Sepsis-associated Coagulopathy Research Articles

Heparin therapy in sepsis and sepsis-associated disseminated intravascular coagulation: a systematic review and meta-analysis

BackgroundSepsis is a life-threatening condition that affects 49 million people annually. Managing sepsis-associated coagulopathy poses a significant challenge due to its high mortality rates in intensive care. Recent reports suggest that administering heparin may offer potential survival benefits in sepsis and coronavirus disease cases. However, there is currently no established evidence supporting the use of heparin for sepsis. Thus, in this study, we aimed to assess the efficacy of heparin administration in patients with sepsis.MethodsA systematic review was conducted following the PRISMA guidelines. The searches included MEDLINE, Cochrane, and Japanese databases up to January 2023. The inclusion criteria consisted of randomized control trials (RCTs) involving adult sepsis patients receiving heparin. The risk of bias was assessed using RoB2, and the data extraction included 28-day mortality and bleeding complications.ResultsOut of 1733 initial articles, only three studies met the inclusion criteria. The analysis, which included 426 patients, showed no significant difference in 28-day and in-hospital mortality between the heparin and control groups (risk ratio [RR] = 0.86, 95% confidence interval [CI]: 0.60–1.24). Subgroup analysis of sepsis-associated disseminated intravascular coagulation (DIC) patients (n = 109) also did not show a significant reduction in mortality (RR = 0.84, 95% CI: 0.51–1.38). Heterogeneity was zero, and no publication bias was observed. Additionally, there was significant difference in bleeding complications (RR = 0.49, 95% CI: 0.24–0.99, p = 0.047).ConclusionsThis meta-analysis did not demonstrate a survival benefit of heparin administration in patients with sepsis and sepsis-associated DIC. Further investigation into the potential benefits of heparin is warranted. Moreover, the analysis revealed no increase in bleeding risks with heparin administration; instead, a significant reduction in the risk of bleeding was noted.Trial registrationThis review was preregistered with PROSPERO (registration: CRD42023385091).

Decreased Protein C Pathway Activity in COVID-19 Compared to Non-COVID Sepsis: An Observational and Comparative Cohort Study.

Sepsis-associated coagulopathy increases risk of mortality. Impairment of the anticoagulant protein C (PC) pathway may contribute to the thrombotic phenotype in coronavirus disease 2019 (COVID-19) sepsis. This study assessed the functionality of this pathway in COVID-19 and non-COVID sepsis by measuring its key enzymes, thrombin and activated PC (APC). The study population included 30 patients with COVID-19, 47 patients with non-COVID sepsis, and 40 healthy controls. In healthy controls, coagulation activation and subsequent APC formation was induced by 15 µg/kg recombinant activated factor VII one hour before blood sampling. APC and thrombin in plasma were measured using oligonucleotide-based enzyme capture assays. The indirect thrombin markers prothrombin-fragment 1+2 (F1+2) and thrombin-antithrombin complex (TAT) were also measured. Compared with stimulated healthy controls, median thrombin, F1+2, and TAT levels were higher in patients with COVID-19 (up to 6-fold, p < 2 × 10-6) and non-COVID sepsis (up to 4.7-fold, p < 0.010). APC levels were 2.4-fold higher in patients with COVID-19 (7.44 pmol/L, p = 0.011) and 3.4-fold higher in non-COVID sepsis patients (10.45 pmol/L, p = 2 × 10-4) than in controls (3.08 pmol/L). Thrombin markers and APC showed correlation in both COVID-19 (r = 0.364-0.661) and non-COVID sepsis patients (r = 0.535-0.711). After adjustment for PC levels, median APC/thrombin, APC/F1+2, and APC/TAT ratios were 2-fold (p = 0.036), 6-fold (p = 3 × 10-7) and 3-fold (p = 8 × 10-4) lower in the COVID-19 group than in the non-COVID sepsis group, and the latter two were also lower in the COVID-19 group than in stimulated healthy controls. In conclusion, it was found that a comparatively lower anticoagulant APC response in COVID-19 patients as compared to non-COVID sepsis patients, potentially linked to endothelial dysfunction, contributes to the prothrombotic phenotype of COVID-19 sepsis.

