New Therapeutic Options for Patients with Sepsis and Disseminated Intravascular Coagulation
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REVIEW ARTICLE New therapeutic options for patients with sepsis and disseminated intravascular coagulation Toshiaki Iba1, Atsushi Yamada1, Naoyuki Hashiguchi1, Isao Nagaoka2 1 Department of Emergency and Disaster Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan 2 Department of Host Defense and Biochemical Research, Juntendo University Graduate School of Medicine, Tokyo, Japan KEY WORDS ABSTRACT anticoagulants, The severity of sepsis increases along with the degree of coagulation disorder, and a fulminant co‑ disseminated agulation abnormality is recognized as disseminated intravascular coagulation (DIC). The mortality in intravascular sepsis ‑associated DIC remains as high as 40%, which is comparable to that in septic shock. Even though coagulation, intensive research is ongoing, there is currently no established therapy for this life ‑threatening complica‑ hemostasis, tion. Heparins are the oldest, most popular, and least‑expensive anticoagulants available; however, their inflammation, sepsis usefulness for the treatment of septic DIC has never been proved. Expectations for antithrombin con‑ centrate were once high, but high ‑dose antithrombin failed to demonstrate a survival benefit, and global sepsis guidelines no longer recommend its use. Recombinant activated protein C was the only recom‑ mended anticoagulant for the treatment of severe sepsis until 2011, but it was subsequently withdrawn from the world market after the failure of the latest clinical trial. Recombinant thrombomodulin is newly developed and has been utilized in Japan since 2008; however, its efficacy has not yet been proved. As shown above, progress has not been as fast as expected, but some new agents are upcoming. The ef‑ ficacy of anticoagulant therapy for septic DIC has long been discussed and aggressively studied, and we have finally realized that correcting the coagulation disorder is not sufficient to conquer this deadly complication. Since many natural anticoagulants have pleiotropic functions, we need to examine these effects and apply them to the right target at the right timing. Introduction The cornerstone for the manage‑ these agents on sepsis ‑associated DIC have not ment of sepsis ‑associated disseminated intra‑ yet been determined. Some subgroup analyses vascular coagulation (DIC) is the management of subjects with sepsis ‑associated DIC in large‑ of the underlying infection.1 No one opposes this ‑scale randomized controlled trials (RCTs) have fundamental strategy, but the management of demonstrated the effects of anticoagulants on Correspondence to: 3,4 Toshiaki Iba, MD, Department of sepsis is not always easy in actual clinical situ‑ mortality. In addition, the physiological dos‑ Emergency and Disaster Medicine, ations. As a result, the mortality rate in sepsis es of natural anticoagulants have been report‑ Juntendo University Graduate remains high. The latest report from the Japa‑ ed to be efficient for the resolution of DIC.5 Un‑ School of Medicine, 2 ‑1‑1 Hongo, nese Association for Acute Medicine (JAAM) re‑ der these circumstances, the “harmonized guid‑ Bunkyo ‑ku, Tokyo 113‑8421, Japan, phone: +81 ‑3‑3813 ‑3111, fax: vealed that a 28 ‑day mortality rate was 21.7% ance for DIC” has been released by the Interna‑ 6 +81 ‑3‑3813 ‑5431, e ‑mail: toshiiba@ for cases with severe sepsis, while it increased to tional Society on Thrombosis and Haemostasis. cf6.so ‑net.ne.jp 38.4% for cases with severe sepsis and DIC.2 As In this guidance, the recommendations for each Received: April 2, 2014. Revision accepted: April 8, 2014. a treatment for severe sepsis, physiological an‑ anticoagulant were graded, and unfractionated Published online: April 15, 2014. ticoagulants with pharmacological doses of ac‑ heparin (UFH) and low ‑molecular ‑weight hepa‑ Conflict of interest: none declared. tivated protein C (APC), antithrombin, and tis‑ rin (LMWH) were recommended with low ‑quality Pol Arch Med Wewn. 2014; sue factor pathway inhibitor (TFPI) have been evidence, while antithrombin concentrate and 124 (6): 321‑328 Copyright by Medycyna Praktyczna, examined, but all of them have failed to demon‑ recombinant thrombomodulin were graded as Kraków 2014 strate a survival benefit. However, the effects of “potentially recommended, but needs further REVIEW ARTICLE New therapeutic options for patients with sepsis and disseminated intravascular coagulation 321 evidence.” The present review will explain the cur‑ Anticoagulant therapy Heparins UFH is a sulfat‑ rent status of these anticoagulant therapies. ed polysaccharide with a heterogeneous structure and a molecular weight of 3 to 57 kDa. UFH binds Pathophysiology of septic disseminated intravascu- to antithrombin and