The effects of emicizumab on in vitro coagulation and fibrinolysis parameters in patients with disseminated intravascular coagulation with and without addition of anti-FVIII antibody.

BACKGROUND: Emicizumab (Emi) is used as haemostatic prophylaxis for patients with haemophilia A (PwHA). Disseminated intravascular coagulation (DIC) is a condition characterized by persistent systemic activation of coagulation, but there is yet no information on coagulation and fibrinolysis potentials in Emi-treated PwHA with DIC. AIM: To examine the effect of Emi on coagulation and fibrinolysis potentials in HA-model DIC plasmas. METHODS: Plasma from a patient with sepsis-DIC (seven patients) was treated with anti-factor (F)VIII monoclonal antibody (HA-model DIC plasma) and incubated with Emi (50 µg/mL). The plasma was then assessed using clot-fibrinolysis waveform analysis (CFWA). Coagulation and fibrinolysis parameters were expressed as ratios relative to normal plasma (|min1|-ratio and |FL-min1|-ratio, respectively). PATIENTS AND RESULTS: In case 1, coagulant potential was slightly high and fibrinolytic potential was extremely low, presenting a coagulant-dominant state (|min1|-ratio/|FL-min1|-ratio: 1.1/.38). In cases 2-5, fibrinolytic potential was not suppressed, but there were marked hypercoagulant potentials, indicating relative coagulant-dominant states. In case 6, coagulant and fibrinolytic potentials were increased but well balanced (|min1|-ratio/|FL-min1|-ratio: 1.38/1.28). In case 7, both potentials were severely deteriorated in not only CFWA but also the thrombin/plasmin generation assay. The addition of Emi into the HA-model DIC plasmas increased |min1|-ratio values in all cases, but the coagulant potentials did not exceed the initial ones (DIC plasma before treatment with anti-FVIII antibody). CONCLUSIONS: The presence of Emi in the HA-model DIC plasma improved coagulation potentials, but did not increase coagulation potentials beyond those of DIC plasma in non-HA states.

Evaluation of soluble fibrin monomer complex in patients in SARS-CoV-2 COVID-19 infection-associated coagulopathy.

Hospitalized patients with COVID-19 infection frequently have coagulopathy resembling disseminated intravascular coagulation (DIC). An elevation of D-dimer level is associated with a poor prognosis; however, the role of other fibrin degradation products, such as soluble fibrin monomers (SFMC), is not known. The objective of the study was to investigate the frequency and prognostic role of elevated SFMC in patients with COVID-19. In this retrospective cohort study, patients hospitalized between April 1, 2020 and December 14, 2020 at Mayo Clinic with COVID-19 infection who underwent DIC panel testing were identified. Results of laboratory tests and outcomes (thrombosis and death) within 40 days of testing were obtained via medical record review. Of 108 patients, D-dimer was elevated in 82 (75.9%) patients. Of those with elevated D-dimer, SFMC was elevated in 19/82 (23%) patients. There were 16 thrombotic events and 16 deaths during the 40-day follow-up. The incidence of overt-DIC was 4.6%. In univariate analysis, D-dimer ≥5 x highest upper limit normal (ULN) and elevated SFMC were each associated with higher 40-day mortality. However, when used in combination with D-dimer ≥5 x highest ULN, an elevated SFMC provided no further mortality predictive value. Compared to 75.9% of patients with elevated D-dimers, of those tested, only 23% had elevated SFMC. These results support the hypothesis that elevated D-dimer in COVID-19 infection is a direct consequence of endothelial damage and not overt-DIC.

Association of coagulation disturbances with severity of COVID-19: a longitudinal study.

