Disseminated Intravascular Coagulation Development Research Articles

Polyunsaturated fatty acid-derived lipid mediator Resolvin D1 alleviates sepsis-induced disseminated intravascular coagulation via Caspase-1/Gasdermin D pyroptotic pathway

Sepsis-induced disseminated intravascular coagulation (DIC) is characterised by abnormal blood clotting resulting from severe infection, contributing to organ dysfunction in sepsis. Resolvin D1 (RvD1) is an endogenous lipid mediator, synthesised from the omega-3 polyunsaturated fatty acid (PUFA) docosahexaenoic acid (DHA) through enzymatic processes involving 15-LOX and 5-LOX. RvD1 is recognised for its protective properties against various inflammatory conditions. This study aims to investigate its potential to modulate coagulation dysfunction in sepsis and to evaluate coagulation disorders in septic patients. Sepsis models were established by intraperitoneal injection LPS (20mg/kg) or cecal ligation and puncture (CLP) followed by injection of RvD1 (10μg/kg) or saline. The impact of RvD1 on coagulation dysfunction was assessed by clotting time and coagulation indicators such as TAT, D-dimer, PAI-1, and fibrinogen. The activity of the coagulation system invivo was observed by evaluating dynamic microcirculation, platelets and thrombin in mice using intravital microscopy. The effect of RvD1 on pyroptosis was investigated by measuring NOD-like receptor protein 3 (NLRP3), Caspase-1, Caspase-11, and Gasdermin D (GSDMD) levels via western blot. Caspase-1 knockout mice, GSDMD knockout mice and bone marrow-derived macrophages (BMDMs) were used to elucidate the underlying mechanisms. Lastly, the concentration of RvD1 in plasma from septic patients was quantified to explore its relationship with coagulation and pyroptosis. RvD1 significantly attenuated coagulation dysfunction in septic mice induced by LPS and CLP, and inhibited Caspase-1/GSDMD-dependent pyroptosis in septic mice and bone marrow-derived macrophages. In septic patients, the plasma concentrations of RvD1 was negatively correlated with both coagulation-related indicators and markers of GSDMD activation. The results suggest that RvD1 can improve coagulation dysfunction in sepsis by regulating the Caspase-1/GSDMD pyroptotic pathway. Additionally, the concentration of RvD1 in septic patient plasma is related to prognosis and DIC development. RvD1 could be a potential biomarker and a promising therapeutic alternative in sepsis-induced DIC.

Single-cell RNA sequencing reveals immune cell dysfunction in the peripheral blood of patients with highly aggressive gastric cancer.

Highly aggressive gastric cancer (HAGC) is a gastric cancer characterized by bone marrow metastasis and disseminated intravascular coagulation (DIC). Information about the disease is limited. Here we employed single-cell RNA sequencing to investigate peripheral blood mononuclear cells (PBMCs), aiming to unravel the immune response of patients toward HAGC. PBMCs from seven HAGC patients, six normal advanced gastric cancer (NAGC) patients, and five healthy individuals were analysed by single-cell RNA sequencing. The expression of genes of interest was validated by bulk RNA-sequencing and ELISA. We found a massive expansion of neutrophils in PBMCs of HAGC. These neutrophils are activated, but immature. Besides, mononuclear phagocytes exhibited an M2-like signature and T cells were suppressed and reduced in number. Analysis of cell-cell crosstalk revealed that several signalling pathways involved in neutrophil to T-cell suppression including APP-CD74, MIF-(CD74+CXCR2), and MIF-(CD74+CD44) pathways were increased in HAGC. NETosis-associated genes S100A8 and S100A9 as well as VEGF, PDGF, FGF, and NOTCH signalling that contribute to DIC development were upregulated in HAGC too. This study reveals significant changes in the distribution and interactions of the PBMC subsets and provides valuable insight into the immune response in patients with HAGC. S100A8 and S100A9 are highly expressed in HAGC neutrophils, suggesting their potential to be used as novel diagnostic and therapeutic targets for HAGC.

