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Two concepts have been proposed for the hemostatic changes occurring early after trauma. Disseminated intravascular coagulation (DIC) with the fibrinolytic phenotype is characterized by activation of the coagulation pathways, insufficient anticoagulant mechanisms and increased fibrinolysis. Coagulopathy of trauma and acute coagulopathy of trauma-shock (COT/ACOTS) occurs as a result of increased activation of the thrombomodulin and protein C pathways, leading to the suppression of coagulation and activation of fibrinolysis. Despite the differences between these two conditions, independent consideration of COT/ACOTS from DIC with the fibrinolytic phenotype is probably incorrect. Robust diagnostic criteria based on its pathophysiology are required to establish COT/ACOTS as a new independent disease concept. In addition, the independency of its characteristics, laboratory data, time courses and prognosis from DIC should be confirmed. Confusion between two concepts may be based on studies of trauma lacking the following: (i) a clear distinction of the properties of blood between the inside and outside of vessels, (ii) a clear distinction between physiologic and pathologic hemostatic changes, (iii) attention to the time courses of the changes in hemostatic parameters, (iv) unification of the study population, and (v) recognition that massive bleeding is not synonymous with coagulation disorders. More information is needed to elucidate the pathogenesis of these two entities, DIC with the fibrinolytic phenotype and COT/ACOTS after trauma. However, available data suggest that COT/ACOTS is not a new concept but a disease entity similar to or the same as DIC with the fibrinolytic phenotype.

Three guidelines have recently been published for the diagnosis and treatment of disseminated intravascular coagulation (DIC) in adults. This communication seeks to harmonize the recommendations in these guidelines using a modified GRADE system. The scoring system for diagnosis of DIC using global coagulation tests is known to correlate with key clinical observations and outcomes (Moderate quality). The cornerstone of DIC treatment is the treatment of the underlying condition (Moderate quality). In general, transfusion of platelets or plasma (components) in patients with DIC should be reserved for patients who are bleeding (Low quality). Therapeutic doses of heparin should be considered in cases of DIC where clinical features of thrombosis predominate. Heparin is not recommended in those patients with a high risk of bleeding, (Moderate quality). However, prophylactic doses of unfractionated heparin or low molecular we ight heparin is recommended in critically ill and non-bleeding patients with DIC for prevention of venous thromboembolism (Moderate to High quality). Although further prospective evidence from randomized controlled trials is required, administration of antithrombin or recombinant thrombomodulin may be considered in certain patients with DIC. In general, patients with DIC should not be treated with antifibrinolytic agents (Low quality). However those who present with severe bleeding, that is characterized by a markedly hyperfibrinolytic state such as leukemia (Low quality) and trauma (Moderate quality), may be treated with antifibrinolytic agents. © 2013 International Society on Thrombosis and Haemostasis.

Introduction Thrombotic microangiopathy (TMA) is one of the important complications occurring after liver transplantation (LT), and it is suggested that a Von Willebrand factor (VWF) and ADAMTS13 may play an important role in the onset of TMA and poor outcome after LT. Materials and Methods In 81 patients after living donor LT (LDLT), 17 patients who had both severe thrombocytopenia and hemolytic anemia with fragmented red cell were diagnosed as TMA- like syndrome (TMALS) and 10 patients died. Results ADAMTS13 activities were slightly low, and plasma levels of VWF and VWF propeptide (VWFpp) antigens and the ratio of VWFpp/VWF were significantly high before LDLT. ADAMTS13 activities were significantly reduced from day 1 to day 28 after surgery, and plasma levels of VWF antigen slightly decreased on day 1 and plasma levels of VWFpp continued to be high. The ratio of VWFpp/VWF was significantly high on day 1 after surgery. The mortality was high in the patients with TMALS and the frequency of TMALS was high in non-survivors. VWF levels were significantly low and the ratio of VWFpp/VWF was significantly high in those with TMALS on day 1 after surgery. The ADAMTS13 activity was significantly low, and the VWFpp and the VWFpp/ADAMTS13 ratio were significantly high in non-survivor on day 28 after surgery. Conclusion These findings suggest that VWF and ADAMTS13 might therefore play an important role in the onset of TMA and poor outcome after LT. The VWFpp may therefore be a more useful marker for the diagnosis of TMALS than VWF.

Objectives Invasive fungal diseases (IFDs) are life-threatening events in patients with haematologic disorders, and the spectrum of the aetiological pathogens continues to expand. This study aimed to evaluate the clinical utility of a panfungal polymerase chain reaction (PCR) assay for the management of IFDs in such patients. Methods We prospectively analysed 273 consecutive blood samples from 64 risk episodes in 51 patients with haematologic disorders at high risk for IFD who were treated at our hospital between April 2007 and October 2010. Results PCR-positive results were obtained in 18 of 64 risk episodes (35.3%). IFD was documented in 14 episodes (21.9%, 9 probable IFDs and 5 possible IFDs) according to the revised criteria of the European Organization for Research and Treatment of Cancer/Mycoses Study Group. PCR was positive in all of these 14 episodes, and in 4 of the 50 episodes with no IFD category. Sensitivity, specificity, positive predictive value, and negative predictive value of our assay were 100%, 92%, 78% and 100% respectively. A considerable number of fungi (44.4%) that are less common than Aspergillus and Candida species were positive by PCR. Molecular diagnoses of Cunninghamella species, Aspergillus ustus, Fusarium species, Scedosporium apiospermum, Rhodotorula species and Rhizopus species were beneficial in selecting suitable treatments. Conclusions Our panfungal PCR approach allows for the highly sensitive and specific detection and identification of a wide spectrum of fungal pathogens, which provides indispensable information for managing IFDs, especially refractory or breakthrough IFDs during antifungal therapy in high-risk patients with haematologic disorders.

