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Aims/Introduction The role of glucagon abnormality has recently been reported in type 2 diabetes; however, its role in gestational diabetes mellitus (GDM) is still unknown. The glucose intolerance in GDM is heterogeneous, and not all patients require insulin treatment during pregnancy. Here, we investigated whether glucagon abnormality is associated with the requirement for insulin treatment during pregnancy. Materials and Methods A total of 49 pregnant women diagnosed with GDM were enrolled. They underwent a 75‐g oral glucose tolerance test during mid‐gestation, and we measured their plasma glucagon levels (by a new sandwich enzyme‐linked immunosorbent assay) at fasting (0 min), and at 30, 60 and 120 min after glucose load in addition to the levels of plasma glucose and serum insulin. All participants underwent another oral glucose tolerance test at postpartum. Results Of the 49 patients, 15 required insulin treatment (Insulin group) and 34 were treated with diet therapy alone until delivery (Diet group). The early‐phase glucagon secretion after glucose load, as determined by the changes in glucagon from the baseline to 30 min, was paradoxically augmented during mid‐gestation in the Insulin group, but not in the Diet group. The impaired glucagon suppression during mid‐gestation in the Insulin group was not associated with insulin secretory/sensitivity indexes studied, and was ameliorated postpartum, although the plasma glucose levels remained higher in the Insulin group versus the Diet group. Conclusions Impaired early‐phase suppression of glucagon could be associated with the requirement for insulin treatment during pregnancy in patients with GDM., We evaluated the glucagon responses to oral glucose load in patients with gestational diabetes mellitus using a new sandwich enzyme‐linked immunosorbent assay. We investigated whether the glucagon abnormality is associated with the requirement for insulin treatment during pregnancy.

Aims: To evaluate the glycaemic control of combination therapy with basal insulin and liraglutide, and to explore the factors predictive of efficacy in patients with type 2 diabetes when switched from longstanding basal-bolus insulin therapy. Methods: We studied 41 patients who switched from basal-bolus insulin therapy of more than 3 years to basal insulin/liraglutide combination therapy. Glycaemic control was evaluated at 6 months after switching therapy and used to subdivide the patients into good-responders (HbA1c, Diabetes Research and Clinical Practice, 144, pp.161-170; 2018

It has been reported that glucose responses during the oral glucose tolerance test differ between healthy women and men. However, it remains unknown what factors contribute to these differences between the sexes. The present study analyzed the insulin and glucagon responses during the oral glucose tolerance test in 25 female and 38 male healthy young adults aged 22–30 years. The plasma glucose levels at 120 min were significantly higher in women than men. Insulin secretion was significantly greater at 30, 90 and 120 min from baseline in women than men. Glucagon suppression was greater at 30 and 120 min from baseline in men than women when determined by a sandwich enzyme‐linked immunosorbent assay glucagon kit. These results suggest that the differences in glucose responses during the oral glucose tolerance test are mediated by the difference between the sexes in bi‐hormonal responses in healthy individuals.

Objective: Synovitis, acne, pustulosis, hyperostosis, osteitis (SAPHO) syndrome is a rare, chronic, relapsing inflammatory osteoarticular disorder with dermatologic manifestations. SAPHO syndrome can be a rare cause of atypical symptoms including neurologic defects. We report a case with SAPHO syndrome with the endocrinologic defects most likely associated with SAPHO syndrome.Methods: Case report and review of the literature.Results: A 61-year-old Japanese female with SAPHO syndrome presented with polyuria and polydipsia. Pituitary magnetic resonance imaging (MRI) with gadolinium enhancement showed an enlarged infundibulum and pituitary with ring-enhancing masses located at the posterior pituitary and upper infundibulum. Extensive diagnostic workup excluded local and systemic infection, brain metastasis, and various secondary hypophysitis as the cause of the infundibular and pituitary lesions. There were spontaneous improvements in the MRI findings taken 4 months after her initial presentation. The patient underwent a biopsy of the anterior pituitary, which showed a sterile lymphocytic infiltration.Conclusion: There are rare cases of SAPHO syndrome patients in which transient neurologic symptoms associated with the self-limiting ring-enhancing lesions consisting of a sterile and nonspecific inflammation are described. Since cystic formation in the infundibulum caused by idiopathic lymphocytic hypophysitis has not been reported, to the best of our knowledge, we concluded that the endocrinologic defects in our patient were most likely associated with SAPHO syndrome. Thus, SAPHO syndrome should be considered as one of the causes not only for ring-enhancing lesions in the brain but also for secondary hypophysitis, especially in patients with dermatologic and osteoarticular manifestations.