Decoding the DIC-Lymphoma Relationship: A Nationwide Analysis of Increased Risk in Adult Patients

Background: Disseminated intravascular coagulation (DIC) is a severe, often fatal condition characterized by systemic coagulation activation leading to both widespread microvascular thrombosis and profuse hemorrhaging. Frequently associated with malignancies, DIC represents a serious clinical challenge. Lymphomas, characterized by their clinical diversity and varying prognoses, may present differing DIC risks across their subtypes. Aim of the study The study aims to understand how various lymphoma subtypes influence the development of DIC in hospitalized individuals, utilizing data from a national inpatient sample. Methods and Materials This study retrospectively examines a cohort of adult patients in the United States, hospitalized with DIC, both with and without lymphoma, utilizing the 2020 National Inpatient Sample (NIS). Patients were identified using the International Classification of Diseases (ICD-10) codes. Patients who were younger than age 18 years were excluded from the study. We used STATA for our analyses. Fisher's exact test was utilized for comparing proportions, while Student's t-test was employed for the comparison of continuous variables. We performed a multivariate logistic regression analysis, taking into consideration various patient, and hospital characteristics including age, gender, race, median zip income, insurance status, hospital geographical region and location, bed size, urban or rural setting, teaching status to identify the adjusted odds ratio for the development of DIC in different lymphoma subtypes. The Charlson comorbidity index was utilized to account for the burden of comorbidities in the analysis. Results Among 48,310 adult DIC patients in the 2020 NIS dataset, 2.48% concurrently had lymphoma. A significant disparity was noted in gender distribution, with fewer females in the lymphoma group (40% vs 49%, p=0.0135). Patients with lymphoma were, on average, older with a mean age of 62.72 years. The racial composition between the two groups was not significantly different (p=0.651). The odds of developing DIC were significantly increased overall in lymphoma patients (aOR=2.14, p <0.001). Of the lymphoma subtypes, other specified types of T/NK- cell lymphoma (natural killer) (grouped under the ICD-10 code: C86, and further sub-categorized into extra-nodal NK/T cell lymphoma, hepatosplenic, intestinal, subcutaneous, angioimmunoblastic, primary cutaneous T cell lymphoma, and blastic NK-cell lymphoma) exhibited the highest risk of DIC development (aOR=16.85, p <0.001). Non-follicular, mature T-NK-cell, other specified and unspecified types of Non-Hodgkin, and Hodgkin lymphomas also showed significant DIC risks (p<0.05), whereas no statistically significant risks were found in follicular lymphoma (p=0.753) and malignant immunoproliferative diseases and certain other B-cell lymphomas (p=0.726). See Table 1 for further details. Conclusion: This study underlines a significant association between lymphoma and elevated risk of DIC, with the highest odds observed in other specified types of T/NK- cell lymphoma. Clinical diversity within lymphoma subtypes influenced DIC risks differently, underlining the importance of individualized care. In clinical practice, increased vigilance for DIC is suggested in lymphoma patients. Prompt identification and management of DIC in this patient population could potentially improve outcomes in healthcare optimization. Further studies are warranted to elucidate the underlying mechanisms and to explore potential targeted interventions.

A prehospital risk assessment tool predicts clinical outcomes in hospitalized patients with heat-related illness: a Japanese nationwide prospective observational study

We previously developed a risk assessment tool to predict outcomes after heat-related illness (J-ERATO score), which consists of six binary prehospital vital signs. We aimed to evaluate the ability of the score to predict clinical outcomes for hospitalized patients with heat-related illnesses. In a nationwide, prospective, observational study, adult patients hospitalized for heat-related illnesses were registered. A binary logistic regression model and receiver operating characteristic (ROC) curve analysis were used to assess the relationship between the J-ERATO and survival at hospital discharge as a primary outcome. Among eligible patients, 1244 (93.0%) survived to hospital discharge. Multivariable logistic regression analysis revealed that the J-ERATO was an independent predictor for survival to discharge (adjusted odds ratio [OR] 0.47; 95% confidence interval [CI] 0.37–0.59) and occurrence of disseminated intravascular coagulation (DIC) on day 1 (adjusted OR 2.07; 95% CI 1.73–2.49). ROC analyses revealed an optimal J-ERATO cut-off of 5 for prediction of mortality at discharge (area under the curve [AUC] 0.742; 95% CI 0.691–0.787) and DIC development on day 1 (AUC 0.723; 95% CI 0.684–0.758). The J-ERATO obtained before transportation could be helpful in predicting the severity and mortality of hospitalized patients with heat-related illnesses.

