Overt Disseminated Intravascular Coagulation Research Articles

Haematological characteristics and risk factors in the classification and prognosis evaluation of COVID-19: a retrospective cohort study

SummaryBackgroundCOVID-19 is an ongoing global pandemic. Changes in haematological characteristics in patients with COVID-19 are emerging as important features of the disease. We aimed to explore the haematological characteristics and related risk factors in patients with COVID-19.MethodsThis retrospective cohort study included patients with COVID-19 admitted to three designated sites of Wuhan Union Hospital (Wuhan, China). Demographic, clinical, laboratory, treatment, and outcome data were extracted from electronic medical records and compared between patients with moderate, severe, and critical disease (defined according to the diagnosis and treatment protocol for novel coronavirus pneumonia, trial version 7, published by the National Health Commission of China). We assessed the risk factors associated with critical illness and poor prognosis. Dynamic haematological and coagulation parameters were investigated with a linear mixed model, and coagulopathy screening with sepsis-induced coagulopathy and International Society of Thrombosis and Hemostasis overt disseminated intravascular coagulation scoring systems was applied.FindingsOf 466 patients admitted to hospital from Jan 23 to Feb 23, 2020, 380 patients with COVID-19 were included in our study. The incidence of thrombocytopenia (platelet count <100 × 109 cells per L) in patients with critical disease (42 [49%] of 86) was significantly higher than in those with severe (20 [14%] of 145) or moderate (nine [6%] of 149) disease (p<0·0001). The numbers of lymphocytes and eosinophils were significantly lower in patients with critical disease than those with severe or moderate disease (p<0·0001), and prothrombin time, D-dimer, and fibrin degradation products significantly increased with increasing disease severity (p<0·0001). In multivariate analyses, death was associated with increased neutrophil to lymphocyte ratio (≥9·13; odds ratio [OR] 5·39 [95% CI 1·70–17·13], p=0·0042), thrombocytopenia (platelet count <100 × 109 per L; OR 8·33 [2·56–27·15], p=0·00045), prolonged prothrombin time (>16 s; OR 4·94 [1·50–16·25], p=0·0094), and increased D-dimer (>2 mg/L; OR 4·41 [1·06–18·30], p=0·041). Thrombotic and haemorrhagic events were common complications in patients who died (19 [35%] of 55). Sepsis-induced coagulopathy and International Society of Thrombosis and Hemostasis overt disseminated intravascular coagulation scores (assessed in 12 patients who survived and eight patients who died) increased over time in patients who died. The onset of sepsis-induced coagulopathy was typically before overt disseminated intravascular coagulation.InterpretationRapid blood tests, including platelet count, prothrombin time, D-dimer, and neutrophil to lymphocyte ratio can help clinicians to assess severity and prognosis of patients with COVID-19. The sepsis-induced coagulopathy scoring system can be used for early assessment and management of patients with critical disease.FundingNational Key Research and Development Program of China.

Disseminated Intravascular Coagulation Is an Independent Predictor of Adverse Outcomes in Children in the Emergency Department with Suspected Sepsis

To evaluate the impact of early disseminated intravascular coagulation (DIC) on illness severity in children using a database of emergency department ED encounters for children with suspected sepsis, in view of similar associations in adults. Laboratory and clinical data were extracted from a registry of emergency department encounters of children with suspected sepsis between April 1, 2012, and June 26, 2017. International Society of Thrombosis and Hemostasis DIC scores were calculated from laboratory values obtained within 24 hours of emergency department admission. Univariate logistic regression, multivariable logistic regression, and Cox regression were used to assess the influence of DIC scores on vasopressor use (primary outcome), mortality, ventilator requirement, pediatric intensive care unit admission, and hospital duration (secondary outcomes). The optimal DIC score cutoff for outcome prediction was determined. Of 1653 eligible patients, 284 had DIC scores within 24 hours, including 92 who required vasopressors and 23 who died within 1 year. An initial DIC score of ≥3 was the most sensitive and specific DIC score for predicting adverse outcomes. Those with a DIC score of ≥3 vs <3 had increased odds of vasopressor use in both univariate (OR, 4.48; 95% CI, 2.63-7.62; P < .001) and multivariable (OR, 3.78; 95% CI, 1.82-7.85; P < .001) analyses. Additionally, those with a DIC score of ≥3 vs <3 had increased 1-year mortality with a hazard ratio of 3.55 (95% CI, 1.46-8.64; P = .005). A DIC score of ≥3 was an independent predictor for both vasopressor use and mortality in this pediatric cohort, distinct from the adult overt DIC score cutoff of ≥5.

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.