The purpose of the present study was to evaluate the pharmacokinetics of beraprost sodium (BPS) and its active enantiomer, BPS-314d, in Japanese subjects with impaired kidney function. The plasma and urine concentrations of BPS and BPS-314d were measured following the single oral administration of 120 μg of BPS as the sustained-release tablet, TRK-100STP, under fasting conditions to 18 subjects with impaired kidney function (stage 2, 3, and 4 chronic kidney disease [CKD] as categorized by the estimated glomerular filtration rate) and to 6 age-, body weight-, and gender-matched subjects with normal kidney function (stage 1 CKD). The Cmax values (mean ± SD) of BPS in stage 1, 2, 3, and 4 CKD, respectively, were 84.9 ± 22.9, 119.8 ± 36.4, 190.6 ± 137.3, and 240.2 ± 110.5 pg/mL; its AUC0-48h were 978 ± 226, 1252 ± 427, 1862 ± 964, and 1766 ± 806 pg·h/mL, respectively, and its cumulative urinary excretion rates were 0.704 ± 0.351%, 0.638 ± 0.292%, 0.485 ± 0.294%, and 0.159 ± 0.136%. The Cmax values of BPS-314d were 22.4 ± 6.4, 30.8 ± 8.5, 46.7 ± 30.6, and 54.4 ± 25.2 pg/mL, its AUC0-48h were 155 ± 56, 226 ± 67, 341 ± 176, and 329 ± 143 pg·h/mL, and its cumulative urinary excretion rates were 0.428 ± 0.242%, 0.349 ± 0.179%, 0.356 ± 0.270%, and 0.096 ± 0.099%, respectively. Adverse events were reported in 2 subjects with stage 2 CKD and 1 subject with stage 4 CKD. The Cmax and AUC0-48h of BPS and BPS-314d were higher based on the severity of impaired kidney function. No relationship was observed between the incidence of adverse events and the severity, and tolerability was confirmed. We consider that dose adjustment is not necessary, but BPS is more carefully treated in patients with impaired kidney function.

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 ADAMTS13 (a disintegrin and metalloprotease with a thrombospondin type I domain 13) related markers were measured in the plasma of healthy volunteers and thrombotic microangiopathy (TMA) patients including thrombotic thrombocytopenic purpura (TTP) to examine their efficacy in the diagnosis of TTP. The plasma levels of the ADAMTS13 antigen and ADAMTS13-factor XI complex were significantly lower in TMA patients with a significant decreased ADAMTS13 activity (and these patients were considered to have TTP) than in the healthy volunteers. The plasma levels of ADAMTS13 antigens closely correlated with those of ADAMTS13-factor XI complex. Autoantibody for ADAMTS 13 was also positive in almost all TTP patients. In addition, the ratio of von Willebrand factor (VWF)/ADAMTS13 activity was significantly high in TTP suggesting that this ratio might be more useful for the differential diagnosis of TTP than the ADAMTS13 assay alone. These findings suggest that ADAMTS13 related markers are useful for the diagnosis and analysis of TTP.

The ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type I domain 13) activity was measured by a fluorescence resonance energy transfer (FRET) assay in the plasma of healthy volunteers and thrombotic thrombocytopenic purpura (TTP) patients to examine its usefulness in the diagnosis of TTP. The plasma levels of the ADAMTS13 activity did not show a normal distribution. Its median value was 107% (range: 55-170%) in healthy volunteers, but was significantly lower in patients with TTP (acquired or familial) and in patients with hematopoietic stem cell transplantation. However, it was not significantly lower in patients with antiphospholipid syndrome (APS). The ADAMTS13 activity by a FRET assay was closely correlated with that by the ADAMTS13 multimer method (r=0.816; p0.001). In 18 patients with less than 10% of ADAMTS13 activity by FRET assay, less than 10% of that by multimer assay was 16, thus suggesting a good correlation for a low level of ADAMTS13. These findings suggest that the ADAMTS13 FRET assay correlates well with the ADAMTS13 multimer method and it is therefore useful for making a diagnosis of TTP.

Vascular events caused by arteriosclerosis are the major cause of death in patients under hemodialysis (HD). Arteriosclerosis is associated with lipoprotein abnormalities such as increased serum levels of low-density lipoprotein (LDL), especially of modified LDL (M-LDL) and oxidized LDL (Ox-LDL). We examined the relationship between markers of arteriosclerosis, hemostasis, and lipid metabolism in patients with chronic renal failure, hyperlipidemia, and healthy volunteers. In patients under HD, the serum levels of total cholesterol, LDL, and triglyceride (TG) were decreased, but the serum levels of M-LDL were increased compared to HL and healthy volunteers. In patients with CRF, the serum levels of OxLDL in patients under HD were lower than in those under continuous ambulatory peritoneal dialysis or conservative therapy. The plasma levels of antithrombin and protein C were significantly lower and the plasma levels of thrombomodulin were significantly higher in patients under HD compared to those under conservative therapy. These data show that patients under HD were more in hypercoagulable state than those under conservative therapy. Among patients under HD, only the plasma levels of von Willebrand factor were significantly increased in patients with more than 30 U/L of Ox-LDL compared to those with less than 30 U/L of Ox-LDL. There was no significant difference in the tests of arteriosclerosis among M-LDL values and OxLDL values. These findings suggest that abnormalities of lipid are not the main risk factor for arteriosclerosis disease in patients under HD.

We measured the plasma level of fibrinogen in 560 patients with disseminated intravascular coagulation (DIC) and evaluated its relationship with outcome and with other hemostatic markers. Forty-seven percent of patients had >200 mg/dL of plasma fibrinogen and 24% had

Before hemodialysis (HD), plasma levels of tissue factor (TF), free-TF pathway inhibitor (TFPI) and thrombo modulin (TM) were significantly higher in patients with HD than in healthy volunteers. Plasma levels of (T-F) TFPI and plasmin plasmin inhibitor complex (PPIC) were significantly higher in patients with HD than in healthy volunteers. During HD, plasma levels of TF and (T-F) TFPI were not significantly increased, but plasma levels of total TFPI and free TFPI at 1 hour after and at the end of HD were significantly increased, compared with levels before start of HD. Plasma level of PPIC 1 hour after start of HD was significantly higher than before start of HD, and plasma levels of thrombin antithrombin com plex (TAT). PPIC. D-dimer. TM, and protein C (PC) at the end of HD were significantly higher than before start of HD. In patients with thrombosis complications, plasma TF levels were significantly higher than in patients without thrombotic com plications during HD. Plasma levels of PC were significantly lower in patients with thrombotic complications than in patients without thrombotic complications. There was no significant difference between both groups during HD in hemostatic pa rameters, with the exception of TF and PC. Hemostatic abnormalities existed in patients with HD; espe cially, increased TF and decreased PC might cause thrombotic complications.

