Yoshinobu Seki

Expert consensus for the treatment of disseminated intravascular coagulation in Japan

The present report from The Japanese Society of Thrombosis and Hemostasis provides an expert consensus for the treatment of disseminated intravascular coagulation (DIC) in Japan. Disseminated intravascular coagulation (DIC) may be classified as follows: asymptomatic type, marked bleeding type, and organ failure type. Although treatment of DIC is important, adequate treatment differs according to type of DIC. In asymptomatic DIC, low molecular weight heparin (LMWH), synthetic protease inhibitor (SPI), and antithrombin (AT) are recommended, although these drugs have not yet been proved to have a high degree of effectiveness. Unfractionated heparin (UFH) and danaparoid sodium (DS) are sometimes administrated in this type, but their usefulness is not clear. In the marked bleeding type, LMWH, SPI, and AT are recommended although these drugs do not have high quality of evidence. LMWH, UFH, and DS are not recommended in case of life threatening bleeding. In case of severe bleeding, SPI is recommended since it does not cause a worsening of bleeding. Blood transfusions, such as fresh frozen plasma and platelet concentrate, are also required in cases of life threatening bleeding. In the organ failure type, including sepsis, AT has been recommended based on the findings of several clinical trials. DIC is frequently associated with thrombosis and may thus require strong anticoagulant therapy, such as LMWH, UFH, and DS.

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.

Modified non‐overt DIC diagnostic criteria predict the early phase of overt‐DIC

Diagnostic criteria for non‐overt disseminated intravascular coagulation (DIC) have been proposed by the International Society of Thrombosis and Hemostasis, but are not useful for the diagnosis of early phase of overt‐DIC (pre‐DIC). Therefore, in the current study the non‐overt DIC diagnostic criteria were modified using the global coagulation tests, the change rate in the global coagulation tests and molecular hemostatic markers to detect the pre‐DIC state and were prospectively evaluated in 613 patients with underlying DIC disease. The frequencies of patients with DIC (DIC positive), late onset DIC, and without DIC (DIC absent) were 29.5%, 7.2%, and 63.3%, respectively. The modified non‐overt‐DIC criteria can correctly predict 43/44 patients (97.7%) who were DIC absent at admission and became DIC positive, within a week (late onset DIC state). The mortality rate was higher in DIC positive compared with pre‐DIC (37.6% vs. 22.7%, P < 0.05) or DIC negative (37.6 vs. 13.7%, P < 0.01). It was also significantly higher in pre‐DIC compared with DIC negative (P < 0.05). Thus, these modified non‐overt DIC diagnostic criteria might therefore be useful for the diagnosis of early‐phase DIC.

Successful All-trans Retinoic Acid Treatment of Acute Promyelocytic Leukemia in a Patient with NPM/RAR Fusion

Acute promyelocytic leukemia (APL) is characterized by a reciprocal chromosomal translocation involving the gene for retinoic acid receptor α (RAR). Most APL patients have a t(15;17) translocation that generates the PML-RAR fusion gene, and such patients respond well to treatment with all-trans retinoic acid (ATRA). Some APL cases also involve rearrangements that fuse RAR to partner genes other than PML, including nucleophosmin (NPM), promyelocytic leukemia zinc finger (PLZF), nuclear mitotic apparatus (NUMA), and Stat5b, but the clinical characteristics of APL without PML-RAR have not been fully clarified. We describe a 64-year-old man with NPM-RAR—positive APL who was receiving hemodialysis therapy for chronic uremia. Complete remission was achieved with ATRA monotherapy and was maintained for 18 months with consolidation chemotherapy. These findings suggest that ATRA can be used to treat APL patients with NPM/RAR as well as APL with PML/RAR.