The Relationship Between Acute Kidney Injury in Sepsis Patients and Coagulation Dysfunction and Prognosis.

The aim of this study was to investigate the relationship between ARF and coagulopathy in patients with sepsis and to explore the prognostic value of these conditions. The data of 271 patients with sepsis-associated coagulopathy admitted from June 2021 to June 2022 were reviewed. The patients were divided into a survival group and a nonsurviving group according to patient prognosis. Independent sample t tests were utilized to compare laboratory parameters within 24 hours of admission, as well as the APACHE II and SOFA scores, between the two patient groups. According to the sepsis-associated coagulation dysfunction (SAC) grading criteria for grading, Spearman correlation analysis was used to study the relationship between blood creatinine and SAC grading and assignment scores, and receiver operating characteristic (ROC) curves and Cox's proportional risk regression model were used to explore the factors affecting the prognosis of SAC patients. Spearman correlation analysis revealed strong associations between serum creatinine (Scr) concentration, SAC classification, and SAC score, with coefficients above 0.7. SAC classification outcomes varied significantly with severity: mild severity had a 77.6% survival rate versus 22.4% mortality; moderate severity had 21.5% survival versus 78.5% mortality; and severe cases had a 0.7% survival rate versus 99.3% mortality (P<0.01 for all). Multivariate analysis revealed significant predictors of outcome, including multiple organ dysfunction syndrome (MODS), with an OR of 2.070 (P=0.019); the SOFA score (OR=1.200, P<0.01); the international normalized ratio (INR) (OR=0.72, P=0.013); and the Scr level (OR=0.995, P<0.01). The areas under the ROC curves for the SOFA score, APACHE II score, and SAC classification were >0.8, all P < 0.05. In patients with sepsis, SAC grade 3 or a SAC score of 4 or higher is associated with poorer prognosis, and the interaction of acute kidney injury exacerbates the degree of SAC, consequently affecting prognosis.

A case report of sepsis associated coagulopathy after percutaneous nephrostomy

BackgroundHemorrhage is a common complication of nephrostomy and percutaneous nephrolithotripsy, and it is caused by surgical factors. Here we report a rare case of hemorrhage caused by sepsis-related coagulation dysfunction.Case presentationA 72-years-old male patient with bilateral ureteral calculi accompanied by hydronephrosis and renal insufficiency developed sepsis and hemorrhage on the third day after bilateral nephrostomy. After vascular injury was excluded by DSA, the hemorrhage was considered to be sepsis-associated coagulopathy(SAC/SIC), finally the patient recovered well after active symptomatic treatment.ConclusionsIn patients with sepsis and hemorrhage, SAC/SIC cannot be excluded even if coagulation function is slightly abnormal after surgical factors are excluded. For urologists who may encounter similar cases in their general urology practice, it is important to be aware of these unusual causes of hemorrhage.

The frequency and timing of sepsis-associated coagulopathy in the neonatal intensive care unit.