This study evaluated hemostatic data in 28 patients with newly diagnosed acute promyelocytic leukemia (APL) and 15 patients with relapsed APL. Activated partial thromboplastin time and prothrombin time were prolonged at initial onset of APL. Plasma level of fibrinogen was significantly decreased in patients with initial disease of APL, but it was not decreased significantly during the relapse of APL. Plasma fibrin and fibrinogen degradation products levels were significantly increased and platelet counts significantly decreased in both groups. Plasma levels of antiplasmin significantly decreased at initial onset but not during relapse. Plasma levels of antithrombin were within normal range in patients with initial disease but significantly decreased in those with relapse. Plasma levels of D-dimer, soluble fibrin monomer (sFM), plasmin-plasmin inhibitor complex (PPIC), and thrombin antithrombin complex (TAT) levels were significantly high in both groups. Plasma levels of PPIC, sFM, and D-dimer were significantly higher at initial onset of APL than during relapse. However, there was no significant difference in DIC score between patients with initial onset and those with relapse; plasma levels of tissue factor (TF) significantly increased in both groups, but they were significantly higher at initial onset of APL than during relapse. TF and tissue type plasminogen activator (t-PA) antigen levels in leukemic cell lysate were significantly increased in both groups, and they were significantly lower during relapse than at initial onset. Hemostatic abnormalities occurring in patients with relapsed APL might be the result of the decrease of TF and t-PA in leukemic cells. These findings suggest that DIC in APL patients with relapse might not be caused only by TF and t-PA and thus should be treated with different therapy from patients with initial onset of APL.

Plasma levels of activated protein C (APC)-protein C inhibitor (PCI) were significantly increased in patients with disseminated intravascular coagulation (DIC), thrombotic thrombocytopenic purpura (TTP), acute myocardial infarction (AMI), pulmonary embolism (PE), or deep vein thrombosis (DVT) and in patients undergoing hemodialysis (HD). Plasma levels of APC-alpha(1)-antitrypsin (AT) complex were significantly increased in patients with DIC and in those with TTP. Plasma levels of PCI were significantly decreased in patients with DIC, non-DIC, or TTP and in those undergoing HD. In the pre-DIC stage, the plasma levels of APC-PCI complex were significantly increased but not those of APC-alpha(1)-AT complex. These data suggest that measurements of APC-PCI complex and APC-alpha(1)-AT complex may be useful for the diagnosis of DIC. After treatment of DIC, the plasma levels of APC-PCI complex and APC-alpha(1)-AT complex were significantly decreased, but not those of PCI. Plasma levels of thrombin-antithrombin complex (TAT), plasmin-alpha(2)-plasmin complex (PPIC), D-dimer, and soluble fibrin monomer (SFM) were markedly increased in patients with DIC or pre-DIC and were moderately increased in patients with non-DIC, TTP, AMI, PE, or DVT and in those undergoing HD. The receiving operating characteristic (ROC) analysis showed that SFM and the APC-PCT complex are useful markers for diagnosis of DIC. The specificity of plasma TAT and PPIC levels was low. The positive rate of APC-PCI complex was higher than 90% with DIC, TTP, AMI, PE, and it was higher than 60% with DVT and HD. Since the APC-PCI complex was elevated not only in patients with venous thrombosis but also in those with arterial thrombosis, components of the protein C pathway might be useful markers for the diagnosis of arterial thrombosis.

Fas, a member of the tumor necrosis receptor superfamily, is 36 kD surface protein containing a single transmembrane region and induces apoptosis by Fas-Fas ligand binding. Soluble Fas (sFas) is produced as the form lacking 21 amino acid residues containing the transmembrane domain by alternative splicing. We found that the plasma sFas levels of 33 patients with thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS), 19 patients with disseminated intravascular coagulation (DIC), and 10 non-DIC patients with multiple organ failure (MOF) were significantly higher than those of 21 non-DIC patients without organ failure and those of 25 healthy volunteers. The plasma sFas ligand levels of the TTP/HUS patients, the DIC patients, and the non-DIC patients with MOF were significantly higher than those of the non-DIC patients without organ failure and those of the healthy volunteers. The plasma sFas levels were significantly correlated with the plasma sFas ligand levels in all subjects. The plasma thrombomodulin (TM) levels were increased significantly in the TTP/HUS patients, the DIC patients, and the non-DIC patients with MOF compared with the levels of the non-DIC patients without organ failure and the healthy volunteers. The plasma sFas antigen levels were correlated significantly with the plasma TM levels in all subjects. These findings suggest that the increases of sFas and sFas ligand that cause apoptosis might be related to the vascular endothelial cell injuries in TTP and DIC with organ failure.