Addition of recommendations for the use of recombinant human thrombomodulin to the “Expert consensus for the treatment of disseminated intravascular coagulation in Japan”

When we published the “Expert consensus for the treatment of disseminated intravascular coagulation in Japan” [1], recombinant human thrombomodulin (rhTM) had not beenmarketed; therefore, recommendations regarding the use of rhTMwere not stated at that time. A phase III trial of rhTM [2] subsequently showed the usefulness of this agent in treating disseminated intravascular coagulation (DIC), and the results of the postmarketing surveillance of rhTM guided by the Japanese Society on Thrombosis and Hemostasis (JSTH) confirmed the results of that trial [3]. In addition, the results of a phase II international trial of rhTM in patients with sepsis were also recently published [4]. Therefore, the JSTH would like to add a recommendation for the use of rhTM in the “Expert consensus for the treatment of disseminated intravascular coagulation in Japan.”

Clinical value of assessing the response to imatinib monitored by interphase FISH and RQ-PCR for BCR-ABL in peripheral blood for long-term survival of chronic phase CML patients: results of the Niigata CML-multi-institutional co-operative clinical study

This retrospective analysis investigated the prognostic value of monitoring the response to imatinib using peripheral blood (PB) samples and the impact of the response on outcome in 133 patients with chronic myeloid leukemia (CML). We divided the response into 3 categories according to the results of neutrophil (N)-FISH and BCR-ABL transcript levels in PB; more than a 3-log reduction [major molecular response (MMR)], between a 2-log and 3-log reduction or negative with N-FISH [complete cytogenetic response equivalent (CCyRe)], N-FISH positive or less than a 2-log reduction (non-CCyRe). The median follow-up was 5.46 years. At 5 years, the overall survival (OS) rate and progression-free survival (PFS) rate were 94.4 and 92.0%, respectively. The estimated rate of the CCyRe and MMR were 81.7 and 67.1%, respectively. 106 patients achieving the CCyRe had significantly better OS and PFS than 27 patients without achieving the CCyRe. Patients with MMR had significantly better survival free from death, progression, imatinib withdrawal and a loss of the CCyRe, than patients whose response level remained in the CCyRe without achieving MMR until 18 months. Our observation suggests that the response level of the CCyRe on PB serve as a prognostic indicator, and achieving MMR provides stable long-term survival.

Analysis of the Cutoff Values in Fibrin-Related Markers for the Diagnosis of Overt DIC

Fibrin-related markers (FRMs) such as fibrin and fibrinogen degradation products (FDPs), d-dimer, and soluble fibrin monomer complex (SFMC) were prospectively evaluated in 522 patients using the overt disseminated intravascular coagulation (DIC) diagnostic criteria. The differences in all FRMs between the DIC group and the non-DIC group, and those between the survivors and nonsurvivors were significant in the patients with infections. In an analysis of all patients, DIC score cutoff values of 2 and 3 points for FDP, d-dimer, and SFMC were recommended to be 8.3 and 42.0 μg/mL, 2.4 and 22.0 μg/mL, and 3.4 and 138.0 μg/mL, respectively. In conclusion, the adequate cutoff value is thus considered to be useful for both making a diagnosis of DIC and for predicting the outcome. Fibrin-related markers are therefore thought to be more useful for making a diagnosis of DIC based on infections than based on any other underlying disorders.

Plasma Urokinase-Type Plasminogen Activator in Patients with Leukemias

Plasma levels of urokinase-type plasminogen activator (u-PA) were measured with an enzyme-linked immunosorbent assay in patients with leukemias. As compared with healthy subjects (0.73 +/- SD 0.17 ng/ml), plasma u-PA antigen level was markedly elevated in patients with acute promyelocytic leukemia (APL) (1.76 +/- 0.89 ng/ml) at disease onset. Mean u-PA concentrations in patients with other acute nonlymphoblastic leukemia (0.57 +/- 0.51 ng/ml), acute lymphoblastic leukemia (0.77 +/- 0.82 ng/ml) and chronic myelocytic leukemia in blastic crisis (1.30 +/- 1.35 ng/ml) were not significantly elevated, but some of them showed an elevation of plasma u-PA. Plasma u-PA values were correlated with some of the fibrinolytic parameters such as FDP and D-dimer. Plasma u-PA antigen was decreased after the administration of antileukemic drugs in patients with APL. These results suggest that the coagulopathy in patients with various leukemias may in part be associated with u-PA release from the leukemic cells, especially in patients with APL.

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.

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.