Anticoagulant therapies against sepsis‐induced disseminated intravascular coagulation

Abstract

Disseminated intravascular coagulation (DIC) is a frequent but lethal complication in sepsis. Anticoagulant therapies, such as heparin, antithrombin, activated protein C, and recombinant human‐soluble thrombomodulin, were expected to regulate the progression of coagulopathy in sepsis. Although a number of randomized controlled trials (RCTs) have evaluated the survival effects of these therapies over the past few decades, there remains no consistent evidence showing a significant survival benefit of anticoagulant therapies. Currently, anticoagulant therapies are not conducted as a standard treatment against sepsis in many countries and regions. However, most of these RCTs were performed overall in patients with sepsis but not in those with sepsis‐induced DIC, who were theoretically the optimal target population of anticoagulants. Actually, multiple lines of evidence from observational studies and meta‐analyses of the RCTs have suggested that anticoagulant therapies might reduce mortality only when used in septic DIC. In addition, the severity of illness is another essential factor that maximally affects the efficacy of the therapy. Therefore, to provide evidence on the true effect of anticoagulant therapies, the next RCTs must be designed to enroll only patients with sepsis‐induced overt DIC and a high severity of illness. To prepare these future RCTs, a novel scientific infrastructure for accurate detection of patients who can receive maximal benefit from anticoagulant therapies also needs to be established.

Short abstract

There remains no consistent evidence showing a significant survival benefit associated with anticoagulant therapies against sepsis. Previous randomized controlled trials were performed overall in patients with sepsis but not in those with sepsis‐induced disseminated intravascular coagulation. To prepare these future randomized controlled trials, a novel scientific infrastructure for the accurate detection of patients who can receive maximal benefit from anticoagulant therapies needs to be established.

INTRODUCTION

Sepsis is now defined as a life‐threatening organ dysfunction caused by a dysregulated host response to infection. ¹ Despite the progress made in its medical management and development of clinical practice guidelines over the past few decades, ² , ³ , ⁴ sepsis remains an important global health problem causing 11 million deaths around the world. ⁵ , ⁶ In sepsis, the blood coagulation system is invariably activated. Microorganisms and their components, described as pathogen‐associated molecular patterns, are known to induce the expression of tissue factor on monocytes and macrophages by binding to pattern‐recognizing receptors on immune cells. Tissue factor has been recognized as the main initiator of coagulation in sepsis, together with the clotting factors of factor VIIa, factor Xa, thrombin, and fibrin. ⁷ As the reactions proceed over time from the onset of sepsis, the pathogenesis of sepsis‐induced coagulopathy (SIC) varies drastically depending on the timing. In the earliest stages of SIC, tissue factors are reported to be expressed on the surface of vascular endothelium and monocytes, which cause small amounts of thrombin production via the exogenous coagulation pathway. When excessive activation of inflammation is prolonged, this small amount of thrombin subsequently activates platelets and coagulation factors V, VIII, and XI, finally leading to a burst of thrombin generation through factor Xa production on activated platelets. ⁸ Although mild and local thromboses potentially act as antimicrobial matrices that mediate host protection against pathogens, ⁹ the large burst of thrombin generation results in the uncontrolled activation of thrombosis, which is represented as an initial physiological stage in the development of disseminated intravascular coagulation (DIC). ¹⁰ , ¹¹ Sepsis‐induced DIC is no longer able to contribute to the host defense but plays a key role in causing microcirculatory dysfunction, multiorgan dysfunction, and subsequent death. ¹²

To regulate the systemic hypercoagulation response and subsequent multiple organ dysfunctions, antithrombotic factors such as antithrombin, thrombomodulin, protein C, and protein S play significant physiological roles. However, activation and expressions of the anticoagulant factors are typically diminished in sepsis as a result of vascular hyperpermeability, consumption, and impaired synthesis, leading to insufficient regulation of the overwhelming hypercoagulability. ¹³ , ¹⁴ Supplementation and activation of anticoagulant proteins by anticoagulant therapies are thus theoretically effective for regulating the pathological progression in sepsis‐induced DIC.

