Non-overt Disseminated Intravascular Coagulation Research Articles

Signal management and risk minimization strategy: a case study on obinutuzumab and non-overt disseminated intravascular coagulation

Introduction: In December 2020, the Italian Medicines Agency (AIFA) in collaboration with the Italian Regional Centers of Pharmacovigilance evaluated four individual case safety reports (ICSRs) reporting obinutuzumab and non-overt disseminated intravascular coagulation (DIC) as a new possible signal. In this study, we described the process of signal management for obinutuzumab-associated non-overt DIC.Methods: In accordance with the Guideline on Good Pharmacovigilance Practices Module IX, we described the process of the Italian and European Union signal management process in five steps: signal detection, signal validation, signal confirmation, signal analysis, and prioritization and signal assessment.Results: In the signal detection phase, four cases of obinutuzumab-associated non-overt DIC met the criteria for signal definition (ROR 213.6 and IC025 77). In the signal validation phase, both the Italian and European databases of spontaneously reported adverse drug reactions were investigated with supporting evidence from medical literature. Four patients (two men and two women aged 67–77) were in treatment with obinutuzumab for chronic lymphocytic leukemia, and they developed a subclinical DIC within 24 h from the administration of the drug. The DIC spontaneously resolved in all cases. Three more ICSRs were reported in the EudraVigilance database. The medical literature provided poor evidence of the possible association between obinutuzumab and DIC. The signal was subsequently validated, first by AIFA and then by EMA. The signal was confirmed by the Pharmacovigilance Risk Assessment Committee (PRAC) Rapporteur in the “signal confirmation” phase, and it entered “signal analysis and prioritization” and “signal assessment”. In these phases, the PRAC assessed and confirmed DIC as a possible adverse reaction to obinutuzumab. Finally, the Summary of Product characteristics was updated with this new risk.Conclusion: Despite the intrinsic difficulties linked to the nature of the event itself, the process of signal detection and the issuing of the risk minimization measures by the Italian Medicines Agency as part of the EU procedures have proven to be efficient.

IMMUNOSUPPRESSION CORRELATES WITH THE DETERIORATION OF SEPSIS-INDUCED DISSEMINATED INTRAVASCULAR COAGULATION.

Background: The dysregulated host responses play a crucial role in the pathophysiology process of sepsis-induced disseminated intravascular coagulation (DIC). The study aimed to characterize the dynamic alternation of immune-related biomarkers and their relationship with the progression of DIC during sepsis. Methods: A prospective, observational study was conducted in a tertiary care academic hospital. Six hundred forty patients with sepsis were classified into three groups according to the International Society on Thrombosis and Hemostasis (ISTH) score: 383 involved patients without DIC (ISTH = 0), 168 sepsis with nonovert DIC (ISTH = 1-4), and 89 sepsis with overt DIC (ISTH ≥5). Eighteen immune-related biomarkers and six routine coagulation variables were examined at D1, D3, and D7 upon enrollment. The association between the immune parameters and the DIC deterioration was assessed during sepsis. Results: The study showed a 40% coagulation disorder and a 14% incidence of overt DIC in patients with sepsis. The patients with overt DIC displayed pronounced immune disorders from D1 to D7 upon sepsis, which was characterized by the decreased percentage of monocyte HLA-DR (mHLA-DR), increased percentage of regulatory T cells, the levels of procalcitonin, neutrophil CD64 index, and systemic inflammatory cytokines relative to nonovert DIC or non-DIC patients. In multivariate analysis, the combination of anti-inflammatory cytokine IL-10 and mHLA-DR at D1 upon enrollment had a superior predictive value for predicting DIC deterioration in sepsis (area under the curve = 0.87, P < 0.0001). Conclusion: These data illustrate that immunosuppression can crosstalk with coagulation disorder during sepsis and present an additional evaluation tool to predict DIC deterioration.

Outcomes of Overt and Non-overt Disseminated Intravascular Coagulation Using the ISTH DIC Scoring System in Children: A Single-Center Study.

