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Introduction: Idarucizumab, a monoclonal antibody fragment that rapidly reverses the anticoagulant effects of dabigatran, was approved in Japan in September 2016, at which time an all-case, postmarketing surveillance (PMS) study was initiated to collect data on idarucizumab in Japanese patients. Interim results were published previously, and the final results are reported herein. Methods: This multicenter, open-label, uncontrolled, non-interventional PMS study was conducted in Japanese patients who received idarucizumab at the approved dose (2 × 2.5 g/50 ml) and had uncontrolled bleeding (group A) or required an emergency procedure (group B). The primary endpoint was the frequency of adverse drug reactions (ADRs). The secondary endpoint was the maximum extent of reversal of the anticoagulant effects of dabigatran, within 4 h of idarucizumab administration, based on activated partial thromboplastin time (aPTT). Results: The final analysis included 804 patients. ADRs during the idarucizumab treatment and post-treatment periods were reported in 17 of 542 patients (3.1%) in group A and 12 of 240 patients (5.0%) in group B. Thrombotic events were reported in 22 patients (4.1%) in group A and 15 patients (6.3%) in group B, and hypersensitivity occurred in four (0.7%) and five patients (2.1%), respectively. Among 793 patients evaluated for effectiveness, 78 in group A and 26 in group B had aPTT data at baseline (immediately before idarucizumab administration) and within 4 h of idarucizumab administration; in these patients, median maximum percentage reversal within 4 h of idarucizumab administration was 100%. Conclusions: The final analysis from the PMS study confirms previous findings suggesting that idarucizumab can safely and effectively reverse the anticoagulant effects of dabigatran in Japanese patients in clinical practice. The results support the continued use of idarucizumab in Japan. Trial Registration: This study is registered with ClinicalTrials.gov (NCT02946931). Plain Language Summary: Atrial fibrillation is an irregular heart rhythm (arrhythmia), and the type of atrial fibrillation not caused by a heart valve problem is known as "non-valvular atrial fibrillation" or NVAF. People with NVAF have an increased risk of ischemic stroke, in which a blood clot (thrombus) blocks an artery in the brain. Drugs that inhibit blood clots, known as anticoagulants, are prescribed to people with NVAF to prevent ischemic stroke. Historically, warfarin has been one of the most prescribed anticoagulant drugs. However, a novel anticoagulant drug, known as dabigatran, has clinical advantages over warfarin and is approved in many countries for people with NVAF. People who take anticoagulants may experience life-threatening bleeding or need urgent surgery, and thus rapid and effective reversal of the anticoagulant effects is critical. The drug idarucizumab specifically binds to dabigatran to reverse its anticoagulant effects in people with uncontrolled bleeding or who require an urgent procedure. Idarucizumab was approved for use in Japan in September 2016. In Japan, drug companies are obligated to collect data after a new drug is launched as an approval condition, which is done through a postmarketing surveillance study. Here, we report the final results of a postmarketing surveillance study conducted between September 2016 and November 2020 to evaluate the safety and effectiveness of idarucizumab in Japanese patients receiving dabigatran. The results of our study show that idarucizumab can safely and effectively reverse the anticoagulant effects of dabigatran in Japanese patients, and support the continued use of idarucizumab in Japan in clinical practice. [ABSTRACT FROM AUTHOR]

Direct oral anticoagulants targeting factor Xa (DXaIs) are administered as prophylaxis for various venothrombotic diseases without routine monitoring required. However, assessment of their anticoagulant effects is necessary to prevent severe events, including major bleeding and/or refractory thrombosis. We examined the correlation of ratio of inhibited thrombin generation (RITG), determined using a novel assay based on dilute prothrombin time (dPT), with coagulant markers and laboratory test results to show drug effects. In addition, RITG usefulness as a confirmation test for DXaI therapy was investigated. Citrated plasma samples were obtained from patients treated with rivaroxaban (n = 882), apixaban (n = 1214), or edoxaban (n = 820) at 4 different institutions in Japan. Laboratory tests, including prothrombin time (PT), activated partial thromboplastin time (APTT), D-dimer, and plasma concentrations of DXaIs, were conducted, with drug concentrations divided into peak and trough groups, within and after 5 h of administration. In each DXaI group, RITG was positively correlated with PT, APTT, and drug concentration, and negatively with D-dimer. RITG fluctuation during the peak and trough periods reflected the anticoagulant activity characteristic of each DXaI, which was different from blood concentration fluctuations. RITG showed a significant decrease in cases with thrombosis, while that was increased in those with hemorrhage. We developed RITG, a novel measurement method based on dPT. RITG represents residual coagulation ability in plasma samples, and is useful for assessment of bleeding and thrombotic tendencies in DXaI patients. RITG can be utilized to confirm the effectiveness of oral anticoagulation therapy with DXaI agents. • Diluted PT (dPT) was found to be well correlated with DXaI blood concentration. • RITG, devised based on dPT, was shown to reflect residual coagulability. • RITG was shown to reflect the anticoagulant characteristics of DXaI agents. • RITG was high in bleeding event cases and low in those with thrombotic events. • RITG is considered to be useful as a confirming test for DXaI therapy. [ABSTRACT FROM AUTHOR]

