Clinical Features of Disseminated Intravascular Coagulation According to the French-American-British Classification in Patients With Acute Leukemia and Thrombomodulin Alfa Treatment-A Cohort Study Using a Postmarketing Surveillance Database.

The aims of this study were to analyze the clinical features of a large number of cases with disseminated intravascular coagulation (DIC) associated with acute leukemia and to assess the safety and efficacy of thrombomodulin alfa (TM-α) using the French-American-British (FAB) classification of hematological malignancies. We retrospectively examined 644 patients with acute leukemia in postmarketing surveillance for TM-α. M3, M2, M4, M1, and M5 subtypes of acute myeloid leukemia (AML) and L2 and L1 subtypes of acute lymphoblastic leukemia (ALL) have been found more frequently among patients with DIC. Bleeding symptoms at baseline were more frequent in M3 and M7 subtypes. Fibrinogen concentrations were lower, and plasmin-plasmin inhibitor complex values were higher in M3 and Philadelphia-positive (Ph+) ALL. Overall DIC resolution rate was 60.2%, higher in L1 and Ph+ ALL, lower in M1, and generally higher in ALL than in AML. Overall survival rate was generally high, at 79.8%, with higher rates in L3, Ph+ ALL, and M3. Regardless of FAB subgroup, TM-α showed improved bleeding symptoms and DIC scores in clinical practice for DIC patients with acute leukemia.

Coagulation phenotypes in sepsis and effects of recombinant human thrombomodulin: an analysis of three multicentre observational studies.

BACKGROUND: A recent randomised trial showed that recombinant thrombomodulin did not benefit patients who had sepsis with coagulopathy and organ dysfunction. Several recent studies suggested presence of clinical phenotypes in patients with sepsis and heterogenous treatment effects across different sepsis phenotypes. We examined the latent phenotypes of sepsis with coagulopathy and the associations between thrombomodulin treatment and the 28-day and in-hospital mortality for each phenotype. METHODS: This was a secondary analysis of multicentre registries containing data on patients (aged ≥ 16 years) who were admitted to intensive care units for severe sepsis or septic shock in Japan. Three multicentre registries were divided into derivation (two registries) and validation (one registry) cohorts. Phenotypes were derived using k-means with coagulation markers, platelet counts, prothrombin time/international normalised ratios, fibrinogen, fibrinogen/fibrin-degradation-products (FDP), D-dimer, and antithrombin activities. Associations between thrombomodulin treatment and survival outcomes (28-day and in-hospital mortality) were assessed in the derived clusters using a generalised estimating equation. RESULTS: Four sepsis phenotypes were derived from 3694 patients in the derivation cohort. Cluster dA (n = 323) had severe coagulopathy with high FDP and D-dimer levels, severe organ dysfunction, and high mortality. Cluster dB had severe disease with moderate coagulopathy. Clusters dC and dD had moderate and mild disease with and without coagulopathy, respectively. Thrombomodulin was associated with a lower 28-day (adjusted risk difference [RD]: - 17.8% [95% CI - 28.7 to - 6.9%]) and in-hospital (adjusted RD: - 17.7% [95% CI - 27.6 to - 7.8%]) mortality only in cluster dA. Sepsis phenotypes were similar in the validation cohort, and thrombomodulin treatment was also associated with lower 28-day (RD: - 24.9% [95% CI - 49.1 to - 0.7%]) and in-hospital mortality (RD: - 30.9% [95% CI - 55.3 to - 6.6%]). CONCLUSIONS: We identified four coagulation marker-based sepsis phenotypes. The treatment effects of thrombomodulin varied across sepsis phenotypes. This finding will facilitate future trials of thrombomodulin, in which a sepsis phenotype with high FDP and D-dimer can be targeted.

PROPOSAL AND APPLICATION OF A NOVEL DISSEMINATED INTRAVASCULAR COAGULATION SCORING SYSTEM IN THE FLORIDA MANATEE (TRICHECHUS MANATUS LATIROSTRIS).