Venous and arterial thromboembolic complications in COVID-19 patients admitted to an academic hospital in Milan, Italy

BackgroundFew data are available on the rate and characteristics of thromboembolic complications in hospitalized patients with COVID-19. MethodsWe studied consecutive symptomatic patients with laboratory-proven COVID-19 admitted to a university hospital in Milan, Italy (13.02.2020–10.04.2020). The primary outcome was any thromboembolic complication, including venous thromboembolism (VTE), ischemic stroke, and acute coronary syndrome (ACS)/myocardial infarction (MI). Secondary outcome was overt disseminated intravascular coagulation (DIC). ResultsWe included 388 patients (median age 66 years, 68% men, 16% requiring intensive care [ICU]). Thromboprophylaxis was used in 100% of ICU patients and 75% of those on the general ward. Thromboembolic events occurred in 28 (7.7% of closed cases; 95%CI 5.4%–11.0%), corresponding to a cumulative rate of 21% (27.6% ICU, 6.6% general ward). Half of the thromboembolic events were diagnosed within 24 h of hospital admission. Forty-four patients underwent VTE imaging tests and VTE was confirmed in 16 (36%). Computed tomography pulmonary angiography (CTPA) was performed in 30 patients, corresponding to 7.7% of total, and pulmonary embolism was confirmed in 10 (33% of CTPA). The rate of ischemic stroke and ACS/MI was 2.5% and 1.1%, respectively. Overt DIC was present in 8 (2.2%) patients. ConclusionsThe high number of arterial and, in particular, venous thromboembolic events diagnosed within 24 h of admission and the high rate of positive VTE imaging tests among the few COVID-19 patients tested suggest that there is an urgent need to improve specific VTE diagnostic strategies and investigate the efficacy and safety of thromboprophylaxis in ambulatory COVID-19 patients.

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

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

Risk factor, monitoring, and treatment for snakebite induced coagulopathy: a multicenter retrospective study.

BackgroundSnakebite can cause various complications, including coagulopathy. The clinical features of snakebite-associated coagulopathy differ from those of disseminated intravascular coagulation (DIC) caused by other diseases and its treatment is controversial.MethodsWe retrospectively reviewed the medical records of patients hospitalized for snakebite between January 2006 and September 2018.ResultsA total of 226 patients were hospitalized due to snakebite. Their median hospital stay was 4.0 days (interquartile range, 2.0 to 7.0 days). Five patients arrived at hospital with shock and one patient died. Twenty-one patients had overt DIC according to the International Society of Thrombosis and Hemostasis scoring system. Two patients developed major bleeding complications. Initial lower cholesterol level at presentation was associated with the development of overt DIC. International normalization ratio (INR) exceeding the laboratory’s measurement limit was recorded as late as 4 to 5 days after the bite. Higher antivenom doses (≥18,000 units) and transfusion of fresh frozen plasma (FFP) or cryoprecipitate did not affect prolonged INR duration or hospital stay in the overt DIC patients without bleeding.ConclusionsInitial lower cholesterol level may be a risk factor for overt DIC following snakebite. Although patients lack apparent symptoms, the risk of coagulopathy should be assessed for at least 4 to 5 days following snakebite. Higher antivenom doses and transfusion of FFP or cryoprecipitate may be unbeneficial for coagulopathic patients without bleeding.

Identifying Sepsis Populations Benefitting from Anticoagulant Therapy: A Prospective Cohort Study Incorporating a Restricted Cubic Spline Regression Model.

Anticoagulant therapy has seldom been achieved in randomized trials targeting nonspecific overall sepsis patients. Although the key components to identify the appropriate target in sepsis may be disseminated intravascular coagulation (DIC) and high disease severity, the interaction and relation of these two components for the effectiveness of therapy remain unknown. This article identifies the optimal target of anticoagulant therapy in sepsis. We used a prospective nationwide cohort targeting consecutive adult severe sepsis patients in 59 intensive care units in Japan to assess associations between anticoagulant therapy and in-hospital mortality according to DIC (International Society on Thrombosis and Haemostasis [ISTH] overt and Japanese Association for Acute Medicine DIC scores) and disease severity (Acute Physiology and Chronic Health Evaluation II [APACHE II] and Sequential Organ Failure Assessment scores). Multivariable Cox proportional hazard regression analysis with nonlinear restricted cubic spline including a two-way interaction term (treatment × each score) and three-way interaction term (treatment × ISTH overt DIC score × APACHE II score) was performed. The final study cohort comprised 1,178 sepsis patients (371 received anticoagulants and 768 did not). The regression model including the two-way interaction term showed significant interaction between intervention and disease severity as indicated by the ISTH overt DIC score and APACHE II score (p = 0.046 and p = 0.101, respectively). Three-way interaction analysis revealed that risk hazard was suppressed in the anticoagulant group compared with the control group in the most severe subset of both scores. Anticoagulant therapy was associated with better outcome according to the deterioration of both DIC and disease severity, suggesting that anticoagulant therapy should be restricted to patients having DIC and high disease severity simultaneously.