OBJECTIVES: Coagulation dysfunction is an evident factor in the clinical diagnosis and treatment of patients with coronavirus disease 2019 (COVID-19), appearing even in COVID-19 patients with normal inflammation indices. Therefore, this study aimed to analyze the characteristics of coagulation function indices in COVID-19 patients to investigate possible mechanisms through the comparison of non-severe and severe COVID-19 patients. METHODS: We included 143 patients whose clinical characteristics, coagulation function, and other indices such as inflammatory factors were collected and compared based on disease severity. RESULTS: Activated partial thromboplastin time (APTT), D-dimer, and fibrinogen levels were evidently higher in the severe group than in the non-severe group. Among non-severe COVID-19 patients, the aforementioned indicators depicted increasing trends, but the fibrinogen level alone was higher than normal. However, in severe COVID-19 patients, values of all three indices were higher than normal. In severe COVID-19 patients, fibrinogen and D-dimer were correlated with several inflammation indices during the early stage of the disease. However, no correlation between fibrinogen and inflammatory factors was observed in non-severe COVID-19 patients at any time point. DISCUSSION: Results revealed that the hypercoagulability tendency of severe COVID-19 patients was more evident. The relationship between coagulation function and inflammatory factors showed that changes in coagulation function in severe COVID-19 patients may be related to abnormal increase in inflammatory factors at an early stage; however, in non-severe COVID-19 patients, there might be other factors leading to abnormal coagulation. CONCLUSION: Inflammatory factors were not the only cause of abnormal coagulation function in COVID-19 patients.

Factor VIIa-AT Complex Is an Independent Prognostic Marker of Disseminated Intravascular Coagulation.

OBJECTIVE: The factor VIIa-Antithrombin (VIIa-AT) complex is a relatively new biomarker associated with the activation of the extrinsic coagulation pathway. Since disseminated intravascular coagulation (DIC) is primarily driven by issue factor (TF)-induced extrinsic coagulation activation, the plasma level of factor VIIa-AT, via its role as an activation marker of the extrinsic pathway, could be a potential marker for DIC. The clinical significance of extrinsic coagulation markers, including factor VIIa-AT, in DIC was investigated. METHODS: The extrinsic coagulation markers, including factor VIIa-AT, TF, factor VII, and antithrombin (AT), were measured in 148 patients clinically suspicious for DIC. Multiple linear regression and Cox proportional-hazard analysis were conducted to evaluate both contributing factors and the prognostic power of the markers. RESULTS: The factor VIIa-AT complex, factor VII, and AT levels were significantly lower in the overt-DIC group and gradually decreased according to the severity of DIC based on the DIC scores. On the contrary, TF was significantly higher in the overt-DIC group. The factor VII level was revealed as a significant independent contributor to the factor VIIa-AT level. Upon multivariable Cox proportional-hazard analysis, the factor VIIa-AT complex showed the highest hazard ratio (3.41; 95% confidence interval 1.11-10.44). CONCLUSION: The factor VIIa-AT complex reflects the severity of DIC and is an independent prognostic factor of DIC. Our findings hint at the potential of the factor VIIa-AT complex to be used as a complementary marker to well-established biomarkers such as AT.

Mesenchymal stem cell transfusion: Possible beneficial effects in COVID-19 patients.

SARS-CoV-2 attaches to the angiotensin-converting enzyme 2 (ACE-2) receptor on human cells. The virus causes hypercytokinemia, capillary leak, pulmonary edema, acute respiratory distress syndrome, acute cardiac injury, and leads to death. Mesenchymal stem cells (MSCs) are ACE-2 negative cells; therefore, can escape from SARS-CoV-2. MSCs prevent hypercytokinemia and help the resolution of the pulmonary edema and other damages occurred during the course of COVID-19. In addition, MSCs enhance the regeneration of the lung and other tissues affected by SARS-CoV-2. The case series reported beneficial effect of MSCs in COVID-19 treatment. However, there are some concerns about the safety of MSCs, particularly referring to the increased risk of disseminated intravascular coagulation, and thromboembolism due to the expression of TF/CD142. Prospective, randomized, large scale studies are needed to reveal the optimum dose, administration way, time, efficacy, and safety of MSCs in the COVID-19 treatment.

Age Is Associated With the Efficacy of Anticoagulant Therapies Against Sepsis-Induced Disseminated Intravascular Coagulation.

