfa in the treatment of infectious patients complicated by disseminated intravascular coagulation: subanalysis from the phase 3 trial. Shock 2011; 35 (04) 349-354
- 31 François B, Fiancette M, Helms J. et al. Efficacy and safety of human soluble thrombomodulin (ART-123) for treatment of patients in France with sepsis-associated coagulopathy: post hoc analysis of SCARLET. Ann Intensive Care 2021; 11 (01) 53
- 32 Weng J, Chen M, Fang D, Liu D, Guo R, Yang S. Therapeutic plasma exchange protects patients with sepsis-associated disseminated intravascular coagulation by improving endothelial function. Clin Appl Thromb Hemost 2021; 27: 10 760296211053313
- 33 Oudemans-van Straaten HM, Bosman RJ, Koopmans M. et al. Citrate anticoagulation for continuous venovenous hemofiltration. Crit Care Med 2009; 37 (02) 545-552
- 34 Thachil J, Iba T, Scarlatescu E, Levy JH. Why is DIC a rare diagnosis in the 21st century?. Juntendo Med J. 2024; Juntendo Med J 2024; 70 (02) 121-124
- 35 Iba T, Levy JH, Yamakawa K, Thachil J, Warkentin TE, Levi M. Scientific and Standardization Committee on DIC of the International Society on Thrombosis and Haemostasis. Proposal of a two-step process for the diagnosis of sepsis-induced disseminated intravascular coagulation. J Thromb Haemost 2019; 17 (08) 1265-1268
- 36 Iba T, Maier CL, Tanigawa T, Levy JH. Risk stratification utilizing sequential organ failure assessment (SOFA) score, antithrombin activity, and demographic data in sepsis-associated disseminated intravascular coagulation (DIC). Sci Rep 2023; 13 (01) 22502
- 37 Levy JH, Sniecinski RM, Rocca B. et al. Defining heparin resistance: communication from the ISTH SSC Subcommittee of Perioperative and Critical Care Thrombosis and Hemostasis. J Thromb Haemost 2023; 21 (12) 3649-3657
- 38 Samuel S, Allison TA, Sharaf S. et al. Antifactor Xa levels vs. activated partial thromboplastin time for monitoring unfractionated heparin. A pilot study. J Clin Pharm Ther 2016; 41 (05) 499-502