Sepsis is a common cause of morbidity and mortality in the neonatal intensive care unit (NICU). The frequency and severity of sepsis-associated coagulopathy as well as its relationship to illness severity are unclear. We performed a single-center, retrospective, observational cohort study of all infants admitted to the University of Florida Health (UF Health), level IV NICU between January 1st 2012 to March 1st 2020 to measure the frequency of sepsis-associated coagulopathy as well as its temporal relationship to critical illness in the NICU population. All clinical data in the electronic health record were extracted and deposited into an integrated data repository that was used for this work. We identified 225 new sepsis episodes in 216 patients. An evaluation for sepsis-associated coagulopathy was performed in 96 (43%) episodes. Gram-negative pathogen, nSOFA score at evaluation, and mortality were greater among episodes that included a coagulopathy evaluation compared with those that did not. Abnormal coagulation results were common (271/339 evaluations; 80%) and were predominantly prothrombin times. Intervention (plasma or cryoprecipitate) followed a minority (84/271; 31%) of abnormal results, occurred in 40/96 (42%) episodes that were often associated with >1 intervention (29/40; 73%), and coincided with thrombocytopenia in 37/40 (93%) and platelet transfusion in 27/40 (68%). Shapley Additive Explanations modeling demonstrated strong predictive performance for the composite outcome of death and/or treatment for coagulopathy in neonates (f1 score 0.8, area under receiver operating characteristic curve 0.83 for those with abnormal coagulation values). The three most important features influencing the composite outcome of death or treatment for coagulopathy included administration of vasoactive medications, hematologic dysfunction assessed by the maximum nSOFA platelet score, and early sepsis (≤72 h after birth). A coagulopathy evaluation was performed in a minority of NICU patients with sepsis and was associated with greater illness severity and mortality. Abnormal results were common but infrequently associated with intervention, and intervention was contemporaneous with thrombocytopenia. The most important feature that influenced the composite outcome of death or treatment for coagulopathy was the administration of vasoactive-inotropic medications. These data help to identify NICU patients at risk of sepsis-associated coagulopathy.

Risk Factors of Sepsis-Associated Thrombocytopenia among Patients with Sepsis Induced Coagulopathy.

The study aims to evaluate the prognosis and risk factors of sepsis-associated thrombocytopenia (SAT) among patients with coagulopathy, and to provide evidence of the relationship between adverse outcomes and potential risks. Patients with sepsis-associated coagulopathy were included in the study from January 2014 to December 2022. The primary outcome was sepsis-associated thrombocytopenia (platelet count less than 100 *109/L), which was evaluated by logistic regression models adjusted for demographic characteristics and comorbidities. Among patients in the SAT group, 54% developed severe SAT, while 16% of these patients recovered from thrombocytopenia. The in-hospital mortality rate was significantly higher in the SAT group compared to the non-SAT group (31% in SAT group vs 23.9% in non-SAT group, p = 0.029). Even after adjusting for age, gender, Charlson comorbidity, white blood cell, and Sequential Organ Failure Assessment score, the differences in mortality rate persisted (Odds Ratio 0.72, [95% Confidence Interval 0.52-0.92]). Correlation analyses revealed that prothrombin time (r = 0.08, p = 0.50), international normalized ratio (r = 0.08, p = 0.42), prothrombin activity (r = -0.06, p > 0.999), D-dimer (r = -0.02, p > 0.999), and inflammatory parameters such as C-reactive protein (r = -0.11, p = 0.37) were not significantly correlated with platelet counts. According to subgroup analyses, patients with lung infection complicated by SAT had slightly higher mortality (OR 0.66, [95% CI, 0.46 to 0.94]). Sepsis-associated coagulopathy indicates a subset of critical ill patients, with those experiencing thrombocytopenia at greater risk for in-hospital death compared to those without it.

A prospective observational study of sepsis-associated coagulopathy (SAC) in septic shock in the pediatric intensive care unit of tertiary care hospital in central rural India

Background: Sepsis-associated coagulopathy (SAC) is a frequently encountered clinical scenario in pediatric critical care practice. The disruptions within the normal coagulation cascade in cases of sepsis significantly impact the ultimate patient outcome. Objective: This study aims to evaluate the associations between sepsis-associated coagulopathy (SAC) in pediatric septic shock cases and their corresponding clinical outcomes. Methods: This study will be conducted within a tertiary care Pediatric Intensive Care Unit (PICU), focusing on children aged one month to 18 years who have been admitted to manage sepsis. Cases diagnosed with sepsis will undergo evaluation and treatment according to the established PICU protocol. Coagulation profiles, encompassing International Normalized Ratio (INR), activated Partial Thromboplastin Time (aPTT), Prothrombin Time (PT), and platelet counts, will be subjected to analysis. Any deviations in coagulation parameters will be compared and correlated with morbidity and mortality outcomes. Expected results: This study will establish correlations between the severity of sepsis and its subsequent outcomes, specifically concerning aberrations in coagulation profile levels. A meticulous analysis will focus on critically ill cases necessitating various interventions and exhibiting deviant coagulation patterns. Conclusions: This research aims to unravel potentially pivotal prognostic correlations within sepsis cases. The coagulation profile, a standard investigation, can be a predictive tool for outcomes within the Pediatric Intensive Care Unit (PICU).