In addition, anticoagulant factors such as heparin, antithrombin, and thrombomodulin were reported to exert direct anti‐inflammatory properties that did not depend on their anticoagulant effects, potentially regulated neutrophil activation, complement activation, or cytokine generations in sepsis. ¹³ , ¹⁵ , ¹⁶ , ¹⁷ In this context, anticoagulant therapies were once expected to be a beneficial adjunctive therapy in sepsis. However, despite the numerous studies focusing on anticoagulant therapies against sepsis, these therapies continue to remain a matter of dispute. The main purposes of this review are to summarize the findings of the previous randomized controlled trials (RCTs), to discuss the potential problems in the RCTs, and to propose several essential qualifications for the future design of RCTs that can provide evidence on the true effect of anticoagulant therapies in sepsis.

EFFICACY OF ANTICOAGULANT THERAPIES FOR SEPSIS IN PREVIOUS RCTS

Heparin/heparinoid

Heparin, a member of the glycosaminoglycan family of sulfated polysaccharides, is one of the oldest anticoagulant agents, having been in clinical use since the 1930s. Heparin exerts its anticoagulant effects mainly by inducing conformational changes in antithrombin and enhancing the activity to inhibit factors Xa, IXa, and VIIa by approximately 1000‐fold. ¹⁸ , ¹⁹ The largest RCT on the efficacy of unfractionated heparin in sepsis, which included 317 patients with sepsis, showed no difference in 28‐day mortality between the treatment and control groups (13.9% vs. 15.7%; p = 0.652). ²⁰ Similarly, another RCT did not find an effect on mortality with the use of low‐dose heparin in patients with SIC (31.8% vs. 40%). ²¹

Antithrombin

Antithrombin, a serine protease inhibitor (SPI) that inactivates factors VIIa, IXa, Xa, XIa, and IIa, is one of the most abundant physiological anticoagulants circulating in plasma. ¹³ Along with its anticoagulant property, antithrombin has an anti‐inflammatory property through its stimulation of prostacyclin generation in endothelial cells, which inhibits cytokine and tissue factor production in endothelial cells and monocytes. ²²

Multiple lines of evidence have shown that the decrease of antithrombin activity in sepsis correlates with a lethal outcome, and therefore antithrombin administration was expected to improve outcomes in sepsis. ²³ , ²⁴ The KyberSept trial, the largest of these trials, enrolled 2314 patients with severe sepsis but showed no difference in 28‐day mortality between patients receiving antithrombin and patients receiving placebo (38.9% vs. 38.7%; p = 0.940). ²⁵ In addition, a number of RCTs have been performed so far to evaluate the survival effect of antithrombin. ²⁶ , ²⁷ , ²⁸ , ²⁹ , ³⁰ , ³¹ , ³² Of note, the dose of antithrombin used in these RCTs ranged widely from approximately 1500 to 9000 IU/day. However, none of the RCTs showed significant survival benefits of antithrombin administration in sepsis, regardless of the dose administered.

Serine protease inhibitors

SPIs comprise a family of molecules that antagonize the various activities of serine proteases, such as inflammatory responses and blood coagulation. As SPIs suppress the excessive coagulation activity induced by sepsis, they have been clinically used as anticoagulant agents against SIC. Two RCTs investigated the effects of SPIs in adult patients with sepsis. One failed to show significant differences in coagulation parameters, recovery from DIC, and mortality between patients treated with gabexate mesylate and with placebo. ³³ Similarly, the other found no significant difference in the concentration of inflammatory mediators and mortality between the studied groups. ³⁴