Introduction: Idarucizumab, a monoclonal antibody fragment, was developed to reverse the anticoagulant effect of dabigatran, and it was approved in Japan in September 2016. An all-case post-marketing surveillance is ongoing to collect data in Japanese patients treated with idarucizumab who had serious bleeding (Group A) or required an urgent procedure (Group B). Methods: The primary endpoint was the incidence of adverse drug reactions (ADRs). The secondary endpoint was the maximum extent of reversal of the anticoagulant effect of dabigatran based on activated partial thromboplastin time (aPTT) within 4 h after idarucizumab administration. Results: This interim analysis included 262 patients who received idarucizumab. Eighteen patients (6.9%) experienced ADRs within 4 weeks. The reversal effect of idarucizumab based on aPTT within 4 h after idarucizumab administration was assessed in 30 patients and the median maximum percentage reversal was 100%. In Group A, the median time to bleeding cessation in patients without intracranial bleeding was 3.3 h. In Group B, normal intraoperative hemostasis was reported in 63 patients (72.4%). Conclusions: The results of this interim analysis suggest that idarucizumab is safe and effective for the reversal of dabigatran in Japanese patients in a real-world setting, and support the continued use of idarucizumab. Trial Registration: ClinicalTrials.gov identifier, NCT02946931. [ABSTRACT FROM AUTHOR]

The aims of this study were to determine the distribution of plasma concentration of edoxaban (PC-Ed) with their 90% interval (on therapy range) and its correlation with anticoagulation markers in patients with non-valvular atrial fibrillation (NVAF). Consecutive 97 NVAF patients under edoxaban therapy were evaluated (60/30 mg dose, n = 48/49; men/women, n = 71/26; age, 69 years). CHADS2 score 0, 1, and ≥ 2 were 27%, 44%, and 29%, respectively. The mean (90% interval) of PC-Ed by LC–MS/MS was 194.3 (49.4–345.3) and 17.0 (4.8–40.7) ng/mL at peak (2–4 h post-dose) and trough (pre-dose), respectively. Correlation of prothrombin time (PT) with PC-Ed was higher than that of activated partial thromboplastin time (aPTT). Among 6 PT reagents, Coagupia PT–N and Simplastin Excel S (both PT reagents) showed the highest predictive capability for the upper outlier of PC-Ed at peak and trough. Among 4 aPTT reagents, only Thrombocheck APTT measured at peak had a significant predictive capability. When using PT reagents, both peak and trough sampling showed a similar predictive capability for the upper outliers of PC-Ed with a high sensitivity, but a relatively low specificity. We demonstrated the distributions of plasma concentration, PT with 6 reagents, and aPTT with 4 reagents under edoxaban therapy in Japanese patients with NVAF, showing their 90% intervals. For predicting the upper outlier of PC-Ed, PT was more sensitive compared with aPTT, whereas predicting capability for the outliers of PC-Ed was mostly similar between peak and trough samplings among PT reagents (UMIN 000032492). [ABSTRACT FROM AUTHOR]