Comparison between sepsis-induced coagulopathy and sepsis-associated coagulopathy criteria in identifying sepsis-associated disseminated intravascular coagulation

Comparison between sepsis-induced coagulopathy and sepsis-associated coagulopathy criteria in identifying sepsis-associated disseminated intravascular coagulation

Sepsis - it is all about the platelets.

Sepsis is accompanied by thrombocytopenia and the severity of the thrombocytopenia is associated with mortality. This thrombocytopenia is characteristic of disseminated intravascular coagulation (DIC), the sepsis-associated coagulopathy. Many of the pathogens, both bacterial and viral, that cause sepsis also directly activate platelets, which suggests that pathogen-induced platelet activation leads to systemic thrombosis and drives the multi-organ failure of DIC. In this paper we review the mechanisms of platelet activation by pathogens and the evidence for a role for anti-platelet agents in the management of sepsis.

Thromboembolic Events, Anticoagulation, and COVID-19: Preemptive Treatments and Risks After Vaccination

Thromboembolic Events, Anticoagulation, and COVID-19: Preemptive Treatments and Risks After Vaccination

Association between Pre-Existing Long-Term β-Blocker Therapy and the Outcomes of Sepsis-Associated Coagulopathy: A Retrospective Study.

Background and Objectives: Previous studies have suggested that long-term β-blocker therapy before sepsis is associated with reduced mortality. Sepsis-associated coagulopathy (SAC) remains a common complication in patients with sepsis and is associated with increased mortality. Adrenergic pathways are involved in the regulation of the coagulation system. Pre-existing long-term β-blocker therapy may have potentially beneficial effects on SAC and has yet to be well characterized. We aimed to assess the potential association between pre-existing long-term β-blocker therapy and the outcomes of patients with SAC. Materials and Methods: This study retrospectively screened the clinical data of adult patients with SAC admitted to the Intensive Care Unit (ICU) and respiratory ICU between May 2020 and October 2022. Patients with SAC who took any β-blocker for at least one year were considered pre-existing long-term β-blocker therapy. All enrolled patients were followed up for 28 days or until death. Results: Among the 228 SAC patients, 48 received long-term β-blocker therapy before septic episodes. Pre-existing long-term β-blocker therapy was associated with reduced vasopressor requirements and a decreased 28-day mortality (log-rank test: p = 0.041). In particular, long-term β-blocker therapy was related to substantially lower D-dimer levels and a trend of improved activated partial thromboplastin time in patients with SAC during initial ICU admission. Multivariable regression analysis showed that long-term β-blocker therapy was significantly and independently associated with a 28-day mortality among patients with SAC (adjusted odds ratio, 0.55; 95% confidence interval, (0.32-0.94); p = 0.030). Conclusions: Pre-existing long-term β-blocker therapy might be associated with reduced vasopressor requirements and a decreased 28-day mortality among patients with SAC, providing evidence for the protective effect of β-blockers against SAC in managing sepsis.

