Treatment Of Disseminated Intravascular Coagulation Research Articles

MiR-19a-3p downregulates tissue factor and functions as a potential therapeutic target for sepsis-induced disseminated intravascular coagulation

Sepsis-induced disseminated intravascular coagulation (DIC) is a common life-threatening terminal-stage disease with high mortality. This study aimed to identify effective miRNAs as therapeutic targets for DIC. Bioinformatics and luciferase reporter gene analyses were performed to predict miR-19a-3p and validate that it targets tissue factor (TF). Quantitative real-time PCR was used to detect the expression of miR-19a-3p and TF, and TF procoagulant activity was determined using the chromogenic substrate method. Western blotting was used to detect the protein levels of TF, AKT serine/threonine kinase (AKT), extracellular regulated protein kinases (ERK), nuclear factor kappa B (NF-κB) P65, NFKB inhibitor alpha (IκB-a) and their phosphorylated counterparts in cell experiments. Furthermore, a rat model was established to explore the potential of miR-19a-3p in DIC treatment. As a result, a human clinical study revealed that miR-19a-3p was downregulated and that TF was upregulated in neonates with sepsis-induced DIC compared with those in the control group. The luciferase reporter assay showed that TF was a direct target of miR-19a-3p. Cell experiments verified that the mRNA and protein levels of TF, and the p-AKT/AKT, p-Erk/Erk, p-P65/P65, p-IκB-a/IκB-a ratios, and TF procoagulant activity were significantly decreased in lipopolysaccharide (LPS) -induced human peripheral blood mononuclear cells (PBMCs) and human umbilical vein endothelial cells (HUVECs) inhibited by overexpression of miR-19a-3p, and that miR-19a-3p regulating TF was dependent on the NF-kB and AKT pathways. In vivo, miR-19a-3p injection into DIC rats suppressed the mRNA expression of TF; more importantly, significant improvements in coagulation function indicators and in histopathologies of lung and kidney were observed. In conclusion, miR-19a-3p may suppress DIC by targeting TF and might be a potential therapeutic target in treating sepsis-induced DIC.

Beyond Cytokine Storm: Optimizing Treatment Strategies to Target the Complex Interplay between CAR Mediated Inflammatory Response, Disseminated Intravascular Coagulation and Macrophage Activation Syndrome