Antiphospholipid antibodies (aPL) including lupus anticoagulant (LA), anticardiolipin antibodies (aCL) IgG and aCL-β2-glycoprotein I (β2GPI) complex IG are causative factors for thrombotic event (THE). We retrospectively investigated relationships between aPLs and THE in 458 patients suspected of having antiphospholipid syndrome. THEs were observed in 232 of 458 patients, including 148 cases of venous thrombosis, 59 of arterial thrombosis, 18 of microthrombosis, and 20 of complications of pregnancy. The frequency of THE was significantly high in patients positive for LA and/or aPL. In patients with autoimmune disease (AID), the frequency of THE was significantly high in patients with any types of aPLs. Additionally, risk of THE was significantly increased in patients with more than two types of aPLs. Prolonged activated partial thromboplastin time indicated a high risk for THE. However, neither thrombocytopenia nor AID was a risk for THE. In conclusion, the presence of aPL is an indicator for high risk of THE in patients in whom THE was suspected. However, the risk of THE in aPL-positive patients varied among patients with different underlying diseases.

One hundred and eleven patients with antiphospholipid antibodies (aPL) were diagnosed at Mie University Hospital during the past 17 years. Two of these patients developed disseminated intravascular coagulation (DIC). The first patient twice developed DIC complicated by pancreatitis and pregnancy, while in the second case, no specific causative complications for DIC were identified. The details of these cases imply that aPL is associated with DIC and/or is a potent triggering factor for DIC.

Background CYP2C19 loss-of-function genotype (*2 and/or *3 alleles) is related to low responsiveness to clopidogrel, which is a risk factor for ischemic cardiac events. The contribution of these genotypes to platelet reactivity in Japanese patients in a steady state receiving dual antiplatelet therapy after coronary stenting was evaluated. Methods and results A total of 155 Japanese patients were classified according to their CYP2C19 loss-of-function genotype. Platelet reactivity was assayed by plasma levels of soluble P-selectin and platelet-derived microparticles, light transmittance aggregometry induced by ADP (ADP-LTA), shear stress-induced platelet aggregometry, vasodilator-stimulated phosphoprotein phosphorylation (VASP) index and the VerifyNow-P2Y12 assay. Linear and logistic regression models were used to assess the associations between CYP2C19 loss-of-function genotype and high on-treatment platelet reactivity. In total, 62 patients (40.0%) were extensive metabolizers (EMs), 70 (45.2%) were intermediate metabolizers (IMs) and 23 (14.8%) were poor metabolizers (PMs). ADP-specific assays (ADP-LTA, the VASP index and VerifyNow-P2Y12) differed according to CYP2C19 genotype, with a significant gene-dose effect (PMs>IMs>EMs). CYP2C19 loss-of-function carrier status was associated with more frequent high platelet reactivity. CYP2C19 loss-of-function genotype alone could explain 12.2%, 14.3%, and 14.7% of the variability in the ADP-LTA, VASP and VerifyNow-P2Y12 assays, respectively. Conclusions CYP2C19 loss-of-function genotype is associated with more frequent high platelet reactivity, as assessed by ADP-specific platelet function tests, in Japanese patients.

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.

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.

Venous thromboembolism (VTE) is a serious, although decreasingly prevalent, complication following major orthopedic surgery, such as total hip replacement and total knee replacement. In Japan, patients undergoing orthopedic surgery are treated with adjusted-dose warfarin, low-dose unfractionated heparin (UFH), fondaparinux, low-molecular-weight heparin (LMWH), and edoxaban postoperatively for VTE prophylaxis. The American College of Chest Physicians guidelines recommend the administration of various anticoagulants, including warfarin, LMWH, UFH, edoxaban, fondaparinux, dabigatran, apixaban, rivaroxaban, and aspirin. Although the prothrombin time (PT) remains constant under monitoring of warfarin therapy, the PT, activated partial thromboplastin time (APTT), and anti-Xa activity may vary under monitoring of treatment with UFH, LMWH, fondaparinux, and/or novel oral anticoagulants (NOACs). Therefore, the monitoring of selective anti-Xa drugs has not yet been established. A marked prolongation of the APTT and PT values in patients treated with NOACs indicates a risk of bleeding, whereas low levels of D-dimer and soluble fibrin suggest the usefulness of anticoagulants for VTE prophylaxis. An elevation of the anti-Xa activity on day 1 in addition to a marked elevation of the D-dimer level reflect the risk of major bleeding in patients undergoing orthopedic surgery treated with fondaparinux postoperatively. However, there are currently no biomarkers for the efficacy of selective Xa or thrombin inhibitors. Therefore, it is necessary to establish further evidence for monitoring the effects of NOACs.

A 76-year-old man was admitted to a community hospital due to a persistent high fever. He became afebrile after the administration of broad-spectrum antibiotics, but developed heart failure due to progressive aortic and mitral valve insufficiency and was transferred to our hospital. Although sequential blood cultures were negative, a broad-range polymerase chain reaction targeting the bacterial 16S-rRNA gene followed by the direct sequencing of whole blood revealed spa(+), mecA(-) and Panton-Valentine leukocidin (PVL)(+). He was finally diagnosed with infective endocarditis (IE) caused by PVL-producing methicillin-susceptible Staphylococcus aureus (MSSA), and underwent cardiac surgery. This is the first reported case of IE due to MSSA producing PVL.

Congenital thrombophilia which is characterized by deficiencies in proteins such as antithrombin (AT), protein C (PC) and protein S (PS), is a major cause of venous thromboembolism (VTE). A total of 130 patients with VTE were evaluated for congenital thrombophilia based on the activity of AT, PC, or PS. Fifteen VTE patients with congenital AT deficiency (11.5 %), 16 with congenital PC deficiency (12.3 %) and eight with congenital PS deficiency (6.2 %) were diagnosed using DNA analysis. The frequency of congenital AT deficiency was significantly higher in subjects with pregnancy-related and idiopathic VTE than in those with VTE due to other causes, and congenital PC and PS deficiency were frequently associated with idiopathic VTE. Among the groups examined, the plasma levels of AT were the lowest in subjects with pregnancy-related VTE. Although our findings may have been influenced by some unintentional bias, congenital thrombophilia is nevertheless a major cause of VTE in pregnant patients as well as in young or middle-aged patients without any underlying diseases.