Sepsis-associated coagulopathy in onco-hematology patients presenting with thrombocytopenia: a multicentric observational study

Coagulation disorders increase mortality rate during septic shock, but the impact of concomitant hematological malignancies remains unknown. The study assessed coagulation disorders in onco-hematological patients with thrombocytopenia (<100 G/L) admitted to ICU for septic shock. Among 146 included patients, 50 patients had lymphoma and 49 patients had acute leukemia. ICU mortality rate was 43.8% (n = 64). Median increase in prothrombin time (PT) at day(d) 1 was 4.7 s (IQR 3.2–7.9) in ICU survivors vs. 6.4 s (IQR 4.5–13.7; p < 0.01) in non-survivors. Fibrinogen kinetics (increase in fibrinogen levels between d1 and d2) was +0.55 (−0.22–1.55) vs. +0.10 g/L (−0.40–0.50; p = 0.03) in surviving and non-surviving patients, respectively. PT increase ≥6 s at d1 (OR 5.5; 95% CI 1.1–6.0; p = 0.03) and mechanical ventilation (OR 7.4; 95% CI 3.3–17.7; p < 0.001) were independently associated with ICU mortality. This study provides information and new ways to identify hematological patients with high-risk mortality.

Platelet glycoprotein VI genetic polymorphism T13254C in neonatal sepsis

Background Neonatal sepsis is a global burden, being a leading cause of neonatal morbidity and mortality worldwide. Platelet glycoprotein VI (GPVI) affects sepsis at multiple stages of the inflammatory response. The expression of the GPVI receptor is genetically determined, thus influencing the coagulation processes. The authors focused in this study on the role of platelet GPVI genetic polymorphism T13254C (rs1613662) in neonatal sepsis in relation to other risk factors, laboratory tests, sepsis progression, and outcome. Methods The authors studied 50 neonates with early-onset sepsis. The authors detected platelet GPVI T13254C polymorphism using the TaqMan allelic discrimination method by the real-time polymerase chain reaction technique. Results The results showed that GPVI mutant polymorphic group was associated with higher D-dimer levels (P=0.032). Moreover, septic neonates with mutant homozygous type showed poor survival (P=0.047). However, GPVI mutant polymorphic types were not significantly related to other demographic, laboratory data, and different scoring systems, such as sepsis-induced coagulopathy score, International Society on Thrombosis and Hemostasis score, and Score for Neonatal Acute Physiology. Conclusion The authors found a relation between platelet GPVI T13254C polymorphism and D-dimer levels, hence suggesting a relation with neonatal sepsis-associated coagulopathy, which might further affect patients’ outcome.

Simvastatin Prevents Liver Microthrombosis and Sepsis Induced Coagulopathy in a Rat Model of Endotoxemia.

Background: Endotoxemia causes endothelial dysfunction and microthrombosis, which are pathogenic mechanisms of coagulopathy and organ failure during sepsis. Simvastatin has potential anti-thrombotic effects on liver endothelial cells. We investigated the hemostatic changes induced by lipopolysaccharide (LPS) and explored the protective effects of simvastatin against liver vascular microthrombosis. Methods and results: We compared male Wistar rats exposed to LPS (5 mg/kg one i.p. dose) or saline in two experimental protocols—placebo (vehicle) and simvastatin (25 mg/kg die, orally, for 3 days before LPS). Morphological studies were performed by light- and electron-microscopy analyses to show intravascular fibrin deposition, vascular endothelial structure and liver damage. Peripheral- and organ-hemostatic profiles were analyzed using whole blood viscoelastometry by ROTEM, liver biopsy and western-blot/immunohistochemistry of thrombomodulin (TM), as well as immunohistochemistry of the von Willebrand factor (VWF). LPS-induced fibrin deposition and liver vascular microthrombosis were combined with a loss of sinusoidal endothelial TM expression and VWF-release. These changes were associated with parenchymal eosinophilia and necrosis. ROTEM analyses displayed hypo-coagulability in the peripheral blood that correlated with the degree of intrahepatic fibrin deposition (p < 0.05). Simvastatin prevented LPS-induced fibrin deposition by preserving TM expression in sinusoidal cells and completely reverted the peripheral hypo-coagulability caused by endotoxemia. These changes were associated with a significant reduction of liver cell necrosis without any effect on eosinophilia. Conclusions: Simvastatin preserves the antithrombotic properties of sinusoidal endothelial cells disrupted by LPS, deserving pharmacological properties to contrast sepsis-associated coagulopathy and hepatic failure elicited by endotoxemia

Sepsis-Associated Coagulopathy Predicts Hospital Mortality in Critically Ill Patients With Postoperative Sepsis.