Disseminated Intravascular Coagulation (DIC) commonly complicates sepsis and considerably worsens mortality. Recent studies suggested that anticoagulant therapies improved mortality only in specific sepsis populations, and key pathologies for selecting optimal targets needed to be identified. Anticoagulant activities were naturally altered with aging. This study aimed to evaluate age-related differences in efficacy of anticoagulant therapies in sepsis. This post hoc analysis of a nationwide multicenter cohort study was conducted in 42 intensive care units in Japan. Adult patients with septic DIC were divided into anticoagulant and control groups. Age-related changes in predicted mortality in both groups were compared using a logistic regression model including 2-way interaction terms. Patients were also stratified into 3 subsets based on age, and propensity score-adjusted Cox regression analyses were conducted to examine survival effect of anticoagulants in each subset. We included 1432 patients with septic DIC; 867 patients received anticoagulants and 565 received none. Age-related change in predicted mortality was significantly different between groups (P for interaction = 0.013), and the gap between groups was broad in the younger population. Similarly, in Cox regression analyses, anticoagulant therapies were associated with significantly lower mortality in the subsets of age ≤ 60 and 60-79 (hazard ratios = 0.461, 0.617, P = 0.007, 0.005, respectively), whereas there was no difference in survival between the groups in the subsets of age ≥ 80. The efficacy of anticoagulant therapies for septic DIC might be associated with patient age.

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

INTRODUCTION: 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. METHODS: 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. RESULTS: 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). CONCLUSION: 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.

DIC, SIC or CAC - the haemostatic profile in COVID-19 patients hospitalised in the intensive care unit: a single-centre retrospective analysis.

INTRODUCTION: Infection with SARS-CoV-2 in its most severe form leads to acute respiratory distress syndrome requiring mechanical ventilation under the conditions of the Intensive Care Unit (ICU). The state of hypercoagulation described in COVID-19 may deepen respiratory failure, leading to increased mortality. The aim of the presented study is to characterise the haemostatic profile based on the results of clotting system parameters and risk assessment of thromboembolic complications of patients hospitalised in the ICU. MATERIAL AND METHODS: This retrospective study covered the first 10 adult patients hospitalised in the ICU of the Hospital for Infectious Diseases in Warsaw in the second quarter of 2020. Demographic, clinical and laboratory parameters of the coagulation system and the risk of thromboembolic complications were assessed. Well known criteria of haemostatic disorders were used to classify the observed derangements. RESULTS: The most frequently observed deviations in the coagulation system were high concentrations of D-dimer and fibrinogen. In select cases the clotting time was prolonged. No severe thrombocytopenia was observed. All patients presented a high risk of thromboembolic complications as assesed by the Padua score. The observed clotting abnormalities did not meet the criteria for DIC (disseminated intravascular coagulation) and SIC (sepsis-induced coagulopathy) diagnosis. CONCLUSIONS: The main elements of coagulopathy that were observed in our cases differ from those usually seen in patients with recognised sepsis. The unique haemostatic profile of COVID-19 patients treated in the ICU has been described as CAC (COVID-19-associated coagulopathy).

COVID-19-related laboratory coagulation findings.

The alterations in the hemostatic balance in COVID-19 patients are strongly disturbed and contribute to a high prothrombotic status. The high rate of venous thromboembolism in COVID-19 patients goes along with derangements in coagulation laboratory parameters. Hemostasis testing has an important role in diagnosed COVID-19 patients. Elevated D-dimer levels were found to be a crucial laboratory marker in the risk assessment of thrombosis in COVID-19 patients. The diagnostic approach also includes prothrombin time and platelet count. Fibrinogen might give an indication for worsening coagulopathy. Other markers (activated partial thromboplastin time (aPTT), fibrinolysis parameters, coagulation factors, natural anticoagulants, antiphospholipid antibodies and parameters obtained by thromboelastography or thrombin generation assays) have been described as being deranged. These may help to understand the pathophysiology of thrombosis in COVID-19 patients but have currently no place in diagnosis or management in COVID-19 patients. For monitoring the heparin anticoagulant therapy, the anti-Xa assay is suggested, because the severe acute-phase reaction (high fibrinogen and high factor VIII) shortens the aPTT.