Several disseminated intravascular coagulation (DIC) scoring systems are used for prognosticating the clinical outcomes of patients with DIC. However, research on children is scarce. Therefore, this study compared the clinical outcomes of overt and non-overt DIC using the International Society on Thrombosis and Hemostasis (ISTH) DIC scoring system. This retrospective study reviewed data on children aged one month to 15 years diagnosed with DIC between 2003 and 2014. Of 244 patients, 179 (73.4%) had overt DIC, and 65 (26.6%) had non-overt DIC. The most common causes were infection (84.8%), tissue injury (7%), and malignancies (2.9%). The 28-day case fatality rate was significantly higher for overt than non-overt DIC (76% vs. 15.6%; P < 0.001). DIC scores were significantly associated with mortality (R2 = 0.89). Each clinical parameter (platelet count, prothrombin time, and fibrin degradation products) was associated with mortality (P = 0.01). On multivariable analysis, the factors associated with death were platelet counts ≤ 50 000 cells/mm3 (OR, 2.42; 95% CI, 1.08-5.42; P = 0.031); overt DIC score (OR, 7.62; 95% CI, 2.94-19.75; P < 0.001); renal dysfunction (OR, 2.92; 95% CI, 1.34-6.37; P = 0.007); shock (OR, 39.62; 95% CI, 4.99-314.84; P = 0.001); and acute respiratory distress syndrome (OR, 25.90; 95% CI, 3.12-214.80; P = 0.003). The 28-day case-fatality rate was significantly higher for patients with overt than non-overt DIC and concordant with ISTH scores. ISTH DIC scores can be used as a clinical predictor for DIC in children.

Diagnosis and treatment of bbstetrics disseminated intravascular coagulation in resource limited settings.

Disseminated intravascular coagulation (DIC) is one of the commonest causes of abnormal bleeding during pregnancy and puerperium. Its successful management is a challenging feat in resource limited settings (RLS). To determine Obstetricians' approach in diagnosing and treating obstetrics DIC in a RLS. A semi-structured pre-tested 4-sectioned questionnaire was used to collect demographic data of Nigerian obstetricians and data on their practice in the diagnosis and treatment of obstetrics DIC. A total of 171 obstetricians responded. Preeclampsia was the most frequent cause identified (70.2%) followed by postpartum haemorrahge (58.3%). Platelet count determination was the test mostly used (95.9%) to make a diagnosis of DIC whereas, antithrombin assay was the least (20.6%) requested investigation. While about two-third would monitor the evolution of DIC, a little less than half of the obstetricians would not repeat laboratory testing more than every 2 days, reason mainly (61.8%) due to patient's financial constraint. Almost three-quarter of them preferred fresh whole blood as the first line of treatment of DIC. DIC remains a challenge in the obstetrics practice in RLS especially in investigations, monitoring and index of suspicion for non-overt DIC.

Urinary thrombin as a marker of local disseminated intravascular coagulation in patients with chronic kidney disease

The aim of this research was to study the diagnostic markers of nonovert local disseminated intravascular coagulation (DIC) syndrome in the urine of patients with chronic kidney disease (CKD). We conducted a prospective study involving 140 patients with CKD, of these patients, 100 patients (71.4%; 95% CI 53.4-76.7) had glomerulonephritis (GN) and 40 patients (28.6%; 95% CI 21.3-36.8) had diabetic nephropathy (DN). We diagnosed overt DIC syndrome on the International Society of Thrombosis and Haemostasis (ISTH) scale (&gt;5 points) in 18.6 % of patients. We determined the level of thrombin in the urine of patients who had &lt;5 points on ISTH scale for the diagnosis of local nonovert DIC syndrome in the kidneys. In the urine of healthy individuals, the level of thrombin did not exceed 1 ng/ml, so we found no thrombinuria at a thrombin level &lt;1 ng/ml. In 56.1% of patients, we found urinary thrombin levels &gt;1 ng/ml. The average level of thrombin in the urine of these patients was 6.5 (4.8; 10.6) ng/ml. In our opinion, the presence of thrombinuria indicates the intensity of monocytic-macrophage inflammation in the glomeruli and may be a criterion for nonovert, local DIC syndrome in the kidneys. The association of overt DIC syndrome with decreased blood albumin, reduced glomerular filtration rate (GFR), increased daily protein excretion (DPE) indicates its occurrence in severe underlying disease, in the presence of nephrotic syndrome and in the severe stages of CKD. Early diagnosis of nonovert local DIC syndrome would be more useful, since the process is still reversible and controlled, and timely use of antiplatelet and anticoagulant therapy would affect the course and the progression of CKD.

