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The contribution of the tumour necrosis factor (TNF) B+ 252 (TNFB) dimorphism and microsatellite polymorphisms of TNFa and TNFb to the pathogenesis of systemic lupus erythematosus (SLE) was studied in Japanese patients. The TNFB dimorphism was determined using the restriction fragment length polymorphism (RFLP) method withNcoI digestion followed by specific polymerase chain reaction (PCR) amplification. TNFa and TNFb microsatellite polymorphisms were determined using the DNA sequencer and GeneScan program (Applera Corporation, Foster City, CA) followed by specific PCR amplification. HLA-DRB1*15 typing was carried out by the PCR-sequence specific conformational polymorphism (SSCP) method. In SLE, the allele frequency of TNFB*2 significantly increased (68.9%,P < 0.05) and the genotype frequency of TNFB*2/2 also increased (52.8%,P < 0.05). TNFB*2 showed no significant linkage disequilibrium with HLA-DRB1*1501. The prevalence of TNFa13 and TNFb4 showed very slight increases, but these increases were not significant. An association analysis indicated that TNFB*2/2 conferred greater, or at least equal, susceptibility to SLE in Japanese patients in comparison with HLA-DRB1*1501. The TNFB*2/2 genotype may contribute additively with DRB1*1501 to SLE in Japanese patients. No association was observed between auto-antibodies and TNF. TNFB*2 is a genetic marker for SLE in Japanese patients, while TNFa and TNFb microsatellites are not associated with SLE. [ABSTRACT FROM AUTHOR]

SUMMARY We conducted this study to determine whether antiprothrombin antibody (aPT) [to prothrombin (PT) alone or PT/phosphatidyl serine (PS) complex] actually existed in patients with lupus anticoagulant (LA) and/or anticardiolipin antibody (aCL). aPT to PT alone was positive in 2/7 LA-positive (29%) and 3/7 LA/aCL-positive (43%) patients. aPT to PT/PS complex was positive in 4/7 LA-positive (57%) and 4/7 LA/aCL-positive (57%) patients in the presence of Ca2+. However, none of the aCL-positive patients without LA or the LA/aCL-negative patients were positive for aPT and aPT/PS. Thus, we confirmed the existence of aPT and aPT/PS specifically among LA-positive patients. However, the clinicopathological significance of aPT and aPT/PS in this clinical setting is yet to be clarified. [ABSTRACT FROM PUBLISHER]

Background: The incidence of venous thromboembolism (VTE; pulmonary embolism [PE] and/or deep vein thrombosis [DVT]) in Japan is increasing, but relatively small numbers of patients from Japan have been included in studies investigating rivaroxaban (a direct factor Xa inhibitor) for the treatment of VTE and preventing its recurrence., Methods and results: An open-label, prospective, observational study (XASSENT [NCT02558465]) investigated the safety profile and effectiveness of rivaroxaban for ≤2 years in the treatment of VTE and prevention of its recurrence in Japanese clinical practice. Primary outcomes were major bleeding and symptomatic recurrent VTE. Statistical analyses were exploratory and descriptive. Overall, 2,540 patients were enrolled (safety analysis population [SAP], n=2,387; effectiveness analysis population [EAP], n=2,386). In the SAP, >80% of patients received the approved rivaroxaban dose, the mean (standard deviation) age was 66.6 (15.0) years, ≈74% were >50 kg, and 43% had a creatinine clearance ≥80 mL/min. PE+DVT, PE only, and DVT only were reported in 42%, 8%, and 50% of patients, respectively, and active cancer in 17% of patients. Major bleeding was reported in 69 patients (2.89%; 3.60%/patient-year; SAP) and symptomatic PE/DVT recurrence in 26 patients (1.09%; 1.36%/patient-year; EAP) during the treatment period., Conclusions: XASSENT provided information on the expected proportions of bleeding and VTE recurrence during rivaroxaban treatment in Japanese clinical practice; no new concerns of safety or effectiveness were found.