A mild deficiency of ADAMTS13 is associated with severity in COVID-19: comparison of the coagulation profile in critically and noncritically ill patients.

Early descriptions of COVID-19 associated coagulopathy identified it as a disseminated intravascular coagulation (DIC). However, recent studies have highlighted the potential role of endothelial cell injury in its pathogenesis, and other possible underlying mechanisms are being explored. This study aimed to analyse the coagulation parameters of critically and noncritically ill patients with COVID-19 bilateral pneumonia, determine if coagulation factors consumption occurs and explore other potential mechanisms of COVID-19 coagulopathy. Critically and noncritically ill patients with a diagnosis of COVID-19 bilateral pneumonia were recruited. For each patient, we performed basic coagulation tests, quantification of coagulation factors and physiological inhibitor proteins, an evaluation of the fibrinolytic system and determination of von Willebrand Factor (vWF) and ADAMTS13. Laboratory data were compared with clinical data and outcomes. The study involved 62 patients (31 ICU, 31 non-ICU). The coagulation parameters assessment demonstrated normal median prothrombin time (PT), international normalized ratio (INR) and activated partial thromboplastin time (APTT) in our cohort and all coagulation factors were within normal range. PAI-1 median levels were elevated (median 52.6 ng/ml; IQR 37.2-85.7), as well as vWF activity (median 216%; IQR 196-439) and antigen (median 174%; IQR 153.5-174.1). A mild reduction of ADAMTS13 was observed in critically ill patients and nonsurvivors. We demonstrated an inverse correlation between ADAMTS13 levels and inflammatory markers, D-dimer and SOFA score in our cohort. Elevated vWF and PAI-1 levels, and a mild reduction of ADAMTS13 in the most severe patients, suggest that COVID-19 coagulopathy is an endotheliopathy that has shared features with thrombotic microangiopathy.

Vaccine-Induced Immune Thrombotic Thrombocytopenia with Disseminated Intravascular Coagulation and Death following the ChAdOx1 nCoV-19 Vaccine.

Coronavirus is a novel human pathogen causing fulminant respiratory syndrome (COVID-19). Although COVID-19 is primarily a disease of the lungs with florid respiratory manifestations, there are increasing reports of cardiovascular, musculoskeletal, gastrointestinal, and thromboembolic complications. Developing an effective and reliable vaccine was emergently pursued to control the catastrophic spread of the global pandemic. We report a fatal case of vaccine-induced immune thrombotic thrombocytopenia (VITT) after receiving the first dose of the ChAdOx1 nCoV-19 vaccine. We attribute this fatal thrombotic condition to the vaccine due to the remarkable temporal relationship. The proposed mechanism of VITT is production of rogue antibodies against platelet factor-4 resulting in massive platelet aggregation. Healthcare providers should be aware of the possibility of such fatal complication, and the vaccine recipients should be warned about the symptoms of VITT.

Heparanase as a potential player in SARS-CoV-2 infection and induced coagulopathy.

During the current formidable COVID-19 pandemic, it is appealing to address ideas that may invoke therapeutic interventions. Clotting disorders are well recognized in patients infected with severe acute respiratory syndrome (SARS) caused by a novel coronavirus (SARS-CoV-2), which lead to severe complications that worsen the prognosis in these subjects. Increasing evidence implicate Heparan sulfate proteoglycans (HSPGs) and Heparanase in various diseases and pathologies, including hypercoagulability states. Moreover, HSPGs and Heparanase are involved in several viral infections, in which they enhance cell entry and release of the viruses. Herein we discuss the molecular involvement of HSPGs and heparanase in SARS-CoV-2 infection, namely cell entry and release, and the accompanied coagulopathy complications, which assumedly could be blocked by heparanase inhibitors such as Heparin and Pixatimod.

