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Disseminated intravascular coagulation (DIC) is a common and life-threatening complication in sepsis. Sepsis-associated DIC is recognized as the systemic activation in coagulation with suppressed fibrinolysis that leads to organ dysfunction in combination with systemic intravascular inflammation. In this process, thrombin contributes a key role in connecting both coagulation and inflammation. Endothelial injury, a result of sepsis, causes DIC due to the effect of multiple activated factors that include neutrophils, platelets, and damage-associated molecular patterns. Recent advances in the understanding of pathophysiology have made it possible to diagnose sepsis-associated DIC at earlier timing with better accuracy. However, progress in the treatment is still limited, and new therapeutics for sepsis-associated DIC are needed.

Recombinant human thrombomodulin (rhTM) is often used concomitantly with antithrombin (AT) to treat disseminated intravascular coagulation (DIC). This observational study aimed to investigate the efficacy and safety of AT+rhTM combination therapy. One hundred twenty-nine patients with severe sepsis and DIC participated in this study. Of these, 78 patients were treated with AT+rhTM (AT+rhTM group) and 51 patients were treated with AT alone (AT group). We compared coagulation and inflammation markers, Sequential Organ Failure Assessment score, and DIC score at day 0 (baseline) and day 7 between the 2 groups. Bleeding events and 28-day mortality were also compared. Platelet counts and D-dimer levels at day 7 significantly improved in the AT+rhTM group compared with the AT group, and 28-day mortality was significantly lower in the AT+rhTM group than in the AT group (AT+rhTM: 15.4% vs AT: 29.4%). During the study period, the incidence of bleeding complications was similar in both groups (AT+rhTM: 6.4% vs AT: 7.8%). Compared with AT monotherapy, combination therapy with AT and rhTM may be more effective in improving platelet counts and D-dimer levels, as well as reducing mortality, in patients with severe sepsis-associated DIC.

Inflammatory mediators and hemostatic markers were evaluated in patients enrolled in a phase-2b study evaluating the safety and efficacy of recombinant thrombomodulin (ART-123) in patients with sepsis and suspected disseminated intravascular coagulation (DIC). In contrast to controls, patients with sepsis and suspected DIC showed an increase in the circulating levels of inflammatory and fibrinolytic markers. The levels of procalcitonin (PCT), interleukin 6 (IL-6), interleukin 10 (IL-10), anaphylatoxin C5a, plasminogen activator inhibitor 1 (PAI-1), and myeloperoxidase were higher in the patients with sepsis and suspected DIC, whereas protein C (PrC) exhibited a significant decrease. When the patients with overt and nonovert DIC were compared, the PrC level was lower, and PCT, PAI-1, IL-6, and IL-10 levels were higher in the patients with overt DIC. These results indicate that inflammation is elevated in sepsis and suspected DIC, and inflammation, impairment of fibrinolysis, and overconsumption of PrC may play a key role in the pathogenesis of DIC.

Collectin kidney 1 (CL-K1) is a recently identified collectin that is synthesized in most organs and circulates in blood. CL-K1 is an innate immune molecule that may play a significant role in host defense. As some collectins also play a role in coagulation, we hypothesized that an effect of CL-K1 may be apparent in disseminated intravascular coagulation (DIC), a gross derangement of the coagulation system that occurs in the setting of profound activation of the innate immune system. DIC is a grave medical condition with a high incidence of multiple organ failure and high mortality and yet there are no reliable biomarkers or risk factors. In our present study, we measured plasma CL-K1 concentration in a total of 659 specimens, including 549 DIC patients, 82 non-DIC patients and 27 healthy volunteers. The median plasma CL-K1 levels in these cohorts were 424, 238 and 245 ng/ml, respectively, with no significant difference in the latter two groups. The incidence of elevated plasma CL-K1 was significantly higher in the DIC patients compared to the non-DIC patients, resulting in an odds ratio of 1.929 (confidence interval 1.041–3.866). Infection, renal diseases, respiratory diseases, and cardiac diseases were more frequently observed in the DIC group than in the non-DIC group. In the DIC group, vascular diseases were associated with elevated plasma CL-K1 levels while age and acute illness had little effect on plasma CL-K1 levels. Independent of DIC, elevated plasma CL-K1 levels were associated with respiratory disease and coagulation disorders. These results suggest that specific diseases may affect CL-K1 synthesis in an organ dependent manner and that elevated plasma CL-K1 levels are associated with the presence of DIC. Further investigations in cohorts of patients are warranted. We propose that elevated plasma CL-K1 may be a new useful risk factor and possibly biomarker for the prediction of developing DIC.