Activated protein C

Protein C is a natural anticoagulant that exhibits an anticoagulant property by inactivating proteins factor Va and factor VIIIa. Recombinant human activated protein C (rhAPC) was the only anticoagulant agent so far to have been recommended for use against severe sepsis in the Surviving Sepsis Campaign guidelines, following the results of the PROWESS trial, which showed a significant reduction in mortality with rhAPC versus placebo (24.7% vs. 30.8%; p = 0.005). ³⁵ However, subsequent RCTs showed no significant reduction in mortality with rhAPC. ³⁶ , ³⁷ , ³⁸ Finally, according to the results of the PROWESS‐SHOCK trial, which included only patients with septic shock and showed no significant survival benefit, rhAPC was withdrawn from the market. ³⁹

Recombinant human thrombomodulin

Thrombomodulin is a cofactor for thrombin‐catalyzed activation of protein C, which expresses on the surface of vascular endothelium. ⁴⁰ Recombinant soluble thrombomodulin (rTM) is a relatively novel anticoagulant agent released to the market in 2008. In patients with sepsis, rTM binds to thrombin, promotes the activation of protein C, and exhibits anticoagulant effects by inhibiting further thrombin generation. ⁴¹ In addition, its unique structure with a lectin‐like domain exhibits anti‐inflammatory and cytoprotective activities. ¹⁵ , ¹⁷

In 2013, a phase 2, international, multicenter RCT including 750 patients with SIC provided evidence suggestive of the efficacy of rTM on survival (28‐day mortality, 17.8% vs. 21.6%; p = 0.273). ⁴² Further, in a post hoc analysis of this RCT, the greatest benefit from rTM was seen in patients with at least one organ dysfunction and an international normalized ratio (INR) of >1.4 at baseline. Based on the results of the phase 2 trial, a phase 3, multinational, multicenter RCT, the SCARLET trial, was conducted to determine the efficacy of rTM in 800 patients with SIC who fulfilled the following criteria: (1) at least one sepsis associated organ dysfunction, (2) prolongation of the INR of >1.4, and (3) reduction of platelet count. However, this study reported no statistically significant difference in 28‐day mortality between the rTM and placebo groups (26.8% vs. 29.4%, p = 0.32). ⁴³

DESIGN FEATURES POTENTIALLY AFFECTING RESULTS IN THE PREVIOUS RCTs

We summarize the findings of the previous RCTs in Table 1. Numerous large‐scale RCTs have been conducted to evaluate the effects of anticoagulant therapies for sepsis, but persistent evidence has not been shown on the survival benefit of anticoagulant therapy. Furthermore, anticoagulant therapies are associated with a potential increase in bleeding complications. Although the rate of occurrence of bleeding events varied in the RCTs, possibly due to differences in the definitions of a bleeding event, a previous meta‐analysis of the RCTs showed a significant increase in the risk of bleeding complications with anticoagulant therapy in sepsis. ⁴⁴ Based on the aforesaid background, anticoagulant therapies are no longer conducted as a standard treatment against sepsis in many countries and regions. However, these past RCTs might not have provided definite evidence on the efficacy of anticoagulant therapies in sepsis because there were several critical issues that would influence the results in some of the RCTs.

TABLE 1.

List of the RCTs evaluating the effects of anticoagulant therapies in adult patients with sepsis.