Specific cytokines in the inflammatory cytokine storm of patients with COVID-19-associated acute respiratory distress syndrome and extrapulmonary multiple-organ dysfunction.

BACKGROUND: To date, specific cytokines associated with development of acute respiratory distress syndrome (ARDS) and extrapulmonary multiple organ dysfunction (MOD) in COVID-19 patients have not been systematically described. We determined the levels of inflammatory cytokines in patients with COVID-19 and their relationships with ARDS and extrapulmonary MOD. METHODS: The clinical and laboratory data of 94 COVID-19 patients with and without ARDS were analyzed. The levels of inflammatory cytokines (interleukin 6 [IL-6], IL-8, IL-10, and tumor necrosis factor α [TNF-α]) were measured on days 1, 3, and 5 following admission. Seventeen healthy volunteers were recruited as controls. Correlations in the levels of inflammatory cytokines with clinical and laboratory variables were analyzed, furthermore, we also explored the relationships of different cytokines with ARDS and extrapulmonary MOD. RESULTS: The ARDS group had higher serum levels of all 4 inflammatory cytokines than the controls, and these levels steadily increased after admission. The ARDS group also had higher levels of IL-6, IL-8, and IL-10 than the non-ARDS group, and the levels of these cytokines correlated significantly with coagulation parameters and disseminated intravascular coagulation (DIC). The levels of IL-6 and TNF-α correlated with the levels of creatinine and urea nitrogen, and were also higher in ARDS patients with acute kidney injury (AKI). All 4 inflammatory cytokines had negative correlations with PaO2/FiO2. IL-6, IL-8, and TNF-α had positive correlations with the APACHE-II score. Relative to survivors, non-survivors had higher levels of IL-6 and IL-10 at admission, and increasing levels over time. CONCLUSIONS: The cytokine storm apparently contributed to the development of ARDS and extrapulmonary MOD in COVID-19 patients. The levels of IL-6, IL-8, and IL-10 correlated with DIC, and the levels of IL-6 and TNF-α were associated with AKI. Relative to survivors, patients who died within 28 days had increased levels of IL-6 and IL-10.

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

INTRODUCTION: 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.

Differences in coagulopathy indices in patients with severe versus non-severe COVID-19: a meta-analysis of 35 studies and 6427 patients.

Coronavirus disease 2019 (COVID-19) is a highly contagious disease that appeared in China in December 2019 and spread rapidly around the world. Several patients with severe COVID-19 infection can develop a coagulopathy according to the ISTH criteria for disseminated intravascular coagulopathy (DIC) with fulminant activation of coagulation, resulting in widespread microvascular thrombosis and consumption of coagulation factors. We conducted a meta-analysis in order to explore differences in coagulopathy indices in patients with severe and non-severe COVID-19. An electronic search was performed within PubMed, Google Scholar and Scopus electronic databases between December 2019 (first confirmed Covid-19 case) up to April 6th, 2020. The primary endpoint was the difference of D-dimer values between Non-Severe vs Severe disease and Survivors vs Non-Survivors. Furthermore, results on additional coagulation parameters (platelet count, prothrombin time, activated partial thromboplastin time) were also analyzed. The primary analysis showed that mean d-dimer was significantly lower in COVID-19 patients with non-severe disease than in those with severe (SMD - 2.15 [- 2.73 to - 1.56], I2 98%, P < 0.0001). Similarly, we found a lower mean d-dimer in Survivors compared to Non-Survivors (SMD - 2.91 [- 3.87 to - 1.96], I2 98%, P < 0.0001). Additional analysis of platelet count showed higher levels of mean PLT in Non-Severe patients than those observed in the Severe group (SMD 0.77 [0.32 to 1.22], I2 96%, P < 0.001). Of note, a similar result was observed even when Survivors were compared to Non-Survivors (SMD 1.84 [1.16 to 2.53], I2 97%, P < 0.0001). Interestingly, shorter mean PT was found in both Non-Severe (SMD - 1.34 [- 2.06 to - 0.62], I2 98%, P < 0.0002) and Survivors groups (SMD - 1.61 [- 2.69 to - 0.54], I2 98%, P < 0.003) compared to Severe and Non-Survivor patients. In conclusion, the results of the present meta-analysis demonstrate that Severe COVID-19 infection is associated with higher D-dimer values, lower platelet count and prolonged PT. This data suggests a possible role of disseminated intravascular coagulation in the pathogenesis of COVID-19 disease complications.

