Criteria For Disseminated Intravascular Coagulation Research Articles

Proposal and Validation of a Clinically Relevant Modification of the Japanese Association for Acute Medicine Disseminated Intravascular Coagulation Diagnostic Criteria for Sepsis.

Japanese Association for Acute Medicine (JAAM) disseminated intravascular coagulation (DIC) criteria were launched nearly 20 years ago. Following the revised conceptual definition of sepsis and subsequent omission of systemic inflammatory response syndrome (SIRS) score from the latest sepsis diagnostic criteria, we omitted the SIRS score and proposed a modified version of JAAM DIC criteria, the JAAM-2 DIC criteria. To validate and compare performance between new JAAM-2 DIC criteria and conventional JAAM DIC criteria for sepsis. We used three datasets containing adult sepsis patients from a multicenter nationwide Japanese cohort study (J-septic DIC, FORECAST, and SPICE-ICU registries). JAAM-2 DIC criteria omitted the SIRS score and set the cutoff value at ≥3 points. Receiver operating characteristic (ROC) analyses were performed between the two DIC criteria to evaluate prognostic value. Associations between in-hospital mortality and anticoagulant therapy according to DIC status were analyzed using propensity score weighting to compare significance of the criteria in determining introduction of anticoagulants against sepsis. Final study cohorts of the datasets included 2,154, 1,065, and 608 sepsis patients, respectively. ROC analysis revealed that curves for both JAAM and JAAM-2 DIC criteria as predictors of in-hospital mortality were almost consistent. Survival curves for the anticoagulant and control groups in the propensity score-weighted prediction model diagnosed using the two criteria were also almost entirely consistent. JAAM-2 DIC criteria were equivalent to JAAM DIC criteria regarding prognostic and diagnostic values for initiating anticoagulation. The newly proposed JAAM-2 DIC criteria could be potentially alternative criteria for sepsis management.

Low ADAMTS13 Activity in Patients with Liver Disease- Thrombotic Thrombocytopenic Purpura or Not?

Introduction: Patients with liver injury have hemostatic defects including reduced ADAMTS13 (A disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13). Severe deficiency of ADAMTS13 (ADMS13) activity (< 10%) is pathognomonic for thrombotic thrombocytopenic purpura (TTP), a rare thrombotic microangiopathy (TMA). Differentiating TTP from severe liver injury is complex for multiple reasons including 1) low baseline ADMS13 2) concomitant coagulopathies complicating differentiation from disseminated intravascular coagulation (DIC) 3) ADMS13 activity (ADMS13:AC) assay interference (hyperbilirubinemia (>30mg/dL) can cause artifactual reduction of ADMS13:AC). Here we sought to characterize the clinical presentation, management, and outcomes of patients with liver injury presenting with thrombocytopenia (TCP), microangiopathic hemolytic anemia (MAHA) and low ADMS13:AC at our institution. Methods: In this retrospective study, after IRB approval, electronic medical records (EMR) of institutional patients who had ADMS13:AC and inhibitor profile performed in our special coagulation laboratory between 2018 and