Significance of plasma fibrinogen level and antithrombin activity in sepsis: A multicenter cohort study using a cubic spline model

IntroductionSepsis leads to coagulopathy by the activation of inflammatory mediators and vascular endothelial cell injury. A number of biomarkers are used to evaluate coagulopathy on sepsis. Fibrinogen and antithrombin activity have been reported as biomarkers of coagulopathy; however, the utility of these two markers has not been well established. This study aimed to evaluate the detailed association between these two markers and clinical outcomes in sepsis patients. Materials and methodsThis was a post hoc analysis of a multicenter, prospective cohort study conducted in 59 intensive care units throughout Japan from January 2016 to March 2017. We included 1103 adult patients with severe sepsis based on the Sepsis-2 criteria. The associations between the coagulation markers and in-hospital mortality were examined using linear and non-linear logistic regression analyses. We also evaluated the associations between the coagulation markers and disseminated intravascular coagulation (DIC) scores. The International Society on Thrombosis and Haemostasis overt DIC score was calculated after subtracting the fibrinogen component. ResultsThe decreased levels of the fibrinogen and antithrombin activity were significantly associated with an increase in mortality (P = 0.011 and 0.002, respectively). In addition, cubic spline regression demonstrated that mortality sharply increased at a fibrinogen level of approximately <200 mg/dL and at an antithrombin activity of approximately <50%. Similarly, the decreased levels of the two markers non-linearly correlated with the elevation of DIC score. ConclusionsThe fibrinogen level and antithrombin activity should be reconsidered as unique biomarkers for sepsis and sepsis-induced DIC.

Anticoagulation Therapy Using rh-Thrombomodulin and/or Antithrombin III Agent is Associated With Reduction in in-Hospital Mortality in Septic Disseminated Intravascular Coagulation: A Nationwide Registry Study.

We analyzed the Nationwide Registry database on sepsis to examine the effects of an anticoagulation therapy, especially with rh-thrombomodulin (rh-TM) and/or antithrombin (AT) III agent, in septic disseminated intravascular coagulation (DIC) patients. In 3,193 patients enrolled after the exclusion, we investigated the association with in-hospital mortality using Cox proportional hazards models. DIC was diagnosed using the Japanese Association of Acute Medicine (JAAM) and the International Society of Thrombosis and Hemostasis (ISTH) criteria. To analyze the separate treatment effects of rh-TM and/or AT III, we excluded the data of 345 patients treated with all available anticoagulation treatments (rh-TM and/or AT III plus "other anticoagulants": protease inhibitors and heparin/heparinoids). The DIC criterion populations were as follows: JAAM DICs, n = 1,891 and ISTH DICs (overt DIC), n = 1,002. Septic DIC patients were divided into 3 groups: Group 1, no anticoagulation therapy for DIC; Group 2, received rh-TM and/or AT III; and Group 3, received only "other anticoagulants." In JAAM DIC patients, Group 2 did not show an independent association with a reduced risk of in-hospital mortality (hazard ratio [HR]: 0.86; 95% confidence interval [CI]: 0.73-1.01]) as compared with Group 1. However, in ISTH DIC patients, Group 2 showed an inverse association with the risk of in-hospital mortality (HR 0.74; 95% CI: 0.60-0.92) as compared with Group 1, but the same was not true for Group 3 (HR 0.73; 95% CI: 0.47-1.14). The present results support previous findings of the beneficial effects of anticoagulation therapies in septic DIC, also expands the importance of using rh-TM and/or AT agent for septic overt DIC.

Analysis of CDSS Experimental Indexes in 333 Cases of Newly Diagnosed Acute Leukemia

To analyze the 5 experimental indexes of CDSS in the patients with acute leukemia (AL) so as to provide the laboratorial basis for the early diagnosis and treatment of the secondary DIC in AL. Three hundred and thirty three patients with AL were divided into 7 groups, such as AML-M1-M5, other AML and ALL. The experimental indexes and CDSS scores of all AL groups were compared and analyzed in pairs, meanwhile 100 healthy persons were taken in the control group. Clinical events such as early death in all cases were also analyzed. The highest positive rate of Platelet was 59.76%, among the 5 experimental indexes, followed by D-D (30.93%), and the lowest APTT with only 2.70%. Compared with the control group, the differences of remaining indexes were statistically significant (P＜0.01), except APTT in group AML-M3 and FIB in the other AML groups. The score of laboratory index was (1.50±1.51) in all AL patients, and the positive rate of overt DIC ( score≥4) was 14.11% ( 47 cases). The highest score of CDSS was (3.34 ±1.71) in group AML-M3. The difference in the incidence of early death and cerebral (pulmonary) hemorrhage in DIC patients were statistically significant (P＜0.05 and P＜0.01). The application of quantitative integral method of experimental indexes in CDSS is objective and feasible, which is of great significance for early diagnosis and early treatment of acute leukemia complicated with DIC.