Author	Year	Intervention	Population	Severity score		Number of patients	Mortality			Bleeding events
				Type	Value		Definition	Treatment (%)	Control (%)	Definition	Treatment (%)	Control (%)
Fourrier et al. 27	1993	AT	Septic shock	SAPS	19	32	28‐day mortality	28.6	50	Serious bleeding	0	5.6
Inthorn et al. 28	1997	AT	Severe sepsis	MOF	4	40	90‐day mortality	65	80	Any bleeding	0	0
Baudo et al. 29	1998	AT	Sepsis	SAPS	16	100	30‐day mortality	55.1	54.9	Serious bleeding	10.2	11.8
Eisele et al. 30	1998	AT	Severe sepsis	APACHE II	14	42	30‐day mortality	25	40.9	Any bleeding	0	13.6
Schorr et al. 31	2000	AT	Peritonitis	APACHE II	14.5	50	90‐day mortality	25	23.1	NA
Bernard et al. 45	2001	APC	Severe sepsis	APACHE II	17.3	131	28‐day mortality	28.9	34.1	Serious bleeding	4.4	4.9
Bernard et al. 35	2001	APC	Severe sepsis	APACHE II	25	1690	28‐day mortality	24.7	30.8	Serious bleeding	3.5	2
Warren et al. 25	2001	AT	Severe sepsis	SAPS II	49	2314	28‐day mortality	38.9	38.7	Serious bleeding	22	12.8
Hsu et al. 34	2004	SPI	Septic coagulopathy	NA		50	Overall mortality	24%	36	Any bleeding	8	24
Abraham et al. 36	2005	APC	Severe sepsis	APACHE II	18.2	2613	28‐day mortality	18.5	17	Serious bleeding	6.8	3.4
Gonano et al. 32	2006	AT	Severe sepsis	APACHE II	53	33	28‐day mortality	29.4	31.3	NA
Jaimes et al. 20	2009	UFH	Sepsis	APACHE II	10	317	28‐day mortality	13.9	15.7	Any bleeding	1.9	1.3
Ranieri et al. 39	2012	APC	Septic shock	APACHE II	25	1680	28‐day mortality	26.4	24.2	Any bleeding	9.8	5.8
Annane et al. 38	2013	APC	Septic shock	APACHE II	56	511	90‐day mortality	47.6	46.3	Serious bleeding	12.5	14.3
Gando et al. 26	2013	AT	Septic DIC a	APACHE II	21	60	28‐day mortality	10	13.3	Serious bleeding	10	6.7
Vincent et al. 42	2013	rTM	Septic coagulopathy	NA		741	28‐day mortality	17.8%	21.6	Serious bleeding	5.1	4.6
Liu et al. 21	2014	UFH	Septic coagulopathy	APACHE II	21	37	28‐day mortality	31.8	40	NA
Vincent et al. 43	2018	rTM	Septic coagulopathy	APACHE II	22	800	28‐day mortality	26.8	29.4	Serious bleeding	5.8	4

Abbreviations: APACHE, Acute Physiology and Chronic Health Evaluation; APC, activated protein C; AT, antithrombin; MOF, multiple organ failure; NA, not applicable; RCTs, randomized controlled trials; rTM, recombinant human‐soluble thrombomodulin; SAPS, Simplified Acute Physiology score; SPI, serine protease inhibitor; UFH, unfractionated heparin.

^a DIC according to the Japanese Association for Acute Medicine disseminated intravascular coagulation (DIC) criteria.

Presence of DIC

First, most RCTs of anticoagulant therapies were performed in patients with sepsis but not consistently with concomitant DIC. Theoretically, anticoagulant therapies against patients with sepsis without DIC are capable of inhibiting host‐defensive immunothrombosis, which would help to capture and ensnare pathogens circulating in the blood. Actually, much evidence from observational studies and subgroup analyses of RCTs has suggested that anticoagulant therapy might reduce mortality only when used in patients with sepsis with DIC. For example, the post hoc subgroup analysis of the KyberSept trial suggested that favorable treatment effects of antithrombin were observed only in the patients suffering from sepsis‐induced DIC but not in the non‐DIC patients. ⁴⁶ Similar findings were also reported from the subgroup analyses of the HETRASE trial, ²⁰ PROWESS trial, ³⁵ and SCARLET trial. ⁴³ Although the difference in survival benefit was not statistically significant between the anticoagulant and control groups in the overall population in the trial, a trend of better 28‐day survival was observed in the subgroup having coagulopathy at baseline (28‐day mortality, 26.7% vs. 32.1%; risk ratio [95% confidential interval], 0.832 [0.652–1.061], Table 2).

TABLE 2.

Subgroup analyses in the RCTs evaluating the effects of anticoagulant therapies.