July 17, 2023, were reviewed. Eligible patients had ADMS13:AC ≤20% were ≥ 18 years and had evidence of liver injury at time of ADMS13. Liver injury was defined as ALT or AST elevations greater than two times the upper level of normal within one month prior to ADMS13:AC testing, history of end stage liver disease or cirrhosis, or liver transplant with evidence of graft dysfunction. Details regarding clinical presentation, management and outcomes were extracted from the EMR. PLASMIC and ISTH DIC scores were retrospectively calculated. Results: 70 patients had at least one ADMS13:AC < 20% during the study period. 28/70 patients met liver injury inclusion criteria and 20/28 had TCP and MAHA. Of those 20 patients, median age at initial ADMS13:AC was 56.5 years (29-85). Most patients (n=14) had ADMS13:AC of 10-20%. ADMS13:AC was < 5% and 5-10% in 3 patients each. Eleven patients had a positive inhibitor with a median Bethesda titer of 1.85 BU (0.5-3.9). Etiology of liver included: ischemic hepatopathy (n=8), liver graft failure (n=4), liver metastasis (n=3), cirrhosis (n=2), alcoholic hepatitis (n=1), unknown (n=2). Median hemoglobin and platelet (plt) count at time of ADMS13 was 7 g/dL (6.4-13.2) and 30 x10 9/L (3-98), respectively. 7/20 patients had a PLASMIC score of ≥5; PLASMIC score was ≥5, in 2/6 patients with ADMS13:AC <10%. 16/18 patients had an ISTH DIC score ≥5. 18/20 patients had a creatinine > 2 mg/dL or were receiving renal replacement therapy the time of ADMS13: AC. 7/20 patients had total or direct bilirubin of >30mg/dL. Eight/20 patients were treated with plasma exchange (PEX) for a median duration of 7 days (2-13). 66.7% of pts with ADMS13:AC <10% received PEX. Glucocorticoids and Rituximab were used with the intent to treat TTP in 7 and 3 patients, respectively. Caplacizumab was used in 2 patients. 3/8 (37.5%) patients receiving PEX demonstrated normalization of MAHA. One of these patients demonstrated improvement but not normalization of plts (Table 1B, case 5). All patients had recurrence of hematologic abnormalities after PEX was stopped. One patient was treated with plasma infusion with stabilization in plt count. There were 13 and 15 deaths within 1 and 6 months of first ADMTS13:AC, respectively. One death was potentially attributable to management of TTP (Table 1B, case 1). There was no difference in time to death or mortality with the use of PEX. Repeat ADMS13:AC remote from PEX, TCP and MAHA was available for 1/5 surviving patients. This patient (Table1, case 2) had normalization of ADMS:AC after undergoing liver transplant. Conclusion: The differential diagnosis of TCP and MAHA in patients with liver injury includes hepatic dysfunction, DIC and TMA. In the current cohort, 89% of evaluable patients met criteria for overt DIC per ISTH criteria. Due to a low ADMTS13:AC, 40% of patients underwent a trial of PEX with 37.5% demonstrating improvement in MAHA that was not sustained upon discontinuation of PEX due to persistent liver dysfunction. Six-month mortality was 75% and use of PEX did not affect mortality. Given the high mortality, further studies evaluating which patients with TMA and liver injury are more likely to benefit from therapies typically used to treat TTP are necessary.