Risk Factors of Bakri Balloon Tamponade Failure for Persistent Postpartum Hemorrhage

Background: The aim of this study was to identify risk factors of Bakri balloon tamponade (BBT) failure for postpartum hemorrhage (PPH) and to evaluate the efficacy of BBT for PPH caused by different etiologies. Methods: All women who underwent BBT for PPH at International Peace Maternity & Child Healthcare Hospital, Shanghai, China were included. Univariate analysis and logistic multivariate models were used to identify prognostic factors for BBT failure. Results: Of 48,511 deliveries during the study period, 487 (1.0%) women underwent BBT for persistent PPH. The overall success rate was 91.8% (447/487). The individual success rates of BBT for PPH caused by uterine atony, placenta previa, placenta accreta spectrum (PAS), and coagulopathy were 95.9%, 90.6%, 50.0%, and 25.0%, respectively. Blood loss before BBT was remarkably higher in the failure group than in the success group. In addition, estimated blood loss (EBL) before BBT insertion, disseminated intravascular coagulation (DIC) development, in vitro fertilization (IVF) pregnancy, and PAS were considered to be independent risk factors of BBT failure. Conclusions: BBT is an effective method in the management of PPH resulting from uterine atony and placenta previa. Risk factors of BBT failure primarily include the EBL before BBT insertion, DIC development, IVF pregnancy and PAS.

An interpretable DIC risk prediction model based on convolutional neural networks with time series data

Disseminated intravascular coagulation (DIC) is a complex, life-threatening syndrome associated with the end-stage of different coagulation disorders. Early prediction of the risk of DIC development is an urgent clinical need to reduce adverse outcomes. However, effective approaches and models to identify early DIC are still lacking. In this study, a novel interpretable deep learning based time series is used to predict the risk of DIC. The study cohort included ICU patients from a 4300-bed academic hospital between January 1, 2019, and January 1, 2022. Experimental results show that our model achieves excellent performance (AUC: 0.986, Accuracy: 95.7%, and F1:0.935). Gradient-weighted Class Activation Mapping (Grad-CAM) was used to explain how predictive models identified patients with DIC. The decision basis of the model was displayed in the form of a heat map. The model can be used to identify high-risk patients with DIC early, which will help in the early intervention of DIC patients and improve the treatment effect.

Pathophysiology of Coagulopathy Induced by Traumatic Brain Injury Is Identical to That of Disseminated Intravascular Coagulation With Hyperfibrinolysis.

Background: Traumatic brain injury (TBI)-associated coagulopathy is a widely recognized risk factor for secondary brain damage and contributes to poor clinical outcomes. Various theories, including disseminated intravascular coagulation (DIC), have been proposed regarding its pathomechanisms; no consensus has been reached thus far. This study aimed to elucidate the pathophysiology of TBI-induced coagulopathy by comparing coagulofibrinolytic changes in isolated TBI (iTBI) to those in non-TBI, to determine the associated factors, and identify the clinical significance of DIC diagnosis in patients with iTBI.Methods: This secondary multicenter, prospective study assessed patients with severe trauma. iTBI was defined as Abbreviated Injury Scale (AIS) scores ≥4 in the head and neck, and ≤2 in other body parts. Non-TBI was defined as AIS scores ≥4 in single body parts other than the head and neck, and the absence of AIS scores ≥3 in any other trauma-affected parts. Specific biomarkers for thrombin and plasmin generation, anticoagulation, and fibrinolysis inhibition were measured at the presentation to the emergency department (0 h) and 3 h after arrival.Results: We analyzed 34 iTBI and 40 non-TBI patients. Baseline characteristics, transfusion requirements and in-hospital mortality did not significantly differ between groups. The changes in coagulation/fibrinolysis-related biomarkers were similar. Lactate levels in the iTBI group positively correlated with DIC scores (rho = −0.441, p = 0.017), but not with blood pressure (rho = −0.098, p = 0.614). Multiple logistic regression analyses revealed that the injury severity score was an independent predictor of DIC development in patients with iTBI (odds ratio = 1.237, p = 0.018). Patients with iTBI were further subdivided into two groups: DIC (n = 15) and non-DIC (n = 19) groups. Marked thrombin and plasmin generation were observed in all patients with iTBI, especially those with DIC. Patients with iTBI and DIC had higher requirements for massive transfusion and emergency surgery, and higher in-hospital mortality than those without DIC. Furthermore, DIC development significantly correlated with poor hospital survival; DIC scores at 0 h were predictive of in-hospital mortality.Conclusions: Coagulofibrinolytic changes in iTBI and non-TBI patients were identical, and consistent with the pathophysiology of DIC. DIC diagnosis in the early phase of TBI is key in predicting the outcomes of severe TBI.

Which Septic Shock Patients With Non-Overt DIC Progress to DIC After Admission? Point-of-Care Thromboelastography Testing.

