Net reclassification index in comparison of prognostic value of disseminated intravascular coagulation diagnostic criteria by Japanese Society on Thrombosis and Hemostasis and International Society on Thrombosis and Haemostasis: a multicenter prospective cohort study.

BACKGROUND: We compared the prognostic value of the Japanese Society on Thrombosis and Hemostasis (JSTH) disseminated intravascular coagulation (DIC) diagnostic criteria with that of the International Society on Thrombosis and Haemostasis (ISTH) DIC diagnostic criteria for 28-day in-hospital mortality. METHODS: We conducted a multicenter prospective cohort study involving two hematology departments, four emergency departments, and one general medicine department in Japan between August 2017 and July 2021. We assessed three ISTH DIC diagnostic criteria categories using low cutoff levels of D-dimer (low D-dimer), high cutoff levels of D-dimer (high D-dimer), and fibrinogen/fibrin degradation products (FDP) as fibrin-related markers. The main outcome was diagnosis-based category additive net reclassification index (NRI). RESULTS: A total of 222 patients were included: 82 with hematopoietic disorders, 86 with infections, and 54 with other diseases. The 28-day in-hospital mortality rate was 14% (n = 31). The DIC rates diagnosed by the JSTH, ISTH-low D-dimer, high D-dimer, and FDP DIC diagnosis were 52.7%, 47.3%, 42.8%, and 27.0%, respectively. The overall category additive NRI by JSTH DIC diagnosis vs. ISTH-low D-dimer, high D-dimer, and FDP DIC diagnosis were - 10 (95% confidence interval [CI]: -28 to 8, p = 0.282), - 7.8 (95% CI: -26 to 10, p = 0.401), and - 11 (95% CI: -26 to 3, p = 0.131), respectively. CONCLUSIONS: JSTH criterion showed the highest sensitivity for DIC diagnosis that did not improve but reflected the same prognostic value for mortality evaluated using ISTH DIC diagnosis criteria. This finding may help clinicians to use JSTH DIC criterion as an early intervention strategy in patients with coagulopathy.

Prognostic value of serum high mobility group box 1 protein and histone H3 levels in patients with disseminated intravascular coagulation: a multicenter prospective cohort study.

BACKGROUND: We compared the prognostic value of serum high mobility group box 1 protein (HMGB1) and histone H3 levels with the International Society on Thrombosis and Haemostasis (ISTH) disseminated intravascular coagulation (DIC) scores for 28-day in-hospital mortality in patients with DIC caused by various underlying diseases. METHODS: We conducted a multicenter prospective cohort study including two hematology departments, four emergency departments, and one general medicine department in Japan, between August 2017 and July 2021. We included patients diagnosed with DIC by the ISTH DIC scoring system. RESULTS: Overall, 104 patients were included: 50 with hematopoietic disorders, 41 with infections, and 13 with the other diseases. The 28-day in-hospital mortality rate was 21%. The receiver operator characteristic (ROC) curve showed that a DIC score of 6 points, serum HMGB1 level of 8 ng/mL, and serum histone H3 level of 2 ng/mL were the optimal cutoff points. The odds ratios of more than these optimal cutoff points of the DIC score, serum HMGB1, and histone H3 levels were 1.58 (95% confidence interval [CI]: 0.60 to 4.17, p = 0.36), 5.47 (95% CI: 1.70 to 17.6, p = 0.004), and 9.07 (95% CI: 2.00 to 41.3, p = 0.004), respectively. The area under the ROC curve of HMGB1 (0.74, 95% CI: 0.63 to 0.85) was better than that of the ISTH DIC scores (0.55, 95% CI: 0.43 to 0.67, p = 0.03), whereas that of histone H3 was not (0.71, 95% CI: 0.60 to 0.82, p = 0.07). Calibration and net reclassification plots of HMGB1 identified some high-risk patients, whereas the ISTH DIC scores and histone H3 did not. The category-free net reclassification improvement of HMGB1 was 0.45 (95% CI: 0.01 to 0.90, p = 0.04) and that of histone H3 was 0.37 (95% CI: - 0.05 to 0.78, p = 0.08). CONCLUSIONS: Serum HMGB1 levels have a prognostic value for mortality in patients with DIC. This finding may help physicians develop treatment strategies.

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.

Severe Antithrombin Deficiency May be Associated With a High Risk of Pathological Progression of DIC With Suppressed Fibrinolysis.