Disseminated intravascular coagulopathy (DIC) is an acquired disorder of hemostasis resulting in activation of the coagulation and fibrinolytic pathways. It is reported secondarily to multiple disease processes and can be associated with increased mortality. Previous research at Tampa's Lowry Park Zoo (LPZ) demonstrated that Florida manatees ( Trichechus manatus latirostris) with cold stress syndrome (CSS) demonstrated thromboembolic disease. The object of this retrospective study was to establish the presence and clinical relevance of DIC in Florida manatees admitted to LPZ for rehabilitation from 07 March 2010 to 15 August 2015. A coagulation panel, including prothrombin time, partial thromboplastin time, platelet count, fibrinogen level, and D-dimer level was used to diagnose DIC. There were 100 cases identified in the study period: 35 trauma, 43 CSS, 17 secondary to harmful algae blooms (HAB), and five miscellaneous. Manatees with CSS had the highest incidence of DIC with 24 of 43 cases (56%) affected, followed by trauma with 18 of 35 cases (52%) affected. None of the manatees with HAB were found to have DIC. Manatees that developed DIC during rehabilitation or when DIC progressed did not survive. Due to the clinical implications of DIC, identifying its presence and recognizing its severity could improve clinical outcomes by enabling more intensive treatment protocols.

Evaluation of obstetrical patients with disseminated intravascular coagulopathy - tertiary center experience.

OBJECTIVE: The purpose of the present study is twofold: (a) to investigate the etiology of disseminated intravascular coagulopathy (DIC) caused by obstetrical conditions and (b) to present parameters that can be used in predicting DIC-related mortality in obstetrical patients. MATERIAL AND METHOD: Obstetrical patients who had a delivery at or were referred (after delivery) to Obstetrics and Gynecology Clinic of Dicle University between July 2006 and December 2013 were retrospectively analyzed in this study. Those patients diagnosed with DIC were included in the study. RESULTS: Fifty-six obstetrical patients carrying the diagnosis of DIC were included in this study. The overall mortality rate was 25% among these patients. More specifically, the mortality rate was 10.7% among patients with a DIC score ≤5 and 40.7% among those with a DIC score > 5. Multiple logistic regression analysis resulted in the finding that international normalized ratio (INR) and urea were among those factors affecting mortality in obstetrical DIC [OR: 8.44 (CI: 1.9-36.8), OR: 1.05 (CI: 1.0-1.1), respectively]. CONCLUSION: DIC is a syndrome that might be caused by obstetrical conditions. It is associated with high mortality and morbidity rates. In obstetrical DIC, urea is the most important factor affecting mortality. In addition, we are of the opinion that DIC score might guide mortality predictions as a determinant of prognosis.

[Treatment of DIC associated with myelogenous leukemia].

Many hematologists believe that anti-tumor drugs and platelet transfusion are enough for the treatment of disseminated intravascular coagulation (DIC) associated with myelogenous leukemia. In this paper, showing the pathophysiology of 3 types of DIC, I insisted the necessity of anticoagulant therapy to avoid the bleeding death or ischemic organ damage before achieving the hematological remission, because myelogenous leukemia is now a curable disease. In addition, I introduced the new Japan-made weapon to DIC, recombinant thrombomodulin, which complexes with thrombin and regulates the coagulation activity by efficient activation of protein C. Using two different natural anticoagulant systems, antithrombin and protein C pathway, we can more effectively improve DIC treatment and alleviate symptoms in DIC patients.

Application of the Japanese Association for Acute Medicine disseminated intravascular coagulation diagnostic criteria for patients at an early phase of trauma.