Disseminated intravascular coagulation (DIC) is a life-threatening complication of septic shock; however, risk factors for its development after admission are unknown. Thromboelastography (TEG) can reflect coagulation disturbances in early non-overt DIC that are not detected by standard coagulation tests. This study investigated the risk factors including TEG findings as early predictors for DIC development after admission in septic shock patients with non-overt DIC. This retrospective observation study included 295 consecutive septic shock patients with non-overt DIC at admission between January 2016 and December 2019. DIC was defined as an International Society on Thrombosis and Hemostasis (ISTH) score ≥ 5. The primary outcome was non-overt DIC at admission that met the ISTH DIC criteria within 3 days after admission. Of the 295 patients with non-overt DIC, 89 (30.2%) developed DIC after admission. The DIC group showed a higher ISTH score and 28-day mortality rate than the non-DIC group (2 vs. 3, P < 0.001; 13.6% vs. 27.0%, P = 0.008, respectively). The DIC rate increased with the ISTH score (7.7%, 13.3%, 15.8%, 36.5%, and 61.4% for scores of 0, 1, 2, 3, and 4, respectively). Among TEG values, the maximum amplitude (MA) was higher in the non-DIC group (P < 0.001). On multivariate analysis, an MA < 64 mm was independently associated with DIC development (odds ratio, 2.311; 95% confidence interval, 1.298-4.115). DIC more often developed among those with admission ISTH scores ≥ 3 and was associated with higher mortality rates. An MA < 64 mm was independently associated with DIC development in septic shock patients.

Assembly of alternative prothrombinase by extracellular histones initiates and disseminates intravascular coagulation

AbstractThrombin generation is pivotal to both physiological blood clot formation and pathological development of disseminated intravascular coagulation (DIC). In critical illness, extensive cell damage can release histones into the circulation, which can increase thrombin generation and cause DIC, but the molecular mechanism is not clear. Typically, thrombin is generated by the prothrombinase complex, comprising activated factor X (FXa), activated cofactor V (FVa), and phospholipids to cleave prothrombin in the presence of calcium. In this study, we found that in the presence of extracellular histones, an alternative prothrombinase could form without FVa and phospholipids. Histones directly bind to prothrombin fragment 1 (F1) and fragment 2 (F2) specifically to facilitate FXa cleavage of prothrombin to release active thrombin, unlike FVa, which requires phospholipid surfaces to anchor the classical prothrombinase complex. In vivo, histone infusion into mice induced DIC, which was significantly abrogated when prothrombin F1 + F2 were infused prior to histones, to act as decoy. In a cohort of intensive care unit patients with sepsis (n = 144), circulating histone levels were significantly elevated in patients with DIC. These data suggest that histone-induced alternative prothrombinase without phospholipid anchorage may disseminate intravascular coagulation and reveal a new molecular mechanism of thrombin generation and DIC development. In addition, histones significantly reduced the requirement for FXa in the coagulation cascade to enable clot formation in factor VIII (FVIII)– and FIX-deficient plasma, as well as in FVIII-deficient mice. In summary, this study highlights a novel mechanism in coagulation with therapeutic potential in both targeting systemic coagulation activation and correcting coagulation factor deficiency.

Plasenta perkreatalı hastaların perinatal sonuçları

Aim: Placental invasion anomalies are rare, but it causes serious fetomaternal morbidity and mortality. In our study, we aimed to evaluate the fetomaternal results of cases with Abnormal Invasive Placenta ( Placenta Percreata).&#x0D; Methods: Patients who underwent a peripartum hysterectomy or whose placenta was left in uterin cavity due to placenta percreata in our hospital were retrospectively analyzed. Data of 20 patients were noted.&#x0D; Results: The mean age of the patients was ± SD (min-max) 33 ± 5,704 (25-46) and 60% (n = 12) of the patients had additional diseases. Fifty five percent of patients (n=11) were operated in emergency conditions and 45% (n = 9) in elective conditions. Surgical complications were 65% (n = 13) bladder injuries, 30% (n = 6) disseminated intravascular coagulation (DIC), 20% (n = 4) infection, 15% (n = 3) relapartomy and 5% (n = 1) was pulmonary embolism. Mortality increased three times (OR; 3.003 (95% CI, 0.372-24.390) in patients with a comorbidity, while 4.7 times (OR; 4.784) in emergency operations. Operations under elective conditions and previously ultrasonographic diagnosis (Odd ratio values ; 0,219 (95% CI, 0,021-2,447) and 0,615 (95% CI, 0,043-8,695), recpectively) decreased maternal mortality.&#x0D; Conclusion: Prenatal diagnosis and performing elective surgeries in percreata cases are important to reduce maternal mortality. Although there are various surgical complications, we think that DIC development is important in mortality and massive transfusion does not decrease the mortality.