Severe sepsis remains the most common cause of death in critically ill patients, and thrombin plays a crucial role in the pathogenesis of sepsis-associated disseminated intravascular coagulation (DIC). The purpose of this study was to profile prothrombin fragment (F1.2), thrombin–antithrombin complex (TAT), and d-dimer (DD) throughout the course of hospital stay in patients identified with sepsis. Plasma samples from patients enrolled in the ART-123 study, a phase 2b, international, multicenter, randomized placebo-controlled trial were analyzed for various parameters using enzyme-linked immunosorbent assay methods. Plasma levels of F1.2, DD, and TAT were measured at several time points following administration of recombinant thrombomodulin or placebo, and the results were tabulated. In the group treated with thrombomodulin, the median F1.2 levels demonstrated a 16% decrease from the baseline to day 7, while the placebo group showed an 8% increase. Both the treatment groups showed a gradual decrease in the TAT and DD, with the group treated with thrombomodulin demonstrating twice the decrease over the 7-day period. Although the data were widely scattered, these results show that DIC represents a hypercoagulable state along with other hemostatic abnormalities and the activation of the inflammatory process. Modulation of these activation processes through targets such as DD, F1.2, and TAT may play an important regulatory role in the pathogenesis of sepsis-associated coagulopathy. Moreover, this study validates the hypothesis that thrombomodulin downregulates the thrombin generation mediators/markers in sepsis-associated DIC.

Disseminated intravascular coagulation (DIC) is an acquired clinicobiological syndrome characterized by widespread activation of coagulation leading to fibrin deposition in the vasculature, organ dysfunction, consumption of clotting factors and platelets, and life-threatening hemorrhage. Disseminated intravascular coagulation is provoked by several underlying disorders (sepsis, cancer, trauma, and pregnancy complicated with eclampsia or other calamities). Treatment of the underlying disease and elimination of the trigger mechanism are the cornerstone therapeutic approaches. Therapeutic strategies specific for DIC aim to control activation of blood coagulation and bleeding risk. The clinical trials using DIC as entry criterion are limited. Large randomized, phase III clinical trials have investigated the efficacy of antithrombin (AT), activated protein C (APC), tissue factor pathway inhibitor (TFPI), and thrombomodulin (TM) in patients with sepsis, but the diagnosis of DIC was not part of the inclusion criteria. Treatment with APC reduced 28-day mortality of patients with severe sepsis, including patients retrospectively assigned to a subgroup with sepsis-associated DIC. Treatment with APC did not have any positive effects in other patient groups. The APC treatment increased the bleeding risk in patients with sepsis, which led to the withdrawal of this drug from the market. Treatment with AT failed to reduce 28-day mortality in patients with severe sepsis, but a retrospective subgroup analysis suggested possible efficacy in patients with DIC. Clinical studies with recombinant TFPI or TM have been carried out showing promising results. The efficacy and safety of other anticoagulants (ie, unfractionated heparin, low-molecular-weight heparin) or transfusion of platelet concentrates or clotting factor concentrates have not been objectively assessed.

Secondary hemophagocytic lymphohistiocytosis (HLH) is a life-threatening disease. In the present retrospective study, we aimed to investigate coagulation disorders and their outcome implications in patients with secondary HLH. We evaluated clinical characteristics and the relationship between coagulation indices and prognosis in HLH patients (n = 141). The information, including clinical symptoms, laboratory indicators, and coagulation indices, was evaluated. Coagulation disorders and bleeding events occurred in 95 (67.4%) and 60 (42.6%) patients, respectively. A coagulation index analysis primarily showed elevated levels of D-Dimer, the international standardized ratio (INR), prothrombin time (PT), activated partial thromboplastin time (APTT), and thrombin time (TT), while the prothrombin activity, fibrinogen levels, and platelet levels were significantly decreased. Dominant disseminated intravascular coagulation (DIC) occurred in 76 patients (53.9%). Patients with lymphoma-associated hemophagocytic syndrome (LAHS) frequently exhibited apparent coagulation disorders. Multivariate analysis revealed that age ≥ 29.5 years, bleeding events, APTT ≥ 47.3 s, fibrinogen ≤ 1.68 g/L, and absolute neutrophil counts (ANC) of ≤ 1.21 × 109/L were independent prognostic factors. We thereby devised a prognostic scoring system and stratified patients into low-risk (0–2 points), intermediate-risk (3–4 points), and high-risk (5–7 points) groups, and the 1-year overall survival rates in the above-mentioned groups were 66.40%, 40.00%, and 2.30%, respectively (P < 0.0001). In conclusion, coagulation dysfunctions and bleeding tendencies were common characteristics in HLH patients. We constructed a novel prognostic score model based on APTT, fibrinogen level, ANC, age, and bleeding events, which had superior prognostic value compared with these markers alone.