induces a conformational lar coagulation and the concept of anticoagulant ther- change that increases the flexibility of the reactive apy The activation of coagulation is an almost site loop of antithrombin, which increases the an‑ universal event during sepsis and is initiated by ticoagulant activity approximately 1000 times. pathogen‑associated molecular patterns (PAMPs) Activated antithrombin inactivates thrombin and such as lipopolysaccharide (LPS), peptidoglycan, other coagulation factors such as factors Xa and and other pathogen‑related components. Since IXa (FIGURE 1). hemostasis is an important host defense mech‑ Even though UFH is widely used for the treat‑ anism, random suppression may not be a good ment of DIC, its efficacy has not yet been proved. treatment strategy.7 However, full ‑blown DIC Until now, only two RCTs have reported results often leads to tissue malcirculation and subse‑ for patients with sepsis ‑associated DIC, and quent death. Tissue factor (TF) expressions on both those trials failed to demonstrate a surviv‑ innate immune cells, including monocytes and al benefit.16,17 macrophages, have been thought to be the ma‑ With respect to LMWH, dalteparin has been jor initiator of the coagulation cascade. More re‑ approved by the Japanese Ministry of Health and cently, TF ‑expressing microparticles from plate‑ Welfare (JMHW) for the treatment of DIC. A mul‑ lets, monocytes, and endothelial cells have been ticenter cooperative double‑blind trial18 showed shown to participate in this mechanism.8 In ad‑ that dalteparin suppressed the development of dition to PAMPs, substances that originate from organ failure (P <0.05), tended to reduce bleed‑ the host cells and induce inflammation, known ing symptoms (P <0.1), and had a better safety as “alarmins” (including histones, nucleosomes, profile than UFH (P <0.05). and high mobility group box 1 [HMGB1]), are also A recent topic regarding the use of heparins capable of inducing coagulation.9 Eventually, in‑ is the suppression of the procoagulant activity flammation and malcirculation result in cell apop‑ of histones. Histones are DNA ‑binding proteins tosis and necrosis, and alarmins released from with a positive charge. Although intranuclear his‑ these dead cells further propagate coagulation.10 tones are harmless, they express strong damag‑ This vicious cycle accelerates both the inflamma‑ ing effects and propagate coagulation activities tion and coagulation systems and progresses un‑ once released into the bloodstream. Heparins til the death of the host. The procoagulant reac‑ are highly sulfated and negatively charged; thus, tion is further accelerated by an increased synthe‑ they can bind to histones and diminish their tox‑ sis of plasminogen activator inhibitor 1 (PAI‑1). icity. However, since high‑dose heparin increas‑ Thrombin ‑activatable fibrinolysis inhibitor (TAFI) es the risk of bleeding, Wildhagen et al.19 devel‑ is also involved in hypofibrinolysis, and the lev‑ oped nonanticoagulant heparin and reported its els of TAFI reportedly increase in patients with efficacy. At the moment, no RCT, systematic re‑ DIC as a complication.11 If the infection can be view, or meta ‑analysis has proven that heparins controlled, this hemostatic imbalance diminish‑ are effective for the treatment of sepsis ‑associated es spontaneously. However, if the insult is strong DIC. However, a recent large ‑scale trial, known as and sustained, the hemostatic sequence results in the XPRESS trial, showed a nonsignificant ben‑ multiple‑organ failure and death. Thus, anticoagu‑ efit of a prophylactic dose of heparin for venous lant treatment seems to be a rational approach. To thromboembolism (VTE) on a 28‑day mortali‑ counteract the hemostatic reaction, natural and ty in patients with severe sepsis compared with artificial coagulation inhibitors, such as heparins, placebo (28.3% vs. 31.9%, P = 0.08).20 Although antithrombin, APC, thrombomodulin, and pro‑ many patients with sepsis are treated with low‑ tease inhibitors, are the treatment of choice. Re‑ ‑dose heparin for the prevention of VTE in in‑ cent studies have revealed that some anticoagu‑ tensive care units, whether these patients may lants also have important functions for modulat‑ benefit in ways other than VTE prevention re‑ ing inflammation. For example, APC ameliorated mains unclear. the inflammatory reactions and improved survival in the animal models of sepsis.12 In mice with ge‑ Antithrombin Antithrombin, a vitamin‑K‑ netic deficiencies of protein C, endotoxemia was ‑independent glycoprotein with a molecular associated with a more marked increase in pro‑ weight of 59 kDa, is an essential inhibitor of ‑inflammatory cytokines, compared with wild‑ thrombin and other serine proteases, such as ‑type mice.13 Similar anti‑inflammatory effects factors Xa and IXa. Antithrombin