Advance in the Management of Sepsis-Induced Coagulopathy and Disseminated Intravascular Coagulation.

Coagulopathy commonly occurs in sepsis as a critical host response to infection that can progress to disseminated intravascular coagulation (DIC) with an increased mortality. Recent studies have further defined factors responsible for the thromboinflammatory response and intravascular thrombosis, including neutrophil extracellular traps, extracellular vesicles, damage-associated molecular patterns, and endothelial glycocalyx shedding. Diagnosing DIC facilitates sepsis management, and is associated with improved outcomes. Although the International Society on Thrombosis and Haemostasis (ISTH) has proposed criteria for diagnosing overt DIC, these criteria are not suitable for early detection. Accordingly, the ISTH DIC Scientific Standardization Committee has proposed a new category termed “sepsis-induced coagulopathy (SIC)” to facilitate earlier diagnosis of DIC and potentially more rapid interventions in these critically ill patients. Therapy of SIC includes both treatment of the underlying infection and correcting the coagulopathy, with most therapeutic approaches focusing on anticoagulant therapy. Recently, a phase III trial of recombinant thrombomodulin was performed in coagulopathic patients. Although the 28-day mortality was improved by 2.6% (absolute difference), it did not reach statistical significance. However, in patients who met entry criteria for SIC at baseline, the mortality difference was approximately 5% without increased risk of bleeding. In this review, we discuss current advances in managing SIC and DIC.

Markers of Fibrinolysis in Indian Patients with Isolated Head Trauma.

Context:Head injury causes disseminated intravascular coagulation as the most severe complication which is associated with high mortality. Elevated levels of markers of fibrinolysis such as D-dimer and fibrinopeptide A (FPA) have been correlated with poor outcome in these patients.Aim:The study aimed to correlate the levels of plasma fibrinogen, D-dimer, and FPA with outcome in patients with isolated head trauma.Settings and Design:This cross-sectional descriptive study was conducted in the Departments of Pathology and Neurosurgery, University College of Medical Sciences and Guru Teg Bahadur Hospital, Delhi, on 100 patients admitted within 12 h of isolated head trauma.Subjects and Methods:Plasma fibrinogen, D-dimer, and FPA were measured in 100 patients admitted within 12 h of isolated head trauma. While plasma fibrinogen and D-dimer were estimated in all patients, FPA was measured in 45 patients.Statistical Analysis:SPSS (20.2) software was used for mean, standard deviation, and median values of the quantitative parameters, and for all qualitative parameters, their frequencies were obtained. P < 0.05 was considered significant.Results:Elevated D-dimer (>250 ng/ml) and FPA (>3 ng/ml) were observed in 64% and 91.1% patients, respectively. Both D-dimer and FPA were elevated in 66.6% of patients. Disseminated intravascular coagulation (DIC) score, calculated using standard criteria, was ≥5 in 28% of patients indicating overt DIC. Hypofibrinogenemia was observed in 48% of patients. D-dimer, FPA, and DIC score was significantly (P < 0.001) higher and plasma fibrinogen significantly (P < 0.001) lower in nonsurvivors as compared to survivors. Elevated D-dimer and FPA and low fibrinogen levels were seen in patients irrespective of severity of injury.Conclusions:Elevated D-dimer and FPA were frequently observed in patients with isolated head trauma. As these markers rise soon after injury and indicate poor outcome, their measurement will help identify patients who will benefit with additional therapy, thus reducing morbidity and mortality.