Prognostic value of thrombin generation parameters in hospitalized COVID-19 patients.

SARS-CoV-2 infection increases the risk of thrombosis by different mechanisms not fully characterized. Although still debated, an increase in D-dimer has been proposed as a first-line hemostasis test associated with thromboembolic risk and unfavorable prognosis. We aim to systematically and comprehensively evaluate the association between thrombin generation parameters and the inflammatory and hypercoagulable state, as well as their prognostic value in COVID-19 patients. A total of 127 hospitalized patients with confirmed COVID-19, 24 hospitalized patients with SARS-CoV-2-negative pneumonia and 12 healthy subjects were included. Clinical characteristics, thrombin generation triggered by tissue factor with and without soluble thrombomodulin, and also by silica, as well as other biochemical parameters were assessed. Despite the frequent use of heparin, COVID-19 patients had similar thrombin generation to healthy controls. In COVID-19 patients, the thrombin generation lag-time positively correlated with markers of cell lysis (LDH), inflammation (CRP, IL-6) and coagulation (D-dimer), while the endogenous thrombin potential (ETP) inversely correlated with D-dimer and LDH, and positively correlated with fibrinogen levels. Patients with more prolonged lag-time and decreased ETP had higher peak ISTH-DIC scores, and had more severe disease (vascular events and death). The ROC curve and Kaplan Meier estimate indicated that the D-dimer/ETP ratio was associated with in-hospital mortality (HR 2.5; p = 0.006), and with the occurrence of major adverse events (composite end-point of vascular events and death) (HR 2.38; p = 0.004). The thrombin generation ETP and lag-time variables correlate with thromboinflammatory markers, and the D-dimer/ETP ratio can predict major adverse events in COVID-19.

Induced normothermia ameliorates the procoagulant host response in human endotoxaemia.

BACKGROUND: Dysregulation of coagulation occurs commonly in sepsis, ranging from mild coagulopathy with decreased platelets to disseminated intravascular coagulation (DIC). We investigated the effect of induced normothermia on coagulation during lipopolysaccharide (LPS)-induced endotoxaemia in healthy volunteers. METHODS: Twelve volunteers received an infusion of bacterial lipopolysaccharide (Escherichia coli; 2 ng kg-1) and were assigned to either induced normothermia or control. Induced normothermia to maintain core temperature at 37°C consisted of external surface cooling, cold i.v. fluids, and medication to reduce shivering (buspirone, clonidine, and magnesium sulphate). The primary outcome was the DIC score (International Society on Thrombosis and Haemostasis guideline). Prothrombin time (PT), activated partial thromboplastin time (aPTT), D-dimer, plasma von Willebrand factor (vWf), and rotational thromboelastometry (ROTEM) were measured before and 1, 3, 6, and 8 h after LPS infusion. Differences between groups were tested with a mixed effects model. RESULTS: In control subjects, lipopolysaccharide caused a fever, transiently decreased platelet levels and lowered activated partial thromboplastin time, while prolonging prothrombin time and increasing D-Dimer and vWf levels. Normothermia prevented the DIC-score exceeding 4, which occurred in 50% of control subjects. Normothermia also reduced the fall in platelet count by 67x109 L-1([95%CI:27-107]; p=0.002), aPTT (mean difference:3s [95%CI:1-5]; p=0.005) and lowered vWf levels by 89% ([95%CI:6-172]; p=0.03), compared to the fever group. ROTEM measurements were unaffected by lipopolysaccharide. CONCLUSION: In human endotoxaemia, induced normothermia decreases markers of endothelial activation and DIC. Maintaining normothermia may reduce coagulopathy in hyperinflammatory states.