Background: Cytokine release syndrome (CRS) is a well described, non-specific toxicity of CAR therapy caused by high-level immune activation. Generally, CRS starts within a week of CAR-T cell infusion, is typically self-limited, and mitigation strategies utilizing tocilizumab (anti-IL6 receptor antibody) and/or corticosteroids are rapidly effective. Despite initial improvement, delayed manifestations including disseminated intravascular coagulation (DIC) and macrophage activation syndrome (MAS) may occur in some for whom CAR mediated inflammatory responses continue to evolve. To improve upon the safety profile of CAR therapy, we report on our experience with DIC and MAS.Design: We report on the toxicity profile of the first 30 children and young adults with relapsed/refractory CD22+ ALL treated on our phase I dose escalation anti-CD22 CAR therapy. All had routine monitoring of cytokines, fibrinogen, D-Dimer, PT/INR, PTT and CBC. Following observations of clinically significant DIC, we prospectively evaluated markers of activated coagulation, including: thrombomodulin, E-selectin, s-VCAM, v-ICAM, P-selectin, prothrombin fragment 1 + 2, tissue factor, and PAI-1. Markers for MAS, including ferritin, triglycerides and soluble IL2R were monitored, as well as immunohistochemical staining for hemophagocytosis on the bone marrow aspirate/biopsy.Results: From December 2014 to July 2017, 30 patients with ALL were treated at 3 dose levels. CRS was seen in 24/30 (80%), which was grade 1-2 in all, except for one grade 4. Eight of 24 (33%) with CRS developed DIC, which was grade 2 (no bleeding) in 3 patients and grade 3 (with bleeding) in 5 patients. Bleeding complications were primarily mucosal and included diffuse alveolar hemorrhage, epistaxis, hematuria, subconjunctival hemorrhage and petechiae/purpura that appeared disproportionate to the platelet count and typically occurred after resolution of acute CRS. Correspondingly, morphologic evaluation revealed hypogranular/agranular platelets seen in 16 of 20 patients (confirmed by electron microscopy in one), of whom 7 had DIC, suggesting an acquired platelet function defect; such patients received higher transfusion support. In those with DIC, PT/INR/PTT and D-Dimer rose with onset of CRS. Fibrinogen, initially elevated with the onset of CRS, fell precipitously with resolution of fever. At the time of clinically evident DIC, in 8 of 12 evaluable subjects, P-selectin values rose at least 50%, on average 17.6 days after CAR-T infusion and in 11 of 12 evaluable subjects, endothelial markers rose and peaked 2 weeks after CAR-T infusion (mean 15.2 days). Treatment of DIC was primarily supportive; methylprednisolone, starting at 0.5-1 mg/kg was initiated in patients with active bleeding, and continued q6-8 hours until stabilization. Resolution of DIC typically coincided with decrease in ferritin, suggesting an inflammatory mediated coagulopathy. Accordingly, patients with DIC also had statistically significantly higher ferritin (median 361,585 v 14,349, p<0.0001) IFN-g, IL-1b, IL-6, IL-8, IL-10 and MIP-1a (p<0.01 for all) than in those without DIC, mimicking elevations seen in MAS. Further supporting the link to MAS, 3 of 4 patients with DIC had soluble IL2R levels > 5-fold x the upper limit of normal at 2 weeks post CAR therapy. Additionally, one patient with DIC had active hemophagocytosis at the 1 month evaluation (Figure), which in the constellation of hepatic transaminitis, cytopenias and hyperferritinemia led to a diagnosis of MAS. Treatment with single agent anakinra, an IL-1 receptor antagonist, initiated as a steroid-sparing agent, was well tolerated and led to full resolution of hemophagocytosis; importantly, it did not impede ongoing CAR response, with clearance of all minimal residual disease from the one month to the two-month restaging time point.Conclusion: An intricate relationship exists between the initial inflammatory CRS, and later complications of DIC and MAS potentially induced by CAR T related inflammation. Although steroids and supportive care measures may stabilize DIC, cytokine profiles, which include elevated IL-1b, can assist when choosing targeted, steroid-sparing therapies such as anakinra. Future directions will include exploring the link between inflammation, DIC, and MAS and optimizing targeted anti-inflammatory strategies earlier in the treatment course to prevent serious complications. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Efficacy and safety of plasma hemodiafiltration (PHDF) in pediatric patients with multiple organ dysfunction syndrome with shock and DIC: a preliminary study

BackgroundMultiple organ dysfunction syndrome is the leading cause of death in pediatric intensive care units and can be very critical when combined with shock and disseminated intravascular coagulation (DIC). Currently, there is no effective treatment. We developed a new hemodiafiltration (HDF) method called plasma HDF (PHDF) that uses fresh frozen plasma as replacement fluid and investigated the safety and efficacy of this treatment.MethodsWe enrolled critically ill children with (1) a Pediatric Logistic Organ Dysfunction 2 (PELOD-2) score ≥ 14, (2) a Japanese Ministry of Health and Welfare (JMHW) DIC score ≥ 7, (3) a vasoactive inotropic score (VIS) ≥ 10, and (4) a serum total protein concentration ≤ 5.0 g/dL. PHDF was performed for 5 h and then switched to continuous HDF. The primary endpoint was the 28-day mortality rate. Secondary endpoints included assessment of vital signs, blood test data, and fluid balance from PHDF start to day 7.ResultsNine patients (four males and five females) between 3 days and 40 months of age, weighing 2.1–13 kg, met the inclusion criteria. Although the median PMR was 0.94 (0.71–0.96), the 28-day mortality rate was 22.2% (2/9). One hour after the start of PHDF, there was an increase in mean arterial pressure and central venous pressure and a decrease in heart rate; by day 7, there was a significant decrease in the PELOD-2 score, the JMHW DIC score, and the VIS. Hypoproteinemia also improved the day after PHDF. Water balance was able to remain negative after day 2.ConclusionsPHDF was found to be effective in the treatment of DIC and circulatory failure by supplementing coagulation and antithrombotic factors as well as by raising colloid osmotic pressure to increase circulating blood volume. PHDF has been shown to be a safe and useful treatment for critically ill children and has the potential to improve 28-day survival.

Disseminated intravascular coagulation: epidemiology, biomarkers, and management.