The Proactive Diagnostic Value of Thrombin-Antithrombin Complex and Antithrombin III in Disseminated Intravascular Coagulation

Introduction Disseminated intravascular coagulation (DIC) is a life-threatening condition with high mortality, necessitating timely and accurate diagnosis for effective management. However, current diagnostic systems can not recognize DIC at its reversible phase, causing suboptimal treatment outcomes. One reason is that most venous thrombosis cases are asymptomatic. Moreover, the focus on abnormalities in coagulation consumption often fails to identify DIC until in a later and irreversible phase. Consequently, the current diagnostic criteria for DIC lacks earlier laboratory indicators. Therefore, our objective was to evaluate the diagnostic potential of selected hemostatic biomarkers (thrombin-antithrombin complex (TAT), soluble thrombomodulin (sTM), tissue plasminogen activator inhibitor complex (tPAI-C), α 2-plasmin inhibitor plasmin complex (PIC) and anti-thrombin III (ATIII)) in assessing DIC before reaching its irreversible phase. Methods We included 451 patients from intensive care unit who met the following criteria:≥18 years old, non-perinatal period, and a hospitalization length of≥3 days, excluding those with primary hematologic diseases, decompensated liver cirrhosis or chemotherapy history. In total, 101, 57, and 293 patients were diagnosed with overt-DIC (decompensated DIC), pre-DIC (compensated DIC), and non-DIC, respectively. The DIC scores were calculated in accordance with the diagnostic criteria outlined by the International Society on Thrombosis and Haemostasis (ISTH). Day 0 was defined as the day on which hemostatic biomarkers were detected. Global parameters including prothrombin time (PT), fibrinogen (FIB), fibrinogen degradation product (FDP), d-dimer, and platelet count were collected on day 0, 1, 3, 5, and 7. The spearman correlation analysis was used to analyze the linear relation. Binary logistic regression analysis and receiver operating characteristic curves were used to calculate the area under the receiver operating characteristic curve (AUC). The cutoff value maximizes the sum of the sensitivity and specificity. P<0.05 was considered statistically significant. Results Correlation analysis revealed significant linear correlations between TAT, ATIII, and the global parameters relevant to DIC (pre-DIC and overt-DIC). Specifically, TAT exhibited positive correlation with d-dimer and FDP, while ATIII was correlated with PT, FIB, and platelet count. Of note, TAT/ATIII ratio on day 0 exhibited strong associations not only with fibrinolytic markers but also with coagulation parameters within a week, indicating its potential to be a valuable diagnostic and predictive tool for DIC assessment. Comparative analysis demonstrated elevated TAT and decreased ATIII levels in DIC group. Remarkably, the TAT/ATIII ratio demonstrated superior diagnostic performance compared to individual biomarkers. Among individual biomarkers, TAT/ATIII ratio had the highest AUC of 0.818 with a cutoff value of 22.1, followed by ATIII (AUC=0.752) and TAT (AUC=0.749). Moreover, when a combination of TAT and ATIII was applied, the AUC increased to 0.847 higher than TAT/ATIII ratio's, improving the diagnostic accuracy for DIC. TAT and ATIII in pre-DIC group were consistent with those observed in DIC group above: elevated TAT levels, decreased ATIII activity, TAT/ATIII ratio with superior diagnostic performance. Among individual biomarkers, TAT/ATIII ratio had the highest AUC 0.771 with a cutoff value of 22.1 that maximized the sum of sensitivity (55%) and specificity (89%), followed by TAT (AUC=0.73) and ATIII (AUC=0.707). The AUC of TAT combination with ATIII was 0.796, higher than AUC 0.771 of TAT/ATIII ratio, suggesting that TAT and ATIII may also identify the pre-DIC status and predict overt-DIC. Conclusion This study underscores the remarkable potential of TAT, ATIII, and the TAT/ATIII ratio in predicting DIC with accuracies of 73%, 71%, and 77%, respectively. Moreover, for patients with an ISTH-DIC score of < 5, the presence of following conditions-TAT level ≥10.8 ng/mL, ATIII activity ≤0.58, or TAT/ATIII ratio ≥22.1-indicates a likelihood of developing into irreversible DIC within 7 days. Integrating TAT, ATIII, and the TAT/ATIII ratio into the diagnostic process holds the potential to expedite clinical interventions during the pre-DIC state and enhance outcomes for DIC patients, further covering the shortage of current ISTH criteria.

Predicting neonatal mortality with a disseminated intravascular coagulation scoring system.

Although disseminated intravascular coagulation (DIC) is a critical disease, its mortality in neonates is hard to predict. The aim of this study was to investigate underlying conditions associated with neonatal DIC to see if a scoring system could predict mortality. We retrospectively evaluated the DIC scores of neonates diagnosed on or after the second day of life, in conjunction with underlying conditions associated with DIC. The diagnosis of DIC was made according to Japan Society of Obstetrical, Gynecological & Neonatal Hematology (JSOGNH) 2016 neonatal DIC criteria. Among 23 neonates with DIC, 8 had gastrointestinal perforation with necrotizing enterocolitis and 6 had congenital heart disease. Although factors such as birth weight, gestational age, D-dimer, and fibrinogen were not predictive of mortality, median PT-INR differed significantly between the two groups (survived 1.69 vs died 2.37, P = 0.004). Furthermore, median DIC scores differed significantly by survival outcome (P = 0.013). DIC scores based on JSOGNH 2016 neonatal DIC criteria are predictive of mortality in infants diagnosed with DIC on or after the second day of life.

Proposal of Quick Diagnostic Criteria for Disseminated Intravascular Coagulation.