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 108 patients with suspected infectious DIC. Material and methods: The diagnoses of the patients were as follows: DIC (n = 63), pre-DIC (n = 22), and non-DIC (n = 45). The efficacy of the diagnostic criteria for DIC was evaluated using a receiver–operating characteristic analysis. Results: Although the area under the curve for global coagulation test (GCT) scores in the diagnosis of “DIC” was high that for the diagnosis of “DIC and pre-DIC” was low, suggesting that the addition of antithrombin (AT), soluble fibrin (SF)/thrombin–AT complex (TAT), and reduced platelet count (PLT) values was required to diagnose “DIC and pre-DIC.” Using GCT score with the AT, SF/TAT, and reduced PLT values, the cutoff value of the DIC score for the diagnosis of “DIC and pre-DIC” was 5 points. Discussion and conclusion: The modified JSTH’s diagnostic criteria for DIC, which used the GCT score and the reduced PLT, AT, and TAT/SF values, were useful for diagnosing “DIC and pre-DIC.”

Plasma levels of thrombin activatable fibrinolysis inhibitor (TAFI) and total plasminogen activator inhibitor-1 (PAI-1) and tissue type plasminogen activator (tPA)/PAI-1 complex in patients with disseminated intravascular coagulation (DIC) to examine the relationship between hypofibrinolysis and the pathogenesis with DIC. We examined 39 patients with DIC, 23 with pre-DIC, 181 without DIC and 17 healthy volunteers. Both plasma levels of total PAI-1 and tPA/PAI-1 complex were significantly high in patients with DIC. Those levels were also high in patients with organ failure, especially sepsis. Both TAFI activity and antigen levels in the plasma were significantly low in patients with DIC. TAFI activity in plasma was correlated with TAFI antigen. TAFI activity and antigen levels were negatively correlated with TAT and D-dimer. The TAFI activity in plasma was significantly low in patients with infection and in those with organ failure, suggesting that TAFI may play an important role in the mechanism of organ failure in DIC-associated sepsis. Regulation of fibrinolysis by TAFI and PAI-1 may play an important role in the pathogenesis of DIC and organ failure.

Neuroendocrine neoplasms (NENs) are derived from endocrine cells in various organs and share common morphological features. This study aimed to clarify whether NENs of different organs are comparable at the molecular pathologic level. We retrospectively collected 99 cases of NENs from gastro-entero-pancreatic, lung, and other organs and reclassified these according to identical criteria. Grade, site, and molecular expression profile including NE markers, Ki-67, p53, somatostatin receptor type 2A (SSTR2A), and phosphatase and tensin homolog (PTEN) were compared. PTEN immunoreactivity was also compared with genomic copy number by fluorescence in situ hybridization (FISH) and droplet digital polymerase chain reaction (ddPCR). No significant differences were observed in the immunoreactivities of NE markers, p53, SSTR2A, or PTEN expression in NENs between the different organ sites. PTEN and p53 functional inactivation along with the loss of membranous SSTR2A expression appeared to be commonly involved in high-grade NEN. FISH results were significantly correlated with the level of PTEN immunoreactivity and with the findings of ddPCR analyses. The demonstration that these tumors are comparable at the molecular level will likely contribute to the broadening of therapeutic options such as the use of somatostatin analogues and mTOR inhibitors against NENs regardless of the affected organ, whereas molecular characterization of tumor grade will be useful for determining treatment strategy.

The precise mechanism of prolonged thrombocytopenia following living donor liver transplantation (LDLT) remains unclear. To determine risk factors associated with prolonged thrombocytopenia following LDLT, with a focus on the activity of ADAMTS13 (a disintegrin-like and metalloproteinase with thrombospondin type-1 motifs member 13) and the influence of splenectomy. Adult LDLT patients were divided into two groups on the basis of platelet counts (100 × 103/μL) on POD 14: high and low platelet (HP and LP) groups. Survival analysis was performed in the 100 patients, and ADAMTS13 activity and von Willebrand factor (VWF) levels in the plasma were measured in 65 adult recipients. The 6-month survival rate was significantly lower in the LP group (n = 36) than in the HP group (n = 62) (61.1 vs. 93.5 %). ADAMTS13 activity had been significantly lower in the LP group (n = 23) than in the HP group (n = 42). The VWF/ADAMTS13 ratio was significantly higher in the LP group than in the HP group. The independent risk factors for thrombocytopenia on POD14 were preoperative AT levels and ADAMTS13 activity on POD14. TPO levels on POD14 were significantly higher in the LP group than in the HP group, while those on POD28 in the LP group were significantly decreased, despite the low platelet levels. Irrespective of splenectomy history, platelet counts and ADAMTS13 activity in the LP group remained low until POD28, while VWF/ADAMTS13 ratio significantly increased until POD28. These results suggest that prolonged thrombocytopenia after LDLT was associated with not only a decrease in ADAMTS13 due to sinusoidal endothelial cell injury, but also low TPO production due to hepatocyte dysfunction, irrespective of history of splenectomy.