Disseminated intravascular coagulation (DIC) is a systemic activation of the coagulation system, which results in microvascular thrombosis and, simultaneously, potentially life-threatening haemorrhage attributed to consumption of platelets and coagulation factors. Underlying conditions, e.g. infection, cancer, or obstetrical complications are responsible for the initiation and propagation of the DIC process. This review provides insights into the epidemiology of DIC and the current understanding of its pathophysiology. It details the use of diagnostic biomarkers, current diagnostic recommendations from international medical societies, and it provides an overview of emerging diagnostic and prognostic biomarkers. Last, it provides guidance on management. It is concluded that timely and accurate diagnosis of DIC and its underlying condition is essential for the prognosis. Treatment should primarily focus on the underlying cause of DIC and supportive treatment should be individualised according to the underlying aetiology, patient's symptoms and laboratory records.

Diagnosis and treatment of disseminated intravascular coagulation in COVID-19 patients: a scoping review.

BackgroundDisseminated intravascular coagulation (DIC) is noted in severe cases of coronavirus disease 2019 (COVID-19). Recently, a number of studies evaluating the diagnosis and treatment of DIC in COVID-19 patients have been reported.ObjectiveThe aim of this study is to identify existing gaps where further research is needed on the diagnosis and treatment of DIC complicated by COVID-19.MethodsWe used the PRISMA Extension for Scoping Reviews. MEDLINE, CENTRAL, WHO-ICTRP, ClinicalTrial.gov and PROSPERO were searched from their inception to 6 October 2020.ResultsSeven studies were selected; five were already published and two are ongoing. DIC was diagnosed using the International Society on Thrombosis and Hemostasis (ISTH) DIC score (n = 4) and the sepsis-induced coagulopathy (SIC) DIC score (n = 5). Seven studies examined the effectiveness of low molecular weight heparin (LMWH); of these, four studies used a prophylactic dose and five used a therapeutic dose of LMWH. A prophylactic dose of unfractionated heparin (UFH) was investigated in two studies.ConclusionStudies on DIC diagnostic criteria and anticoagulants were limited to the ISTH or SIC scores and heparinoids, particularly LMWH. Further studies are needed to compare these with other available DIC scoring systems and anticoagulants.

Factors influencing the effectiveness of recombinant human soluble thrombomodulin on disseminated intravascular coagulation: a retrospective study

BackgroundAlthough recombinant human soluble thrombomodulin (rTM) has been widely used to treat disseminated intravascular coagulation (DIC) in Japan, there is no consensus regarding rTM efficacy. Therefore, if the factors influencing rTM efficacy is revealed, it may be possible to demonstrate the effectiveness of rTM by limiting the patients who use rTM. This study investigated the factors of rTM treatment which influence DIC status.MethodsThis retrospective case-control study enrolled hospitalized adult patients treated with rTM from October 2010 to May 2020. Among these patients, 227 who were diagnosed with DIC according to the Japanese Association for Acute Medicine DIC scoring system were assessed. The primary endpoint was the 28-day mortality after rTM treatment. For Cox-proportional hazards model, explanatory factors determined using univariate analysis with p < 0.1 were used. In addition, some factors considered to affect DIC-related mortality such as age ≥ 75 years, rTM dose ≥380 U/kg, antithrombin III treatment, and diseases with a poor prognosis (sepsis, solid tumors, and trauma) were added as covariates.ResultsUnivariate analyses suggested that male sex (p = 0.029), treatment in intensive care unit (p = 0.061), and prothrombin time-international normalized ratio (PT-INR) (p < 0.001) were the factors influencing DIC-related 28-day mortality after rTM treatment. According to Cox-proportional hazard analysis, the adjusted odds ratio for DIC-related 28-day mortality in patients with PT-INR ≥ 1.67 was 2.23 (95% confidence interval: 1.451–3.433, p < 0.001), age ≥ 75 years was 1.57 (95% confidence interval: 1.009–2.439, p = 0.046), and male sex was 1.66 (95% confidence interval: 1.065–2.573, p = 0.025), respectively. As life-threatening bleeding events were not observed, prolonged PT-INR might directly or indirectly affect DIC-related mortality caused by rTM treatment.ConclusionrTM treatment for DIC was less effective in male patients with PT-INR ≥ 1.67 and age ≥ 75 years.

Focus on coronavirus disease 2019 associated coagulopathy.

Focus on coronavirus disease 2019 associated coagulopathy.

Advances in the diagnosis and treatment of disseminated intravascular coagulation in haematological malignancies.