Background. The diagnostic criteria for disseminated intravascular coagulation (DIC) vary and are complicated and the cut-off values are different. Simple and quick diagnostic criteria for DIC are required in physicians for critical care. Material and methods. Platelet counts, prothrombin time–international normalized ratio (PT-INR) and D-dimer levels were examined in 1293 critical ill patients. Adequate cut-off values of these parameters were determined and a quick DIC score using these biomarkers was proposed. The quick DIC score was evaluated using a receiver operating characteristic (ROC) analysis. Results. Using the Japanese Ministry of Health, Labor and Welfare diagnostic criteria, 70 and 109 patients were diagnosed with DIC and pre-DIC, respectively. The ROC analysis of factors difference between DIC and non-DIC, revealed the following cut-off values: PT-INR, 1.20; platelet count, 12.0 × 1010/L and D-dimer, 10.0 μg/mL. Based on the above results, the quick DIC score system was proposed. All patients with DIC had a quick DIC score of 3, 4 or 5, and 85.3% of the patients with pre-DIC had a quick DIC score of ≥3 points. All patients with pre-DIC had a score of ≥2 points. In the ROC analysis, the area under the curve was 0.997 for DIC vs. non-DIC, and 0.984 for pre-DIC + DIC vs. non-DIC, and the cut-off value was 3 points for DIC and 2 points for DIC + pre-DIC. The quick DIC scores of non-survivors were significantly higher than those of survivors. Conclusions. The Quick DIC score system is a simple and useful tool that can be used for the diagnosis of DIC and pre-DIC. Further evaluation of the quick DIC score system in a large-scale study is required.

Agreement on Overt Disseminated Intravascular Coagulation in Sepsis Patients between International Society of Thrombosis and Haemostasis Criteria and Japanese Ministry of Health and Welfare Criteria

Disseminated Intravascular Coagulation (DIC) is an acquired syndrome characterized by the activation of intravascular coagulation which is most commonly caused by sepsis. There are two types of DIC disease: overt and non-overt DICs. The International Society of Thrombosis and Haemostasis (ISTH) criteria are more frequently used in the diagnosis of overt DIC compared to Japanese Ministry of Health and Welfare (JMHW). One of the different parameters of the two criteria is the D-Dimer element in the ISTH criteria and Fibrin Degradation Products (FDP) in the JMHW criteria. The availability of fibrin-related markers is different in each health center. This study aimed to see the agreement of the DIC diagnosis based on the ISTH and JMHW criteria and to analyze the correlation between D-Dimer and FDP in sepsis patients to help clinician decide which criteria is better to use. An analytical cross-sectional study was carried out on patients with sepsis based on the clinical diagnosis from the laboratory order forms and the DIC criteria according to the ISTH and JMHW. Patients included in this study were those visiting Dr. Hasan Sadikin General Hospital Bandung from August 2019-April 2020. Data collected were analyzed statistically using Cohen's Kappa test and Spearman test, both were performed in SPSS 17.0 program.There were 35 subjects participating in this study with overt and non-overt DIC with a composition based on the ISTH and JMHW criteria of 31 and 19 vs. 4 and 16, respectively. The Kappa coefficient between ISTH and JMHW was 0.266 (p 0.021) and the correlation between the D-Dimer and the FDP was 0.88 based on the Spearman test. There is a fair agreement on the DIC diagnosis and strong correlation between the FDP and the D-Dimer in sepsis patients when assessed using the ISTH and JMHW criteria. Both criteria are equally able to assist clinicians in determining the type of DIC depending on the type of fibrin-related markers available in the health centers.

Application of the International Society on Thrombosis and Haemostasis Scoring System in Evaluation of Disseminated Intravascular Coagulation in Patients with Acute Leukemias.

Background Coagulation abnormalities are common in acute leukemia (AL) and disseminated intravascular coagulation (DIC) frequently complicates the onset of AL. Aim To determine the prevalence of overt DIC in AL using the International Society on Thrombosis and Haemostasis (ISTH) scoring system. Materials and Methods This prospective observational study was performed on 57 newly diagnosed or relapsed cases of AL. Detailed clinical history and coagulation profile of the patients were evaluated. Diagnosis of overt and nonovert DIC was established using the ISTH scoring system and results tabulated. Observations A total of 57 patients with AL participated in the study, including 31 (54.39%) patients with acute lymphoblastic leukemia (ALL) and 26 (45.61%) with acute myeloid leukemia (AML). In total, 18 of 57 patients (31.58%) with AL fulfilled the criteria of overt DIC according to the ISTH scoring system, including 10 (32.25%) patients with ALL and 8 (30.76%) patients with AML. The highest prevalence of DIC was seen in the M3 subtype among AML and the L1 subtype among ALL, respectively. The mean ISTH score in patients of overt DIC in ALL and AML patients was 5.1 and 5, respectively. Abnormalities in platelet count and D-dimer levels were the most useful parameters in diagnosing overt DIC and the difference between overt DIC and nonovert DIC groups was highly significant. Conclusions Overt DIC was observed in approximately one-third of patients with AL. Prevalence of overt DIC was found to be comparable in patients with ALL and AML. Mean platelet count and D-dimer levels were the most useful parameters in detecting overt DIC.