Various hemostatic and vascular endothelial cell markers were measured in patients with disseminated intravascular coagulation (DIC), non-DIC, or thrombotic thrombocytopenic purpura (TTP) and in healthy volunteers to examine the relationships between the hemostatic abnormalities or vascular endothelial cell injuries and the patients' outcomes. Although the plasma levels of soluble fibrin monomer, thrombin-antithrombin complex, plasmin-plasmin inhibitor complex, and D-dimer were significantly increased in the DIC patients, there were no significant differences in these markers between the DIC patients who survived and those who died, suggesting that these markers might not be directly related to the patient outcome. The plasma thrombomodulin (TM) levels in the DIC and TTP patients were significantly higher than those in the healthy volunteers, and the plasma TM levels in the patients who died were significantly higher than those in the patients who survived. These findings showed that the TM level reflected the outcome, and that the outcome of the diseases underlying DIC and TTP might depend on vascular endothelial cell injuries. The plasma protein C and antithrombin activities were markedly reduced in the DIC, non-DIC, and TTP patients who died compared to those who survived. These findings suggest that reduced plasma antithrombin and protein C activities are useful markers of systemic vascular endothelial injuries. Although the plasma tissue factor (TF) levels were significantly increased in the DIC patients, there was no significant difference in the plasma TF levels between the DIC patients who died and those who survived. In conclusion, we found that the outcome of the diseases underlying DIC and TTP is related to vascular endothelial cells, and that plasma TM, antithrombin, and protein C are useful markers for systemic vascular endothelial cell injury.

Plasma-soluble fibrin monomer (SFM) level in patients with disseminated intravascular coagulation (DIC) was significantly higher than the level in patients with pre-DIC or in non-DIC patients, and the level in patients with pre-DIC was significantly higher than that in non-DIC patients. There was no significant difference in plasma SFM levels among various diseases underlying DIC. Plasma SFM level in patients with good outcome was significantly decreased after treatment for DIC. The sensitivity of fibrin degradation products and platelet number was high for DIC, but not for pre-DIC. The sensitivity of thrombin-antithrombin III complex, plasmin-plasmin inhibitor complex, and SFM was high for both DIC and pre-DIC. The specificity of these markers was also high. Receiver operating characteristic analysis suggests that plasma SFM level could be the most useful marker for the diagnosis of both DIC and pre-DIC.

The plasma level of tumor necrosis factor (TNF) was determined in 20 normal individuals, 52 patients with disseminated intravascular coagulation (DIC), 22 pre-DIC patients, and 39 non-DIC patients. TNF was not detected in the normal subjects, and the level was very low in non-DIC patients. However, the TNF level was significantly elevated in DIC patients, and it was moderately increased in pre-DIC patients shortly before the onset of DIC. This increase in circulating TNF may be associated with DIC. TNF was higher in DIC associated with solid cancer than in DIC associated with leukemia or sepsis. The increase in plasma TNF level was mildly correlated with DIC score, and it was significantly increased in patients with poor prognosis. However, the plasma TNF level in DIC patients with organ failure was not significantly different from those without organ failure. We conclude that the increase in circulating TNF reflects the pathogenic factors in DIC rather than being a consequence of organ failure due to DIC.

SummaryThe plasma level of interleukin-1β (IL-1β) was determined in normal individuals, patients with disseminated intravascular coagulation (DIC), patients in the pre-DIC period (within 7 days before the onset of DIC), and non-DIC patients to examine the relationship between DIC and the plasma ILlp level. The plasma IL-1β level was 0-0.085 ng/ml in normal individuals, with little difference being seen according to related age. It was significantly higher in the DIC group (0.19 ± 0.19 ng/ml) than in the pre-DIC group (0.05 ± 0.08 ng/ml) or the non-DIC group (0.09 ± 0.01 ng/ml). The plasma IL-1β level was not markedly elevated in leukemia patients, even in the DIC group, but it was significantly increased in the DIC group of solid cancer patients and was generally elevated in patients with sepsis. It was markedly elevated to 0.39 ± 0.26 ng/ml in patients with organ failure. When mononuclear cells were incubated with lipopolysaccharide, it was found that IL-1β, tumor necrosis factor, and tissue factor (TF) were released into the medium, and there was an increase of TF release from endothelial cells incubated with this medium. These results suggest that the increase in IL-Iβ reflected the activation of monocytes and may be an important factor in DIC and its associated organ failure.

