We investigated the age-related differences in the survival benefit of anticoagulant therapy in sepsis in accordance with the JAAM DIC diagnostic criteria. The results of this study indicate that anticoagulant therapy is associated with better outcomes consistent with a higher DIC score in patients aged 60 to 70 years. Moreover, anticoagulant therapy in patients with sepsis and low DIC scores may be associated with the deterioration of organ function and could lead to poor outcomes.
Previous studies have demonstrated that patients with sepsis and DIC exhibit an increased prevalence of multiple organ dysfunction and that the mortality rate of such patients is significantly higher than that of non-DIC patients16,20, suggesting that the development of DIC in sepsis is an indicator of poor prognosis. A recent nationwide multicenter retrospective cohort study suggested that screening for DIC was associated with a survival benefit in patients with sepsis21. These results imply that the evaluation and subsequent intervention for coagulofibrinolytic changes related to sepsis may contribute to improved outcomes in patients with sepsis. To date, however, there is no clear evidence that treating sepsis-induced coagulopathy leads to improved outcomes in patients with sepsis.
The important point is that most of the RCTs that evaluated the effect of anticoagulant therapy have targeted patients with “sepsis.” Although the KyberSept trial, a mega-RCT, demonstrated that antithrombin treatment did not affect 28-day mortality in adult patients with sepsis and septic shock5, its post hoc analysis suggested that antithrombin therapy was associated with a significant reduction in mortality only in patients with DIC but not in non-DIC patients22. These results indicate the importance of selecting the target population for anticoagulant therapy against sepsis. Studies showing that the optimal target for anticoagulant therapy is a patient population fulfilling three factors, namely, sepsis, DIC, and high disease severity, have recently been published13,14,23−25.
A recent global analysis demonstrated that 1 in 5 deaths around the world is caused by sepsis, leading to 11 million deaths annually worldwide, thus surpassing cancer mortality26. Older people constitute the major population of patients with sepsis, and mortality increases at more advanced ages27,28. Although it is well known that advancing age is associated with increased coagulation, this propensity for a deteriorating coagulation disorder during sepsis remains unknown27. Innate immune cells, such as neutrophils and macrophages, show age-related functional alteration, resulting in a diminished ability to rapidly respond to foreign pathogens29. In addition to the innate immune system, an attenuation of the adaptive immune functions in old age has been confirmed30. A prolonged inflammatory response in aged patients has been noted, as high levels of inflammatory cytokines have been found31–34. The interaction between the effect of anticoagulant therapy and the DIC score in patients aged 80 years that was found in our study may support these previous studies. In other words, the onset of sepsis itself may determine the outcome regardless of the severity of DIC in the elderly. In contrast, patients aged 50 years showed a different interaction between anticoagulant therapy and the DIC score. Relatively young patients with sepsis are expected to respond well to the treatment of underlying infection, followed by the modulation of dysregulated inflammatory and coagulofibrinolytic reactions. Therefore, it is presumed that the development of DIC in relatively young patients with sepsis may have minimal effect on the outcome, although the detailed underlying mechanisms remain unclear.
The present study failed to show a beneficial effect of anticoagulant therapy on the SOFA score of the population in any age group. However, this does not mean that organ dysfunction cannot be improved by anticoagulant therapy, because the SOFA scores were evaluated relatively early (72 h after admission). As anticoagulant therapy improved hospital mortality in certain ages, it may improve SOFA scores later than 72 h after admission. Our results should be considered when setting up the study designs of future RCTs to validate the effects of anticoagulant therapy against sepsis.
The main pathophysiology of DIC is uncontrolled thrombin generation, leading to ischemic organ dysfunction due to microvascular thrombosis, which is detrimental in the context of pathology. In contrast, the concept that microvascular thrombosis produced by innate immunity is a physiological process to maintain body homeostasis has come to be known as immunothrombosis3,35. From these perspectives, individuals who could be at an advantage with regard to immunothrombosis, namely, non-DIC patients, should not be treated with anticoagulant therapy. The harmful effects of anticoagulant therapy against non-DIC patients were confirmed in the present study (Figs. 3 and 4).
The current study has several limitations. First, although the present data set was prospectively collected, causal relationships could not be defined because of the study’s retrospective design. Second, this study did not assess the dosage and duration of anticoagulant agents. Additionally, this study was unable to evaluate the effects of individual anticoagulant agents or combination therapy because we defined anticoagulant therapy as the administration of antithrombin, recombinant human thrombomodulin, or their combination. Third, the present study data set did not include information on adverse effects, including serious bleeding complications associated with anticoagulant therapy, which can cause unfavorable outcomes. Fourth, data elements required to control potential confounders might have resulted in biased effect estimates. Finally, the study being conducted in a single country may limit the generalizability of the obtained results.
In conclusion, anticoagulant therapy, namely, the administration of antithrombin, recombinant human thrombomodulin, or their combination, showed a beneficial effect on hospital mortality according to a higher JAAM DIC score in patients aged 60 to 70 years with sepsis. Anticoagulant therapy, however, was not associated with a better outcome in relatively young (50 years) and older (80 years) patients. In addition, anticoagulant therapy in patients with low DIC scores was associated with the deterioration of organ function and poor outcomes, which may be caused by the destruction of the physiological hypercoagulative state and immunothrombosis. We suggest setting the inclusion criteria of future RCTs examining the effects of anticoagulant therapy against sepsis based on the results obtained from the present study.