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

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

Clinical value of pediatric sepsis‐induced coagulopathy score in diagnosis of sepsis‐induced coagulopathy and prognosis in children

BackgroundIn adults, sepsis‐induced coagulopathy (SIC) is diagnosed by the SIC score, known as sepsis‐3. There is no pediatric SIC (pSIC) score at present. ObjectivesWe proposed a pSIC scoring method and evaluated the diagnostic efficacy of the score in the diagnosis of SIC in children. Patients/MethodsPatient data were retrospectively analyzed from Shanghai Children's Medical Center between February 2014 and January 2015. The pSIC score was modified from the SIC score. The area under ROC curve (AU‐ROC) was used to compare the prognostic values of pSIC with other scores for pediatric sepsis‐induced disseminated intravascular coagulation (DIC) to arrive at a 28‐day outcome. Results and ConclusionsThere were 54 patients in the pSIC group and 37 in the non‐pSIC group. The Kaplan–Meier survival curve analysis showed that the 28‐day prognosis was better in the non‐pSIC than in the pSIC group (p < .001). The AU‐ROC of the pSIC score in predicting 28‐day mortality in sepsis was 0.716, with the optimal cutoff value of >3 inferior to that of pediatric sequential organ failure (0.716 vs. 0.921, p < .001). The AU‐ROC of pSIC in predicting nonovert DIC was 0.845 and the optimal cutoff value was >3. The AU‐ROC of pSIC in predicting overt DIC was 0.901, with the best optimal cutoff value of >4. The pSIC score can be used to diagnose SIC in children, screen potential nonovert DIC, and assess the severity of sepsis, organ dysfunction, and 28‐day outcome in children.

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

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

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

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

Upregulation of Cortisol in Sepsis and Its Association with Markers of Hemostatic Dysregulation

Introduction:Sepsis is a life-threatening condition in which the host's response to a systemic infection contributes significantly to mortality. Patients with sepsis are at risk of developing a coagulation disorder leading to disseminated intravascular coagulation (DIC). In DIC, widespread activation of the coagulation cascade leads to microvascular thrombosis and organ failure. This consumes platelets and coagulation factors, putting the patient at risk for bleeding. Cortisol is a steroid hormone released in response to stress. Cortisol levels have been found to be increased in sepsis patients, and high cortisol levels have been correlated with increased mortality. However, the association of cortisol levels with the severity of coagulopathy in patients with DIC remains unclear. Cortisol levels may also be relevant to disease progression as a link between the stress response and the immune system. The purpose of this project is to assess the association of plasma cortisol levels with severity of coagulopathy in a population of patients with sepsis and clinically confirmed DIC. Furthermore, the association of cortisol with markers of hemostatic status, inflammation, and platelet function were also assessed.Materials and Methods:Citrated, de-identified plasma samples were collected from 52 adults with sepsis and suspected DIC at the time of ICU admission. Samples were collected at the University of Utah and transferred to LoyolaUniversity Chicago under an IRB approved protocol. Plasma samples from healthy individuals were acquired from a commercial source (George King Biomedical, Overland, KS). Samples were stored at -80˚C prior to analysis. Platelet count was determined as part of standard clinical practice. PT/INR and fibrinogen were measured using standard techniques on the ACL-ELITE coagulation analyzer. Cortisol, D-dimer, PAI-1, CD40L, inflammasomes (NLRP3), and microparticles were measured using commercially available ELISA kits and were performed according to the manufacturer's instructions. DIC score was calculated using the ISTH scoring algorithm. A score of 0-2 was classified as no DIC, 3-4 was classified as non-overt DIC, and 5 or greater was classified as overt DIC. Results were analyzed using GraphPad Prism.Results:Cortisol showed significant variation based on DIC status (Kruskal-Wallis ANOVA, p < 0.0001) . Patients with non-overt DIC and overt DIC exhibited significantly elevated cortisol levels compared to healthy controls (p < 0.0001 for both groups). Furthermore, cortisol levels showed significant variation amongst sepsis patients based on DIC score. Patients with sepsis and overt DIC had elevated cortisol compared to patients with sepsis and no DIC (p = 0.0069). Data is shown in Figure 1.Correlations were evaluated between cortisol and the hemostatic markers platelets, fibrinogen, INR, D-Dimer, and PAI-1 as well as with the inflammatory marker, inflammasomes (NLRP3) and the platelet markers CD40L and microparticles. Cortisol showed significant correlations with D-Dimer, PAI-1, and INR. (D-Dimer Spearman r = 0.480, p = 0.001; PAI-1 Spearman r = 0.415, p = 0.002; INR Spearman r = 0.305, p = 0.037). No significant correlations were observed between cortisol and the markers of inflammation or platelet activation.Conclusions:Cortisol showed a significant association with hemostatic status in a population of patients with sepsis and well-defined coagulopathy. Cortisol levels were significantly elevated in patients with overt or non-overt DIC compared to healthy individuals and in patients with overt DIC compared to those with sepsis without DIC. Cortisol also showed significant correlations with markers of hemostatic activation but not with markers of inflammation and platelet activation. This suggests that elevated levels of cortisol may play a specific role in the progression of hemostatic dysregulation observed in sepsis and DIC. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Evaluation the Value of TAT, PIC, tPAIC, TM in Diagnosing Disseminated Intravascular Coagulation in Chinese population: a Multi-Center Prospective Observational Study