Background  Disseminated intravascular coagulation (DIC) is not a homogeneous condition, but rather includes heterogeneous conditions, and its pathophysiology and outcome vary considerably depending on the background. Although anticoagulant therapy is expected to be of benefit in the treatment of DIC, previous studies have suggested that the benefits are limited only to a specific subtype. Objects  The purpose of this study was to identify the group that would benefit from combination therapy using thrombomodulin/antithrombin. Methods  The data from 2,839 patients registered in the postmarketing surveillance of thrombomodulin were evaluated. The patients were divided into four groups depending on antithrombin and fibrinogen levels, and the additive effects of antithrombin on thrombomodulin were examined in the groups. Results  The DIC score, Sequential Organ Failure Assessment score, and mortality were significantly higher in the DIC group with low-antithrombin/low-fibrinogen than in the DIC groups without either low antithrombin or low fibrinogen. The survival curve was significantly higher in DIC patients with combination therapy than in patients treated with thrombomodulin monotherapy, but this effect was seen only in patients with infection-based DIC. Conclusion  DIC patients with low-antithrombin/low-fibrinogen risk poor outcomes, but they can be the target of combination therapy with antithrombin and thrombomodulin as long as the DIC is due to infection., Competing Interests: Conflict of Interest T.U., S.M., N.T., K.S., Y.S., and K.O. received personal fees from Asahi Kasei Pharma Corporation outside the present work. H.W. received grants and personal fees from Asahi Kasei Pharma Corporation and the Japan Blood Products Organization outside the present work. K.K. and T.I. received grants and personal fees from Asahi Kasei Pharma Corporation outside the present work. T.I. received personal fees from Asahi Kasei Pharma Corporation and received research grants from Japan Blood Products Organization and Japan Immunoresearch Laboratories outside the present work. G.H. is an employee of Asahi Kasei Pharma Corporation. N.K. did not receive any grants or personal fees., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. ( https://creativecommons.org/licenses/by/4.0/ ).)

Introduction: A criterion for disseminated intravascular coagulation (DIC) that reflects the status of controlled coagulopathy would be useful for determining when to stop treatment. Use of the DIC criteria of the Japanese Society on Thrombosis and Hemostasis (JSTH) for predicting the outcome during recombinant soluble thrombomodulin (thrombomodulin alfa, TM-α) treatment was evaluated., Methods: A retrospective, multicenter survey was conducted in 798 medical facilities in Japan. Of the 4342 patients who underwent TM-α treatment, 193 with infection-associated DIC were investigated., Results: The 28-day mortality rate increased with the increase in JSTH DIC scores at the end of TM-α treatment, with a Cramer's coefficient of association of 0.431. A reduced platelet count (odds ratio [OR]: 0.847, P < .001), prolonged prothrombin time ratio (OR: 5.681, P < .001), decreased fibrinogen level (OR: 0.995, P < .001), higher level of fibrinogen and fibrin degradation products (OR: 1.009, P = .026), and lower antithrombin activity (OR: 0.973, P < .001) were correlated with 28-day mortality. On multivariate analysis, the JSTH DIC score at the completion of TM-α therapy was a predictor of mortality (OR: 1.591, 95% CI: 1.219-2.077)., Conclusion: The JSTH DIC score at the end of anticoagulation therapy may be a reliable tool for predicting the outcome in patients with infection-associated DIC., (© 2021 John Wiley & Sons Ltd.)