We measured plasma level of tissue type plasminogen activator (t-PA) antigen in patients with disseminated intravascular coagulation (DIC). Plasma levels of t-PA, PA inhibitor-1 (PAT-1), t-PA-PAI-1 complex, von Willebrand factor, thrombin-antithrombin III Complex (TAT), plasmin-α2 plasmin inhibitor complex (PIC), and FDP-D-dimer were markedly increased at the time of the onset of DIC but decreased after treatment. In most patients without leukemia, as the DIC score increased, plasma t-PA increased to 20 ng/ml or more. Plasma t-PA level before treatment for DIC was slightly higher in those showing poor outcome than it was in those showing good outcome. After treatment, t-PA level increased slightly in those showing poor outcome but decreased significantly in those showing good outcome. Plasma t-PA level was significantly higher in patients with organ failure than in those without. Positive correlation of plasma t-PA antigen level to PAI-1

We examined 159 patients with thrombotic throm bocytopenic purpura and hemolytic uremic syndrome in Japan. The subjects were divided in three groups; 90 patients with thrombotic thrombocytopenic purpura, 51 patients with vero toxin-induced hemolytic uremic syndrome, and 18 patients with drug-induced hemolytic uremic syndrome. Eighty-two percent of the patients with thrombotic thrombocytopenic pur pura had associated neurological disorders and 78% of drug- induced hemolytic uremic syndrome associated with pulmo nary edema. Renal insufficiency was noted in the 69% cases with both hemolytic uremic syndrome groups. Seventeen pa tients with thrombotic thrombocytopenic purpura had systemic lupus erythematosus and 6 were pregnant. Autoantibody were positive in 53% of thrombotic thrombocytopenic purpura. Sev enty-seven percent of patients with thrombotic thrombocytope nic purpura received plasma exchange at 4,000 mL/day three times a week, 71 % antithrombotic agents, and 78% steroid administration, respectively. However, 27% of the patients with hemolytic uremic syndrome were treated by hemodialysis in addition to antithrombotic agents. When drug-induced hemo lytic uremic syndrome was diagnosed, the drug was immedi ately discontinued and the patients were treated with antiplate let agents. Seventy-four percent of the patients with thrombotic thrombocytopenic purpura were alive at 26 weeks compared with 95% of those with hemolytic uremic syndrome. As throm botic thrombocytopenic purpura had a high mortality rate in Japan, we should carry out early diagnosis and early treatment.

The blood level of tumor necrosis factor (TNF) was determined in 20 normal individuals, 52 patients with disseminated intravascular coagulation (DIC), 22 pre-DIC patients, and 39 non-DIC patients and 10 thrombotic thrombocytopenic purpura (TTP) patients. TNF was not detected in the normal subjects and the level was very low in non-DIC patients. However, the level was significantly elevated in DIC patients. TNF was also increased significantly in pre-DIC patients shortly before the onset of DIC as compared with non-DIC patients. This increase in circulating TNF may be associated with DIC. In TTP, the blood level of TNF was increased at onset but decreased at remission. According to underlying diseases, TNF was higher in DIC associated with solid cancer than in DIC associated with leukemia or sepsis. In solid cancer, a large amount of tissue factor may be produced as the immune system is activated, cytokines such as TNF are released into the circulation, and endothelial cells and monocytes are activated. The blood TNF level was not significantly different between DIC patients with organ failure and DIC those without organ failure. From these findings, the increase in circulating TNF is considered to be a direct pathogenic factor in DIC or TTP rather than a consequence of organ failure due to DIC.