Haematological malignancies, including acute leukaemia and non-Hodgkin lymphoma, are one of the underlying diseases that frequently cause disseminated intravascular coagulation (DIC), an acquired thrombotic disorder. Concomitant DIC is associated with the severity of the underlying disease and poor prognosis. The Japanese Society on Thrombosis and Hemostasis released the new DIC diagnostic criteria in 2017. This criteria include coagulation markers such as soluble fibrin and the thrombin-antithrombin complex to more accurately evaluate the hypercoagulable state in patients. Among several groups of anticoagulants available, recombinant human soluble thrombomodulin is most frequently used to treat DIC caused by haematological malignancies in Japan. DIC is remitted in parallel with the improvement of the underlying haematological diseases; thus, there is room for debate regarding whether the treatment of DIC would improve the prognosis of patients. Haematopoietic stem cell transplantation as well as the recently introduced chimeric antigen receptor (CAR)-T-cell therapy are innovative therapies to produce a cure in a subset of patients with haematological malignancies. However, coagulopathy frequently occurs after these therapies, which limits the success of the treatment. For example, DIC is noted in approximately 50% of patients after CAT-T-cell therapy in conjunction with cytokine release syndrome. Hematopoietic stem cell transplantation (HSCT) causes endotheliitis, which triggers coagulopathy and the development of potentially lethal complications, such as sinusoidal obstruction syndrome/veno-occlusive disease and transplant-associated thrombotic microangiopathy. This review article describes the pathogenesis, clinical manifestation, diagnosis, and treatment of DIC caused by haematological malignancies, CAR-T-cell therapy, and HSCT.

Risk factors and treatments for disseminated intravascular coagulation in neonates

BackgroundAlthough disseminated intravascular coagulation (DIC) is a critical disease, there is few gold standard interventions in neonatal medicine. The aim of this study is to reveal factors affecting neonatal DIC at birth and to assess the effectiveness of rTM and FFP for DIC in neonates at birth.MethodsWe retrospectively evaluated DIC score on the first day of life in neonates with underlying conditions associated with DIC. DIC in neonates was diagnosed according to Japan Society of Obstetrical, Gynecological & Neonatal Hematology 2016 neonatal DIC criteria.ResultsComparing neonates with DIC scores of ≥3 (n = 103) to those < 3 (n = 263), SGA, birth asphyxia, low Apgar score, hemangioma, hydrops, PIH, and PA were statistically increased. Among 55 neonates underwent DIC treatment, 53 had birth asphyxia and 12 had intraventricular hemorrhage. Forty-one neonates received FFP or a combination of FFP and antithrombin (FFP group), while 14 neonates received rTM or a combination of rTM, FFP, and antithrombin (rTM group). DIC score before treatment in the rTM group was significantly higher than in the FFP group (4.7 vs 3.6, P < 0.05). After treatment, DIC scores in both groups were significantly reduced on Day 1 and Day 2 (P < 0.05).ConclusionsAmong various factors associated with DIC in neonates at birth, birth asphyxia is particularly significant. Furthermore, rTM in combination with FFP therapy was effective for neonatal DIC at birth.

Prognostic value of selected hypercoagulability markers in sepsis. A prospective study

Introduction. Sepsis is a heterogeneous syndrome caused by an unbalanced host response to an infection, resulting in organ dysfunction. Disseminated intravascular coagulation (DIC) varies widely from 30 % to 60 % and depends on different scoring systems. An overt DIC easily identified, while the pre-existing phase of hypercoagulability can’t be detected by screening coagulation tests. Preventive DIC treatment is hardly possible without an early diagnostics. Objectives. The aim of the study is identifying the hypercoagulabiliy markers in septic patients with hypercoagulability pattern on thromboelastometry (TEM) and matching them to the outcome. Materiasl and methods. ROTEM screening of septic patients revealed 85 ones with pattern of hypercoagulability. Thrombin generation test with thrombomodulin, screening coagulation tests, anticoagulants levels and selected hypercoagulability markers were performed from frozen plasma samples. According to the outcome patients were divided to survivors and nonsurvivors. Results. The survivors group included 62 patients and nonsurvivors — 19. Thrombin generation test revealed only 7 cases of hypercoagulability. There was no significant difference in endogenous thrombin potential 20 (10; 25) % vs 14 (10; 31) % and peak thrombin 8 (2,9; 16) % vs 7 (3; 18) % in survivors and nonsurvivors, respectively. Other significant differences between survivors vs nonsurvivors are: protein C 79,5 ± 28 % vs 64,9 ± 25 %, FVIII 226,4 ± 66 % vs 276,6 ± 94 % , von Willebrand factor 269 ± 129 % vs 435 ± 181 %, Аntithrombin 82 (60; 94) % vs 65 (41; 80) %, and D-dimer 2157 (1341; 3964) mcg/l vs 3253 (1911; 6914) mcg/l, respectively. Conclusion. Septic patients with TEM criteria of hypercoagulability may have unique set of thrombophilia markers. Local screening coagulation tests do not affect the prognosis. Low level of protein C and antithrombin, as well as high FVIII, von Willebrand factor, D-dimer worsen outcome.