Background  The efficacy and safety of rivaroxaban have been demonstrated in phase 3 trials of patients with venous thromboembolism (VTE; pulmonary embolism [PE] and deep vein thrombosis [DVT]). Data regarding rivaroxaban treatment of VTE in routine Japanese clinical practice remain limited. Objectives  XASSENT will evaluate rivaroxaban treatment of VTE in real-world Japanese clinical practice. We report the study design and baseline patient characteristics. Methods  XASSENT (NCT02558465) is an open-label, prospective observational, post-marketing surveillance cohort study in patients receiving rivaroxaban treatment for VTE. Enrolment took place between November 2015 and March 2018. XASSENT will follow patients for up to 2 years. Primary outcome variables: major bleeding and symptomatic recurrent VTE. Statistical analyses are exploratory and descriptive. Results  Baseline patient characteristics at June 2020 ( n  = 2,299) are presented (58.2% female; mean age 66.7 years; mean weight 60.9 kg). The population encompasses patients with wide-ranging characteristics including older age, low weight, and renal dysfunction. Most participants (67.6%) had a history of VTE risk factors at baseline. Half of the population (50.4%) had DVT only; 41.4% had DVT with PE; 8.2% had PE only. Overall, 68.4% were inpatients and 77.1% had symptomatic VTE. Rivaroxaban was prescribed for initial treatment in 84.6% of patients and maintenance treatment in 15.4%. Most were prescribed the approved dose of rivaroxaban for initial (30 mg daily; 84.4%) or maintenance (15 mg daily; 81.9%) treatment of VTE in Japan. The most common reason for selecting non-recommended dose was 'elderly'. Conclusions  Results from XASSENT will complement phase 3 trial data and inform clinical practice., Competing Interests: Conflict of Interest IF has received payment or honoraria from Bayer Yahukin Ltd., Daiichi Sankyo Co. Ltd. and Pfizer. AH has received grants or contracts from Boston Scientific Japan K.K., Fukuda Denshi Co., Ltd., St. Jude Medical Co., Ltd., Medtronic Japan Co., Ltd. and Japan Lifeline Co., Ltd, and payment or honoraria from TOA EIYO Ltd., Nippon Boehringer Ingelheim Co., Ltd., Amgen Astellas BioPharma K.K., Sanofi K.K., Astellas Pharma Inc., Sumitomo Dainippon Pharma Co., Ltd., Bristol-Myers Squibb K.K., AstraZeneca K.K., Daiichi Sankyo Co., Ltd., Bayer Yakuhin, Ltd. KK has received payment or honoraria from Bayer Yahukin Ltd. MN has received payment or honoraria from Daiichi Sankyo Co., Ltd.. NY has received payment or honoraria from Bayer Yakuhin, Ltd., Pfizer Japan Inc., Daiichi Sankyo Co., Ltd. TK, HM and NN have no conflict of interest. TT, SI, YO, TS, KH and TH are employees of Bayer Yakuhin, Ltd., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. ( https://creativecommons.org/licenses/by/4.0/ ).)

Thromboembolic events remain clinically unresolved after transcatheter aortic valve implantation (TAVI). The use of direct oral anticoagulant (DOAC) to reduce thrombosis associated with TAVI remains controversial. This study aimed at investigating the periprocedural change in blood coagulation and thrombolysis parameters in 199 patients undergoing transfemoral TAVI. Prothrombin activation fragment 1 + 2 (F1 + 2), thrombin-antithrombin complex (TAT), soluble fibrin monomer complex (SFMC), and fibrin/fibrinogen degradation product (FDP) levels were measured before and 1 hour after TAVI and 1, 2, and 7 days postoperatively. Of the 199 patients, 49 were treated with DOAC (apixaban in 32, edoxaban in 10, and rivaroxaban in 7). The F1 + 2 and TAT levels immediately increased 1 hour after TAVI and then gradually decreased in both groups. The SFMC level also significantly increased with a peak on day 1. The FDP level gradually increased, peaking on day 2. The values of F1 + 2, TAT, SFMC, and FDP in patients who used DOAC were significantly lower than those who did not use DOAC at 1 hour after TAVI in F1 + 2 (600 [452 to 765] vs 1055 [812 to 1340] pmol/L; p < 0.001), TAT (21.4 [16.2 to 37.0] vs 38.7 [26.4 to 58.7] μg/mL; p < 0.001) and on day 1 in SFMC (18.2 [9.4 to 57.9] vs 113.4 [70.9 to 157.3] μg/mL; p < 0.001) and day 2 in FDP (6.0 [4.7 to 10.0] vs 12.6 [8.2 to 17.4] μg/mL; p < 0.001). Ischemic stroke within 30 days after TAVI occurred in 3 patients (1.5%), who were not treated with DOAC. Coagulation cascade activation was observed after TAVI. DOAC could reduce transient hypercoagulation following TAVI., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: In patients with infectious diseases, disseminated intravascular coagulation (DIC) is often diagnosed without the fibrinogen value. The relationship between hypofibrinogenemia and outcomes of DIC in infectious diseases has thus remained unclear., Methods: We analyzed 3204 patients who received with thrombomodulin alfa (TM-α) for DIC and suspected DIC. Hypofibrinogenemia was defined by a fibrinogen level < 1.5 g/L., Results: Hypofibrinogenemia was observed in 10.3% of patients with infectious diseases. The frequencies of both bleeding and organ failure symptoms, and the scores for organ failure or the DIC diagnostic criteria were significantly higher in infectious disease patients with hypofibrinogenemia, suggesting that in patients with infectious diseases, hypofibrinogenemia is associated with more progressive and severe DIC. Although the 28-day survival rate and the DIC resolution rate were both significantly lower for infectious disease patients with DIC with hypofibrinogenemia than for those without hypofibrinogenemia, this difference was not observed in DIC patients with hematological diseases., Conclusions: Hypofibrinogenemia among infectious disease patients with DIC may reflect increased consumption of fibrinogen due to accelerated coagulation reactions, while hypofibrinogenemia among hematological disease patients with DIC may be caused by fibrinogenolysis due to hyperfibrinolysis, and frequently results in bleeding and multiple-organ failure.