Author	Year	Intervention	Population		Outcome	Number of patients	Mortality
			Overall	Subgroup			Treatment (%)	Control (%)	Risk ratio with 95% CI
Warren et al. 25	2001	AT	Severe sepsis	Septic DIC a	28‐day mortality	229	25.4	40.0	0.64 (0.43–0.94)
				High severity b	28‐day mortality	1008	35.7	44.4	0.80 (0.61–1.06)
Bernard et al. 35	2001	APC	Severe sepsis	High severity c	28‐day mortality	321	24.7	29.5	NA
Jaimes et al. 20	2009	UFH	Sepsis	Septic DIC a	28‐day mortality	240	16.3	20.5	0.79 (0.46–1.36)
Ranieri et al. 39	2012	APC	Septic shock	Septic coagulopathy	28‐day mortality	389	36.5	38.7	0.95 (0.73–1.22)
Bernard et al. 35	2001	APC	Severe sepsis	Septic DIC a	28‐day mortality	454	30.5	43	0.71 (0.55–0.91)
Vincent et al. 43	2018	rTM	Septic coagulopathy at confirmation of eligibility	Septic coagulopathy at baseline d	28‐day mortality	634	26.7	32.1	0.83 (0.65–1.06)

Abbreviations: APC, activated protein C; AT, antithrombin; CI, confidence interval; DIC, disseminated intravascular coagulation; NA, not applicable; RCTs, randomized controlled trials; rTM, recombinant human‐soluble thrombomodulin; UFH, unfractionated heparin.

^a DIC according to the International Society on Thrombosis and Hemostasis overt DIC criteria.

^b Patients with predicted mortality between 30% and 60% according to the baseline Simplified Acute Physiology II score (SAPS II).

^c Acute Physiology and Chronic Health Evaluation (APACHE) score of 25 or more.

^d Baseline indicated the timepoint after randomization and before receiving the intervention.

We also conducted a meta‐analysis of RCTs focusing on three specific populations with sepsis, that is, those with overall sepsis, SIC, and sepsis‐induced DIC. ⁴⁴ This analysis found no significant reductions in mortality in the overall sepsis population and the population with SIC; however, a significant reduction in mortality was observed in the population with sepsis‐induced DIC (risk ratio, 0.72; 95% confidence interval [CI], 0.62–0.85). In addition, a multicenter observational study including 2663 patients with sepsis showed that survival effects of anticoagulant therapies as adjusted by propensity score methods were observed only in the patients with DIC (adjusted hazard ratio [HR], 0.609; 95% CI, 0.456–0.814) but not in the patients without DIC. ⁴⁷ These lines of evidence clearly suggested that sepsis‐induced DIC is an essential key pathology in which anticoagulant therapy could achieve maximum efficacy. Another multicenter observational study including 1178 patients with sepsis showed significant interaction on reduced mortality between anticoagulant therapies and disease severity as indicated by the Acute Physiology and Chronic Health Evaluation (APACHE) II score (p = 0.101), suggesting that anticoagulant therapies were especially effective in patients with a high severity of illness. ⁴⁸

Severity of illness

Second, a greater number of the previous RCTs included patients with a mild‐to‐moderate severity of illness. In a previous meta‐analysis including RCTs for anticoagulants against sepsis, only 5 of 17 RCTs included patients had a mean APACHE II score of 25 or more. ⁴⁴ As anticoagulant therapies possess specific anti‐inflammatory activities unrelated to anticoagulant activity, the clinical efficacies of the anticoagulant therapies are theoretically high, especially in severe cases of sepsis, in which an uncontrolled inflammatory response causes vascular endothelial integrity and subsequent multiple organ dysfunctions. Along with the presence of DIC, severity of illness is thus another key component potentially affecting the efficacy of anticoagulant therapies. Actually, evidence from the subgroup analyses of the RCTs suggested that favorable treatment effects of anticoagulants were observed in the patients with high severity scores. For example, a subgroup analysis of the PROWESS trial suggested that the survival benefit associated with the administration of activated protein C tended to increase with a higher severity of illness at baseline. ⁴⁹ Further, a post hoc subgroup analysis of the KyberSept trial including only patients with a predicted mortality rate of 30%–60% as defined by the Simplified Acute Physiology Score II reported that treatment with antithrombin might improve survival in this population (Table 2). ⁵⁰ An association between the effect of anticoagulant therapies and the severity of illness was reported from a systematic review including several previous RCTs. ⁵¹ In that study, meta‐regression analysis was conducted to evaluate the relationship between the survival effect of rTM therapy and the control mortality, and it showed that the probability of benefit of rTM therapy was significantly increased in accordance with the increasing risk of death in the control group (p = 0.0119). Similar findings were reported in a multicenter observational study described above. ⁴⁷ In that study, survival benefits associated with anticoagulant therapies were also found in patients with a high severity of illness (Sequential Organ Failure Assessment score, 13–17; adjusted HR, 0.601; 95% CI, 0.451–0.800).