INTRODUCTION: To validate the diagnostic criteria for disseminated intravascular coagulation (DIC) established by the Japanese Association for Acute Medicine (JAAM) at an early stage of trauma and to evaluate the hypothesis that the JAAM criteria can diagnose DIC with a higher sensitivity than the International Society on Thrombosis and Haemostasis (ISTH) overt DIC criteria. MATERIALS AND METHODS: Based on a review of medical records, the data of 314 trauma patients were retrospectively obtained at 4 time points within 24 hr after arrival to the Emergency Department. RESULTS: One hundred and forty-one JAAM DIC patients (44.9%) showed differences in the prevalence of massive bleeding and multiple organ dysfunction syndrome (MODS), and the outcome in comparison to the non-DIC patients. A stepwise logistic regression analysis showed that the maximum JAAM DIC scores independently predicted the patient death. All of the patients who developed ISTH overt DIC could be identified by the JAAM DIC criteria at early time points. The mortality rate and the incidence of massive bleeding and MODS of the patients with the ISTH overt DIC were higher than those only met the JAAM DIC criteria. Stepwise increases in the ISTH overt DIC scores and the incidence of the overt DIC were observed in accordance with the increases in the JAAM DIC scores. While the mortality rates were identical, there were marked differences in the incidence of MODS and Sequential Organ Failure Assessment scores between the DIC patients associated with trauma and sepsis. CONCLUSIONS: The results show that the JAAM scoring system has acceptable validity for the DIC diagnosis at an early phase of trauma, and also that the scoring system can diagnose DIC with a higher sensitivity than the criteria of the ISTH overt DIC. Bleeding as well as MODS may affect the prognosis of the patients associated with DIC.

[Summary of pathophysiology and diagnosis of patients with platelet abnormality].

In hematological disorders, thrombocytopenia is frequently observed, and it is sometimes difficult to diagnose the underlying disease. In this symposium, laboratory tests for platelet abnormality were reviewed. Tests for platelet aggregation were reported to be important for the diagnosis of platelet dysfunction. Thrombocytopenia is caused by disseminated intravascular coagulation (DIC), thrombotic microangiopathy (TMA), heparin-induced thrombocytopenia (HIT), antiphospholipid syndrome (APS), idiopathic thrombocytopenic purpura (ITP), etc. As DIC is classified according to the degree of fibrinolysis, it was stated that the measurement of hemostatic molecular markers was further required. TMA is caused by abnormality of ADAMTS13, verotoxin, DIC, etc. HIT is diagnosed by anti-PF4 antibody, but its specificity is not high. Further investigation of TMA and HIT is required. APS is one of the most important diseases which cause thrombosis or abortion, suggesting that a differential diagnosis of APS is important. It was reported that diagnostic criteria of ITP have been established using a new antibody assay for platelets, immature platelet fractions, thrombopoietin, etc. In myeloproliferative disorders such as polycythemia vera and essential thrombocythemia, the mutation of JAK2 V617F was reported to be an important risk factor for thrombosis.

Implementation of the ISTH classification of non-overt DIC in a thromboplastin induced rabbit model.

Validation of animal models of disseminated intravascular coagulation (DIC) to human DIC is crucial in order to translate findings in research models to treatment modalities for DIC in humans. ISTH classifications of overt and non-overt human DIC have proven to have a high diagnostic accuracy, but the scoring systems have rarely been applied to animal models of DIC. In this study, we use rabbit brain thromboplastin (thromboplastin) to induce DIC in a rabbit model and test the applicability of the ISTH criteria for standardized diagnosis of DIC. Cardiovascular and haematological parameters from rabbits, either saline-injected or administered 0.625, 1.25, 2.5 or 5 mg thromboplastin/kg as a single bolus, were collected at four timepoints over a 90 minute period. All groups of rabbits were scored at each time point according to the ISTH diagnostic criteria for non-overt DIC. Injection of 5 mg thromboplastin/kg was lethal. For the remaining groups, a dose dependent decrease in blood pressure, platelet count and fibrinogen level together with a dose dependent increase in prothrombin time, activated partial thromboplastin time, level of thrombin-antithrombin complexes, fibrin degradation products and number of thrombi in lung vasculature was seen. The administration of a bolus of 1.25 - 2.5 mg thromboplastin/kg to rabbits induced a reproducible dose dependent model of non-overt DIC according to the ISTH diagnostic criteria. We conclude that the non-overt ISTH score can be applied to evaluate severity and progression of DIC in a standardized manner in this thromboplastin induced rabbit model.

A Prospective comparison of new Japanese criteria for disseminated intravascular coagulation: new Japanese criteria versus ISTH criteria.

