Journal of Thrombosis and Haemostasis, 13: 1–3

DOI: 10.1111/jth.12868

COMMENTARY

Recombinant soluble thrombomodulin: coagulation takes another chance to reduce sepsis mortality M. LEVI Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands

To cite this article: Levi M. Recombinant soluble thrombomodulin: coagulation takes another chance to reduce sepsis mortality. J Thromb Haemost 2015; DOI: 10.1111/jth.12868. See also Yamakawa K, Aihara M, Ogura H, Yuhara H, Hamasaki T, Shimazu T. Recombinant human soluble thrombomodulin in severe sepsis: a systematic review and meta-analysis. J Thromb Haemost 2015; DOI: 10.1111/jth.12841.

The striking coagulopathy in patients with severe sepsis and the increasing insight into the intricate link between inflammation and coagulation has been an inspiration for many researchers and pharmaceutical companies to explore potential therapeutic interventions for severe sepsis [1]. Indeed, in view of the high incidence of severe sepsis and sepsis mortality ranging from 20% to 50%, there is an urgent need for better treatment options [2]. Because dysfunctional physiological anticoagulant regulators, such as antithrombin, activated protein C, and tissue factor pathway inhibitor, were shown to be key players in the sepsisassociated activation of coagulation and animal studies supported the hypothesis that restoration of these pathways resulted in attenuation of coagulopathy and organ dysfunction and reduced mortality, large clinical studies were performed to establish the beneficial effect of these interventions in patients with severe sepsis [2–5]. Although some of these studies demonstrated some advantage in subgroups of patients with most extreme coagulopathies, an overall reduction in mortality was not confirmed. The disappointing results of these large clinical trials resulted in gloomy views toward the concept that targeting the coagulation system might have a beneficial effect in severe sepsis. That may not be justified as there is ample evidence supporting the idea of coagulopathy being a pivotal player in sepsis pathogenesis and hence a point of impact for treatment [6]. First, postmortem findings in patients with severe sepsis and coagulopathy revealed Correspondence: Marcel Levi, Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands. Tel.: +31 20 5662171; fax: +31 20 6919658. E-mail: [email protected] Received 20 January 2015 Manuscript handled by: F. R. Rosendaal Final decision: F. R. Rosendaal, 23 January 2015 © 2015 International Society on Thrombosis and Haemostasis

hemorrhagic necrosis of tissue, microclots in small blood vessels, and thrombi in mid-sized and larger arteries and veins. Second, experimental animal studies of disseminated intravascular coagulation demonstrated fibrin deposition in various organs and amelioration of the hemostatic defect by various interventions improved organ failure and mortality. Last, deranged coagulation was shown to be an independent predictor of organ failure and mortality in patients with sepsis. Hence, there is ample reason to further explore potentially beneficial interventions aimed at coagulation and inflammation in severe sepsis. In this respect, the activated protein C system has been a prominent target for the past few decades, which is understandable since the pathway interacts with a myriad of downstream coagulation and inflammatory mediators [1]. Administration of recombinant activated protein C therefore was an promising approach, but it failed to show convincing advantage in patients with sepsis, partly due to variable results in clinical trials and an increased bleeding risk [5,7]. However, another central component of the protein C system, the endothelial cell–associated receptor thrombomodulin, now takes the stage as an auspicious candidate to improve outcome in patients with sepsis and a deranged coagulation system [8]. In this issue of the Journal of Thrombosis and Haemostasis, Yamakawa et al. present a systematic review and meta-analysis of studies on the effect of recombinant human soluble thrombomodulin in severe sepsis [9]. They demonstrated a pooled relative risk of 0.81 (95% confidence interval [CI] 0.62–1.06) in three randomized trials encompassing 838 patients and a relative risk of 0.59 (95% CI 0.45–0.77) in nine observational studies including 571 patients. Interestingly, meta-regression of the combined results revealed a strong relationship between the effect size of recombinant soluble thrombomodulin treatment and baseline mortality risk, which is reminiscent of a similar relationship in patients who were treated with activated protein C [5,10]. Importantly, the authors did not find any indication of an

2 Commentary

increased incidence of major bleeding complications or any other safety issue in patients treated with soluble thrombomodulin. Why would thrombomodulin work while activated protein C (and other interventions aimed at restoration of physiological anticoagulant pathways) failed? First, thrombomodulin has unique and distinct properties aimed at both the coagulation and inflammation systems, many of which are independent of the actions of activated protein C. Thrombomodulin (CD141) is a transmembrane multidomain glycoprotein receptor that is expressed primarily on vascular endothelial cells but also on monocytes, neutrophils, osteoblasts, synovial cells, and dendritic cells [11,12]. Soluble thrombomodulin encompasses several domains, including a lectin-like domain, and six epidermal growth factor (EGF)-like repeats [13]. The binding of thrombin to thrombomodulin occurs at the site of the EGF repeats [14]. This binding not only results in an ~ 100-fold increase in the activation of protein C but also prohibits the thrombin-mediated conversion of fibrinogen into fibrin and blocks the binding of thrombin to other cellular receptors on platelets and inflammatory cells. The central domain of thrombomodulin contains six EGF-like repeats, three of which provide critical cofactor activity for thrombin-mediated generation of activated protein C and of activated thrombin activatable fibrinolysis inhibitor. Thrombin activatable fibrinolysis inhibitor inactivates the complement fragments and anaphylatoxins C3a and C5a, thereby dampening the innate immune response. Thrombomodulin also interferes with inflammatory activity, predominantly mediated by its N-terminal C-type lectin-like domain [12]. This structure interferes with neutrophil adhesion, complement activation, and cytokine generation, and mice with a targeted disruption of the lectin-like domain of thrombomodulin (thrombomodulinLeD/LeD mice) exhibit increased sensitivity to tissue injury in models of bacteremia, ischemia– reperfusion, and acute inflammation. Importantly, deletion of the lectin-like domain of thrombomodulin did not interfere with the capacity of thrombomodulin to activate protein C, demonstrating that the anti-inflammatory effects of this part of thrombomodulin are not mediated by activated protein C. In addition, the mostly indirect effects of soluble thrombomodulin on coagulation may mitigate potential systemic anticoagulant effects, explaining the lack of bleeding complications of patients receiving this treatment. The systematic review and meta-analysis by Yamakawa et al. indicates that recombinant human soluble thrombomodulin may be a very talented candidate for treatment of patients with severe sepsis and associated coagulopathy. However, it is too early to predict whether this intervention will pass the finish line as a winner. Indeed, severe sepsis has shown to be a resistant target, possibly due to patient heterogeneity, inconsistent disease manifestation, variability in underlying causes,