The frequency of severe antithrombin deficiency (SAD) was examined in the hematopoietic disorder-, infectious-, and basic-types of the disseminated intravascular coagulation (DIC). A posthoc analysis of 3008 DIC patients (infectious-type, 1794; hematological disorder-type, 813; and basic-type, 401) from post-marketing surveillance data of thrombomodulin alfa was performed. The clinical features of patients and outcomes were compared between patients with and without SAD, using an antithrombin cutoff value of 50%. Patients with SAD accounted for 40.4% of infectious-type DIC, 8.0% of hematopoietic disorder-type DIC, and 26.7% of basic-type DIC. There was no significant difference in thrombin-antithrombin complex levels between patients with and without SAD. The decreased fibrinogen level and differences in clinical features were significantly greater but the increases in fibrinolytic markers were significantly lower in patients with SAD than in those without. The 28-day survival rate was significantly lower in patients with SAD than in those without. Severe antithrombin deficiency was observed in all types of DIC, including hematopoietic disorders. Both hypofibrinolysis and hypercoagulability in patients with SAD may cause multiple organ failure and poor outcomes.

Analysis of the association between resolution of disseminated intravascular coagulation (DIC) and treatment outcomes in post-marketing surveillance of thrombomodulin alpha for DIC with infectious disease and with hematological malignancy by organ failure.

BACKGROUND: Although disseminated intravascular coagulation (DIC) is life-threatening, any organ failure associated with DIC resolution and outcomes have been unclear. PATIENTS AND METHODS: A total of 2795 DIC patients (infection: 1990, hematological malignancy: 805) were analyzed in the post-marketing surveillance of thrombomodulin alpha (TM-α). The background factors of sequential organ failure assessment (SOFA) and antithrombin (AT) were investigated in DIC with infectious disease for their association with DIC resolution and outcome using κ statistics, indicating DIC resolution and survival or DIC non-resolution and non-survival. The same analyses were performed for total bilirubin, creatinine, lactate dehydrogenase, and underlying disease in DIC with hematological malignancy. RESULTS: In DIC with infectious disease, higher SOFA score severity was closely correlated with lower overall survival in both the DIC resolution and non-resolution groups, but AT activity was not. κ coefficients were 0.234, 0.295, and 0.311 for the SOFA score 0-6, 7-12, and 13-24 groups, respectively. In DIC with hematological malignancy, κ coefficients of total bilirubin were 0.251 and 0.434, and those of creatinine were 0.283 and 0.437 in the normal and abnormal groups, respectively, showing better concordance in the abnormal group than in the normal. Other factors had poor concordance. CONCLUSION: In DIC with infectious disease, DIC resolution is an important therapeutic target in patients who have higher SOFA score severity. In DIC with hematological malignancy, DIC resolution is similarly important in patients with abnormality of bilirubin and/or creatinine. TRIAL REGISTRATION: The clinical characteristics and treatment outcomes of patients with DIC treated with TM-α between May 2008 and April 2010 were retrospectively analyzed by subgroup analysis of the post-marketing surveillance data.

Evaluation of the Diagnostic Criteria for the Basic Type of DIC Established by the Japanese Society of Thrombosis and Hemostasis.

We evaluated the diagnostic criteria for disseminated intravascular coagulation (DIC), which was published by the Japanese Society of Thrombosis and Hemostasis (JSTH), in 232 patients with suspected DIC without hematopoietic injury or infection. The diagnoses of the patients were as follows: DIC (n = 116), pre-DIC (n = 54), and non-DIC (n = 63). The efficacy of the diagnostic criteria for DIC was evaluated using a receiver operating characteristic analysis. The area under the curve and odds ratio for the global coagulation test (GCT) scores in the diagnosis of "DIC" were high, whereas those for the diagnosis of "DIC and pre-DIC" were low, suggesting that the addition of a reduced platelet count (RPC), antithrombin (AT), and soluble fibrin (SF)/thrombin AT (TAT) complex was required to diagnose DIC and pre-DIC. When the GCT score with the RPC, AT, and TAT/SF values was used, the cutoff DIC score for the diagnosis of DIC or DIC and pre-DIC was 6 points. For predicting the outcome, a scoring system that used the GCT result was useful, but the addition of RPC, AT, or SF/TAT was not. The modified diagnostic criteria of JSTH, which included the GCT score and the RPC, AT, and TAT/SF values, were useful for diagnosing both DIC and pre-DIC.

Proposal for new diagnostic criteria for DIC from the Japanese Society on Thrombosis and Hemostasis.