In Japan, early diagnosis and early treatment of disseminated intravascular coagulation (DIC) based on the old Japanese criteria have greatly improved the outcomes of DIC patients with hematopoietic malignancy. However, the prognoses of critically ill patients with DIC have remained poor. To overcome this situation, new Japanese DIC criteria for critically ill patients were established in 2002. The new Japanese DIC criteria adopted a concept of coagulopathy associated with systemic inflammatory response syndrome. In the present study, we prospectively investigated the relationships between the new criteria and organ failure, prognosis, and other sets of DIC criteria. This study included 74 patients whose platelet counts were below 150 x 10(9)/L. Daily DIC scores and sequential organ failure assessment scores were recorded from days 0 to 4 once the patient was included in the study. The new Japanese DIC criteria diagnosed DIC earlier than both the non-overt DIC and the old Japanese criteria did (P = .0005). The new Japanese criteria diagnosed more DIC patients prior to the establishment of multiple organ failure than the other sets (P = .023). The new Japanese criteria tended also to predict prognoses more efficiently than the other two sets. In conclusion, the diagnostic sensitivity of the new Japanese criteria was as high as that of the non-overt DIC criteria. Furthermore, the new Japanese criteria provided the earliest detection and most accurate outcome prediction of DIC among the DIC criteria sets.

New disseminated intravascular coagulation score: A useful tool to predict mortality in comparison with Acute Physiology and Chronic Health Evaluation II and Logistic Organ Dysfunction scores.

OBJECTIVE: To compare the performance of a coagulation score-the new scoring system for diagnosing disseminated intravascular coagulation (DIC)-with the Acute Physiology and Chronic Health Evaluation (APACHE) II and Logistic Organ Dysfunction score in mortality prediction. DESIGN: Single-center retrospective study. SETTING: Medical intensive care unit of the University of Munich. PATIENTS: A total of 797 patients admitted to the intensive care unit between January 1, 1996, and January 1, 2001. METHODS: A retrospective analysis of all patients was done if the coagulation variables d-dimer, platelet count, fibrinogen, and prothrombin index were available within the first 12 hrs after admission. Patients with missing values, fibrinolytic therapy, or unknown survival status were excluded from analysis. As a marker of fibrin generation, d-dimer was measured and integrated into the scoring system for DIC together with prothrombin time, fibrinogen, and platelet count. A coagulation score was calculated in analogy with the scoring system for DIC in patients not typically developing DIC. MEASUREMENTS AND RESULTS: Overall, the mean result of the scoring system for DIC was 2.2 points. An increasing scoring system for DIC was associated with increasing mortality in patients with serious infections. Use of the scoring system for DIC in addition to the APACHE II score helps to predict mortality better than the APACHE II score alone, especially in patients with infections. The Cox regression analysis showed that the DIC and APACHE II scores correlated independently with survival time with a greater effect of the DIC score than the APACHE II or the Logistic Organ Dysfunction score. Similar results were obtained using the coagulation score in patients with cardiocirculatory diseases. CONCLUSION: Our retrospective data suggest that a combination of the APACHE II score and the scoring system for DIC predicts mortality in critically ill patients with available variables better than the APACHE II score alone. This effect is most pronounced among patients with active infection. These results of our retrospective analysis have to be confirmed in a prospective study.

Fresh frozen plasma transfusion in critically ill medical patients with coagulopathy.