In addition, an observational study that stratified patients with sepsis‐associated DIC into several subsets according to disease severity as determined by the APACHE II score reported that anticoagulant therapy was significantly associated with lower mortality only in the high‐severity subset (APACHE II score, 24–29; adjusted HR, 0.281; 95% CI, 0.093–0.850), whereas there were no effects on mortality in the other subsets. ⁵² In another multicenter observational study, the three‐way interaction analysis on mortality between anticoagulant therapies, DIC score, and disease severity suggested that anticoagulant therapy might be beneficial if the patients had both DIC and a high disease severity simultaneously. ⁴⁸

These findings suggested that the survival effect of anticoagulant therapies might be different even among patients with sepsis‐induced DIC on the basis of the severity of illnesses (in other words, the presence of organ dysfunctions in other anatomical sites). Therefore, further RCTs of anticoagulant therapies should be designed to enroll patients with DIC and a high severity of illness.

Timing of anticoagulant therapies

There are several methodological concerns in the previous RCTs that potentially affect the results. For example, most of the previous RCTs were not designed to aim at initiating anticoagulant agents at the optimal time, and thus timing of anticoagulant therapies was suboptimal in several of the RCTs. For example, the SCARLET trial designated the maximum time between the first eligibility assessment and drug administration to be 40 h, which was too late in the clinical setting. In fact, approximately 20% of patients in each of the study groups had an INR of ≤1.4 during the periods after their initial confirmation of eligibility. ⁴³ Activation of the coagulation system in sepsis changes dynamically over time. Among 675 placebo patients in a previous large RCT, prothrombin time worsened in 128 (19.0%) patients, D‐dimer worsened in 328 (48.6%), antithrombin worsened in 117 (17.3%), and protein C worsened in 177 (26.2%) patients within the first 24 h from the baseline values. ⁵³ Further, worsening of coagulation parameters over time was reported to be highly correlated with death during the next 28 days.

Although there is no gold standard for a time limit for anticoagulant therapies in sepsis, this finding suggested that the early initiation of treatment, at the latest within 24 h, is extremely important so as not to miss therapeutic opportunities. Otherwise, a delay in intervention can cause progression of illness that is no longer able to benefit from anticoagulant therapy. ⁵⁴ , ⁵⁵ In the clinical setting, anticoagulant therapies were generally performed within a few hours of patients being diagnosed as having sepsis‐induced DIC, and thus the results of some of the RCTs might not reflect the true effect of anticoagulant therapy.

DEVELOPING A SCIENTIFIC INFRASTRUCTURE FOR FUTURE RCTS

According to the lines of evidence obtained from the previous RCTs and observational studies, the survival benefit associated with anticoagulant therapies would be expected only in patients with DIC and a high severity of illness. Besides, as overt DIC is a late‐phase and sometimes decompensated coagulation disorder, anticoagulant therapies should ideally be administrated to patients with sepsis‐induced DIC at an earlier time before they progress to the overt stage. However, it is extremely difficult to simultaneously reconcile the aforementioned requirements because the methods for appropriately diagnosing overt DIC at an earlier time are not sufficiently established.