Disseminated intravascular coagulation (DIC) is a serious disease that, in the presence of underlying disease, causes persistent, generalized, marked coagulation activation. Early treatment based on an appropriate diagnosis is very important for improving patients' prognosis, to which end diagnostic criteria play a key role. Several criteria have been proposed, but each has its strengths and weaknesses, and improved criteria are needed. Widespread use of coagulofibrinolytic markers has elucidated that the pathology of DIC differs greatly as a function of the underlying disease. Thus, discriminating use of DIC diagnostic criteria that take underlying diseases into account is important. DIC diagnostic criteria that are well known in Japan include the Japanese Ministry of Health and Welfare's old DIC diagnostic criteria (JMHW criteria), the International Society on Thrombosis and Haemostasis's DIC diagnostic criteria (ISTH criteria), and the Japanese Association for Acute Medicine's acute-stage DIC diagnostic criteria (JAAM criteria). Those criteria have their respective drawbacks: the sensitivity of the ISTH criteria is poor, the JAAM criteria cannot be applied to all underlying diseases, and the JMHW criteria have poor sensitivity in the case of infections, do not use molecular markers, and result in misdiagnosis. The Japanese Society on Thrombosis and Hemostasis's newly proposed provisional draft DIC diagnostic criteria (new criteria) use diagnostic criteria classifications of "hematopoietic disorder type", "infectious type", and "basic type" based on the underlying pathology. For the hematopoietic disorder type the platelet count is omitted from the score, while for the infectious type, fibrinogen is omitted from the score. Also, points are added if the platelet count decreases with time. In the new criteria, molecular markers and antithrombin activity have been newly included, and as a countermeasure for misdiagnosis, 3 points are deducted if there is liver failure. In this paper, we discuss various problems encountered with DIC diagnosis, and we describe the new criteria together with the events that led to their creation. These new diagnostic criteria take into account the underlying diseases of wide area, and we expect that they will serve clinicians well due to the above adaptations and improvements.

Increased ratio of soluble fibrin formation/thrombin generation in patients with DIC.

The generation of thrombin-antithromin (AT) complex (TAT) or soluble fibrin (SF) was prospectively compared with prothrombin fragment 1 + 2 (F1 + 2) generation in patients with disseminated intravascular coagulation (DIC). The plasma levels of TAT, SF, and F1 + 2 were significantly higher in the DIC group than in the non-DIC group. The differences in these levels between the DIC group and non-DIC group were significantly related to infections and hematopoietic tumors. There were no significant differences in the TAT/F1 + 2 ratio between DIC and non-DIC patients, but the SF/F1 + 2 ratio was significantly higher in the DIC group than the non-DIC group. The plasma AT activity was significantly higher in patients with DIC with resolution than in those without resolution, and in survivors than in nonsurvivors. These findings suggest that the ratio of TAT/thrombin is constant between the patients with and without DIC but that the ratio of fibrin formation/thrombin might increase in DIC.

Prospective evaluation of hemostatic abnormalities in overt DIC due to various underlying diseases.

Patients with suspected disseminated intravascular coagulation (DIC) were prospectively evaluated for various types of underlying diseases, and the usefulness of hemostatic markers were examined for each patient with DIC due to various underlying diseases. The main underlying disease of DIC was infectious diseases, hematologic malignancies, and solid tumors, and a high resolution rate from DIC was observed in obstetric diseases and hematologic malignancies. The diagnosis of DIC was related to a poor outcome in trauma/burn victims and those with infectious disease. In the main underlying disease, it is suggested that DIC would be excluded in patients with hematologic malignancies or solid tumors with a platelet count of more than 100,000/µl and in the patients with an FDP of less than 10 µg/ml, and fibrinogen of less than 100mg/dl, suggesting the presence of DIC. The prothrombin time was a sensitive marker, but fibrinogen levels were not sensitive for DIC due to infectious diseases. The plasmin plasmin inhibitor complex in hematologic malignancy, and soluble fibrin monomer complex, antithrombin and thrombomodulin in patients with infectious disease, were sensitive markers for the diagnosis of DIC. Although hemostatic markers were useful for the diagnosis of DIC, the usefulness varied depending on the different underlying diseases.

Primary cutaneous CD5+ marginal zone B-cell lymphoma resembling the plasma cell variant of Castleman's disease. Case report.

Marginal zone B-cell lymphoma (MZBL) is occasionally associated with prominent plasma cell differentiation. However, MZBL rarely exhibits histological features that resemble plasmacytoma arising from a localized plasma cell variant of Castleman's disease (PCCD). We here report a histologically similar case that was associated with primary cutaneous tumor. The patient was a 57-year-old woman with a 5-year history of cutaneous nodules. Histologically, a prominent proliferation of plasma cells occupied the interfollicular area of the central portion of the cutaneous tumor, whereas various numbers of CD5+ centrocyte-like (CCL) cells, which were arranged in a marginal zone distribution pattern, occupied the peripheral region of the tumor. The majority of the lymphoid follicles had atrophic or regressive germinal centers resembling hyaline-vascular Castleman's disease. CCL cells were observed to have colonized a few of the lymphoid follicles. Immunohistochemistry revealed that these cells had a monotypic intracytoplasmic kappa chain. Without treatment, the patient was quiescent, but 2 years later, there was a transformation to the large cell type. These observations suggest that MZBL needs to be distinguished from PCCD, and that untreated cutaneous MZBL may undergo a high-grade blastic transformation similar to other indolent lymphoproliferative disorders.