Clinical Characteristics and Risk Factors of Disseminated Intravascular Coagulation in Patients with COVID-19 in Wuhan, China

Background: Coronavirus disease 2019 (COVID-19) has spread globally. However, the association between COVID-19 and disseminated intravascular coagulation (DIC) has been scarcely addressed. We aimed to systematically characterize the clinical features and examine risk factors for DIC development in COVID-19 patients. Methods: In this single-centered, retrospective, and observational study, all patients with DIC (N=59) and 270 patients without DIC were matched by propensity score matching based on age, sex, and comorbidities. Demographic data, symptoms, radiological, laboratory examinations, and clinical outcomes were compared between patients with and without DIC. Furthermore, univariable and multivariable logistic regression were used to explore the risk factors associated with DIC development in COVID-19 patients. Findings: Higher proportion of patients with DIC and COVID-19 (54 of 59 [91·53%]) developed into death than non DIC patients (58 of 270 [21·48%]). Patients with DIC presented aggravated inflammation responses, liver damage, and especially coagulation dysfunction. Moreover, in addition to previously reported coagulation-related markers, such as FDP, D-dimer, and platelet, we also identified several novel risk factors associated with DIC development, including decreased fibrinogen (OR=0·476, 95%CI=0·380-0·596, P Interpretation: Patients with DIC and COVID-19 were predisposed to poor clinical outcomes. These risk factors identified may be helpful for early surveillance of disease progression and making standardized treatment strategies. Funding: The National Key Research and Development Plan for the Emergency Management of Novel Coronavirus Pneumonia (No. 2020YFC0845100); China National Natural Science Foundation (No. 81974400).Declaration of Interests: The authors report no conflicts of interest.Ethics Approval Statement: This study was approved by the Ethics Committee of Tongji Hospital, Tongji Medical College, HUST, and granted a waiver of informed consent from study participants.

A multicenter prospective validation study on disseminated intravascular coagulation in trauma‐induced coagulopathy

BackgroundTrauma‐induced coagulopathy (TIC) may progress to disseminated intravascular coagulation (DIC) due to dysregulated inflammatory and coagulofibrinolytic responses to trauma. ObjectivesWe explored how DIC and TIC elicit the same coagulofibrinolytic changes which lead to massive transfusion. MethodsSeverely injured trauma patients with an injury severity score ≥ 16 were prospectively included. Platelet counts, global markers of coagulation and fibrinolysis and specific markers of thrombin and plasmin generation, anticoagulation, endothelial injury, and inhibition of fibrinolysis were measured at presentation to the emergency department (0 hour) and 3 hour after arrival. The patients were subdivided into those with and without DIC and those with and without TIC using the 0‐hour data. Time courses of specific markers and the frequency of massive transfusion were evaluated. The association of various variables with DIC development was also confirmed. ResultsTwo hundred and seventy‐six patients were eligible for the analyses. The severity of injury (odds ratio; 1.038, P = .022) and thrombin generation (odds ratio; 1.014, P = .024) were associated with the development of DIC. Both DIC and TIC patients showed increased thrombin generation, insufficient anticoagulation controls, endothelial injury and increased fibrinolysis followed by elevated plasminogen activator inhibitor‐1 levels at 0 and 3 hours. The frequency of massive transfusion was higher in both DIC (33.6% vs 7.9%, P < .001) and TIC (50.0% vs 13.3%, P < .001) patients than in those without DIC or TIC, respectively. ConclusionsDisseminated intravascular coagulation and TIC evoked the same coagulofibrinolytic responses in severely injured trauma patients immediately after trauma and needed massive transfusion.

Plasma Endothelial Glycocalyx Components as a Potential Biomarker for Predicting the Development of Disseminated Intravascular Coagulation in Patients With Sepsis.

Sepsis coagulopathy or disseminated intravascular coagulation (DIC) mainly due to progressive endothelial disruption and damage. The glycocalyx is expressed on the endothelial cell surface and contributes to anti-thrombogenicity, anti-inflammatory, and regulates vascular permeability. We aimed to evaluate the clinical utility of plasma glycocalyx components as biomarkers in predicting the onset of DIC in sepsis. This was a prospective observational study of 45 patients with sepsis (June to December 2018). Demographic, clinical (Acute Physiology, Age, Chronic Health Evaluation II [APACHE II], Sequential Organ Failure Assessment [SOFA]), and laboratory data from medical records were analyzed. Endothelial glycocalyx components (syndecan-1, heparan sulfate, hyaluronan) were measured using an ELISA kit. Among the 45 patients (23, sepsis; 22, septic shock), plasma syndecan-1, heparan sulfate, and hyaluronan levels were higher in those with septic shock and were positively correlated with disease severity as determined by the APACHE II and SOFA scores and lactate levels. Receiver operating characteristic curve analysis revealed high sensitivity and specificity of syndecan-1 for predicting septic shock. Further, these levels were compared between patients with or without the development of DIC. Plasma syndecan-1 and hyaluronan levels were significantly elevated in patients with DIC compared to those in patients without DIC and were strongly associated with activated partial thromboplastin time, prothrombin time, and platelet counts. Area under the curve values for predicting DIC based on syndecan-1 and hyaluronan levels measurements were 0.774 and 0.740, respectively. Increased plasma syndecan-1 and hyaluronan levels may be indicators of disease severity and useful predictors for DIC development in sepsis.