Background: Venous thromboembolism (VTE) has been shown to be more frequent in inflammatory bowel disease (IBD) than in the general population in Western studies. However, the actual state of VTE in Asian IBD remains poorly understood. Aims: To reveal the incidence of VTE in IBD patients in Japan. Methods: Eighty-five patients admitted to 3 gastroenterology centers were registered from 2013 to 2018. The incidence of VTE in patients with IBD (n = 42) was prospectively compared to that among patients with other digestive diseases (n = 43). The presence of VTE was surveyed using contrast-enhanced computed tomography and/or ultrasonography at admission and at 1–2 weeks after admission. The patient characteristics and laboratory data of IBD patients with or without VTE were compared to determine the risk factors for VTE. Results: The incidence of VTE with IBD was 16.7%, which was significantly more frequent than with other digestive diseases (2.3%; p = 0.0296). In IBD patients, VTE was detected in 6 of 22 patients with ulcerative colitis (27.2%) but in only 1 of 20 patients with Crohn's disease (5.0%). VTE was diagnosed at admission in 4 IBD patients and 2 weeks after admission in 3 IBD patients. The risk factors of VTE in IBD were the presence of an indwelling central venous catheter, a low level of total protein, a low activated partial thromboplastin time, and a high level of fibrinogen degradation products. Conclusion: VTE was frequently detected in Japanese IBD patients both at and after admission. Adequate screening and prophylaxis for VTE is deemed necessary in IBD. [ABSTRACT FROM AUTHOR]

Introduction: The substantial interpatient variability in heparin requirement has led to the use of a heparin dose response (HDR) technique. The accuracy of Hepcon-based heparin administration in achieving a target activated clotting time (ACT) using an HDR slope remains controversial. Methods: We prospectively studied 86 adult patients scheduled for cardiac surgery requiring cardiopulmonary bypass. The total dose of calculated heparin required for patient and pump priming was administered simultaneously to achieve a target ACT of 450 s for HDR on the Hepcon HMS system. Blood samples were obtained after the induction of anesthesia, at 3 min after heparin administration and after the initiation of CPB to measure kaolin ACT, HDR slope, whole-blood heparin concentration based on the HDR slope and anti-Xa heparin concentration, antithrombin and complete blood count. Results: The target ACT of 450 s was not achieved in 68.6% of patients. Compared with patients who achieved the target ACT, those who failed to achieve their target ACT had a significantly higher platelet count at baseline. Correlation between the HDR slope and heparin sensitivity was poor. Projected heparin concentration and anti-Xa heparin concentration are not interchangeable based on the Bland–Altman analysis. Conclusion: It can be hypothesized that the wide discrepancy in HDR slope versus heparin sensitivity may be explained by an inaccurate prediction of the plasma heparin level and/or the change in HDR of individual patients, depending on in vivo factors such as extravascular sequestration of heparin, decreased intrinsic antithrombin activity level and platelet count and/or activity. [ABSTRACT FROM AUTHOR]

Background Soluble fibrin monomer complex ( SFMC) and fibrin monomer ( FM) are well known as markers for hypercoagulability, but such measurements have not been investigated in detail for the neonate. To identify the presence of a hypercoagulable state in sick newborns, the behavior of SFMC with special reference to those of other coagulation tests, and the relationships with other parameters of blood coagulation as well as lactate, which is considered to be the gold standard for assessing tissue hypoxia, were studied. Methods Records of 216 sick newborns, who had undergone blood coagulation tests, were retrospectively studied based on their medical records. Results SFMC had a significant correlation with d-dimer in infants with birthweight <1500 g, but no correlation was observed with prothrombin time ( PT), activated partial thromboplastin time ( APTT), fibrinogen, anti-thrombin or platelet count. In contrast, in infants with birthweight ≥1500 g, SFMC was correlated with PT, APTT, fibrinogen, and d-dimer, but no correlation was observed with anti-thrombin or platelet count. In addition, SFMC was significantly higher in the high lactate group (lactate ≥4 mmol/ L), compared with the low lactate group (<4 mmol/ L). Conclusion Measurement of blood SFMC is useful to monitor hypercoagulable state in sick newborns with hypoxia. [ABSTRACT FROM AUTHOR]