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.

An evaluation of the Japanese Society on Thrombosis and Hemostasis criteria for disseminated intravascular coagulation as a predictor of prognosis in patients with infection.

A criterion for disseminated intravascular coagulation (DIC) that reflects the status of controlled coagulopathy would be useful for determining when to stop treatment. Use of the DIC criteria of the Japanese Society on Thrombosis and Hemostasis (JSTH) for predicting the outcome during recombinant soluble thrombomodulin (thrombomodulin alfa, TM-α) treatment was evaluated. A retrospective, multicenter survey was conducted in 798 medical facilities in Japan. Of the 4342 patients who underwent TM-α treatment, 193 with infection-associated DIC were investigated. The 28-day mortality rate increased with the increase in JSTH DIC scores at the end of TM-α treatment, with a Cramer's coefficient of association of 0.431. A reduced platelet count (odds ratio [OR]: 0.847, P<.001), prolonged prothrombin time ratio (OR: 5.681, P<.001), decreased fibrinogen level (OR: 0.995, P<.001), higher level of fibrinogen and fibrin degradation products (OR: 1.009, P=.026), and lower antithrombin activity (OR: 0.973, P<.001) were correlated with 28-day mortality. On multivariate analysis, the JSTH DIC score at the completion of TM-α therapy was a predictor of mortality (OR: 1.591, 95% CI: 1.219-2.077). The JSTH DIC score at the end of anticoagulation therapy may be a reliable tool for predicting the outcome in patients with infection-associated DIC.

Disseminated Intravascular Coagulopathy in Critically Ill Patients in Amman, Jordan.

The disseminated intravascular coagulation (DIC) is under-recognized in critically ill patients. The International Society of Thrombosis and Haemostasis (ISTH; DIC) provides a useful scoring system for accurate DIC identification. The study investigated the period prevalence of ISTH DIC from 2015 to 2017 in critically ill patients. In this multi-center, retrospective observational study, we included all patients identified with a DIC code or medically diagnosed with DIC during all admissions. Based on ISTH DIC scores ≥ 5, patients were classified with overt DIC. A total of 220 patients were included in this study. The period prevalence of DIC was 4.45%. The point prevalence of DIC has increased from 3.49% to 5.58% from 2015 to 2017 (27.7% female; median age 61.6 years). Based on the ISTH-Overt DIC criteria, 45.2% of the sample had sepsis. Overt DIC patients had significantly lower baseline hemoglobin (HB; t = 2.137, df = 193, p = 0.034), platelet count (t = 3.591, df = 193, p < 0.001) and elevated serum creatinine level (M = 2.1, SD = 1.5, t = 2.203, df = 193, p = 0.029) compared to non-Overt DIC. There was a statistically significant elevation in FDPs among Overt DIC compared to non-Overt DIC (χ2 = 30.381, df = 1, p < 0.001). Overt DIC patients had significantly prolonged PT (U = 2,298, z = 5.7, p < 0.001), PTT (U = 2,334, z = 2.0, p = 0.045) and INR (U = 2,541, z = 5.1, p < 0.001) compared to those with non-Overt DIC. The ISTH overt-DIC score can be used in critically ill patients regardless of the underlying disease. Efforts are required to predict and identify overt DIC using a valid scoring system on admission and follow-up of adult patients admitted to ICU.

Can disseminated intravascular coagulation scores predict mortality in COVID-19 patients?