The International Society on Thrombosis and Hemostasis (ISTH) overt DIC criteria are strictly designed to avoid overdiagnosis and are thus superior at definitely diagnosing patients as having DIC. ⁵⁶ Therefore, patients diagnosed as having overt DIC according to the ISTH criteria would be the optimal population who might receive maximal efficacy from anticoagulant therapies. Nevertheless, the ISTH overt DIC criteria are not suitable for initiating anticoagulant therapies because they sometimes detect the target population at timing that is too late for anticoagulant therapies to more effectively regulate the progression of disease.

Recently, the ISTH DIC Scientific Standardization Committees proposed a new category identifying an earlier phase of DIC called “sepsis‐induced coagulopathy” (SIC). ⁵⁷ SIC was developed to predict overt DIC with high sensitivity at an earlier timing. However, it was also reported that only about half of SIC‐positive patients subsequently developed overt DIC, and the positive predictive value of SIC might be suboptimal. ⁵⁸ , ⁵⁹ Similarly, the Japanese Association for Acute Medicine (JAAM) DIC criteria were designed to detect patients with DIC at an earlier time and are especially useful in the emergency and critical care fields. ⁵⁴ Actually, the JAAM DIC criteria were reported to detect two times as many DIC cases at an earlier time compared with the ISTH overt DIC criteria. ⁶⁰ , ⁶¹ However, the JAAM DIC criteria were reported to have low sensitivity for poor outcomes, that is, not all patients positive for JAAM DIC suffered from overwhelming coagulation disorders requiring anticoagulant therapies. ⁶² Therefore, RCTs using SIC or JAAM as inclusion criteria will include patients with mild‐to‐moderate coagulation disorders who are not expected to receive maximal efficacy from the therapies. This will diminish the effect size and lead to an enormous increase in the required sample size to evaluate the true effect.

Hematological molecular markers, such as the thrombin–antithrombin complex, antithrombin III activity, and plasminogen activator inhibitor‐1, have been reported to aid in an earlier and more accurate diagnosis of DIC, but the measurements are still costly and can be performed only in limited facilities. Therefore, at the present time, we should aim to develop a novel scientific infrastructure to easily, immediately, and accurately detect those patients who would receive maximal benefit from anticoagulant therapies. Application of new candidate technologies, such as bioinformatics, real‐world data, and artificial intelligence, will enable the establishment of highly accurate algorithms to detect the optimal target populations for anticoagulant therapies.

SUMMARY

Over the past few decades, a number of RCTs have evaluated the effects of anticoagulant therapies for sepsis and concluded that there was no significant benefit on mortality. However, recent studies have suggested that the survival benefit of anticoagulant therapies is limited only to a specific population, such as patients with septic DIC and a high severity of illness. Therefore, to prepare future well‐designed RCTs, further investigations are required to establish a reliable method to detect those patients who can receive maximal benefit from anticoagulant therapies.

FUNDING INFORMATION

The authors declare that they have no sources of funding to report.

CONFLICT OF INTEREST STATEMENT

Dr. Hiroshi Ogura is an Editorial Board member of the AMS Journal and a coauthor of this article. To minimize bias, the author was excluded from all editorial decision‐making related to the acceptance of this article for publication. Dr. Jun Oda is Editor‐in‐Chief of the journal and coauthor of this article. The author was excluded from the peer‐review process and all editorial decisions related to the acceptance and publication of this article. Peer review was handled independently by Acute Medicine and Surgery editorial office and Dr. Yausyuki Kuwagata as the Editor to minimize bias.

ETHICS STATEMENT

We waived the informed consent, registration of the study protocol and ethical review by the Institutional Review Board for this article because it included the findings reported by already published studies.

Umemura Y, Nishida T, Yamakawa K, Ogura H, Oda J, Fujimi S. Anticoagulant therapies against sepsis‐induced disseminated intravascular coagulation. Acute Med Surg. 2023;10:e884. 10.1002/ams2.884

DATA AVAILABILITY STATEMENT

Data sharing is not applicable to this article as no new data were created or analyzed in this study.