This randomized, double-blind, placebo-controlled, multiple ascending-dose study evaluated safety, tolerability, pharmacokinetics, and pharmacodynamics of multiple doses of milvexian, an oral small-molecule FXIa inhibitor, in healthy Japanese participants. Participants received oral milvexian daily under fasted (50 mg and 200 mg) or fed conditions (500 mg) or placebo over 14 days; 24 participants (8/cohort: 6 milvexian; 2 placebo) were planned. Due to an unblinding event, participants in one cohort (200 mg daily) were discontinued, and a second cohort enrolled; 32 participants were included in safety and pharmacodynamic analyses, and 24/32 in pharmacokinetic analyses. Milvexian up to 500 mg daily for 14 days was generally well tolerated, with no deaths, serious adverse events, or discontinuations due to adverse events. Milvexian exposure increased between 50-mg and 200-mg doses. Median T max was similar with 50-mg and 200-mg doses (2.5-3.0 h) and delayed under fed conditions (500 mg, 7.0-8.0 h). Median T 1/2 was similar across doses (8.9-11.9 h). Multiple oral milvexian administrations resulted in concentration-related prolongation of aPTT and decreased FXI clotting activity. Milvexian was generally safe and well tolerated. The pharmacokinetic and pharmacodynamic profile of milvexian demonstrates suitability for further clinical development in Japanese participants., (© 2022. The Author(s).)

Introduction: The one-stage clotting assay is used to measure factor IX (FIX) activity in patients' plasma samples and in FIX products for hemophilia treatment. However, the diversity of reagents and instruments has resulted in significant FIX assay variability., Methods: The accuracy of the one-stage clotting assay to measure recombinant FIX Fc fusion protein (rFIXFc) activity was evaluated by major Japanese hemophilia treatment centers and commercial laboratories that measure factor IX activity for a majority of hemophilia B patients in Japan. Plasma-derived FIX (pdFIX) and recombinant FIX (rFIX) products were used as comparators. FIX-deficient plasma was spiked with four levels of FIX products based on label potency and measured under blinded conditions by routine one-stage clotting assay procedures in 19 participating laboratories. Interlaboratory coefficient of variation and spike recovery were calculated., Results: Interlaboratory coefficient of variation of rFIXFc was not significantly different from that of rFIX, but appeared larger than that of pdFIX. Mean spike recovery for rFIXFc was generally comparable to rFIX and pdFIX. However, larger discrepancies between pdFIX and rFIX were observed in three of nine laboratories using ellagic acid-based activated partial thromboplastin time reagents., Conclusion: Recombinant FIX Fc fusion protein activity was found to be similar to that of rFIX or pdFIX by the one-stage clotting assay. However, minimizing interlaboratory variability is vital for optimizing future patient care., (2019 Sanofi K.K. International Journal of Laboratory Hematology published by John Wiley & Sons Ltd.)

Heparin anticoagulant therapy for thromboembolic disorders during pregnancy is problematic due to unexpected adverse bleeding. To avoid bleeding, we have used a less-intensive anticoagulation protocol of unfractionated heparin (UFH). The protocol had a therapeutic activated partial thromboplastin time (APTT) ratio of 1.5-2.0 with the control value, a UFH dose of ≤ 30,000 U/day, and an antithrombin (AT) activity target of ≥ 70%. In the present study, we evaluated this protocol using an anti-Xa assay. We collected UFH-treated plasma samples from ten consecutive pregnant Japanese patients with current or previous thromboembolic disorders. Seven patients remained in the therapeutic APTT ratio range (heparin-sensitive [HS] group). The other three patients had difficulty remaining within the therapeutic range (heparin-resistant [HR] group). In the HR group, two had AT deficiency and one had congenital absence of the inferior vena cava. Of the HS and HR samples, 73% and 31%, respectively, were within the therapeutic anti-Xa activity range 0.3-0.7 U/mL, indicating difficulty for the HR group to remain within the therapeutic range. Neither major bleeding nor symptomatic thromboembolic episodes occurred in either group. These findings suggest that the less-intensive anticoagulation protocol is permissive and may be beneficial in the HS group.

Lupus anticoagulant-hypoprothrombinemia syndrome (LAHPS) is a rare bleeding disorder caused by antiprothrombin antibodies. LAHPS is associated with systemic lupus erythematosus (SLE) or infections. We describe two Japanese brothers with immunoglobulin-A vasculitis (IgAV) who met the diagnostic criteria of LAHPS. They presented with palpable purpura and abdominal pain, and had a prolonged activated partial thromboplastin time (APTT) and prothrombin deficiency with the presence of lupus anticoagulant. Pediatric LAHPS was reviewed in abstracts from the Japan Medical Abstracts Society that were written in Japanese and PubMed or Web of Science-listed articles in English between 1996 and 2019. Including our cases, pediatric LAHPS has been reported in 40 Japanese and 46 non-Japanese patients. We summarized the clinical and laboratory characteristics of all 86 cases, and found only one Japanese LAHPS case with IgAV, except for our cases. Of the 86 cases, most were associated with infections followed by SLE. The presence of SLE, older age, lower prothrombin levels, severe bleeding symptoms, and positivity of immunoglobulin G anticardiolipin antibodies and anticardiolipin/β 2 -glycoprotein I antibodies and/or β 2 -glycoprotein I-dependent anticardiolipin antibodies had higher odds of requiring treatment. Measuring the APTT and prothrombin time (PT) might be required in patients with IgAV when they do not have a typical clinical course or distinctive symptoms. LAHPS should be considered with prolongation of the APTT and/or PT. Additionally, it is important to maintain a balance between the risk of thrombosis and hemorrhage when normalization of the PT and FII levels occurs in LAHPS cases under treatment.