Tetrahydropalmatine has a therapeutic effect in a lipopolysaccharide-induced disseminated intravascular coagulation model.

ObjectivesThe aim of this study was to determine the therapeutic effects of tetrahydropalmatine (Tet) on disseminated intravascular coagulation (DIC) by exploring the role of Tet using a lipopolysaccharide (LPS)-induced DIC model.Methods/Materials: We established a mouse DIC model by injecting LPS. Hematoxylin-eosin (HE) staining was performed to detect liver and kidney damage. Blood samples were obtained to determine liver and kidney injury indexes, coagulation indexes, and inflammatory cytokines. An in vitro cell inflammation model was also established. Tumor necrosis factor-α (TNF-α) levels and nuclear factor kappa B (NF-κB) signaling pathway activation were determined by western blot.ResultTet ameliorated the damage to organ tissues, improved coagulation indexes, and reduced the inflammatory cytokine production in LPS-induced mouse DIC. Tet also inhibited TNF-α expression by suppressing NF-κB signaling pathway activation in an in vitro LPS model using RAW 264.7 macrophages.ConclusionsTet has a mitigating and therapeutic effect on the LPS-induced DIC model via anticoagulant and anti-inflammatory effects, showing its potential as an adjunct to DIC treatment.

Aneurysm-related disseminated intravascular coagulation successfully treated by endovascular repair.

Aortic abdominal aneurysm (AAA) is an uncommon etiology of disseminated intravascular coagulation (DIC). The authors report a case of an 81-year-old male patient who presented with hematuria, intraoral hemorrhage, melaenas and ecchymosis of the lower back and of the abdominal wall, after being medicated with etoricoxib for a back pain. During the study, an abdominal aortic aneurysm, which prolonged to the left common and internal iliac artery, was discovered. The diagnosis of AAA induced DIC was made. After endovascular aneurysm repair (EVAR), the patient’s hemorrhagic manifestations disappeared and the laboratory findings normalized. In conclusion, the state-of-the-art treatment of DIC is the elimination of the underlying disease; in this case, EVAR was proven to be effective in treating the aortic aneurysm and the AAA-related DIC.

Bacterial Endotoxin Activates the Coagulation Cascade through Gasdermin D-Dependent Phosphatidylserine Exposure

Excessive activation of the coagulation system leads to life-threatening disseminated intravascularcoagulation (DIC). Here, we examined the mechanisms underlying the activation of coagulation by lipopolysaccharide (LPS), the major cell-wall component of Gram-negative bacteria. Wefound that caspase-11, a cytosolic LPS receptor,activated the coagulation cascade. Caspase-11 enhanced the activation of tissue factor (TF), an initiator of coagulation, through triggering the formation of gasdermin D (GSDMD) pores andsubsequent phosphatidylserine exposure, in a manner independent of cell death. GSDMD poresmediated calcium influx, which induced phosphatidylserine exposure through transmembrane protein 16F, a calcium-dependent phospholipid scramblase. Deletion of Casp11, ablation of Gsdmd, orneutralization of phosphatidylserine orTF prevented LPS-induced DIC. In septic patients, plasma concentrations of interleukin (IL)-1α andIL-1β, biomarkers of GSDMD activation, correlated with phosphatidylserine exposure in peripheral leukocytes and DIC scores. Our findings mechanistically link immune recognition of LPS to coagulation, with implications for the treatment of DIC.

Therapeutic and Adverse Effects of Thrombomodulin Alfa to Treat Sepsis-Induced Disseminated Intravascular Coagulation.