ObjectivesComplications related to coronavirus disease 2019 (COVID-19) may lead to disseminated intravascular coagulation (DIC), which has been reported to be among the known causes of mortality in such patients. This study aims to analyse the incidence of DIC in COVID-19 non-survivors and to assess the association between DIC and its comorbidities. MethodsThe medical records of 154 non-survivors of COVID-19, hospitalised between April 2020 and July 2020, were retrospectively analysed. The International Society on Thrombosis and Haemostasis (ISTH) criteria for DIC were applied to identify the occurrence of coagulopathy. The receiver-operating characteristic (ROC) analysis was used to assess the association between DIC and its comorbidities. ResultsOut of 154 non-survivors, non-overt DIC was observed in 94.8% of the patients, whereas only 5.2% fulfilled the overt criteria of DIC with a mean age 64.6 years. The mortality rate was 4.5 times higher among men than women. The D-dimer level was >250 ng/ml in 68.8% of the patients including 88.9% of the non-overt and 100% of the overt DIC patients. Prothrombin time (PT) in non-overt and overt DIC cases was 17.3 s and 24.4 s, respectively. Thrombotic event and chronic kidney disease were found to be the main predictors of DIC (p < 0.0001 and 0.03, respectively) followed by diabetes mellitus (DM) and hypertension (statistically insignificant). ConclusionsOur study concludes that the ISTH DIC score cannot predict mortality as the COVID-19 related DIC differs from the sepsis-induced DIC. Among the seriously ill, older patients with comorbidities, increased levels of D-dimer and prolonged PT are more reliable parameters among COVID-19 non-survivors.

Use of fibrin monomer and D-Dimer in assessing overt and nonovert disseminated intravascular coagulation.

Early diagnosis of disseminated intravascular coagulation (DIC) before its progression to an overt stage is beneficial for its treatment and prognosis.This retrospective study aimed to evaluate the diagnostic performance of D-dimer and fibrin monomer in the early stage of DIC.A total of 707 patients suspected of having DIC, 302 healthy people were enrolled and divided into four groups: overt DIC, nonovert DIC, non-DIC based on the International Society of Thrombosis and Hemostasis scoring for overt DIC and the modified nonovert DIC criteria, healthy people as control group. Quantitative determination was done by immunoturbidimetry for D-dimer and fibrin monomer.The median of fibrin monomer in overt, nonovert and non-DIC was 41.65, 26.89 and 8.68 μg/ml, respectively. The median of D-dimer in overt, nonovert and non-DIC was 9.69, 3.98 and 3.08 μg/ml, respectively. D-dimer and fibrin monomer values were higher in overt DIC than other groups, but there was no difference between nonovert DIC and non-DIC in D-dimer. Unlike D-dimer, statistically significant differences were found in fibrin monomer between nonovert and non-DIC. At receiver operator characteristic curve-generated cutoff values, fibrin monomer had much excellent predictive performance compared with D-dimer for distinguishing nonovert DIC from non-DIC. D-dimer and fibrin monomer had same diagnostic performance in distinguishing overt DIC from non-DIC.Fibrin monomer is a better indicator compared with D-dimer in distinguishing patients with nonovert DIC from non-DIC. Hence, it might serve as an excellent negative exclusion marker to provide a reference for early clinical diagnosis and intervention through more studies.

Autopsy and statistical evidence of disturbed hemostasis progress in COVID-19: medical records from 407 patients

BackgroundThe progression of coagulation in COVID-19 patients with confirmed discharge status and the combination of autopsy with complete hemostasis parameters have not been well studied.ObjectiveTo clarify the thrombotic phenomena and hemostasis state in COVID-19 patients based on epidemiological statistics combining autopsy and statistical analysis.MethodsUsing autopsy results from 9 patients with COVID-19 pneumonia and the medical records of 407 patients, including 39 deceased patients whose discharge status was certain, time-sequential changes in 11 relevant indices within mild, severe and critical infection throughout hospitalization according to the Chinese National Health Commission (NHC) guidelines were evaluated. Statistical tools were applied to calculate the importance of 11 indices and the correlation between those indices and the severity of COVID-19.ResultsAt the beginning of hospitalization, platelet (PLT) counts were significantly reduced in critically ill patients compared with severely or mildly ill patients. Blood glucose (GLU), prothrombin time (PT), activated partial thromboplastin time (APTT), and D-dimer levels in critical patients were increased compared with mild and severe patients during the entire admission period. The International Society on Thrombosis and Haemostasis (ISTH) disseminated intravascular coagulation (DIC) score was also high in critical patients. In the relatively late stage of nonsurvivors, the temporal changes in PLT count, PT, and D-dimer levels were significantly different from those in survivors. A random forest model indicated that the most important feature was PT followed by D-dimer, indicating their positive associations with disease severity. Autopsy of deceased patients fulfilling diagnostic criteria for DIC revealed microthromboses in multiple organs.ConclusionsCombining autopsy data, time-sequential changes and statistical methods to explore hemostasis-relevant indices among the different severities of the disease helps guide therapy and detect prognosis in COVID-19 infection.