Antithrombotic effects of water-extractive components (extracts) from heshiko and narezushi, traditional fermented aquatic products in Japan, were investigated in terms of blood coagulation and fibrinolysis by means of animal experiments. Blood clot formation was suppressed by administration of heshiko and narezushi extracts to both groups of Wistar rats fed artificial and high-fat experimental diets. Prothrombin time and activated partial thromboplastin time of plasma prepared from the rats, as indices of blood coagulation, were not prolonged by administration of heshiko or narezushi extracts. In contrast, the activities of plasmin and tissue plasminogen activator (tPA), key enzymes in the fibrinolytic system, were significantly increased by administration of heshiko and narezushi extracts. These results suggest that the anticoagulating effects of heshiko and narezushi extracts are associated with the promotion of the fibrinolytic system via enhancement of plasmin and tPA activities.

Objectives: In Japan, low-dose rivaroxaban [15 mg QD/10 mg QD for creatinine clearance of 30-49 mL/min] was approved for clinical use in NVAF patients partly because of its unique pharmacokinetics in Japanese subjects. The aim of the study was to determine the anticoagulation intensity of rivaroxaban and its determinant factors in Japanese stroke patients., Methods: Consecutive stroke patients with NVAF admitted between July 2012 and December 2013 were studied. Prothrombin time (PT), activated partial thromboplastin time (aPTT), and estimated plasma concentration of rivaroxaban (Criv) based on an anti-factor Xa chromogenic assay were measured just before and 4 and 9 h after administration at the steady state level of rivaroxaban. Determinant factors for Criv were explored using a linear mixed-model approach., Results: Of 110 patients (37 women, 75±9 years old), 59 took 15 mg QD of rivaroxaban and 51 took 10 mg QD. Criv at 4 h was 186 ng/mL for patients taking 15 mg QD and 147 ng/mL for those taking 10 mg QD. Both PT and aPTT were positively correlated with Criv. Criv was 72% lower at 4 h in 15 patients receiving crushed tablets than in the other patients, and tablet crushing was significantly associated with lower Criv (adjusted estimate -0.43, 95% CI -0.60 to -0.26) after multivariate-adjustment., Conclusion: The anticoagulation effects of rivaroxaban in the acute stroke setting for Japanese NVAF patients were relatively low as compared with those in the ROCKET-AF and J-ROCKET AF trials. Tablet crushing, common in dysphagic patients, decreased Criv.

We investigated a mildly hemorrhagic patient with factor X (FX) deficiency to identify the nature of his defect by comprehensive analyses. A 42-year-old Japanese man was admitted to our hospital for uncontrolled gingival hemorrhage. His FX activity based on prothrombin time (PT) and activated partial thromboplastin time (aPTT) and FX antigen were <1, 6.5 and 11 %, respectively. A homozygous M402T missense mutation (c.1205 t>c; p.Met402Thr) was identified in the FX gene (F10) from both the patient and his brother. The mutation was not detected in the F10 of 82 unrelated normal Japanese individuals. We studied the functional consequences of this mutation by expressing mutant FX-M402T protein in HEK293 cells. This analysis revealed that the antigen of the FX-M402T mutants was approximately 26 % that of the wild-type FX in conditioned media. The FX-specific activity of FX-M402T mutants measured by a one-stage clotting assay based upon PT and aPTT, and a chromogenic assay using Russell's viper venom in the concentrated media was 7.7, 31.7, and 41.2 % of wild type, respectively. The results suggest that the mutation FX-M402T may cause a secretion defect and a molecular abnormality in FX.