Coagulopathy in cytogenetically and molecularly distinct acute leukemias at diagnosis: Comprehensive study

We analyzed the characteristics of coagulopathy in cytogenetically and molecularly distinct acute leukemias. We retrospectively analyzed 211 adult patients with de novo non-acute promyelocytic leukemia (APL) and acute myeloid leukemia (AML), and 105 newly diagnosed patients with B-cell acute lymphoblastic leukemia (B-ALL). Disseminated intravascular coagulation (DIC) occurrence was assessed according the International Society of Thrombosis and Haemostasis (ISTH) criteria. Further, we analyzed the associations of the cytogenetics and mutations with DIC development and coagulation profile. Significant differences were observed between APL and non-APL AML (P = 0.001), APL and B-ALL (P = 0.002), and non-APL AML and B-ALL (P = 0.009) in the distribution of ISTH DIC scores of the acute leukemia patients that met the criteria for diagnosis of DIC. Except for the elevated leukocyte count, a normal karyotype with NPM1 mutations or/and FLT3-ITD mutations was independently associated with the development of DIC in non-APL AML, characterized by significant PT prolongation and significantly elevated D-Dimers. The P210BCR-ABL1 transcript strongly predicted hypofibrinogenemia in B-ALL in the final multivariate model, but Philadelphia chromosome negatively affected elevated D-dimers. In conclusion, DIC occurrence and the coagulation profile were associated with the cytogenetics and mutations in acute leukemia.

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.

Relationship of Markers of Inflammation, Infection and Endothelial Function to Mortality and Severity of Coagulopathy in Patients with Sepsis-Associated DIC

Background: Sepsis-associated disseminated intravascular coagulation (DIC) is a complex clinical scenario involving derangement of many processes, including hemostasis. Assessment of markers of these other aspects of disease, including inflammation, immunity, endothelial function, and endogenous anticoagulants may provide insight into DIC pathophysiology and lead to improved methods for assessment of patient condition and response to treatment. This study was designed to measure biomarkers representative of multiple systems involved in DIC development in a cohort of patients with sepsis and DIC and determine the association of these biomarkers with disease severity and mortality.Materials and Methods: Citrated plasma samples were prospectively collected from 102 patients with sepsis and suspected DIC at ICU admission (day 0) and again serially on ICU days 4 and 8 under an IRB approved protocol. DIC score was determined using the ISTH scoring algorithm (e.g. platelet count, PT/INR, fibrinogen, and D-Dimer). Plasma from healthy individuals was purchased from a commercial laboratory (George King Biomedical, Overland, KS). . CD 40 Ligand (CD40L), Plasminogen inhibitor 1 ( PAI-1), nucleosomes, Procalcitonun (PCT), Microparicle Tissue Factor (MP-TF), and Prothrombin Fragment 1.2 (F1.2) were measured using commercially available ELISA kits. Protein C activity was measured using a clot-based assay. Interleukin 6 (IL-6), Interleukin 8 (IL-8), Interleukin 10 (IL-10) , Tumor Necrosis Factor Alpha (TNFα) , Monocyte Chemoattractant protein 1 (MCP-1) were measured using a biochip technology.Results: Significant differences in levels of Protein C (p=0.009), PCT (p=0.0005), IL-6 (p=0.019), IL-8 (p= 0.015), and PAI-1 (p=0.015) were observed between survivors and non-survivors (Table 1). Significant variation of Protein C (p=0.002), nucleosomes (p=0.05), PCT (P<0.001), IL-6 (p=0.001), IL-8 (p=0.003), IL-10 (p=0.011), TNFα (p=0.021), and MCP-1 (p=0.21), were observed based on severity of DIC score.Conclusion: Markers from multiple systems perturbed in DIC were associated with mortality suggesting that while these systems may not be routinely evaluated in the course of patient care, dysfunction of these system contribute significantly to mortality. In addition, numerous inflammatory cytokines showed an association with DIC score. This study suggests that the measurement of additional markers in sepsis-associated DIC may be of value in the prediction of mortality and may be helpful in guiding treatment for these patients. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Histones Bind Prothrombin to Generate Alternative Prothrombinase Complexes That Can Disseminate Intravascular Coagulation