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.

Factor XII (FXII) deficiency is a rare coagulation disorder, and its potential relationship with venous thrombosis was reported. Here we present a case of a 67-year-old woman with FXII deficiency who successfully underwent endovenous thermal ablation (ETA) for primary varicose vein due to the incompetent great saphenous vein (GSV). The FXII deficiency was revealed through preoperative examinations, and the patient underwent ETA as a day surgery. For prophylaxis of thrombosis, she received compression therapy alone. Her postoperative course was uneventful, without any kind of thrombosis. In the presence of FXII deficiency, ETA could be safely performed., Competing Interests: Disclosure StatementAll authors declare that there is no conflict of interest., (© 2020 The Editorial Committee of Annals of Vascular Diseases.)

Background: The frequency and predictors of thrombocytopenia after transcatheter aortic valve implantation (TAVI) are unclear., Methods and results: This study enrolled 342 patients undergoing TAVI (245 with a percutaneous transfemoral approach, 65 with transfemoral surgical cutdown, and 32 with a non-transfemoral approach). Balloon-expandable and self-expanding valves were implanted in 235 and 107 patients, respectively. Platelet counts started to drop immediately, reaching a nadir 2-4 days after TAVI. Clinically significant thrombocytopenia (CSTP) was defined as a platelet count ≤50×10 9 /L at the time of the nadir or both a platelet count between 80 and 51×10 9 /L and a decrease in platelet count ≥50%. CSTP occurred in 16.7% patients. Approach site and TAVI valve selection significantly predicted CSTP. In multivariate analysis, independent predictors of CSTP were liver cirrhosis (odds ratio [OR] 7.22; 95% confidence interval [CI] 1.05-49.82), baseline platelet count ≤120×10 9 /L (OR 2.98; 95% CI 1.20-7.38), multiple blood transfusions (OR 4.03; 95% CI 1.72-9.41), and the use of balloon-expandable valves (OR 2.38; 95% CI 1.04-5.46). Kaplan-Meier survival analysis with a generalized Wilcoxon test revealed that mid-term (2 years) mortality was greater for patients with than without CSTP (31.4% vs. 15.5%; P=0.008)., Conclusions: TAVI-related CSTP was not rare and was associated with poor mid-term outcomes. CSTP was not only caused by patients' comorbidities and TAVI complications, but also related to TAVI procedural factors.