APTT is widely used for serial monitoring of treatment with unfractionated heparin. However, since its sensitivity to heparin varies significantly from one reagent to another, it is suggested that the therapeutic range had to be defined for each brand of APTT reagents. In this study, to investigate the affect of these variables, we compared various reagents of APTT and instruments for APTT measurements in different laboratories of university hospitals and related hospitals in Kyushu area. Same sample of normal pooled plasma added unfractionated heparin were measured in each laboratory. Prolongation of APTT by unfractionated heparin differed between laboratories. In addition, we examined prolongation of APTT by unfractionated heparin in normal plasma obtained from single donor. The prolongation of APTT differed between single donor samples even in the using of single APTT reagent and instrument. No correlation was observed between prolongation ratio of APTT and antithrombin concentration. These results indicate that sensitivity to heparin varies between individual in addition to brand of APTT reagent.

Aim: Data from Japanese women have been lacking regarding hemorrhagic complications due to low-molecular-weight heparin (LMWH) as thromboprophylaxis. Thus, targeting Japanese women, we made an effort to determine: (i) whether the administration of LMWH soon after cesarean section increases the risk of hemorrhagic complications compared to that of unfractionated heparin; and (ii) how it elongates the activated partial thromboplastin time., Materials and Methods: We administered unfractionated heparin in the first half of the study period, and LMWH in the latter half. We examined: (i) the incidence rate of hemorrhagic complications; and (ii) preoperative and postoperative activated partial thromboplastin time, and we compared these in cases using unfractionated heparin and LMWH., Results: No clinically discernable thromboembolism occurred in either group. Hemorrhagic complications occurred in two of 140 women in the unfractionated heparin group and one of 131 women in the LMWH group. LMWH prolonged the activated partial thromboplastin time from 29.8±2.6 to 34.8±4.0 s. This prolongation was significantly shorter than that with unfractionated heparin (from 30.2±2.6 to 36.5±6.2 s)., Conclusions: Compared with thromboprophylaxis with unfractionated heparin, thromboprophylaxis with early administration of LMWH after cesarean section did not increase the incidence of hemorrhagic complications and caused less prolongation of the activated partial thromboplastin time in Japanese women., (© 2011 The Authors. Journal of Obstetrics and Gynaecology Research © 2011 Japan Society of Obstetrics and Gynecology.)

Introduction: Although nafamostat mesilate, a synthetic serine protease inhibitor, has been commonly used in Japan as an anticoagulant during continuous renal replacement therapy (CRRT), its clinical utility has not been well determined. The aim of this study was to evaluate the efficacy (filter survival) and safety (bleeding complications) of nafamostat mesilate in CRRT for acute kidney injury (AKI) among critically ill patients., Methods: We retrospectively studied consecutive patients with AKI treated with continuous veno-venous hemodialysis and nafamostat mesilate from April 2005 to March 2008. Demographic, clinical and laboratory data were extracted from the clinical chart., Results: Fifty-eight patients were enrolled in this study (45 males with an average age of 66±15 years). The median filter survival was 21.8 h (range: 2.8-55.5 h), and the mean was 20.8±8.4 h. Only 38 out of 181 filters (21%) were interrupted because of filter failure within 24 hours and 89 filters (49%) were electively renewed within 24 hours. Activated partial thromboplastin time was elevated especially during the first 24 hours (46.7±13.1 s at baseline versus 73.9±24.3 s at day 1; ANOVA p<0.01). Hematocrit level was kept around 30% and did not change significantly (ANOVA p=0.69). No patients experienced major bleeding while treated with CRRT., Conclusions: Nafamostat mesilate provided sufficient filter survival without causing major bleeding complications despite the prolongation of APTT.