Objectives: To provide a review of the definition, pathophysiology, differential diagnosis, and treatment of disseminated intravascular coagulation (DIC). Methods: A case scenario and a review of the literature related to the pertinent facts concerning DIC are provided. Results: DIC is a systemic pathophysiologic process and not a single disease entity, resulting from an overwhelming activation of coagulation that consumes platelets and coagulation factors and causes microvascular fibrin thrombi, which can result in multiorgan dysfunction syndrome from tissue ischemia. Some conditions associated with acute DIC include septic shock, exsanguinating trauma, burns, or acute promyelocytic leukemia. Conclusions: The massive tissue factor stimulus results in excess intravascular thrombin, which overcomes the anticoagulant systems and leads to thrombosis. Because of consumption of coagulation factors and platelets, DIC also has a hemorrhagic phase. Treatment of the bleeding patient with DIC is supportive with the use of blood components.

Severe heatstroke is often complicated by disseminated intravascular coagulation (DIC). The aim of this study was to evaluate platelet function assessed through thromboelastography (TEG) at the emergency department (ED) and DIC severity among patients with heatstroke. We performed a retrospective single-tertiary hospital cohort study. Patients admitted to an intensive care unit (ICU) with heatstroke were enrolled. Platelet function was evaluated as the difference between citrated functional fibrinogen-maximum amplitude (CFF-MA) and citrated rapid TEG-maximum amplitude (CRT-MA) at the ED. DIC was defined as a score ≥ 4 points based on the Japanese Association of Acute Medicine score. A total of 31 patients with heatstroke were enrolled. The median platelet count was 18.1 × 104/μL, (interquartile range [IQR]: 12.6–25.0 × 104/μL), and the median platelet function evaluated as CFF-MA-CRT-MA was 34.4 mm (IQR: 27.8–37.8 mm). Among several clinical and TEG-related parameters, the platelet function was strongly correlated with the DIC score (R = −0.63, p < 0.001) and significantly associated with DIC development (area under the receiver operating characteristic curve 0.87 [95 % confidence interval: 0.72–0.99]). These results suggested that platelet dysfunction occurs in heatstroke-induced DIC, indicating that platelet function evaluation by TEG can provide complementary information and enhance our understanding about the subtypes of heatstroke. •TEG measurement of platelet function correlates with DIC severity in heatstroke, and facilitates early diagnosis and phenotyping.

We investigated the epidemiology and outcome of disseminated intravascular coagulation (DIC) in patients with sepsis. We analyzed data from a multicenter observational study (Japan Septic Disseminated Intravascular Coagulation [JSEPTIC-DIC] study) conducted in 42 intensive care units in Japan. DIC scores were calculated using two scoring systems: the International Society on Thrombosis and Haemostasis (ISTH) and Japanese Association for Acute Medicine (JAAM) criteria. We compared demographics and clinical characteristics of patients with and without DIC, and performed multivariable logistic regression analyses to assess the association of diagnosis and scores for DIC with in-hospital mortality. Of 1895 eligible patients, 1162 (61%) and 554 patients (29%) were diagnosed as having DIC by the JAAM and ISTH criteria, respectively. Patients with DIC had higher in-hospital mortality compared with those without DIC (33% vs. 20% in JAAM and 38% vs. 24% in ISTH). However, in multivariable analysis, the JAAM score (odds ratio 1.026, 95% confidence interval 0.958–1.097; p = 0.465) and the ISTH score (odds ratio 1.049, 95% confidence interval 0.969–1.135; p = 0.238) did not have an independent association with in-hospital mortality. Patients with sepsis and DIC have high mortality. However, the DIC are not independently associated with in-hospital mortality. •We investigated the epidemiology and outcome of disseminated intravascular coagulation (DIC) in patients with sepsis.•We analyzed data from a multicenter observational study (JSEPTIC-DIC) conducted in 42 ICUs in Japan.•Of 1895 eligible patients, 61% and 29% were diagnosed as having DIC by the JAAM and ISTH criteria, respectively.•DIC had higher in-hospital mortality compared with those without DIC.•In multivariable analysis, both scores did not have an independent association with in-hospital mortality.