Acute fibrinolysis shutdown occurs early in septic shock and is associated with increased morbidity and mortality: results of an observational pilot study

BackgroundSeptic coagulopathy represents a very dynamic disease entity, tilting from initial hypercoagulability towards a subsequent hypocoagulable disease state, entitled overt disseminated intravascular coagulation. Acute fibrinolysis shutdown has recently been described to be a crucial component of initial hypercoagulability in critically ill patients, although the underlying pathomechanisms, the specific temporal kinetics and its outcome relevance in patients with sepsis remain to be determined.MethodsIn total, 90 patients (30 with septic shock, 30 surgical controls and 30 healthy volunteers) were enrolled. Blood samples were collected at sepsis onset or prior and immediately after the surgical procedure as well as 3 h, 6 h, 12 h, 24 h, 48 h and 7 d later, whereas blood samples from healthy volunteers were collected once. Besides viscoelastic and aggregometric point-of-care testing (POCT), enzyme-linked immunosorbent and thrombin generation assays and liquid chromatography–mass spectrometry-based measurements were performed.ResultsAs assessed by viscoelastic POCT, fibrinolysis shutdown occurred early in sepsis. Significant increases in tissue plasminogen activator had no effect on thromboelastometrical lysis indices (LIs). Contrariwise, plasminogen activator inhibitor-1 was already significantly increased at sepsis onset, which was paralleled by significantly increased LIs in patients suffering from septic shock in comparison with both control groups. This effect persisted throughout the 7-day observation period and was most pronounced in severely ill as well as non-surviving septic patients. Thromboelastometrical LI, therefore, proved to be suitable for early diagnosis [e.g. LI 45 min: area under the curve (AUC) up to 0.933] as well as prognosis (e.g. LI 60 min: AUC up to 1.000) of septic shock.ConclusionsEarly inhibition of plasminogen activation leads to acute fibrinolysis shutdown with improved clot stability and is associated with increased morbidity and mortality in septic patients.Trial registration This study was approved by the local ethics committee (Ethics Committee of the Medical Faculty of Heidelberg; Trial-Code No. S247-2014/German Clinical Trials Register (DRKS)-ID: DRKS00008090; retrospectively registered: 07.05.2015). All study patients or their legal representatives signed written informed consent.

The reduced form of coagulation factor XI is associated with illness severity and coagulopathy in critically-ill septic patients.

Coagulation Factor XI (FXI) contributes to the pathobiology of sepsis-associated thrombosis and is a target for new therapeutics. Through cleavage of disulfide bonds, FXI becomes reduced (rFXI), accelerating intrinsic coagulation cascade activation. The role of rFXI in human sepsis has never been studied. We determined levels of total FXI and rFXI in critically-ill septic patients with and without overt disseminated intravascular coagulation (DIC, a dysregulated pro-thrombotic condition). Total FXI and rFXI plasma levels were measured on ICU admission in prospectively enrolled septic patients (n = 32) from three academic medical centers and matched, healthy controls (n = 15). In septic patients, hematologic and physiologic parameters and pathological thrombosis (presence or absence of overt DIC) were determined. rFXI was higher in septic patients than controls (p < 0.05). In septic patients, rFXI was significantly associated with platelet count (r = 0.3511, p < 0.05) and APACHE II score (r = - 0.359, p < 0.05), indices of illness severity. rFXI was lower in patients with overt DIC (p = 0.088), suggesting a consumptive coagulopathy. In contrast, while total FXI levels were reduced in sepsis, they failed to correlate with illness severity, thrombosis, or hematologic parameters. We establish, for the first time, that rFXI is increased in patients with sepsis and correlates with illness severity (APACHE II score and platelet count) and pathological coagulopathy (overt DIC). Total FXI levels, in contrast, are decreased in sepsis but fail to associate with any indices. These findings suggest that rFXI has unique activity in human sepsis.

Endothelial Dysfunction Is Associated with Mortality and Severity of Coagulopathy in Patients with Sepsis and Disseminated Intravascular Coagulation.

The role of the endothelium in sepsis-associated disseminated intravascular coagulation (DIC) is multifaceted and may contribute substantially to disease severity and outcome. The purpose of this study was to quantify measures of endothelial function, including markers of activation (endocan, Angiopoietin-2 [Ang-2], and von Willebrand Factor), endogenous anticoagulants (tissue factor pathway inhibitor and protein C), and damage-associated factors (High Mobility Group Box 1 [HMGB-1]) in the plasma of patients with sepsis and DIC, and to determine the relationship of these factors with severity of illness and outcome. Plasma samples were collected from 103 adult patients with sepsis within 48 hours of intensive care unit admission. Biomarker levels were measured using commercially available, standardized methods. Disseminated intravascular coagulation was diagnosed according to the International Society of Thrombosis and Hemostasis scoring algorithm. Twenty-eight-day mortality was used as the primary end point. In this study, endothelial damage and dysfunction were associated with the severity of coagulopathy and mortality in DIC patients. Loss of the endogenous anticoagulant protein C and elevation in the vascular regulator Ang-2 were associated with the development of overt DIC. In addition to Ang-2 and protein C, endocan, a biomarker of endothelial activation, and HMGB-1, a mediator of endothelial damage and activation, were significantly associated with mortality. This underscores the contribution of the endothelium to the pathogenesis of sepsis-associated DIC.