OBJECTIVE: Although restrictive red cell transfusion practice has become a standard of care in the critically ill, data on the use of fresh frozen plasma (FFP) are limited. We hypothesized that the practice of FFP transfusion in the medical intensive care unit is variable and that liberal use may not be associated with improved outcome. DESIGN: Retrospective cohort study. SETTING: A 24-bed medical intensive care unit in a tertiary referral center. PATIENTS: All patients admitted to a medical intensive care unit during a 5-month period who had abnormal coagulation defined as international normalized ratio (INR) of > or = 1.5-times normal. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We collected data on demographics, severity of illness as measured by Acute Physiology and Chronic Health Evaluation (APACHE) III scores, INR, bleeding episodes, and transfusion complications. We identified 115 patients with coagulopathy (INR of > or = 1.5) but without active bleeding. A total of 44 patients (38.3%) received FFP transfusion. INR was corrected in 16 of 44 patients (36%) who received transfusion. Median dose of FFP was 17 mL/kg in patients who had INR corrected vs. 10 mL/kg in those who did not (p = .018). There was no difference in age, sex, APACHE III scores, liver disease, Coumadin treatment, or INR level between those who did and did not receive FFP. Invasive procedures (68.2% vs. 40.8%, p = .004) and history of recent gastrointestinal bleeding (41% vs. 7%, p < .001) were more frequent in the group with transfusion. Although there was no difference in new bleeding episodes (6.8% in transfused vs. 2.8% in nontransfused group, p = .369), new onset acute lung injury was more frequent in the transfused group (18% vs. 4%, p = .021). Adjusted for severity of illness, hospital mortality and intensive care unit length of stay among survivors were not different between the two groups. CONCLUSION: The risk-benefit ratio of FFP transfusion in critically ill medical patients with coagulopathy may not be favorable. Randomized controlled trials evaluating restrictive vs. liberal FFP transfusion strategies are warranted.

Modified score for disseminated intravascular coagulation in the critically ill.

OBJECTIVE: To assess the value of the diagnosis of overt disseminated intravascular coagulation (DIC) according to the International Society on Thrombosis and Haemostasis (ISTH) criteria and that of the parameters included in the ISTH score for overt DIC in predicting day 28 mortality in intensive care patients. Also, to assess the value of the components of the score in the diagnosis of overt DIC. DESIGN AND SETTING: Retrospective clinical study in a university hospital intensive care unit. PATIENTS AND PARTICIPANTS: 494 consecutive patients admitted in the ICU between January 2002 and October 2003. MEASUREMENTS AND RESULTS: Clinical and laboratory data, including hemostatic parameters, were collected from computerized databases and patient files. Altogether 19% (95/494) of the patients fulfilled the criteria for overt DIC. Their day 28 mortality rate was higher than that of patients without overt DIC (40% vs. 16%). The lowest platelet count (area under curve, AUC, 0.910), highest plasma D-dimer (AUC 0.846), lowest antithrombin (AUC 0.823), and Owren-type prothrombin time activity (AUC 0.797) discriminated well the patients with and without overt DIC, whereas plasma fibrinogen (AUC 0.690) had poor discriminative power. No patient with the diagnosis of overt DIC had decreased plasma fibrinogen. Day-1 SOFA and APACHE II score, the first CRP measurement, and the lowest antithrombin were independent predictors of day 28 mortality. CONCLUSIONS: The diagnosis of overt DIC was not an independent predictor of day 28 mortality. In ICU patients plasma antithrombin seems a promising candidate in the panel of indicators for overt DIC whereas the value of plasma fibrinogen is in doubt.

Evaluation of new Japanese diagnostic criteria for disseminated intravascular coagulation in critically ill patients.

New Japanese diagnostic criteria were prepared for disseminated intravascular coagulation (DIC) in critically ill patients and their usefulness was compared with the criteria of the International Society of Thrombosis and Haemostasis (ISTH) and those of the Japan Ministry of Health and Welfare (JMHW). In a retrospective study of patients with platelet counts of less than 150 x10(3)/mL, 52 cases (33.3%), 66 cases (42.3%), and 101 cases (64.7%) were diagnosed as DIC by the ISTH, JMHW, and new Japanese DIC criteria, respectively. The DIC state as diagnosed by the new Japanese DIC criteria included both DIC states as diagnosed by ISTH or JMHW criteria. Some DIC states diagnosed by the JMHW criteria included those diagnosed by ISHT criteria but this was not universal. The mortality of DIC as diagnosed by the ISTH or JMHW criteria was markedly high, compared to that for DIC diagnosed by the new Japanese criteria. The mortality of patients without DIC by ISTH was also high when they were diagnosed as DIC by the new Japanese criteria. The frequency of DIC by each set of diagnostic criteria was significantly higher in patients with infection than in those without infection. The mortality of DIC by each set of diagnostic criteria was significantly higher in patients with infection than in those without infection, and the mortality of overt-DIC by ISTH diagnostic criteria was also high in patients without infection.