BackgroundThe incidence of coagulopathy, which was responsible for poor outcomes, was commonly seen among patients with sepsis. In the current study, we aim to determine whether the presence of sepsis-associated coagulopathy (SAC) predicts the clinical outcomes among critically ill patients with postoperative sepsis.MethodsWe conducted a single-center retrospective cohort study by including patients with sepsis admitted to surgical ICU of Chinese PLA General Hospital from January 1, 2014 to December 31, 2018. Baseline characteristics and clinical outcomes were compared with respect to the presence of SAC. Kaplan-Meier analysis was applied to calculate survival rate, and Log-rank test was carried out to compare the differences between two groups. Furthermore, multivariable Cox and logistic and linear regression analysis were performed to assess the relationship between SAC and clinical outcomes, including hospital mortality, development of septic shock, and length of hospital stay (LOS), respectively. Additionally, both sensitivity and subgroup analyses were performed to further testify the robustness of our findings.ResultsA total of 175 patients were included in the current study. Among all included patients, 41.1% (72/175) ICU patients were identified as having SAC. In-hospital mortality rates were significantly higher in the SAC group when compared to that of the No SAC group (37.5% vs. 11.7%; p < 0.001). By performing univariable and multivariable regression analyses, presence of SAC was demonstrated to significantly correlate with an increased in-hospital mortality for patients with sepsis in surgical ICU [Hazard ratio (HR), 3.75; 95% Confidence interval (CI), 1.90–7.40; p < 0.001]. Meanwhile, a complication of SAC was found to be the independent predictor of the development of septic shock [Odds ratio (OR), 4.11; 95% CI, 1.81–9.32; p = 0.001], whereas it was not significantly associated with prolonged hospital LOS (OR, 0.97; 95% CI, 0.83–1.14; p = 0.743).ConclusionThe presence of SAC was significantly associated with increased risk of in-hospital death and septic shock among postoperative patients with sepsis admitted to ICU. Moreover, there was no statistical difference of hospital LOS between the SAC and no SAC groups.

Relative platelet reductions provide better pathophysiologic signatures of coagulopathies in sepsis

In sepsis-associated coagulopathies and disseminated intravascular coagulation, relative platelet reductions may reflect coagulopathy severity. However, limited evidence supports their clinical significance and most sepsis-associated coagulopathy criteria focus on the absolute platelet counts. To estimate the impact of relative platelet reductions and absolute platelet counts on sepsis outcomes. A multicenter retrospective observational study was performed using the eICU Collaborative Research Database, comprising 335 intensive care units (ICUs) in the United States. Patients with sepsis and an ICU stay > 2 days were included. Estimated effects of relative platelet reductions and absolute platelet counts on mortality and coagulopathy-related complications were evaluated. Overall, 26,176 patients were included. Multivariate mixed-effect logistic regression analysis revealed marked in-hospital mortality risk with larger platelet reductions between days one and two, independent from the resultant absolute platelet counts. The adjusted odds ratio (OR) [95% confidence intervals (CI)] for in-hospital mortality was 1.28[1.23–1.32], 1.86[1.75–1.97], 2.99[2.66–3.36], and 6.05[4.40–8.31] for 20–40%, 40–60%, 60–80%, and > 80% reductions, respectively, when compared with a < 20% decrease in platelets (P < 0.001 for each). In the multivariate logistic regression analysis, platelet reductions ≥ 11% and platelet counts ≤ 100,000/μL on day 2 were associated with high coagulopathy-related complications (OR [95%CI], 2.03 and 1.18; P < 0.001 and P < 0.001), while only platelet reduction was associated with thromboembolic complications (OR [95%CI], 1.43 [1.03–1.98], P < 0.001). The magnitude of platelet reductions represent mortality risk and provides a better signature of coagulopathies in sepsis; therefore, it is a plausible criterion for sepsis-associated coagulopathies.