Optimal Timing and Early Intervention With Anticoagulant Therapy for Sepsis-Induced Disseminated Intravascular Coagulation.

Optimizing diagnostic criteria to detect specific patients likely to benefit from anticoagulants is warranted. A cutoff of 5 points for the International Society on Thrombosis and Haemostasis overt disseminated intravascular coagulation (DIC) scoring system was determined in the original article, but its validity was not evaluated. This study aimed to explore the optimal cutoff points of DIC scoring systems and evaluate the effectiveness of early intervention with anticoagulants. We used a nationwide retrospective registry of consecutive adult patients with sepsis in Japan to develop simulated survival data, assuming anticoagulants were conducted strictly according to each cutoff point. Estimated treatment effects of anticoagulants for in-hospital mortality and risk of bleeding were calculated by logistic regression analysis with inverse probability of treatment weighting using propensity scoring. Of 2663 patients with sepsis, 1247 patients received anticoagulants and 1416 none. The simulation model showed no increase in estimated mortality between 0 and 3 cutoff points, whereas at ≥4 cutoff points, mortality increased linearly. The estimated bleeding tended to decrease in accordance with the increase in cutoff points. The optimal cutoff for determining anticoagulant therapy may be 3 points to minimize nonsurvival with acceptable bleeding complications. The findings of the present study suggested a beneficial association of early intervention with anticoagulant therapy and mortality in the patients with sepsis-induced DIC. Present cutoff points of DIC scoring systems may be suboptimal for determining the start of anticoagulant therapy and delay its initiation.

External Validation of the Two Newly Proposed Criteria for Assessing Coagulopathy in Sepsis.

Two different criteria for evaluating coagulopathy in sepsis were recently released: sepsis-induced coagulopathy (SIC) and sepsis-associated coagulopathy (SAC). Although both use universal haemostatic markers of platelet count and pro-thrombin time, significance and usefulness of these criteria remain unclear. This article validates and evaluates the significance of SIC and SAC criteria compared with the International Society on Thrombosis and Haemostasis (ISTH) overt disseminated intravascular coagulation (DIC) and Japanese Association for Acute Medicine (JAAM) DIC criteria. Clinical characteristics of patients from a nationwide Japanese cohort were classified by SIC, SAC or DIC status and relations between criteria were examined. We evaluated associations between in-hospital mortality and anticoagulant therapy according to the SIC, SAC or DIC status to clarify the significance of criteria for introducing anticoagulants. Intervention effects were analysed by Cox regression analysis adjusted by propensity scoring. Incidences of coagulopathy diagnosed by SIC and JAAM DIC were similar, whereas those of SAC and ISTH overt DIC were about half of the former two (61.4%, 60.8% vs. 45.3%, 29.3%). Severity and mortality of all criteria were almost comparable. For validating initiation of anticoagulation, favourable effects of anticoagulant therapy were observed only in sub-sets with, and not without, coagulopathy diagnosed by all four criteria. Slight non-significant differences between anticoagulant groupings were found in ISTH overt DIC- and SAC-negative populations, suggesting that some patients even 'without' these criteria may benefit from anticoagulant therapy. Newly developed SIC diagnostic criteria for coagulopathy may be valuable in detecting appropriate candidates for anticoagulant therapy in sepsis and a useful alternative to conventional DIC scoring systems.

Hypofibrinogenemia and Disseminated Intravascular Coagulation Rarely Complicate Treatment-Naive Acute Lymphoblastic Leukemia