fluctuating case severity, and complicating factors such as comorbidity, A recent retrospective observational study demonstrated a lack of association between the use of recombinant soluble thrombomodulin and mortality in patients with severe pneumonia, which is often the cause of severe sepsis [15]. However, these results were obtained in a patient population with a relatively low disease severity, in which thrombomodulin appears to be less effective. Another limitation of the study may be that propensity matching of thrombomodulin-treated patients with controls may have been incomplete. In fact, retrospective observational studies should always be considered with appropriate caution, because selection bias, missing data, and other methodological limitations may have confounded the results. In that light, the present meta-analysis of Yamakawa et al. (which also contained more retrospective observational data than results from prospective randomized controlled studies) should be viewed as a strong and urgent encouragement to design and execute convincing studies demonstrating the benefit of recombinant human soluble thrombomodulin on coagulopathy, multiple organ dysfunction, and mortality in patients with severe sepsis. Disclosure of Conflict of Interest The author states that he has no conflicts of interest. References 1 Levi M, van der Poll T. Inflammation and coagulation. Crit Care Med 2010; 38: S26–34. 2 Angus DC, van der Poll T. Severe sepsis and septic shock. N Engl J Med 2013; 369: 840–51. 3 Warren BL, Eid A, Singer P, Pillay SS, Carl P, Novak I, Chalupa P, Atherstone A, Penzes I, Kubler A, Knaub S, Keinecke HO, Heinrichs H, Schindel F, Juers M, Bone RC, Opal SM. Caring for the critically ill patient. High-dose antithrombin III in severe sepsis: a randomized controlled trial. JAMA 2001; 286: 1869–78. 4 Abraham E, Reinhart K, Svoboda P, Seibert A, Olthoff D, Dal Nogare A, Postier R, Hempelmann G, Butler T, Martin E, Zwingelstein C, Percell S, Shu V, Leighton A, Creasey AA. 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: 2081–9. 5 Bernard GR, Vincent JL, Laterre PF, LaRosa SP, Dhainaut JF, Lopez-Rodriguez A, Steingrub JS, Garber GE, Helterbrand JD, Ely EW, Fisher CJJ. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 2001; 344: 699–709. 6 Levi M, Schultz M, van der Poll T. Sepsis and thrombosis. Semin Thromb Hemost 2013; 39: 559–66. 7 Ranieri VM, Thompson BT, Barie PS, Dhainaut JF, Douglas IS, Finfer S, G ardlund B, Marshall JC, Rhodes A, Artigas A, Payen D, Tenhunen J, Al-Khalidi HR, Thompson V, Janes J, Macias WL, Vangerow B, Williams MD. Drotrecogin Alfa (Activated) in Adults with Septic Shock. N Engl J Med 2012; 366: 2055–64. 8 Levi M, van der Poll T. Thrombomodulin in sepsis. Minerva Anestesiol 2013; 79: 294–8. © 2015 International Society on Thrombosis and Haemostasis

Commentary 3 9 Yamakawa K, Aihara M, Ogura H, Yuhara H, Hamasaki T, Shimazu T. Recombinant human soluble thrombomodulin in severe sepsis: a systematic review and meta-analysis. J Thromb Haemost 2015; doi: 10.1111/jth.12841. 10 Dhainaut JF, Yan SB, Joyce DE, Pettila V, Basson BR, Brandt JT, Sundin D, Levi M. Treatment effects of drotrecogin alfa (activated) in patients with severe sepsis with or without overt disseminated intravascular coagulation. J Thromb Haemost 2004; 2: 1924–33. 11 Schouten M, de Boer JD, van ‘t Veer C, Roelofs JJ, Meijers JC, Levi M, Conway EM, van der Poll T. The lectin-like domain of thrombomodulin hampers host defense in pneumococcal pneumonia. Eur Respir J 2012; 41: 935–42. 12 Conway EM. Thrombomodulin and its role in inflammation. Semin Immunopathol 2012; 34: 107–25.

© 2015 International Society on Thrombosis and Haemostasis

13 Esmon CT. New mechanisms for vascular control of inflammation mediated by natural anticoagulant proteins. J Exp Med 2002; 196: 561–4. 14 Zushi M, Gomi K, Yamamoto S, Maruyama I, Hayashi T, Suzuki K. The last three consecutive epidermal growth factorlike structures of human thrombomodulin comprise the minimum functional domain for protein C-activating cofactor activity and anticoagulant activity. J Biol Chem 1989; 264: 10351–3. 15 Tagami T, Matsui H, Horiguchi H, Fushimi K, Yasunaga H. Recombinant human soluble thrombomodulin and mortality in severe pneumonia patients with sepsis-associated disseminated intravascular coagulation: an observational nationwide study. J Thromb Haemost 2014; 12: 1–10.

Recombinant soluble thrombomodulin: coagulation takes another chance to reduce sepsis mortality.

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