Thrombophilia such as protein C (PC), antithrombin (AT), or protein S (PS) deficiency can cause either fatal or frequent venous thromboembolism (VTE); however, Japanese individuals have few factor V Leiden or prothrombin mutations. The a-fibrinogen (FGA): p.Thr331Ala polymorphism occurs in a region that is important for FXIII-dependent cross-linking, and it may therefore affect the clot structure or degree of rigidity. A significant association has been observed between FGA: p.Thr331Ala and poststroke mortality in participants with atrial fibrillation, and this fibrinogen polymorphism has also been reported to be associated with VTE; the genotype distribution of patients with pulmonary embolism (TT 1⁄4 49%, TA 1⁄4 36%, AA 1⁄4 15%) differed significantly from healthy control participants (TT, wild type 1⁄4 60%, TA, heterozygous 1⁄4 34%, AA, homozygous 1⁄4 6%). The frequency of the FGAThr312Ala polymorphism was reported to be 46.5% in Japanese individuals and 29.9% in Europeans. A previous report suggested that FGA: p.Thr331Ala may cause early pregnancy loss. Therefore, FGA: p.Thr331Ala polymorphism was examined in 27 pregnant women without early pregnancy loss and 26 those with more than 1 experience of suffering early pregnancy loss, including 14 patients with thrombophilia according to a genetic analysis (4 with hereditary AT deficiency, 9 with hereditary PC deficiency, and 1 with hereditary PS deficiency) and 8 patients with hypofibrinogenemia (less than 1.5 g/L vs normal range 1.8-2.8 g/L). Of 14 patients with hereditary thrombophilia, 12 patients experienced VTE and 5 patients experienced pregnancy loss. All patients with AT deficiency were diagnosed during pregnancy, but 9 patients with PC deficiency and 1 with PS deficiency were diagnosed after delivery. The diagnosis of AT, PC, or PS deficiency was reported previously. Thirtyseven cases of thrombophilia (14 with AT deficiency, 16 with PC deficiency, and 7 with PS deficiency) with VTE were diagnosed at Mie University Hospital. The Japanese birth rate was 8.0 per 1000 in 2015, and the pregnancy loss rate varied with age. Early pregnancy loss was defined as an unknown cause, and more than 1 abortion before 10 weeks of pregnancy occurred. Early pregnancy loss was found to be associated with 8 (57.1%) of 14 women demonstrating homozygous FGA: p.Thr331Ala polymorphism, in 17 (54.8%) of 31 women with heterozygous FGA: p.Thr331Ala polymorphism and in 1 (12.5%) of 8 women with FGA: p.Thr331. The rate of pregnancy loss was 1 in 10 cases, 2 in 9 cases, 3 in 6 cases, and 8 in 1 case, respectively. Although FGA: p.Thr331Ala polymorphism was found to increase the risk of early pregnant loss, thrombophilia reduced the risk of early pregnant loss (Table 1). The risk of early pregnancy loss was significantly higher in women with homozygous or heterozygous FGA: p.Thr331Ala polymorphism than in women with FGA: p.Thr331 (Odds ratio: 8.84, P < .05). Although the risk of early pregnancy loss tended to be low in the thrombophilic women with either homozygous or heterozygous FGA: p.Thr331Ala polymorphism than in the other women, it was significantly higher in the nonthrombophilic women with homozygous or heterozygous FGA: p.Thr331Ala polymorphism than in the other women (odds ratio: 4.85, P < .01). These findings suggest that thrombophilia might provide some advantage for preserving pregnancy in women with an abnormal fibrinogen function, but thrombophilia causes thrombosis in pregnant women. As our analysis was small and there may have been some bias in the selection of samples, further investigation is therefore required. In conclusion, although FGA: p.Thr331Ala polymorphism increased the risk of early pregnant loss, thrombophilia reduced the incidence of early pregnant loss in women with FGA

A pre-thrombotic (hypercoagulable) state is observed in patients with thrombophilia, malignant diseases, pregnancy, auricular fibrillation, connective tissue diseases, prosthetic replacement arthroplasty, infection, or old age, and these states are also caused by dehydration, remaining in the same position for a long time, or estrogen drugs. Such patients have a high risk of developing thrombosis. The pre-thrombotic state is diagnosed or excluded by fibrin-related markers (FRMs), such as soluble fibrin (SF), fibrinogen and fibrin degradation products (FDP), and D-dimer. The cut-off values of FRMs are higher in patients with pregnancy or malignant diseases than in other patients. Patients with more than two of the eight underlying states and three causative factors for pre-thrombotic conditions or those with one of those conditions and high levels of FRMs are diagnosed as being in a prethrombotic state. These patients should receive treatment with anticoagulant therapy.

Introduction Although antithrombin is commonly used for the treatment of sepsis-associated disseminated intravascular coagulation (DIC) in Japan, the factors influencing the incidence of bleeding complications have not been sufficiently studied. The purpose of this survey was to identify the factors that predict clinically relevant bleeding in patients receiving antithrombin for DIC. Methods We analyzed data from 1026 sepsis-associated DIC patients with a baseline antithrombin activity ≤70% who underwent antithrombin supplementation at two dosages (1500IU/day or 3000IU/day) for three consecutive days. The patients' demographic characteristics, parameters before and after the treatment, and co-administered anticoagulants were analyzed in relation to the bleeding events. Results Overall, 55 patients (5.36%) experienced bleeding events (major bleeding: 1.75%). Logistic regression analysis revealed that sustained DIC>7days was significantly associated with bleeding (odds ratio: 2.761, P =0.001). In contrast, the higher dose of antithrombin or the co-administration of recombinant thrombomodulin or heparins were not associated with bleeding events. Conclusion A higher dose of antithrombin or the concomitant use of other anticoagulants were not associated with bleeding events. On the other hand, sustained DIC lasting more than one week was associated with an increased risk of bleeding in patients with sepsis-associated DIC.

Blood coagulation factors play an essential role in pregnancy. We describe a 30-year-old pregnant woman whose course was complicated by dysfibrinogenemia with polymorphism of fibrinogen AαThr312Ala (rs6050) GG genotype. She was admitted to our hospital for genital bleeding and a huge subchorionic hematoma at 6 gestational weeks. Her first pregnancy and delivery had been uneventful, whereas her second and third pregnancies had resulted in spontaneous abortions with massive subchorionic hematomas. Her fibrinogen activity level was 125 mg/dl and this was lower than her fibrinogen antigen level. We administered tranexamic acid early in the pregnancy, and the subchorionic hematoma diminished in size in accordance with the increase of her fibrinogen level. At 16 gestational weeks, her D-dimer levels were elevated, and heparin treatment was initiated as an alternative. A male infant was delivered at 36 gestational weeks. Intrapartum hemorrhage was 600 g. Patients with coagulation abnormalities are often asymptomatic in the absence of pregnancy. However, when they become pregnant, the spontaneous abortion rate is high. Careful observation and effective management of coagulation abnormalities are essential for such patients to carry their pregnancies to term.