Introduction: Hypofibrinogenemia (HF) in acute leukemia has largely been attributed to disseminated intravascular coagulation (DIC). Pathological alterations in hemostasis through various mechanisms by circulating leukemia cells have been implicated in the pathogenesis of DIC, particularly in acute promyelocytic leukemia (APL) (Tallman et al., Leuk Lymphoma, 1993). In adult acute lymphoblastic leukemia (ALL), DIC is rare at presentation, but is significantly more common during induction chemotherapy, with varying degrees of reported morbidity and mortality (Higuchi et al., Leuk Lymphoma, 2005; Sarris et al., Leuk Lymphoma, 1996). Conversely, hyperfibrinogenemia at presentation has also been observed, possibly due to increased synthesis as an acute phase reactant in the setting of inflammation (Al-Mondhiry H et al., Cancer, 1975). Discrepant reports in plasma fibrinogen levels and potentially serious hemostatic complications led us to investigate the incidence of HF and DIC among adults with untreated ALL at our center.Methods: Using a DataLine search and ICD-9 and ICD-10 codes (204.00, 204.01, 204.02, C91.00, C91.01, C91.02), all patients aged 18 years or older with a diagnosis of ALL treated at Memorial Sloan Kettering Cancer Center (MSKCC) between August 30, 1989 and April 27, 2018 were retrospectively identified. HF was defined as a fibrinogen level < 190 mg/dL. The diagnosis of DIC was made using the scoring system for overt DIC from the International Society on Thrombosis and Haemostasis (Toh et al., J Thromb Haemost, 2007). Patients who received any chemotherapy, including asparaginase and glucocorticoids, or who had a potential alternative cause of acquired HF such as sepsis or significant liver disease prior to their initial encounter were excluded. Data collection was approved by the MSKCC Institutional Review Board.Results: A total of 275 adult patients with treatment-naive ALL were identified. The median age at presentation was 44 years. The study population consisted of 122 patients with B-ALL, 81 with T-ALL and 72 with ALL of unspecified lineage. Of these, 187 had a fibrinogen level obtained prior to initiation of therapy. Eight patients (4.3%) had HF at initial assessment with a mean level of 141 mg/dL. Of these 8 patients, 5 had B-ALL, 2 had T-ALL and 1 had ALL of unspecified lineage. Four of these 8 patients required fresh frozen plasma (FFP) and/or cryoprecipitate during their hospitalization for prevention of overt coagulopathy. Three of the 4 patients who required FFP and/or cryoprecipitate went on to receive an asparaginase containing induction regimen. One patient with B-ALL met criteria for overt DIC without clinical complications. One patient with HF experienced WHO grade 2 epistaxis and hematochezia. No deaths in our study population were attributable to DIC at presentation.Discussion: Our study demonstrated that HF and DIC in treatment-naive ALL are uncommon. The rare incidence of DIC in our population is consistent with prior studies in adult ALL (Sarris et al., Blood, 1992). Our findings are also similar to those reported in patients with non-APL acute myeloid leukemia (Weltermann et al., Leukemia, 1998). In contrast, most patients with APL exhibit HF (Lou et al., Leuk Res, 2016). Proposed mechanisms of coagulopathy in APL include primary activation of fibrinolysis, as well as expression of tissue factor and cancer procoagulant by the malignant promyelocytes themselves; these mechanisms appear to be significantly less prevalent in ALL (Breen et al., Br J Haematol, 2012). DIC, when present at initial assessment, is generally subclinical and seldom leads to morbidity and mortality. Although the incidence of HF and DIC was low at diagnosis in our study population, we recommend pre-treatment screening for DIC to identify patients with overt coagulopathy at presentation and to establish baseline values, given the risk of coagulopathic complications during induction chemotherapy for ALL, particularly among patients receiving asparaginase products (Truelove et al., Leukemia, 2012). Further characterization of the ALL microenvironment in patients developing HF and DIC may elucidate mechanisms of procoagulant expression and increased fibrinolysis in this subgroup. Assessing predictors and clinical implications of baseline HF in adults with ALL in a larger series may help to guide early supportive management. DisclosuresGeyer:Dava Oncology: Honoraria. Park:Adaptive Biotechnologies: Consultancy; AstraZeneca: Consultancy; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Shire: Consultancy; Kite Pharma: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Juno Therapeutics: Consultancy, Research Funding. Mantha:Janssen Pharmaceuticals: Research Funding; Heidell, Pittoni, Murphy & Bach, LLP: Consultancy; GLG: Consultancy. Tallman:Orsenix: Other: Advisory board; Daiichi-Sankyo: Other: Advisory board; Cellerant: Research Funding; BioSight: Other: Advisory board; AROG: Research Funding; AbbVie: Research Funding; ADC Therapeutics: Research Funding.

Development of an Algorithm to Predict Mortality in Patients with Sepsis and Coagulopathy