Aim: Hemorrhage is an important complication of heparin-thromboprophylaxis after surgery. We attempted to clarify the incidence rate of prolonged activated partial thromboplastin time (APTT), representative of hemorrhagic tendency, in Japanese women who received thromboprophylaxis with unfractionated subcutaneous heparin administration after cesarean section (CS). We also determined factors which affected postoperative APTT., Methods: We studied 280 women who were administered thromboprophylaxis with unfractionated subcutaneous heparin 5000 IU two times per day after CS. Postoperative APTT under heparin was measured and the incidence of its prolongation was determined. Preoperative APTT, blood loss during surgery, postoperative hematocrit, postoperative serum total protein level, and postpartum body weight were measured, and their correlation with postoperative APTT was determined., Results: Preoperative and postoperative APTT values were 28.3 (26.7-30.3) and 33.8 (31.0-37.5) seconds for median (interquartile range), respectively. Overall, 7.1% of patients showed >or=45 s postoperative APTT. Two patients (0.7%) showed >or=60 s APTT, one of whom suffered subcutaneous hemorrhage around the abdominal incision with complete healing. There were no other hemorrhagic complications. Preoperative APTT positively, and postpartum body weight inversely, correlated with postoperative APTT. The amount of blood loss, postoperative hematocrit, and postoperative serum total protein level did not correlate with postoperative APTT. No discernible deep vein thrombosis or pulmonary embolism occurred., Conclusion: Although 7.1% of women under heparin-thromboprophylaxis showed a prolonged APTT that was 150% of the preoperative APTT, serious side effects were not observed. Subcutaneous administration of unfractionated heparin, if checking APTT prolongation 1 day after surgery, may be safe method of thromboprophylaxis after CS.

Objective: To determine the effects of disseminated intravascular coagulation (DIC) and head injury on posttrauma coagulation and fibrinolysis., Design: Case-control study., Setting: General ICU (tertiary care center) in a city hospital serving a population of 150 million people., Patients: Forty trauma victims: 15 with DIC; 25 without DIC., Interventions: Measurement of six types of coagulation and fibrinolytic molecular markers (fibrinopeptide A, fibrinopeptide B beta 15-42, plasmin antiplasmin complex, D-dimer, tissue plasminogen activator antigen concentration, tissue plasminogen activator activity) immediately after trauma, 3 days later, and 6 days later. Anticoagulant treatment with gabexate mesilate at 1.45 +/- 0.06 mg/kg/hr., Measurements and Main Results: Fibrinopeptide A, fibrinopeptide B beta 15-42, plasmin antiplasmin complex, and D-dimer showed high values immediately after trauma and exceeded normal activity for the first 6 days. When trauma was complicated with DIC, the molecular markers showed significantly higher values than those for non-DIC patients on all days. In the head-injured patients, such effect was not noted. Tissue plasminogen activator antigen concentration and tissue plasminogen activator activity were within a normal physiologic range of variation. By contrast, tissue plasminogen activator antigen concentration increased significantly after trauma in patients with DIC. When anticoagulant treatment was found effective, it caused a reduction in fibrinopeptide A., Conclusions: a) Fibrinolytic shut-down and its reactivation cannot be confirmed after trauma. b) Head injury does not lead to an increase in posttrauma coagulation or fibrinolytic activity. c) DIC enhances posttrauma coagulation and fibrinolytic activity and plasminogen activator inhibitor activity can be inferred in DIC patients. d) Increase in tissue plasminogen activator antigen concentration without tissue plasminogen activator activation may be a prognostic factor indicative of DIC and its chances of improvement, and fibrinopeptide A as an assessment criterion for the effectiveness of anticoagulant treatment.

A multicenter cooperative study was designed to evaluate the efficacy and safety of Fragmin (FR-860) as an anticoagulant in hemodialysis. Sixty-one stable maintenance hemodialysis patients were enrolled from 14 institutions in Japan. The study period was fixed at 2 weeks. Dosage requirements were 15.0 to 20.0 anti-Xa U/kg as bolus and 7.5 to 10.0 anti-Xa U/kg/hr as continuous infusion. The total dosage of Fragmin was 2505 +/- 127 anti-Xa U compared with 6124 +/- 190 U of conventional heparin. No differences were observed in residual blood in extracorporeal circuits between the groups. The hemostasis times at puncture sites after completion of dialysis were significantly shortened in the Fragmin group (7.9 +/- 0.7 minutes) when compared with the conventional heparin group (11.4 +/- 1.1 minutes; p less than 0.01). Plasma anti-Xa levels were 0.24 +/- 0.03 and 0.36 +/- 0.04 U/ml 1 hour after the initiation and at the completion of dialysis, respectively. ACTs, measured by the Hemochron method, were not prolonged during dialysis. APTTs varied from 34.3 +/- 1.2 before dialysis to 41.0 +/- 1.9 (p less than 0.01) 1 hour after the start of dialysis and 39.9 +/- 1.6 seconds (p less than 0.01) at the end of dialysis. Plasma AT III activity increased from 96.8 +/- 2.5% before dialysis to 113.0 +/- 3.2% (p less than 0.01) at the end of dialysis. No significant changes were observed in both ADP- and collagen-induced platelet aggregation during dialysis. Dialysis efficiency was the same for both groups. Slight itching developed in one of 61 cases. No abnormal laboratory data were observed during the study. The efficacy, safety, and utility rates were 98.4, 98.5, and 98.4%, respectively. Fragmin proved to have a higher utility rate and was a good and convenient alternative to conventional heparin as an anticoagulant in hemodialysis treatment.