Thrombotic thrombocytopenic purpura (TTP) frequently develops in patients with connective tissue diseases (CTDs). ADAMTS13 and von Willebrand factor (VWF) are closely related to the onset of TTP. We investigated the roles of ADAMTS13 and VWF in thrombotic events of patients with CTD. ADAMTS13 activity and VWF and VWF propeptide (VWFpp) levels in CTD, primary antiphospholipid antibody syndrome (pAPS), and controls were measured to examine their relationship with thrombosis. ADAMTS13 activity levels were significantly low in the patients with CTD but not in the patients with pAPS. No significant difference in the ADAMTS13 activity levels among the various CTD subgroups was found. The levels of VWF and VWFpp were significantly elevated in the patients with pAPS and CTD compared with that of control groups. Eleven patients with CTD developed TTP, and their ADAMTS13 activity levels were significantly lower than patients having CTD without TTP. However, the ADAMTS13 activity levels showed no difference between the patients having CTD with and without thrombotic events. The VWF antigen levels were significantly high in the patients having CTD with TTP. There were no significant differences in the VWF levels of the patients having CTD with TTP and thrombosis. The VWFpp levels were significantly high in the patients having CTD with TTP and thrombosis. The VWF and VWFpp levels were significantly high in the patients with pAPS. Decreased ADAMTS13 activity and elevated VWF and VWFpp levels were observed in patients with CTD. These abnormalities in patients with CTD may represent the increased risk of thrombosis in CTD.

Objective: The cutoff values of fibrin-related markers (FRMs) diagnosing or predicting the occurrence of a venous thromboembolism (VTE) were evaluated. Materials and Methods: Fibrin-related markers such as fibrin monomer complex (FMC), D-dimer, and fibrinogen and fibrin degradation products (FDPs) before surgery were measured in 326 patients undergoing orthopedic surgery to diagnose subclinical VTE or predict postoperative VTE. Results: Although the FMC, D-dimer, and FDP levels were all useful for the diagnosis of acute VTE, the FDP level was not useful for diagnosing subclinical VTE or predicting postoperative VTE. The results of several D-dimer assays closely correlated with other D-dimer assays. There were various cutoff ranges for diagnosing or predicting VTE. Some D-dimer assays were useful for diagnosing low levels of D-dimer and others were useful for diagnosing moderate to high D-dimer levels. Increased D-dimer levels were useful for diagnosing acute (cutoff values: 2.0-5.9 μg/mL) or about 10% of subclinical VTE (cutoff values: 3.4-5.3 μg/mL), for predicting about 10% of postoperative VTE (cutoff values: 3.4-5.3 μg/mL), and for excluding VTE. Conclusion: Although increased D-dimer levels were useful for diagnosing subclinical VTE and predicting the risk of VTE, there were various cutoff values for the diagnosis or prediction of VTE.

SummaryThe cornerstone of the management of disseminated intravascular coagulation (DIC) is the treatment of the underlying condition triggering the coagulopathy. However, a number of uncertainties remain over the optimal supportive treatment. The aim of this study was to provide evidence and expert-based recommendations on the optimal supportive haemostatic and antithrombotic treatment strategies for patients with DIC. A working group defined five relevant clinical scenarios. Published studies were systematically searched in the MEDLINE and EMBASE databases (up to May 2014). Seven internationally recognised experts were asked to independently provide clinical advice. A two-phase blinded data collection technique was used to reach consensus. Only three randomised controlled trials (RCTs) on the supportive management of DIC were identified. The RCTs (overall less than 100 patients) investigated the use of fresh frozen plasma and platelet transfusion and found no differences in survival between the intervention and control groups. The experts’ approach was heterogeneous, although there was consensus that supportive management should vary according to the underlying cause, clinical manifestations and severity of blood test abnormalities. Platelet transfusion should be given to maintain platelet count > 50×109/l in case of bleeding while a lower threshold of 20 to 30×109/l may be used in DIC without bleeding. Thromboprophylaxis with low-molecular-weight heparin is advised until bleeding ensues or platelet count drops below 30×109/l. In conclusion, in the absence of solid evidence from RCTs, an individualised supportive management of DIC is advisable based on the type of underlying disease, presence of bleeding or thrombotic complications and laboratory tests results.Supplementary Material to this article is available online at www.thrombosis-online.com.

Although supplementation with antithrombin (AT) concentrates has been widely accepted for the treatment of disseminated intravascular coagulation (DIC) in Japan, the effects and adverse effects have not been investigated.We conducted a nonrandomized multi-institutional survey. A total of 729 septic DIC patients with AT activity levels of 70% or lower, who had undergone AT substitution at either 1500 IU/day or 3000 IU/day for consecutive 3 days were analyzed. Of these, 650 and 79 patients had received 1500 IU/day (AT1500 group) and 3000 IU/day (AT3000 group), respectively.Bleeding events were observed in 6.52% of patients (severe bleeding, 1.71%). A significant decrease in initial AT level (below 50%) was observed in 69.6% of patients in AT3000 group and 48.2% in AT1500 group, and this difference was significant (P0.01). A logistic-regression analysis conducted using age, gender, body weight, initial AT activity, and supplemented AT dose, revealed that higher initial AT activity (odds ratio (OR), 1.032; P0.001), AT dose of 3000 IU/day (OR, 1.912; P=0.026), and age (OR, 0.985; P=0.023) were significant factors for improved survival.The risk of severe bleeding is less than 2%, and concomitant administration of heparin did not increase the risk. The survival in AT1500 group was 65.2%, while that in AT3000 group was 74.7%.

Staphylococcus aureus (SA) directly activates eosinophils via PAF receptor to induce degranulation, superoxide, and cytokine production, suggesting that SA colonization has pathological significance in atopic dermatitis. Colonization by SA is associated with exacerbation of AD. Eosinophilic inflammation is a cardinal pathological feature of AD, but little is known about possible direct interaction between SA and eosinophils. PAFR appears to be involved in phagocytosis of Gram-positive bacteria by leukocytes. The objective of this study was to investigate whether SA directly induces eosinophil effector functions via PAFR in the context of AD pathogenesis. Peripheral blood eosinophils were cultured with heat-killed SA, and EDN release, superoxide generation, and adhesion to fibronectin-coated plates were measured. Cytokines, released in the supernatants, were quantified by multiplex bead immunoassays. FISH-labeled SA was incubated with eosinophils and visualized by confocal laser-scanning microscopy. PAFR-blocking peptide and PAFR antagonists were tested for inhibitory effects on SA-induced reactions. SA induced EDN release and superoxide generation by eosinophils in a dose-dependent manner. IL-5 significantly enhanced SA-induced EDN release. IL-5 and IL-17A significantly enhanced SA-induced superoxide generation. SA enhanced eosinophil adhesion to fibronectin, which was blocked by anti-CD49d, and induced eosinophil secretion of various cytokines/chemokines (IL-2R, IL-9, TNFR, IL-1β, IL-17A, IP-10, TNF-α, PDGF-bb, VEGF, and FGF-basic). After incubation of eosinophils with SA, FISH-labeled SA was visualized in the eosinophilsˈ cytoplasm, indicating phagocytosis. A PAFR-blocking peptide and two PAFR antagonists completely inhibited those reactions. In conclusion, SA directly induced eosinophil activation via PAFR. Blockade of PAFR may be a novel, therapeutic approach for AD colonized by SA.