Introduction: Sepsis is a systemic response to infection which results in a high rate of mortality worldwide. The pathophysiology of sepsis is complex; although sepsis is often defined on the basis of the overwhelming host inflammatory response, this disease process also involves infection response, hemostatic dysregulation, endothelial dysfunction, and platelet activation. Improved ability to predict mortality in sepsis patients would have implications for the appropriate administration of therapies in this population. Several approaches to this problem have been tried, focused on clinical scoring systems or biomarkers of a single physiological system, with modest success. The purpose of this study was to develop an equation incorporating biomarker levels at intensive care unit (ICU) admission to predict mortality in patients with sepsis, based on the hypothesis that a combination of biomarkers representative of multiple physiological systems would provide improved predictive value over a single biomarker or system.Materials and Methods: Plasma samples were collected from 103 adult patients with sepsis at the time of ICU admission. Levels of 28 biomarkerss were measured using commercially available, standardized methods. Clinical data, including the ISTH overt DIC score, SOFA score, and APACHE II score was also collected. 28-day mortality was used as the primary endpoint. Stepwise linear regression modeling was performed. This modeling approach used an iterative mathematical process to select the most relevant biomarkers to include in an equation to predict patient survival vs. non-survival.Results: Differences in biomarker levels between survivors were quantified and using the Mann-Whitney test and the area under the receiver operating curve (AUC) was used to describe predictive ability. Significant differences (p<0.05) were observed between survivors and non-survivors for PAI-1 (AUC=0.70), procalcitonin (AUC=0.77), HMGB-1 (AUC=0.67), IL-6 (AUC=0.70), IL-8 (AUC=0.70), protein C (AUC=0.71), Angiopoietin-2 (AUC=0.76), endocan (AUC=0.58), and platelet factor 4 (AUC=0.70). A predictive equation for mortality was generated using stepwise linear regression modeling. This model incorporated procalcitonin, VEGF, the IL-6:IL-10 ratio, endocan, and PF4, and demonstrated a better predictive value for patient outcome than any individual biomarker (AUC=0.87). This supports the hypothesis that a panel of biomarkers representative of multiple physiological systems would perform better than biomarkers representative of a single system. This model accounts for infection response (procalcitonin), inflammation and the balance of pro- vs. anti-inflammatory factors (VEGF, IL-6:IL-10 ratio), endothelial function (endocan), and platelet function (PF4). Incorporation of clinical data such as SOFA or APACHE II scores did not result in improved model performance; the model developed including this information incorporated white blood cell count, APACHE II score, and procalcitonin had an AUC of 0.84.Conclusions: The use of a mathematical modeling approach resulted in the development of a predictive equation for sepsis-associated mortality with better accuracy than any individual biomarker or clinical scoring system. In addition, this equation incorporates biomarkers representative of multiple physiological systems that are involved in the pathogenesis of sepsis and may better represent the complete pathophysiology of this syndrome to predict the high mortality that exists in these patients.[MTR1]Would add a sentence on the mortality endpoint DisclosuresNo relevant conflicts of interest to declare.

Coagulation Derangements in Patients With Refractory Cardiac Arrest Treated With Extracorporeal Cardiopulmonary Resuscitation

Extracorporeal cardiopulmonary resuscitation (eCPR) with venoarterial extracorporeal membrane oxygenation (VA-ECMO) is gaining importance as a rescue therapy for refractory cardiac arrest. VA-ECMO, especially in the setting of eCPR, is plagued by hemorrhagic and thromboembolic complications. The authors' aims were to describe the coagulation profile in refractory cardiac arrest and assess its prognostic role. Single-center retrospective study. Cardiac surgical intensive care unit of a university hospital. One hundred eighty-eight patients treated with eCPR for intra-hospital and out-of-hospital refractory cardiac arrest, between 2008 and 2017. The authors retrospectively analyzed data from the first blood sample drawn during cannulation for VA-ECMO to understand the association of coagulation parameters with survival to hospital discharge, number of blood components transfused, anticoagulation therapy, serum lactate levels, no-flow time, and low-flow time. Platelet count was 126 ± 79 × 109/L and in 17% of the population it was lower than 50 × 109/L, prothrombin time was 3.22 ± 4.01, activated partial thromboplastin time was 117 ± 78 seconds, fibrinogen was 186 ± 148 mg/dL, antithrombin was 47 ± 16%, and D-dimer was ≥2-fold the normal upper limit in 95% of patients. Fifty percent of patients had a disseminated intravascular coagulation (DIC) score ≥6 (52% among out-of-hospital cardiac arrest, 33% among in-hospital cardiac arrest), according to the criteria of the Japanese Society on Thrombosis and Hemostasis (2016). The median DIC score was 5.5 points (interquartile range 4-8), significantly different between survivors and nonsurvivors (4 [3-6] v 6 [4-8], p = 0.007). Every DIC score point contributed to the mortality risk (OR 1.34, 95% CI 1.09-1.67, p = 0.006). Patients with overt DIC less frequently received anticoagulants (28.6% v 55.9%, p = 0.002), started anticoagulant therapy later (12 [10-23] v 8.5 [5-12] hours, p = 0.045), and received a larger quantity of blood products (11 [4-23] v 3 [0-8.5] units, p < 0.0001). Coagulation derangements are frequent in patients with refractory cardiac arrest and have important consequences for eCPR management for anticoagulant therapy and blood product transfusion. The presence of DIC diagnostic criteria should be considered among the prognostic factors in this population of patients.