Types, Clinical Features, and Survival Outcomes of Patients with Acute Myeloid Leukemia in Thailand: A 3-Year Prospective Multicenter Study from the Thai Acute Leukemia Study Group (TALSG).

BACKGROUND: Acute myeloid leukemia (AML) is a common, challenging hematologic malignancy worldwide. Thai data on its characteristics and outcomes have never been systematically reported, to our knowledge. The objective of this study was to determine the clinical features and outcomes of Thai patients with AML. PATIENTS AND METHODS: This was a prospective observational study of nine academic hospitals. Patients with newly diagnosed AML were invited to register online. RESULTS: A total of 679 patients with AML were included. The presence of circulating peripheral blood blasts was correlated with a high white blood cell count. Acute promyelocytic leukemia (APL) had predominantly lower white blood cell counts and higher proportions without peripheral blood blasts compared with non-APL AML. Disseminated intravascular coagulation was commonly presented in APL (37.7%). Splenomegaly and normal platelet count were more frequently seen in patients with Philadelphia chromosome-positive AML. The median follow-up time for those who survived more than 1 year was 28.0 months. One-year overall survival rates for non-APL AML and APL were 31.9% and 88.2%, respectively; 2-year overall survival rates were 29.6% and 88.2%, respectively. Hematopoietic stem cell transplantation could improve survival in non-APL AML. CONCLUSION: APL should be considered despite absence of peripheral blood blast. This study demonstrates poor outcome of Thai AML and more research to improve outcomes are underway. Expanding access to hematopoietic stem cell transplantation should be considered in Thailand.

Massive intraperitoneal hemorrhage in patients with COVID-19: a case series.

Coronavirus disease (COVID-19) initiates several life-threatening complications including coagulopathies with a unique characteristic that made this problem challenging. Here we presented 4 cases of RT-PCR positive patients that have experienced deadly intraperitoneal hemorrhage with fourth WHO Bleeding Grade after overcoming their respiratory phase. COVID-19 could induce several coagulopathies with different features that besides iatrogenic interventions increases its mortality and morbidity due to lack of clinical evidence based on well-designed randomized clinical trials on anticoagulation therapies (AT) and administration of varieties of newly approved and non-approved medicines. This report showed the urgent need for investigation on the pathophysiology of COVID-19-associated coagulopathy esp. in hemorrhagic events which are needed to make the best therapeutic decision.

Detailed exploration of pathophysiology involving inflammatory status and bleeding symptoms between lipopolysaccharide- and tissue factor-induced disseminated intravascular coagulation in rats.

Lipopolysaccharide (LPS) and tissue factor (TF) have frequently been used to induce disseminated intravascular coagulation (DIC) in experimental animal models. We have previously reported that the pathophysiology of DIC differs according to the inducing agents. However, inflammatory status and bleeding symptoms have not been fully compared between rat models of the two forms of DIC. We attempted to evaluate detailed characteristic features of LPS- and TF-induced DIC models, especially in regard to inflammatory status and bleeding symptoms, in addition to selected hemostatic parameters and pathologic findings in the kidneys. The degree of hemostatic activation in both types of experimental DIC was identical, based on the results of thrombin-antithrombin complex levels. Markedly elevated tumor necrosis factor, interleukin-6, and high-mobility group box-1 concentrations were observed with severe organ dysfunction and marked fibrin deposition in the kidney on administration of LPS, whereas markedly elevated D-dimer concentration and bleeding symptoms were observed with TF administration. Pathophysiology such as fibrinolytic activity, organ dysfunction, inflammation status, and bleeding symptom differed markedly between LPS- and TF-induced DIC models in rats. We, therefore, recommend that these disease models be assessed carefully as distinct entities to determine the implications of their experimental and clinical use.