Biomarkers of Platelet Activation and Their Prognostic Value in Patients in Sepsis Associated Coagulopathy

Introduction:Sepsis-associated disseminated intravascular coagulation (SAC) is associated with marked hemostatic changes including transient thrombocytopenia due to their enodogenous activation / consumption. Platelets are decreased in SAC and exhibit compromised function. Patients with SAC are at an increased risk of thrombosis and / or bleeding. The widespread activation of platelets contribute to vascular occlusions, fibrin deposition, multi-organ dysfunction, contributing to a two-fold increase in mortality. At this time there is no single biomarker or laboratory test that can effectively diagnose SAC; however, the International Society on Thrombosis and Hemostasis (ISTH) has introduced a scoring system based on laboratory parameters such as platelet count, clotting time, and levels of markers of thrombosis to calculate SAC severity in terms of DIC score. Measurement of activation markers that describe the interplay between inflammation and platelet function may provide insight into the pathogenesis of SAC. The purpose of this study was to measure markers of platelet function in the plasma of patients with clinically established SAC and to determine their association to disease severity and outcome.Materials and Methods:Plasma samples from 103 adult intensive care unit (ICU) patients with sepsis and suspected disseminated intravascular coagulation (DIC) were acquired from the University of Utah Hospital at the time of ICU admission as well as on days 4 and 8. Samples with relevant clinical information were transported to Loyola University Chicago under an IRB-approved protocol and stored at -80˚C prior to analysis. Plasma samples from healthy individuals (n=50) were purchased from George King Biomedical (Overland, KS). DIC scores were calculated using the ISTH scoring algorithm which incorporates platelet count, D-Dimer, INR, and fibrinogen. Patients were categorized as having no DIC, non-overt DIC, or overt DIC. Plasma levels of CD40L, von Willebrand Factor (vWF), platelet factor-4 (PF-4), and microparticles (MP) were quantified using commercially available ELISAs performed according to manufacturer instructions.Results:Markers of platelet activation were significantly elevated in patients with sepsis alone and with suspected DIC compared to normal healthy individuals on ICU day 0 (p<0.001). Levels of platelet-associated biomarkers were compared between survivors and non-survivors. PF-4 was significantly decreased in non-survivors compared to survivors (p = 0.0156). No other significant variations based on survival or based on DIC score category were observed.Since platelet count is often dramatically reduced in patients with DIC, the relationship between platelet count and levels of markers of platelet activity was also evaluated. Patients were stratified based on platelet count and levels of markers were compared between groups. CD40L, vWF, PF4, and MP showed significant variation based on platelet count, with all markers exhibiting stepwise elevation with increasing platelet count (Table 1).Conclusion: Markers of platelet activation were significantly elevated in patients with SAC compared to healthy individuals. This increase was independent of platelet count, underscoring the importance of activation processes to this disease process. Of the markers studied, PF4 showed significant difference based on DIC score or mortality, and differentiated the non-survivors compared to survivors. Levels of CD40L, vWF, PF4, and MP showed significant association with platelet count, increasing in a stepwise manner with increases in platelet count. These studies also suggest that the markers of platelet activation in SAC are primarily regulated by the number of circulating platelets and may be independent of the factors leading to their endogenous consumption. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Efficacy and safety of human soluble thrombomodulin (ART-123) for treatment of patients in France with sepsis-associated coagulopathy: post hoc analysis of SCARLET