Background: Increased thrombin generation in vivo is pivotal to the development of disseminated intravascular coagulation (DIC). Typically, thrombin is generated when the prothrombinase complex, composed of activated factor X (FXa), activated co-factor V (FVa) and phospholipids, cleaves prothrombin in the presence of calcium. In critical illness, extensive cell death releases histones into the circulation, which can increase thrombin generation. However, the underlying pathophysiological mechanisms remains to be fully elucidated.Methods: In vitro: Isolation of histone-binding proteins with mass spectrometry analysis. Surface plasmon resonance binding studies, prothrombin cleavage and thrombin generation assays. In vivo: histone infusion mouse models (C57BL/6 mice) with or without prothrombin fragment F1+F2 infusion. Clinical: a prospective cohort of 129 adult intensive care unit patients (ICU) with sepsis and analysed for DIC.Results: Histone-conjugated Sepharose beads were used to pull down proteins from human plasma. Histone-binding proteins were subjected to 2D gel electrophoresis and sequenced by liquid chromatography-mass spectrometry. Prothrombin was the only coagulation factor identified. Histones directly bind to prothrombin (H3 [Kd = 6.8 x 107 M] and H4 [Kd = 7.0 x 107 M]), specifically prothrombin fragments F1+F2, to facilitate FXa-induced prothrombin cleavage and thrombin generation (H4 [12.25 ± 1.25 fold] and H3 [8.82 ± 0.67 fold]). FXa levels are the limiting factor of histone-enhanced thrombin generation since this process was inhibited in FX-deficient plasma unless exogenous FXa was added. Specifically, using either heparin or anti-histone antibodies to block histones, histone-prothrombin interactions, prothrombin cleavage and subsequent thrombin generation were significantly reduced. Unlike FVa which requires a phospholipid surface to form functional prothrombinase complexes, histones can substitute for FVa in the absence of phospholipids. The addition of histones to FV-deficient plasma restored thrombin generation, suggesting that histones can bypass FVa to induce thrombin generation.In vivo, infusion of histones into mice caused significant decreases in platelet counts and fibrinogen levels with elevations in thrombin-antithrombin complexes, D-dimer and prothrombin time in a dose-dependent manner. Pathological examination indicated intravascular thrombi with various organs, particularly in within lung tissues. These histone-induced DIC changes were significantly abrogated when prothrombin fragments F1+F2 were infused prior to histones to act as a decoy for binding of histones to circulating prothrombin. Analysis of DIC scores in ICU patients (n=129) with sepsis showed circulating histone levels to strongly correlate with DIC scores (r=0.446, p<0.0001).Conclusions: Histones can replace FVa in prothrombinase and not require phospholipid surfaces. This alternative histone-assembled prothrombinase can explain how thrombin could be generated and amplified away from cell surfaces to cause systemic dissemination of its effects and potentiate DIC. This study also identifies circulating histones as a potential target for therapeutic intervention in reducing DIC development and subsequent multi-organ failure in ICU patients. DisclosuresNo relevant conflicts of interest to declare.

Circulating syndecan-1 predicts the development of disseminated intravascular coagulation in patients with sepsis

PurposeOne of the pathophysiological processes in sepsis is endothelial dysfunction, which leads to disseminated intravascular coagulation (DIC). Syndecan-1 is a major structural component of the endothelium and plays a key role in endothelial function. The purpose of this study was to assess the value of syndecan-1 as a predictive marker for DIC in sepsis. MethodsWe performed a prospective observational study of patients with sepsis from February 2014 to July 2015. Serial change of hemostatic markers, anticoagulant and fibrinolytic markers (antithrombin, PAI-1), endothelial markers (syndecan-1, VCAM-1, E-selectin), and inflammatory markers (IL-1β, IL-6, IL-8, HMGB-1, histone-H3) were analyzed. Clinical data including APACHE II, SOFA, and DIC scores and 28-day mortality were also evaluated. ResultsDuring the study, 39 septic patients and 15 healthy controls were included. Syndecan-1 levels were significantly increased in the septic patients compared with the healthy controls. Of the septic patients, non-survivors had higher syndecan-1 levels than did the survivors on days 1, 2, and 4. Significant correlations on day 1 were found between syndecan-1 levels and APACHE II, SOFA, and DIC scores, hemostatic markers, IL-1β, IL-8, and PAI-1. Syndecan-1 levels on day 1 were also significantly higher in patients with than without DIC and had strong discriminative power for the prediction of both DIC development and subsequent mortality, with AUCs of 0.79 and 0.85, respectively. ConclusionSyndecan-1 levels were associated with not only the severity of illness and mortality but also DIC development in sepsis, suggesting that syndecan-1 could be a predictive marker of DIC.