In the treatment of disseminated intravascular coagulation (DIC), which is a complication of underlying diseases such as infections and malignant tumors, effective plasma concentrations of thrombomodulin (TM) alfa range from 300 to 900 ng/mL; however, appropriate concentrations when treating sepsis-induced DIC are unknown. Thus, our aim was to determine the relationship between plasma concentrations of TM alfa and its therapeutic effects, and hemorrhagic adverse events. First, we calculated the plasma trough concentrations of TM alfa in septic DIC patients. Next, we divided patients into two groups according to their plasma concentrations into a low- and high-concentration group based on a cut-off value of 600 ng/mL. Fourteen and 35 patients were included in the low- and high-concentration groups, respectively. The Japanese Association for Acute Medicine DIC diagnostic criteria score 4 days after TM alfa administration decreased significantly by 2.06 points from baseline in the high-concentration group compared with 0.71 points in the low-concentration group. The 90-day survival rate was significantly higher in the high-concentration group (85.4%) than in the low-concentration group (49.0%) (hazard ratio, 0.27; 95% confidence interval: 0.09-0.86). In contrast, the incidence of serious hemorrhage was not significantly different between the groups. The recommended plasma concentration of TM alfa in the treatment of septic DIC was determined to be higher than 600 ng/mL, and a dose of 380 U/kg (0.06 mg/kg) was necessary to achieve this concentration.

Human Soluble Recombinant Thrombomodulin, ART-123, Resolved Early Phase Coagulopathies, but Did Not Significantly Alter the 28 Day Outcome in the Treatment of DIC Associated with Infectious Systemic Inflammatory Response Syndromes.

Disseminated intravascular coagulation (DIC) is a catastrophic systemic disorder of coagulation, resulting in uncontrollable bleeding, multiple organ failure, and death. Sepsis is one of the common causes of DIC. Despite many attempts to correct these coagulation pathologies, no adjunctive treatments have been shown to improve the mortality of DIC associated with sepsis. Although some clinical studies showed a recently developed human recombinant thrombomodulin, ART-123, might be effective in the treatment of DIC, few randomized, placebo-controlled studies have been conducted. In this study, we treated 60 DIC patients associated with systemic inflammatory response syndrome (SIRS) using ART-123 (n = 29) or saline as a placebo (n = 31). The basal clinical characteristics were similar in both groups. We compared clinical severity scores and DIC score in acute phase, and 28 day mortality between the two groups. Our study demonstrated the DIC score improved a few days earlier in the ART-123 group than the placebo group, and there were no major life-threatening adverse events in both groups. The overall survival rate at day 28 was not significantly altered. In conclusion, ART-123 can be used safely in DIC associated with infectious SIRS patients; however, its true efficacy in the treatment of DIC needs to be further investigated.

Comparison of Danaparoid Sodium and Synthetic Protease Inhibitors for the Treatment of Disseminated Intravascular Coagulation Associated with Hematological Malignancies: A Retrospective Analysis

Background: Danaparoid sodium and synthetic protease inhibitors (SPIs) have been approved for the treatment of disseminated intravascular coagulation (DIC) in Japan. Objectives: To compare the clinical results of the treatment of DIC with danaparoid or SPIs. Methods: We retrospectively examined 188 patients with hematological malignancy-related DIC. Results: DIC resolution rate in the danaparoid group was higher than that in the SPIs group (61.5 vs. 42.6%; p = 0.031) on day 7. Multivariate analysis identified the response to chemotherapy as independent predictive factor for DIC resolution on day 7 (odds ratio, OR, 2.28; 95% confidence interval, CI, 1.21–4.31; p = 0.011). While there was no significant difference in the DIC resolution rate on day 14 (75.0 vs. 62.4%; p = 0.117), in a subgroup analysis of patients who did not show an improvement in the underlying disease, the danaparoid group showed a significantly better DIC resolution rate (OR 3.89; 95% CI 1.15–13.2; p = 0.030). There was no difference in the rate of cumulative mortality from bleeding within 28 days between the 2 groups (6.6 vs. 3.3%; p = 0.278). Conclusions: Danaparoid may be associated with more frequent resolution of DIC in patients with refractory underlying disease.