Objective: Accurate and early diagnosis are important in the management of disseminated intravascular coagulation (DIC). New specific coagulation markers have always been explored. In this study, we employed new automation technology to detect plasma biomarkers, including Thrombin-Antithrombin Complex (TAT), α2-Plasmininhibitor-Plasmin Complex(PIC), thrombomoduline (TM), tissue plasminogen activator-inhibitor Complex (tPAIC), and evaluated their diagnostic performance for DIC in Chinese population.Method: A prospective observational study was conducted in 9 hospitals located across the entire China. 406 patients suspected DIC and 137 normal people were included. These four molecular markers were measured by qualitative chemiluminescence enzyme immunoassay performed on automated analyzers HISCL. All patients suspected DIC were followed for development of overt-DIC in 7 days, and for mortality in 28 days.Results: The plasm level of TAT, PIC, tPAIC and TM in normal Chinese people were 1.1 (0.7-1.6), 0.44 (0.37-0.56), 7.2(5.1-9.3) and 8.6 (7.3-9.9). According to the ISTH scoring system, 146 patients were diagnosed as overt-DIC, and 37 were diagnosed as pre-DIC. All four biomarkers were significantly higher in DIC group than non-overt DIC group, and tPAIC and TM were significantly higher in pre-DIC group than non-overt DIC group (Table 1). Besides, these molecular markers were different among various underlying diseases(Fig.1). As shown in the ROC assay, the efficiency of TAT, PIC, tPAIC and TM discriminated well between overt- DIC with pre-DIC and non-overt DIC (AUROC, 0.64 (95% CI, 0.58 to 0.69); 0.63 (0.57 to 0.68); 0.63 (0.58 to 0.69);0.73 (0.68 to 0.78), respectively)(Table 2). In the combination assay, the AUROC rose up to 0.955 (0.94 to 0.97) when in addition with global coagulation tests (Fig.2). Moreover, the ISTH DIC scores showed significant correlation with these molecular markers' levels. The mortality of DIC, pre-DIC and non-DIC was 33.56%, 51.35% and 8.97%, respectively. Among the significant diagnostic markers for DIC, TAT, tPAIC and TM were also good predictors of 28-day mortality (AUROC, 0.65, 0,76 and 0.76, respectively), high levels of them were associated with poor outcome(Fig.3).Conclusion: These four biomarkers have good diagnostic performance and prognostic value in DIC patients with different underlying diseases. They can also be applied in classification and stages of DIC. Moreover, combination of four makers demonstrate better behavior than single one. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

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.

Hypocoagulable Tendency on Thromboelastometry Associated With Severity and Anticoagulation Timing in Pediatric Septic Shock: A Prospective Observational Study.

Objective: To identify whether coagulation profiles using thromboelastometry are associated with outcomes in pediatric septic shock. The primary outcomes were the development of disseminated intravascular coagulation (DIC) and the severity of the pediatric intensive care unit (PICU) existing scoring systems, while the secondary outcome was hospital mortality. This study aimed to contribute to current findings of the limitations of conventional tests in determining the optimal timing of anticoagulation in sepsis.Design: A prospective, observational study conducted between August 2019 and August 2020.Setting: PICU at a pediatric tertiary hospital in Hanoi, Vietnam.Patients: Fifty-five pediatric patients who met the septic shock criteria were enrolled.Measurements and Main Results: Fifty-five patients with septic shock were recruited. At the time of diagnosis, thromboelastometry revealed normocoagulability, hypercoagulability, and hypocoagulability in 29, 29, and 42% of the patients, respectively (p > 0.05); however, most patients in the overt DIC and non-survival groups progressed to hypocoagulability (82 and 64%, respectively). The overt DIC, PELOD-2 > 8, PRISM-III > 11, and non-survival group had a significant hypocoagulable tendency according to thromboelastometry parameters [prolonged clotting time (CT) and clot formation time (CFT); and reduced α-angle (α), maximum clot firmness (MCF), thrombodynamic potential index (TPI)] compared to the non-overt DIC, PELOD-2 ≤ 8, PRISM-III score ≤ 11 and survival group (p < 0.05). Conventional parameters between the normocoagulable and hypercoagulable groups were not different (p > 0.05). Hypocoagulability was characterized by lower platelet count and fibrinogen level, higher prolonged prothrombin time (PT), international normalized ratio (INR), and activated partial thromboplastin time (APTT), and higher D-dimer level than in hypercoagulability (p < 0.05). Hypocoagulable tendency on thromboelastometry had a higher hazard at a PT > 16.1 s [area under the curve (AUC) = 0.747, odds ratio (OR) = 10.5, p = 0.002], INR > 1.4 (AUC = 0.754, OR = 6.9, p = 0.001), fibrinogen <3.3 g/L (AUC = 0.728, OR = 9.9, p = 0.004), and D-dimer > 3,863 ng/mL (AUC = 0.728, OR = 6.7, p = 0.004).Conclusions: Hypocoagulable tendency using thromboelastometry is associated with the severity of septic shock. Conventional coagulation tests may fail to detect hypercoagulability, which is crucial in determining anticoagulation timing.