Administration of recombinant thrombomodulin before progression of disease causing disseminated intravascular coagulation might be better compared with administration after progression of disease

As disseminated intravascular coagulation (DIC) causes multiple organ failure, recombinant thrombomodulin (rTM) is widely used in Japan for treating DIC. However, the optimal timing of rTM administration has not yet been determined. We hypothesized that the administration of rTM before progression of disease causing DIC might be better for the treatment of DIC than that after progression of disease. A total of 101 patients received rTM in the intensive care unit (ICU) between August 2008 and November 2013 were enrolled. Depending on survival at hospital discharge, the patients were divided into survivor (group S) and non-survivor groups (group NS). Patient characteristics before DIC development, acute physiology and chronic health evaluation II (APACHEII) score and sequential organ failure assessment (SOFA) score at the start of rTM administration, rTM administration dose, duration of time between the onset of disease causing DIC and rTM administration, and combination therapy were collected. Group S had 57 patients, and group NS had 44 patients. More than 70% of patients in group S were administrated rTM within 1 day from the onset of disease causing DIC (0 days, 40% vs 20%; 1 day, 33% vs 30%; more than 2 days, 26% vs 50%). At the start of the rTM administration, the APACHEII and SOFA scores were significantly lower in group S (26 ± 6 vs 32 ± 6, p < 0. 001; 9.5 ± 4.2 vs 13.4 ± 3.6, p < 0.001). Multivariate logistic regression analysis of outcomes was performed. The duration of time between the onset of disease causing DIC and rTM administration, the APACHEII score, the SOFA score, and use of continuous renal replacement therapy (CRRT) were selected as candidate variables (p < 0.05). The SOFA scores and use of CRRT were highly correlated with the APACHEII score (Pearson correlation = 0.63 and 0.43, respectively). Therefore, the SOFA score and the use of CRRT were excluded from this model. Late administration of rTM (more than 2 days between the onset of disease and rTM administration) was associated with undesirable outcome (odds ratio = 3.36, 95% confidence interval = 1.03–10.92, p = 0.044). This study suggested that the administration of rTM before the progression of disease causing DIC might be better than that after progression of disease causing DIC. Further randomized clinical trials are required to elucidate whether early administration of rTM is actually effective.

Mechanisms of Development of Hemostatic Disorders after Liver Resection

Objective: to reveal the mechanisms of development of hemostatic disorders after liver resection. Material and methods. One hundred and twenty cases of liver resections for primary hepatic cancer were retrospectively analyzed. Patients with an uncomplicated postoperative period (Group 1.1), isolated hepatic coagulopathy (Group 1.2), and developed multiple organ dysfunction (MOD) (Group 1.3) were analyzed. The values of hemostasis, hemodynamics, and oxygen status (oxygen delivery, uptake, and utilization) and biochemical and acid-base homeostatic parameters were monitored in these patients twice daily. Results. A significant reduction in Factor VII levels within the immediate hours after surgery was an early hemostasiological marker of the development of hepatic coagulopathy (isolated or as part of MOD). In patients with further evolved MOD, the level of hemostatic system activation markers (fibrin degradation products and D-dimer) was increased from the first 24 postoperative hours, which suggested the development of disseminated intravascular coagulation (DIC) concurrent with hepatic coagulopathy. The development of energy deficiency was at least 24 hours ahead of the clinical manifestation of hepatic coagulopathy and DIC in the patients undergoing liver resection. Hypoxic energy deficiency (the decreased delivery and uptake of oxygen and its higher utilization coefficient, and elevated blood lactate values) was a predictor of the development of isolated hepatic coagulopathy. Further worsening of hypoxic energy deficiency (an increase in blood lactate values and a reduction in venous oxygen saturation) or its transformation to enzyme energy deficiency (lowered oxygen uptake and utilization) was a predictor of DIC development. Conclusion. In the patients undergoing liver resection, the development of energy deficiency is at least 24 hours ahead of the clinical manifestation of hepatic coagulopathy (which evolves in the presence of hypoxic – energy deficiency) and DIC (which manifests in the presence of enzyme energy deficiency). To correct the existing Адрес для к°рреспонденции (Correspondence to): energy deficiency is the key condition to determine the effectiveness of performed hemostasis-modulating therapy. Key words: liver resection, hepatic coagulopathy, disseminated intravascular coagulation, energy deficiency.