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.

ADAMTS13, endothelial von Willebrand factor (VWF) and related proteins are involved in the pathogenesis of some life threatening systemic thrombotic coagulopathies. Changes of plasma ADAMTS13 activity in thrombotic thrombocytopenic purpura (TTP) is well known but is also involved in septic disseminated intravascular coagulation (DIC). Here we investigated the ADAMTS13 activity, VWF and VWF propeptide (VWFpp) antigens in 69 patients with DIC, 143 with non-DIC, 21 with thrombotic thrombocytopenic purpura (TTP) and 23 with atypical hemolytic uremic syndrome (aHUS) for diagnosis of DIC. The plasma ADAMTS13 activity was significantly low in patients with DIC, and the plasma levels of VWF and VWFpp antigens, were the highest in these patients, but there were no significant differences in the plasma VWFpp levels between the patients with DIC and those with aHUS. The difference in the plasma ADAMTS13 activity, the VWF and VWFpp antigens between DIC and non-DIC cases was significant in those with infectious and malignant diseases, but the difference in the VWFpp/ VWF ratio were significant only in subjects with infectious diseases. As an indicator for prognosis, the plasma levels of VWFpp were significantly higher in non-survivors than in survivors. Then, VWFpp/ VWF ratio and VWFpp/ADAMATS13 ratio will be potent informative indicators in DIC. These findings suggest that ADAMTS13/VWF profiles may have important roles in the pathogenesis of DIC, and that ADAMTS13 and VWFpp are useful indicators for the diagnosis and prognosis of DIC.

The aim of the present study was to evaluate the influence of donor age on liver regeneration and surgical outcomes in recipients and donors.Among 101 cases of adult-to-adult living donor liver transplantation (LDLT) between March 2002 and March 2011, according to donor age: younger (Y)50 years of age or older (O) ≥ 50 years of age, the donors and recipients using right (R) or left (L) graft were divided into groups Y/R (n = 51) and O/R (n = 17), and groups Y/L (n = 26) and O/L (n = 7), respectively. Remnant liver volume (RemLV) and graft liver volume (GLV) were estimated by computed tomography (CT) volumetry. A disintegrin and metalloprotease with thrombospondin type I domain 13 (ADAMTS13) activities and von Willebrand factor (vWF) antigen levels were measured as factors reflecting thrombotic microangiopathy.Among the donors, RemLV/total liver volume (TLV) was lower in group O/R than in group Y/R, although there were no significant differences by t-test with the Bonferroni correction (rough p value = 0.02 at 6 months and rough p value0.05 at 1, 3, and 12 months). Donor age (≥ 50 years) was independently correlated with impaired remnant liver regeneration at 6 months in right lobe LDLT (p = 0.04). Among the recipients, GLV/standard liver volume (SLV) was lower during the first month, although there were no significant differences between the two groups by t-test with the Bonferroni correction (rough p value = 0.03 at 1 week and rough p value0.05 at 2 weeks and 1 and 3 months). Donor age (≥ 50 years) was independently correlated with impaired graft liver regeneration at 1 week in both right and left lobe LDLT (p0.05). ADAMTS13 activities were lower in group O/R than in group Y/R, although there were no significant differences by t-test with the Bonferroni correction (rough p value = 0.049 on postoperative days (POD) 1 and 28 and rough p value0.05 on POD 7 and 14). vWF/ADAMTW13 ratios were higher on POD 14, although there were no significant differences between the two groups by t-test with the Bonferroni correction (rough p value = 0.044 on POD 14 and rough p value0.05 on POD 1, 7, 14, and 28).The surgical outcomes using older donor livers for LDLT were comparable to those using younger donor livers. When using older donor livers, however, we should pay attention to the liver volume for recipients as well as donors, because older donor livers might have impaired regenerative ability.

Thrombophilia is frequently associated with venous thromboembolism (VTE) including cerebral venous sinus thrombosis (CVST). The possibility of thrombophilia was examined in 12 patients with CSVT diagnosed in the past 9 years. Thrombophilia due to abnormalities in antithrombin (AT), protein C (PC), or protein S (PS) or antiphospholipid syndrome (APS) was evaluated. Nine patients with abnormally decreased AT, PC or PS and one patient with APS were examined. Of the nine patients examined by a gene analysis of AT, PC, or PS, one had a congenital AT deficiency, one had a congenital PC deficiency, and two had congenital PS deficiencies including a novel mutant (Gly189Ala). AT, PC and PS levels were all decreased in one patient, PS level was decreased in three patients, and AT level was decreased in one patient at the onset of CVST, but these concentrations improved after treatment. CVST is frequently associated with thrombophilia and a transient decrease in AT, PC or PS may be a causal factor.

We look at the structure of and give a mass formula for self-dual codes over the ring $${{\bf Z}_{2^s}}$$ of integers modulo 2 s . Together with earlier work on the case of odd primes, this completes the mass formula for self-dual codes for $${{\bf Z}_{p^s}}$$ , for all prime numbers p and positive integers s.