Multicenter clinical experience with recombinant soluble thrombomodulin for disseminated intravascular coagulation associated with severe acute cholecystitis

BackgroundSevere acute cholecystitis (AC) is defined by the association of organ dysfunction, including hematological dysfunction, with AC. Severe AC is often complicated by disseminated intravascular coagulation (DIC), the diagnostic criteria of which overlap with AC-associated hematological dysfunction. Since the diagnosis of DIC often delays definitive surgical management of severe AC, treatment of DIC in this setting is clinically important. Recombinant human soluble thrombomodulin (rTM) is a new agent that has proven clinically useful for treating DIC. However, the relevance of rTM to sepsis-induced DIC caused by AC has not been clinically evaluated. This retrospective multicenter study aimed to determine the clinical impact of rTM on sepsis-induced DIC caused by AC. MethodsThis retrospective multicenter study initially included 68 consecutive patients and proceeded between July 2014 and December 2017. The inclusion criterion was sepsis-induced DIC caused by severe AC due to benign disease. Sixteen of the 68 patients were excluded in this study due to having advanced malignant tumors. Finally, 42 patients were enrolled in this study. We treated DIC with AC using Recomodulin® Injection (rTM) at doses of 130 or 380 U/kg/day. Results17 and 25 patients were treated with and without rTM, respectively. Values on days 3 and 7 did not significantly differ between the groups for PT-INR (P = 0.38 and P = 0.16, respectively) and FDP (P = 0.06 and P = 0.08, respectively), and PLT was significantly increased in the rTM group at day 7 (P = 0.03). Resolution rates of DIC on day 7 were significantly higher in the group treated with, than without rTM (94.1% [16/17] vs. 68.0% [17/25], P = 0.04). Two patients in each group died of sepsis-induced DIC associated with severe AC, and thus mortality rates did not significantly differ. ConclusionsrTM can may be improve the resolution rate of sepsis-induced DIC due to severe AC. Future studies should include more patients to validate our findings.

Management of disseminated intravascular coagulation associated with placental abruption and measures to improve outcomes

Placental abruption is a condition that should be carefully considered in perinatal management because it is associated with serious events in both the mother and neonate, such as intrauterine fetal death, cerebral palsy, obstetric critical bleeding, and uncontrollable bleeding. The concomitant presence of disseminated intravascular coagulation (DIC) more easily causes critical bleeding that may necessitate hysterectomy or multi-organ failure resulting in maternal death. Therefore, early management should be provided to prevent progression to serious conditions by performing both hemostatic procedures and DIC treatment. To take measures to improve the outcomes in both the mother and neonate, health guidance for pregnant women, early diagnosis, early treatment, development of the emergency care system, and provision of a system for transport to higher-level medical institutions should be implemented.

DIC: state-of-the-art in diagnosis and management

Disseminated intravascular coagulation (DIC) is a serious disease that, in the presence of underlying disease, causes persistent, generalized, marked coagulation activation and recurrent formation of microthrombi in microvessels. Although the DIC pathophysiology differs from that of thrombotic microangiopathy (TMA), distinguishing the two is sometimes challenging. At least, differential diagnosis using coagulation tests of values such as PT and APTT is difficult. While the mechanisms of DIC development differ according to the underlying disease, tissue factor plays a vital role in common. The classification of the DIC type is essential not only for understanding pathophysiology but also for the appropriate choice of DIC treatment. As a revision of the old DIC diagnostic criteria of the Japanese Ministry of Health, Labour and Welfare, new diagnostic criteria for DIC have been established by the Japanese Society on Thrombosis and Hemostasis (2017 edition). The new criteria are estimated to play a pivotal role in the future diagnosis of DIC. From the perspective of analysis by genetic techniques, the protein C/thrombomodulin system and plasminogen activator inhibitor play crucial roles in the control and development of DIC.

Nationwide registry of sepsis patients in Japan focused on disseminated intravascular coagulation 2011\u20132013

Sepsis is a syndrome with physiologic, pathologic, and biochemical abnormalities induced by infection. Sepsis can induce the dysregulation of systemic coagulation and fibrinolytic systems, resulting in disseminated intravascular coagulation (DIC), which is associated with a high mortality rate. Although there is no international consensus on available treatments for sepsis-induced DIC, DIC diagnosis and treatment are commonly performed in Japanese clinical settings. Therefore, clinical data related to sepsis-induced DIC diagnosis and treatment can be obtained from Japanese clinical settings. We performed a retrospective nationwide observational study (Japan Septic Disseminated Intravascular Coagulation [J-SEPTIC DIC] study) to collect data regarding characteristics of sepsis patients in Japan, with a focus on coagulofibrinolytic dysregulation and DIC treatment received by each patient. The J-SEPTIC DIC study collected information for a total of 3,195 patients with severe sepsis and septic shock and is the largest data set in Japan on DIC diagnosis and treatment in clinical settings.