BackgroundThe phase 3 multinational SCARLET study evaluated the efficacy and safety of a recombinant human soluble thrombomodulin (ART-123) for treatment of sepsis-associated coagulopathy (SAC), which correlates with increased mortality risk in patients with sepsis. Although no significant reduction in mortality was observed with ART-123 compared with placebo in the full analysis set (FAS), an efficacy signal of ART-123 was observed in subgroups of patients who sustained coagulopathy until the first treatment and those not administered concomitant heparin. Post hoc analysis was performed of patients treated in France, the country with the largest enrollment (19% of the FAS) and consistent patient enrollment throughout the study duration.MethodsAdult patients with SAC (international normalized ratio > 1.4; platelets > 30 × 109/L to < 150 × 109/L or platelet decrease > 30% within 24 h) and evidence of bacterial infection were included. The primary efficacy outcome was 28-day all-cause mortality. Safety outcomes included adverse, serious adverse, and major bleeding events. This analysis assessed patient characteristics and efficacy and safety outcomes in France compared with the rest of the world (ROW; excluding France). Mortality rates were assessed in patients in France or the ROW with characteristics previously associated with ART-123 efficacy.ResultsBaseline characteristics were similar between France and the ROW, but some measurements of disease severity were higher in patients in France. The 28-day all-cause mortality absolute risk reductions (ARRs) with ART-123 were 8.3% in France and 1.1% in the ROW. The greater ARR in France may be related to a higher rate of sustained coagulopathy and lower rate of heparin use. In France and the ROW, 84.6% and 78.0% of patients sustained coagulopathy from the time of initial SAC diagnosis to first treatment with the study drug, and 65.8% and 43.9% did not receive heparin, respectively. The ARRs for these subgroups of patients in France were 13.4% and 16.6%, respectively. Safety of ART-123 was comparable between France and the ROW.ConclusionsResults from this exploratory analysis suggest that patients with sustained SAC not receiving concomitant heparin may benefit from ART-123, a fact that should be confirmed in future studies with more restrictive inclusion criteria.

Successful systemic fibrinolysis in a patient with Covid- 19: Case report

The new coronavirus 2019-nCov or SARS-Cov-2 is responsible for the most important pandemic in the 21st century: the coronavirus disease (COVID-19).&#x0D; The 2019-nCov infection elicits a hyper-coagulable state, conditioning a worse outcome in these patients. The pathophysiology of the exaggerated coagulation activation in these patients is still unknown, and probably involves several mechanisms, different from those involved in sepsis-associated coagulopathy.&#x0D; This article discusses the case of a patient with no remarkable medical history, who after 7 days of fever, diarrhea and epigastric pain was diagnosed with COVID-19 bilateral pneumonia, further aggravated by severe Acute Respiratory Distress Syndrome. In this context, the patient experienced a massive acute pulmonary thromboembolism accompanied by an acute thrombus in the heart’s right ventricle, leading to hemodynamic instability. For the first time in our center in these patients, systemic fibrinolysis was successfully performed, with resolution of the intracavitary thrombus and the acute hemodynamic shock.

Sepsis Produces Microthrombosis and Not Coagulation: Implications for Sepsis Therapy

Abstract The hemostatic abnormalities which may accompany sepsis have been attributed to disseminated intravascular coagulation (DIC) initiated by tissue factor (TF) activating FVII leading to TF-FVII a complex formation and triggering the extrinsic coagulation cascade. Recently, a new theory of hemostasis has been proposed in which sepsis is associated with endothelial damage releasing unusually large von Willebrand factor (ULVWF). The ULVWF multimers, following exocytosis from sepsis-induced endothelialopathy, become anchored to the endothelial cell membrane as elongated strings which recruit platelets from the circulation forming platelet-ULVWF complexes which become microthrombi. The process is called microthrombogenesis and the resultant disorder is disseminated intravascular thrombosis (DIT) which is a major factor leading to organ dysfunction. Thus, the sepsis-associated coagulopathy is not a coagulation disorder, but is a microthrombotic disorder. This conceptual reinterpretation entails a significant paradigm shift in the understanding of sepsis pathophysiology and treatment.