Nogo-B, located in the endoplasmic reticulum, is an isoform belonging to the reticulon protein family, which is expressed specifically in cholangiocytes and non-parenchymal cells in the liver. Nogo-B expression is down-regulated with the progression of liver fibrosis, but its distinct function in liver malignancies has not been fully clarified. We have hypothesized that Nogo-B expression may be altered in intrahepatic cholangiocarcinoma (ICC), a relatively rare type of primary liver cancer with highly malignant behavior. The present study aimed to investigate the relationship between Nogo-B expression, assessed by immunohistochemical staining, and clinicopathological factors and prognosis in 34 ICC patients. Positive expression was observed in 19 (56%) of 34 ICC specimens: 6 patients (18%) with positivity levels of 1+ (positive cells in 10-50% of cancer cells) and 13 patients (38%) with 2+ (positive cells over 50%). Importantly, the remaining 15 patients (44%) were categorized as negative expression (Nogo-B-positive cells, less than 10%). Conversely, the mass-forming type of ICC tended to express Nogo-B with the degree of 2+ positivity, compared to the periductal infiltration type (p = 0.064), and the mass-forming type showed a better 5-year survival rate (66% vs. 5%) after hepatectomy (p < 0.05). However, the degree of positivity was not associated with tumor relapse rate, disease-free and overall survival, although each of the periductal infiltration type, intrahepatic metastasis, larger tumor size, and lower microvessel counts was associated with lower survival rates. We propose that Nogo-B expression is down-regulated in ICC, the implication of which, however, remains to be investigated., The Tohoku Journal of Experimental Medicine, 238(1), pp.9-16; 2016

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.

Objectives: Sepsis caused by the bacterial contamination of blood products is a major infection risk associated with blood transfusion. Diversion of the initial 25 mL of blood and prestorage leukoreduction were implemented in Japan in 2007 for all donated blood products. We assessed the efficacy of these new collection procedures in preventing bacterial contamination of red blood cell (RBC) concentrates. Methods: Broad-range 16S ribosomal RNA polymerase chain reaction was used to determine bacterial contamination in segment samples of RBCs before and after implementation of the new collection procedures. To evaluate whether these new procedures reduced bacterial contamination, we compared bacterial contamination rates of blood samples from diversion pouches with those of segment samples from the same donor's RBCs. Results: The rate of bacterial contamination of RBCs before implementation of the new collection procedures was 1·27%. Most of the isolated bacteria were Staphylococcus epidermidis or Propionibacterium acnes. After implementation, this rate was significantly reduced to 0·10%. Of the 233 whole blood samples obtained from the Mie Red Cross Blood Center, 1·72% of blood samples from diversion pouches were contaminated, but no bacterial contamination was detected in segment samples from the same donor's RBCs after prestorage leukoreduction. Conclusions: The new collection procedure significantly reduced bacterial contamination of RBC concentrates.

The efficacy of measuring anti-Xa activity was evaluated in major orthopedic surgery patients receiving thrombo-prophylaxis with Fondaparinux. Although 98 orthopedic patients including those receiving total hip replacement (THR) and total knee replacement (TKR) were treated with 1.5 mg of Fondaparinux for prophylaxis of deep vein thrombosis (DVT). Sixteen patients developed DVT, but none was associated with a fatal pulmonary embolism. There was a wide range of anti-Xa activity, but there were no patients with less than 0.15 mg/l or more than 0.90 mg/l. Anti-Xa activity gradually increased from days 1 to 8 and showed no significant difference between patients with and without DVT. Anti-Xa activity was correlated with weight, height, body mass index, and antithrombin activity. Postoperative plasma levels of D: -dimer and soluble fibrin (SF) were markedly high, and those were significantly reduced at days 1 and 4 of treatment with Fondaparinux. Plasma levels of SF were significantly reduced at days 8 and 15, but D: -dimer was not. These findings suggested that there was continued thrombin generation after the injection of Fondaparinux until day 8 and secondary fibrinolysis occurred on day 8. In conclusion, 1.5 mg of Fondaparinux may not be sufficient for the prophylaxis of silent DVT, but it was found to be useful for that of fatal pulmonary embolism. Consequently, monitoring anti-Xa activity may be unnecessary for the administration of Fondaparinux at such doses.

Grain hardness of wheat is determined by the hardness (Ha)-locus region, which contains three friabilin-related genes: puroindoline-a (Pina), puroindoline-b (Pinb) and GSP-1. In our previous study, we produced the transgenic rice plants harboring the large genomic fragment of the Ha-locus region of Aegilops tauschii containing Pina and GSP-1 genes by Agrobacterium-mediated transformation. To examine the effects of the transgenes in the rice endosperms, we firstly confirmed the homozygosity of the T-DNAs in four independent T2 lines by using fluorescence in situ hybridization (FISH) and DNA gel blot analyses. The transgenes, Pina and GSP-1, were stably expressed in endosperms of the T3 and T4 seeds at RNA and protein levels, indicating that the promoters and other regulatory elements on the wheat Ha-locus region function in rice, and that multigene transformation using a large genomic fragment is a useful strategy. The functional contribution of the transgene-derived friabilins to the rice endosperm structure was considered as an increase of spaces between compound starch granules, resulting in a high proportion of white turbidity seeds.

Introduction Autoantibodies to ADAMTS13 have a pivotal role in the pathogenesis of acquired thrombotic thrombocytopenic purpura (TTP). By decreasing the function of ADAMTS13, autoantibodies impair the cleavage of ultra-large von Willebrand factor (UL-VWF) multimers into smaller sizes, leading to lethal platelet-VWF thrombi in the microcirculation. We therefore aimed to determine the sites of autoantibody recognition on ADAMTS13. Materials and Methods In this study, IgG purified from 13 acquired TTP patients were examined to determine their binding sites on ADAMTS13. Immobilized IgG on microtiter plate or proteinG beads was screened by phage library expressing various peptides of ADAMTS13. Results In screening, diverse peptide sequences were obtained from almost all of the ADAMTS13 domains, including the spacer domain, which is considered a major binding site. In particular, we detected an identical amino-acid sequence in the C-terminus of the spacer domain from Gly662 to Val687 that was recognized by autoantibodies from 5 TTP patients. The specific autoantibody was expected to be associated with the plasma levels of the ADAMTS13 antigen or activity, and with the quantity of ADAMTS13 autoantibodies or the inhibitory autoantibody titer in TTP patient plasma. These measurements, however, did not seem to be related to the presence or absence of the specific autoantibody. Conclusions These findings indicate that the specific autoantibody might be a feature of acquired TTP, although its clinical significance remains to be elucidated.