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

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

English

BACKGROUND Obstetric practitioners routinely deal with antenatal patients who have high risk of developing established coagulopathy, which leads to a very high incidence of maternal morbidity and mortality. We wanted to assess the role of blood components in preventing disseminated intravascular coagulation (DIC) in highrisk patients and determine the amount of blood components required along with the rate of improvement in the DIC score, during treatment of high-risk obstetric patients of DIC and in patients with established DIC. METHODS This is an interventional study. 274 obstetric patients who were at high risk for developing DIC and / or with established DIC admitted during the 20 months study duration were included in the study. Patients were categorized in to three groups based on the DIC score according to ISTH scoring system in to non-overt and overt DIC groups. Those with DIC score &lt; 5 were grouped as IA and IB randomly and those with DIC score &gt; / = 5 were grouped as II. Software used was ANOVA using variance ratio F test for testing the significance between groups and chisquare test was used to find out the association between the groups or parameter. RESULTS Prophylactic transfusion of blood components showed faster rate of improvement than control group. Average consumption of blood components was more in patients of established coagulopathy as compared to non-overt group. CONCLUSIONS Transfusion of blood components can prevent overt DIC in high-risk patients. KEYWORDS DIC - Disseminated Intravascular Coagulation, PPH - Post Partum Haemorrhage, Coagulopathy, Component Therapy

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

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

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

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

Biomarkers of Platelet Activation and Their Prognostic Value in Patients With Sepsis-Associated Disseminated Intravascular Coagulopathy

Sepsis-associated disseminated intravascular coagulation (DIC) is related to marked hemostatic changes such as transient thrombocytopenia secondary to the endogenous activation and consumption of platelets. This study measured markers of platelet function in 103 adult ICU patients with clinically established sepsis-associated DIC to determine the biomarker association with disease severity. Patients were categorized as having no DIC, nonovert DIC, or overt DIC using the International Society of Thrombosis and Hemostasis scoring system. Plasma levels of CD40L, platelet factor 4 (PF4), platelet-derived microparticles, and microparticle-associated tissue factor were quantified. Markers of platelet activation were significantly elevated in patients with DIC compared to healthy individuals. This increase was independent of platelet count. Levels of PF4 differed based on the severity of DIC and differentiated nonsurvivors and survivors. These findings suggest that the markers of platelet activation in DIC may not be regulated by the number of circulating platelets and may be independent of the factors leading to their consumption.

The association between plasminogen activator inhibitor type-1 and clinical outcome in paediatric sepsis.

: Acute phase protein plasminogen activator inhibitor type-1 (PAI-1) is a key element in fibrinolysis inhibition in sepsis-induced disseminated intravascular coagulation (DIC). Elevated PAI-1 level is related to worse outcome in sepsis. The aim of this study was to investigate the relationship between plasma PAI-1 level and clinical outcome in children with sepsis. A total of 35 children with sepsis were enrolled into this prospective study. Plasma PAI-1 was measured on day-1 and day-4. Systemic coagulation profile was measured on day-4. Individuals were followed up until 28 days. The mean PAI-1 from day-1 to day-4 in overt DIC children was not statistically significant. Contrarily, among nonovert DIC individuals, there was a significant difference (P ≤ 0.001) in PAI-1 levels on day-1 compared with day-4 were 95.25 ± 46.57 vs. 60.36 ± 37.31 ng/ml, respectively. Among survivors, mean PAI-1 level on day-1 was statistically higher than PAI-1 level on day-4 (82.47 ± 44.43 vs. 58.39 ± 32.98 ng/ml), P = 0.021. There was no significant difference between PAI-1 levels on day-1 compared with day-4 in nonsurvivors. PAI-1 was correlated to DIC score with r = 0.606 (P ≤ 0.001). PAI-1 levels significantly decreased on day-4 compared with day-1 among nonovert DIC individuals, and not in overt DIC individuals. Changes in PAI-1 levels in nonsurvivors did not differ. PAI-1 level was positively correlated with DIC score.

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.