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., Competing Interests: Competing interestsAsahi Kasei Pharma Corporation absorbed expense for the analysis and the native check of manuscript. NK has no grant and personal fee. HW received grants and personal fees from Asahi Kasei Pharma Corporation and Japan Blood Products Organization outside the present work. TU, SM, NT, KS, YS, and KO received personal fees from Asahi Kasei Pharma Corporation outside the present work. KK and TI received grants and personal fees from Asahi Kasei Pharma Corporation outside the present work. TH is an employee of Asahi Kasei Pharma Corporation., (© The Author(s). 2020.)

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.

As proposed diagnostic criteria for DIC from the Japanese Society on Thrombosis and Hemostasis has been approved and revised, the contents and changes are informed.

Objective: We evaluated the modified diagnostic criteria for disseminated intravascular coagulation (DIC), which was published by the Japanese Society of Thrombosis and Hemostasis (JSTH), in 274 suspected DIC patients with hematopoietic injury., Materials and Methods: The diagnoses of the patients were as follows: DIC (n=125); pre-DIC (n=42) and non-DIC (n=107). The efficacy of the diagnostic criteria for DIC was evaluated using a receiver operating characteristic (ROC) analysis., Results: The area under the curve (ARC) and odd's ratio for the global coagulation test (GCT) scores in the diagnosis of "DIC" were high, while those for the diagnosis of "DIC and pre-DIC" were low, suggesting that the addition of antithrombin (AT) and soluble fibrin (SF)/thrombin antithrobin complex (TAT) was required to diagnose "DIC and pre-DIC". Although the addition of the AT and SF/TAT values to the GCT did not increase its ability to predict a poor outcome, the JSTH's modified diagnostic criteria scores were correlated with the odds ratio for death., Discussion and Conclusion: The JSTH's modified diagnostic criteria for DIC, which included the GCT score, and the AT, and TAT/SF values, were useful for diagnosing DIC and pre-DIC, and predicting a poor outcome., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background and Aim: Although several non-vitamin K oral anticoagulants have been developed to prevent cardiogenic thrombosis, the status of hemorrhagic complications in the clinical setting among Asian populations, including Japan, remains unclear. We conducted this retrospective cohort study to clarify the current status of hemorrhagic events during antithrombotic therapy with non-vitamin K oral anticoagulants, with particular focus on gastrointestinal bleeding., Methods: Medical charts of 475 patients prescribed dabigatran, rivaroxaban, or apixaban between April 2011 and September 2014 were reviewed to examine whether any hemorrhagic events occurred, compared with 135 patients who received warfarin between April 2009 and March 2011., Results: Incidences of total and actionable hemorrhage in patient taking non-vitamin K oral anticoagulants were 13.8% per year and 4.6% per year, respectively, showing no significant differences from those in warfarin users (9.3% per year and 5.0% per year, respectively). In addition, actionable gastrointestinal hemorrhage occurred at similar rates in non-vitamin K oral anticoagulants users (2.1% per year) and warfarin users (1.5% per year). Most hemorrhages were from the lower gastrointestinal tract, and considerable events involved perianal bleeding. Multiple regression analysis showed that age, concomitant dual antiplatelet therapy, and concomitant nonsteroidal anti-inflammatory drug therapy were significant factors related to actionable gastrointestinal bleeding., Conclusions: Risk of gastrointestinal hemorrhage in patients taking non-vitamin K oral anticoagulants was similar to that in patients taking warfarin. The dominant bleeding site was the lower gastrointestinal tract.
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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.

The effects of oral rivaroxaban (RX), a direct inhibitor of activated factor X (Xa), on prothrombin time (PT) and activated partial thromboplastin time (APTT) were examined. PT and APTT before and after administration of 15 mg RX in 10 healthy subjects were measured by using various reagents. In addition, the blood Xa inhibitor concentration was measured and its correlation with PT and APTT, as measured by each reagent, was examined. Furthermore, the relationship (sensitivity) between the prolongation ratio and FX activity was evaluated. Prolongation of both PT and APTT was observed after RX administration, and maximal prolongation was observed four hours after administration for each reagent. The prolongation ratio was different among the reagents used for examination, and the reagent with the highest sensitivity to FX and factor VII showed the largest prolongation ratio. PT and APTT were positively correlated with RX concentration when measured by any reagent. In this study, neither PT, APTT, nor RX concentration returned to the values measured prior to dosing even at 24 hours after administration of RX. Our results suggest that approximate concentration of remaining RX may be estimated by PT (second) when using a reagent showing a larger prolongation ratio.