Cultivating a Better Understanding of COVID-19 Amidst a Shifting Landscape.

As COVID-19 swept across the globe, emergency physicians stood on the front lines of a pandemic unlike any seen in our lifetimes. In areas where cases surged, we rapidly assessed and stabilized large numbers of critically ill patients using the limited data available to us, for that is, fundamentally, what we do. In the beginning, we relied on first principles. Vital signs are vital. Isolate the infected. Intubate ARDS early.

Non-Overt Coagulopathy in Non-ICU Patients with Mild to Moderate COVID-19 Pneumonia.

Introduction: Aim of the study is to assess the occurrence of early stage coagulopathy and disseminated intravascular coagulation (DIC) in patients with mild to moderate respiratory distress secondary to SARS-CoV-2 infection. Materials and methods: Data of patients hospitalized from 18 March 2020 to 20 April 2020 were retrospectively reviewed. Two scores for the screening of coagulopathy (SIC and non-overt DIC scores) were calculated. The occurrence of thrombotic complication, death, and worsening respiratory function requiring non-invasive ventilation (NIV) or admission to ICU were recorded, and these outcomes were correlated with the results of each score. Chi-square test, receiver-operating characteristic curve, and logistic regression analysis were used as appropriate. p Values < 0.05 were considered statistically significant. Results: Data of 32 patients were analyzed. Overt-DIC was diagnosed in two patients (6.2%), while 26 (81.2%) met the criteria for non-overt DIC. Non-overt DIC score values ≥4 significantly correlated with the need of NIV/ICU (p = 0.02) and with the occurrence of thrombotic complications (p = 0.04). A score ≥4 was the optimal cut-off value, performing better than SIC score (p = 0.0018). Values ≥4 in patients with thrombotic complications were predictive of death (p = 0.03). Conclusions: Overt DIC occurred in 6.2% of non-ICU patients hospitalized for a mild to moderate COVID-19 respiratory distress, while 81.2% fulfilled the criteria for non-overt DIC. The non-overt DIC score performed better than the SIC score in predicting the need of NIV/ICU and the occurrence of thrombotic complications, as well as in predicting mortality in patients with thrombotic complications, with a score ≥4 being detected as the optimal cut-off.

Serum histone H3 levels and platelet counts are potential markers for coagulopathy with high risk of death in septic patients: a single-center observational study

BackgroundRecent studies have suggested that anticoagulant therapy does not confer a survival benefit overall in sepsis, but might be beneficial in sepsis-associated disseminated intravascular coagulation (DIC). In particular, those with high Sequential Organ Failure Assessment (SOFA) scores might be the optimal target for anticoagulant therapy. However, both DIC and SOFA scores require the measurement of multiple markers. The purpose of this study was to explore a minimal marker set for determining coagulopathy at high risk of death in septic patients, wherein histone H3 levels were evaluated as indicators of both organ failure and coagulation activation.MethodsWe analyzed correlations among levels of serum histone H3 and other coagulation markers in 85 cases of sepsis using Spearman’s rank correlation test. We then compared the utility of histone H3 to that of other coagulation markers in predicting the traditional DIC state or 28-day mortality by receiver-operating characteristics analysis. Finally, we suggested cut-off values for determining coagulopathy with high risk of death, and evaluated their prognostic utility.ResultsSerum histone H3 levels significantly correlated with thrombin-antithrombin complex (TAT) levels (Spearman’s ρ = 0.46, p < 0.001), and weakly correlated with platelet counts (Spearman’s ρ = − 0.26, p < 0.05). Compared to other coagulation markers, histone H3 levels showed better performance in predicting 28-day mortality. When combining serum histone H3 levels with platelet counts, our new scoring system showed a concordance rate of 69% with the traditional four-factor criteria of DIC established by the Japanese Association for Acute Medicine. The 28-day mortality rates of the new and the traditional criteria-positive patients were 43% and 21%, respectively. Those of the new and the traditional criteria-negative patients were 5.7% and 9.4%, respectively.ConclusionsSerum histone H3 levels and platelet counts are potential markers for determining coagulopathy with high risk of death in septic patients. Further studies are needed to clarify the utility of serum histone H3 levels in the diagnostic of coagulopathy/DIC.

