2
Strasbourg University Hospital, Medical Intensive Care Unit - NHC, INSERM (French National Institute of Health and Medical Research), Strasbourg University (UNISTRA), UMR 1260, Regenerative Nanomedicine (RNM), FMTS, Strasbourg, France
4
Department of Anesthesiology, Critical Care, and Surgery, Duke University School of Medicine, Durham, North Carolina
› Author AffiliationsFunding 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.
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.
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.
Thieme Medical Publishers, Inc. 333 Seventh Avenue, 18th Floor, New York, NY 10001, USA
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
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
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
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
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
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; 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
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