The aim of this study was to examine the effects of NOACs (dabigatran, rivaroxaban, and apixaban) on the thrombin generation assay (TGA) in vivo. We administered healthy volunteers regular doses of NOACs, and measured TGA before and after administration. As a result, rivaroxaban and apixaban, which are direct Xa inhibitors, significantly decreased thrombin generation after administration within four to six hours. With apixaban, thrombin generation was significantly inhibited after administration within 24 hours. Also, with rivaroxaban, although there were milder effects as compared with apixaban, thrombin production was significantly decreased after administration within 24 hours. On the other hand, with dabigatran, which is a direct thrombin inhibitor, a paradoxical effect was seen in the peak and ETP, which are criteria to evaluate TGT after administration. However, a prolonged lag time was observed in each time zone after administration, and similarly to apixaban, such prolongation was also observed 24 hours after the initiation of administration. From these results, it is suggested that TGA is useful for assessing the influence of NOACs on coagulation.

In order to elucidate the mechanism of hyperuricemia in hematologic malignancies, we have retrospectively investigated the uric acid metabolism in 418 chemotherapy-naïve patients with hematologic malignancies. Hyperuricemia was present in 116 (27.8%) of these patients on initial hospitalization. Among 65 hyperuricemic patients analyzed uric acid metabolism, six (9.2%) had overproduction type, 52 (80.0%) had underexcretion type, and seven (10.8%) had a mixed type. Fourteen patients (3.3%) developed tumor lysis syndrome in 418 patients.

Objective: Disseminated intravascular coagulation (DIC) is often associated with infection and a poor outcome. In this study, useful markers for predicting poor outcomes were examined., Methods: The frequency of DIC and organ failure, outcomes and hemostatic markers were prospectively evaluated in 242 patients with infections., Results: Seventy-seven patients were diagnosed with DIC, 36 of whom recovered from the condition. The rate of DIC or resolution of DIC was highest in the patients with sepsis and lowest in the patients with respiratory infections. Mortality tended to be high in the patients with respiratory infections. The DIC score, sepsis-related organ failure assessment (SOFA) score, prothrombin time (PT) ratio and thrombin-antithrombin complex level were significantly high in the patients who did not recover from DIC. The age, DIC score, SOFA score, PT ratio and levels of thrombomodulin and plasminogen activator inhibitor (PAI)-I were significantly high in the non-survivors. Factors related to a poor outcome included resolution of DIC, the SOFA score, age and the PT ratio. Factors related to resolution of DIC included the SOFA score and age, while factors related to the SOFA score included the levels of PAI-I, leukocytes, fibrinogen, D-dimer and platelets., Conclusion: The outcomes of septic patients primarily depend on the SOFA score and the resolution of DIC, which are related to organ failure.

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.

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.

We recently reported that chronic myelogenous leukemia (CML) cells converted into myofibroblasts to create a microenvironment for proliferation of CML cells in vitro. To analyze a biological contribution of CML-derived myofibroblasts in vivo, we observed the characters of leukemic nonobese diabetes/severe combined immunodeficiency (NOD/SCID) mouse. Bone marrow nonadherent mononuclear cells as well as human CD45-positive cells obtained from CML patients were injected to the irradiated NOD/SCID mice. When the chimeric BCR-ABL transcript was demonstrated in blood, human CML cells were detected in NOD/SCID murine bone marrow. And CML-derived myofibroblasts composed with the bone marrow-stroma, which produced significant amounts of human vascular endothelial growth factor A. When the parental CML cells were cultured with myofibroblasts separated from CML cell-engrafted NOD/SCID murine bone marrow, CML cells proliferated significantly. These observations indicate that CML cells make an adequate microenvironment for their own proliferation in vivo.