SummaryThere are three different diagnostic score systems for disseminated intravascular coagulation (DIC) established by the Japanese Ministry Health and Welfare (JMHW), the International Society on Thrombosis and Haemostasis (ISTH) and the Japanese Association for Acute Medicine (JAAM). The JMHW criteria are still used in Japan. In the present study, all three diagnostic criteria were used to prospectively evaluate 413 patients with different underlying diseases of DIC who were treated at the Mie University Hospital (JMHW, n= 166; ISTH, n=143; JAAM, n=291). The odds ratio (95% confidence interval) for death was 1.88 (1.22 – 2.90) in JMHW, 2.55 (1.65 – 3.95) in ISHT and 1.99 (1.19 – 3.32) in JAAM. The platelet count, prothrombin time, fibrin and fibri-nogen degradation products and fibrinogen were significantly important for diagnosis of DIC by all three diagnostic criteria. Haemostatic molecular markers were significantly high in all patients and were useful for the diagnosis of DIC. The JAAM diagnostic criteria displayed a high sensitivity for DIC and the ISTH overt-DIC diagnostic criteria displayed a high specificity for DIC. All three diagnostic criteria for DIC were related to a poor patient outcome.

Background: Elevated levels of Factor VIII (FVIII) have been suggested as important for the pathogenesis of venous thromboembolism (VTE). The objective of this study was to explore the association between elevated FVIII level and VTE in Japan. Methods and Results: 68 patients with objectively documented VTE and 40 controls were included. In the patients, the FVIII level was measured for a mean follow-up period of 52.6 months (3-348 months) after the onset of VTE, in order to avoid an acute-phase response. The VTE patients had a higher mean FVIII level than the controls (154.5±55.8IU/dl vs. 114.3±16.0IU/dl, P

大腸癌イレウスに消化管穿孔を続発し，急速な経過を辿った大腸未分化癌の1例を報告する．症例は90歳の女性．腹痛と嘔吐を認め近医を受診し，消化管穿孔が疑われ当科紹介となった．腹部CTにて多量の腹腔内遊離ガスと上行結腸に腫瘍性病変を認めた．緊急手術を施行したところ上行結腸に硬い腫瘤を触知し，同部より口側腸管はイレウスを呈していた．またTreitz靱帯から120cmの部位より回腸末端まで血流障害をきたしており，腫瘍より口側5cmの盲腸に径1cmの穿孔を認めた．血流障害をきたした小腸を含む右半結腸切除と洗浄ドレナージを行った．切除標本では上行結腸に4×6cm大，4型の全周性腫瘍を認め，病理所見では異型の強い腫瘍細胞が充実胞巣状に認められ，一部漿膜に露出し脈管侵襲が著明だった．組織学的には，腺管形成や粘液産生を認めず大腸未分化癌の像を示した．術後汎発性腹膜炎，敗血症を併発し多臓器不全にて死亡した．大腸未分化癌は極めて稀であり，文献的考察を加え報告する．

Thrombotic microangiopathy (TMA) is associated with vascular endothelial cell injury and is sometimes linked with poor outcome. Von Willebrand factor (VWF) propeptide (VWFpp) is considered to be a marker of vascular endothelial cell injury. The plasma levels of VWF, VWFpp, and thrombomodulin (TM) were evaluated for their use in the diagnosis of TMA in 75 patients with TMA. There were 30 TMA patients with marked decreases in ADAMTS13 (TMA/ADAMTS13) and 45 without the decrease (TMA/other). The plasma levels of TM, VWF, and VWFpp values were significantly high in patients with TMA, especially TMA/other group. The plasma levels of TM and VWFpp were significantly high in non-survivor with TMA. In the TMA/other group, the plasma levels of VWFpp were negatively correlated with ADAMTS13 activity. The plasma levels of TM correlated with the renal function, but the plasma levels of VWFpp did not. A ROC analysis indicated that VWFpp and TM were useful markers for the prediction of a poor outcome. These findings suggest that VWFpp is an useful marker for the diagnosis of TMA and for the prediction of poor outcome.

Deep vein thrombosis (DVT) is a multifactorial disease caused by acquired risk factors such as a bed rest, surgery and malignancies. Although the factor V Leiden and the prothrombin-20210G>A mutation do not exist in Japanese populations, a mutation in protein S (PS) Tokushima (K196E) has been attracting attention in Japan. In this study, the genetic contribution of PS Tokushima (K196E) was evaluated in 60 Japanese patients with thrombosis in comparison to 234 healthy volunteers and 88 patients without thrombosis. Genes associated with the response to warfarin, cytochrome P450 2C9 (CYP2C9), vitamin K epoxide reductase complex subunit 1 (VKORC1), and γ-glutamyl carboxylase (GGCX) were also investigated simultaneously. PS Tokushima (K196E) was detected in 6 patients with thrombosis, in 3 without thrombosis and in 3 healthy volunteers, indicating that there is a high frequency of the PS Tokushima (K196E). There were no significant differences of CYP2C9, VKORC1 or GGCX between the patients with and without DVT. Therefore, PS Tokushima (K196E) is an important genetic risk factor for DVT in the Japanese population.

Group-A-streptococcus-(GAS)-induced toxic shock syndrome (TSS) is uncommon, but carries a high risk of maternal mortality during pregnancy. The onset of gravidic GAS-TSS has been reported mostly during the puerperium. A 16-year-old woman, who was at 37 weeks of gestation, and without obstetrical care during the last 30 weeks, was referred to our hospital. She complained of fever for one day with headache and abdominal pain after the fever developed. On admission, her consciousness was drowsy, intrauterine fetal death was recognized, and she rapidly developed shock status with coma and hypotension, hemolysis, disseminated intravascular coagulation (DIC), and multi-organ failure. Although we had not obtained the results of a bacterial culture, we suspected sepsis with DIC with homolysis and multi-organ failure resulting from an infection. The patient was treated with antibiotics and intubation because of respiratory insufficiency. Twelve hours after admission to the intensive care unit in our hospital, she died. Cultures from blood, subcutaneous tissue, vaginal discharge, and pharynx all revealed GAS bacteria, and therefore she was diagnosed as having GAS-TSS. GAS-TSS in pregnancy is rare. However, once the infection occurs in a pregnant woman, it rapidly develops into sepsis with multi-organ failure. Therefore, early recognition and intensive treatment for GAS during pregnancy is recommended in women with high fever, muscular pain, hemolysis and DIC during pregnancy.