Effects of cefminox (CMNX) on hemostasis and blood coagulation system were studied. Adult in-patients admitted to 237 centers (310 clinics) nationwide in Japan during the period from April 1988 to March 1989 were followed up using a newly designed uniformed protocol. Case cards recovered were inspected by an evaluation committee and patients to be included in analysis were determined according to the protocol. Presence or absence of abnormalities in the hemostasis and blood coagulation system was examined objectively using criteria for evaluation prepared by the committee. Out of 1,374 patients included in analysis, 10 patients were judged as having abnormalities which were suspected to have causal relationships with CMNX. Prolongation in prothrombin time was observed in 4 cases (0.29%), prolongation in activated partial thromboplastin time in 4 cases (0.29%), and decrease in fibrinogen in 2 cases (0.15%). Decrease in platelet count was not detected in any of the cases. Cross-sectional analysis according to background factors in these 10 cases revealed that abnormalities of the hemostasis and blood coagulation systems were significantly higher (P less than 0.01) for the group positive for underlying disease or complications ("positive" group) than the "negative" group. Five out of 9 patients of the positive group had malignant neoplasm. Other than this factor, no items showed statistically significant differences. From these results it is considered that the administration of CMNX is nearly free of effects on the hemostasis and blood coagulation system and development of laboratory abnormalities is chiefly due to the patients' condition.

Disseminated intravascular coagulation (DIC) occurs most frequently during the newborn period. Some clinical and laboratory criteria are available for the diagnosis of DIC in adults. However, they are not necessarily applicable in the diagnosis of DIC in newborn infants since the physiological state of coagulation during the newborn period differs from that in adults. We therefore reviewed 74 cases of DIC in newborns, including 34 cases at our own newborn care units. Criteria for the diagnosis of DIC in newborn infants were established.

Plasma samples of 125 patients from 80 kindreds with hereditary plasma thromboplastin antecedent (PTA, factor XI) deficiency were tested by factor XI radioimmunoassay (RIA) and electroimmunoassay (EIA) in an attempt to detect variant molecules. Ninety-six patients (70 kindreds) were Jewish, and 29 (10 kindreds) were of other ethnic backgrounds, namely, Japanese, black American, Korean, Arab, Indian, and English. Seventy-eight patients were homozygotes, and 47 were heterozygotes. Both non-Jewish homozygotes and heterozygotes had lower factor XI activity than respective Jewish subjects. Twenty-eight homozygotes whose factor XI clotting activities (XI:C) were 1.5% to 13% had factor XI-related antigen (XI:RAG) levels less than 10% by EIA. In 72 homozygotes, including 22 patients who were also tested with EIA, XI:C was 2.9% +/- 3.0% (mean +/- SD) and XI:RAG tested by RIA, 2.9% +/- 3.0%. In 47 heterozygotes, XI:C and XI:RAG tested by RIA were 51.9% +/- 16.6% and 51.0% +/- 16.2%, respectively. Similar results were obtained when only unrelated patients (62 homozygotes and 27 heterozygotes) were analyzed. There was a highly significant correlation between XI:C and XI:RAG (RIA) in 38 homozygotes and 47 heterozygotes (r = 0.94, n = 85, P less than 0.001). Thus, we failed to identify functionally abnormal factor XI molecules (CRM+ variant) in these patients with hereditary factor XI deficiency.

Asymptomatic, female, 56-year-old identical Japanese twins were found to have a severe abnormality in the surface-mediated intrinsic coagulation, fibrinolysis and esterolytic activity. These defects were thought to be due to the lack of Fitzgerald factor, because of the prolongations of kaolin-activated partial thromboplastin time and kaolin-activated euglobulin lysis time that were not corrected by the addition of Fitzgerald trait-plasma but were corrected to normal levels by the addition of isolated bovine high-molecular-weight kininogen, Fletcher trait-plasma or Hageman trait-plasma.