Supportive care for hemostatic complications associated with pediatric leukemia: a national survey in Japan.

Optimal supportive care for disseminated intravascular coagulation (DIC) and hemostatic complications by asparaginase is indispensable for the successful treatment of pediatric leukemia. However, the situation regarding this type of care in Japan is unclear. We conducted a questionnaire-based survey at 155 institutions treating childhood leukemia in Japan. The questionnaire asked about the supportive care provided by each institution to acute leukemia patients with DIC and asparaginase-induced hemostatic alterations. Ninety-eight institutions responded. The most common diagnostic criteria for DIC were those established by the Japanese Ministry of Health and Welfare. Regardless of the etiology underlying DIC, recombinant human thrombomodulin and synthetic protease inhibitors were used as anticoagulation therapy by around 70% and 40% of institutions, respectively. Additionally, 92%, 93%, and 73% of institutions measured plasma antithrombin, fibrinogen, and D-dimer/fibrin degradation products, respectively, more than twice per week during induction therapy for acute lymphoblastic leukemia. Survey responses indicate that 95% and 24% of the institutions used antithrombin replacement and fresh-frozen plasma, respectively. Supportive care for DIC and/or asparaginase-induced hemostatic alterations at Japanese pediatric centers was intensive and differs markedly from protocols in other countries. The efficacy of supportive care should be evaluated prospectively in the setting of pediatric leukemia.

Effectiveness of Soluble Recombinant Human Thrombomodulin in Patients with Severe Acute Pancreatitis Complicated by Disseminated Intravascular Coagulation.

We aimed to evaluate retrospectively the effect of soluble recombinant human thrombomodulin (rTM) on prognosis in patients with severe acute pancreatitis complicated by disseminated intravascular coagulation (DIC). Based on Japanese diagnostic criteria of acute pancreatitis and DIC, patients who entered our intensive care unit (ICU) were selected. Comparisons were made between patients treated with rTM (rTM group) and without rTM (control group). A total of 38 patients were selected, and rTM was administered to 13 patients. Mortality on the 60th day after entering the ICU was significantly lower in the rTM group (15%) as compared with the control group (56%) (p=0.036). Although the platelet count was significantly lower in the rTM group at the start of treatment, the reversal rate from DIC was significantly higher than in the control group (rTM 62%, control 24%, p=0.035). According to logistic regression analysis of therapeutics, only rTM contributed to survival on the 60th day (odds ratio, 12.5; 95% confidence interval, 1.80-160; p=0.009). In patients with severe acute pancreatitis complicated by DIC, it was suggested that rTM might improve the prognosis of survival, even if the platelet count was markedly reduced.

Diagnosis of sepsis-induced disseminated intravascular coagulation and coagulopathy.

Disseminated intravascular coagulation (DIC) is a frequent complication in sepsis. Once patients develop DIC, the mortality rate increases significantly. Moreover, recent studies have suggested that coagulation disorder plays a significant role in the development of organ dysfunction in sepsis. Thus, the early detection of DIC is vital in sepsis care, and the Japanese Association for Acute Medicine established a set of original diagnostic criteria in 2006 (JAAM DIC). Since then, the usefulness of the JAAM DIC has been repeatedly reported, and these criteria have been widely adopted in emergency and critical care settings in Japan. Different criteria have also been released by the International Society on Thrombosis and Haemostasis (ISTH overt‐DIC), and the latter criteria are presently considered to be the international standard. Compared with the JAAM DIC, the ISTH overt‐DIC criteria are stricter and the timing of diagnosis is later. This discrepancy is because of conceptual differences. As many physicians think sepsis‐associated DIC is the target of anticoagulant therapies in Japan, the JAAM DIC criteria were designed to allow the early initiation of treatment. As other countries do not provide DIC‐specific treatments, early diagnosis is not necessary, and this situation has led to a significant gap. However, as overt‐DIC is a late‐phase coagulation disorder, a need for early detection has been advocated, and members of the ISTH have recently proposed the category of sepsis‐induced coagulopathy. In this review, we introduce the strengths and weaknesses of the major criteria including JAAM‐DIC, ISTH overt‐DIC, sepsis‐induced coagulopathy, and Japanese Society on Thrombosis and Haemostasis‐DIC.

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.