The blood level of interleukin-1β (IL-1β) was determined in 100 normal individuals, 10 patients with thrombotic thrombocytopenic purpura (TTP), 41 patients with established disseminated intravascular coagulation (DIC), 15 in pre-DIC period (within 7 days before the onset of DIC), and 23 non-DIC patients. In TTP, the blood IL-1β concentration was increased at onset but decreased at remission. The blood IL-1β concentration was significantly higher (p

Disseminated mycobacterial infection was found at autopsy in a male patient with hemophilia B and acquired immunodeficiency syndrome (AIDS). In May 1986, 23 months before death, the patient had encephalitis for one month and in July he developed a fever, malaise and generalized lymphoadenopathy. Human immunosuppressive virus (HIV) was positive and the CD 4/8 ratio of lymphocyte surface markers was 0.1, but mycobacterium was not detected. In September 1986, he had severe dyspnea due to interstitial pneumonia and he was treated with high-dose methylprednisolone. He died after a 23-month course of fever, severe weight loss and terminal progressive deterioration, although he was treated with antibiotics, antifungal agents, gamma-globulin, steroid and a Azidothymidine.

The mortality rate is high in patients receiving hemodialysis (HD), atherosclerotic diseases being the major cause of death. As marker of clinical outcome, a prospective examination of atherosclerotic tests and atherosclerotic risk factors in patients receiving HD was performed. On April 2000, 84 patients receiving HD were followed up until April 2002. At entry to the study, several atherosclerotic tests, including ankle-arm blood pressure index (API), aortic calcification index (ACI), and atherosclerotic risk factors, were performed. In 36 patients with old thrombotic events, 26 had new thrombotic events. Of 48 patients without previous thrombotic events, 15 had new thrombotic events. During 2 years, 41 patients had new thrombotic events and 15 patients died due to thrombotic disorders. The HD durations were significantly longer in non-survivors than survivors and the body mass index was lower in non-survivors than survivors. There was a significant difference in the values of ACI and API between survivors and non-survivors, and between patients with and without thrombotic events. These findings suggest that the ACI and API have a prognostic value because they might predict the occurrence of thrombosis.

Plasma levels of soluble fibrin (SF) were measured in 1184 patients with disseminated intravascular coagulation (DIC) according to Japanese Ministry of Health and Welfare (JMHW) criteria. The usefulness of SF for the diagnosis of DIC was compared with other hemostatic molecular markers. Most hemostatic markers were significantly increased in patients with DIC than in those without DIC. Plasma levels of fibrin and fibrinogen degradation products, thrombin-antihtrombin complex, plasmin-plasmin inhibitor complex, D-dimer, thrombomodulin, and SF levels were also significantly higher in those with pre-DIC than in those without DIC. In classification of overt DIC by International Society of Thrombosis and Haemostasis (ISTH) criteria, most hemostatic markers were significantly increased in patients with overt DIC than in those without overt DIC. Plasma levels of SF 'in patients with DIC were significantly higher than those in patients with pre-DIC, which were significantly higher than in those without DIC. Plasma levels of SF were also significantly higher in patients with overt DIC than in those with non-overt DIC. The correlation between plasma SF levels and DIC score according to JMHW criteria or ISTH criteria was good. Receiver operating characteristic analysis shows that SF was the best marker for the diagnosis of DIC or overt DIC. These findings suggest that plasma SF might be useful marker for the diagnosis of DIC or overt DIC.

Changes of hemostatic markers in 226 patients with disseminated intravascular coagulation (DIC) and hematopoietic disorders were examined after treatment of DIC. The changes in prothrombin time (PT) ratio, fibrinogen, fibrin and fibrinogen degradation products (FDP), antithrombin, and protein C, thrombin-antithrombin complex (TAT), plasmin-plasmin inhibitor complex (PPIC), and soluble fibrin monomer complex (SFMC) in all patients with DIC were significant during the clinical course of DIC, but those of D-dimer, thrombomodulin (TM), tissue factor (TF), and tissue factor pathway inhibitor (TFPI) were not. Activated partial thromboplastin time (aPTT) and PT were significantly longer in the poor response group than in good response group. Plasma levels of FDP, TAT, PPIC, SFMC, TM, and DIC score were significantly higher in poor response group than in good response. Protein C and antithrombin levels were significantly lower in poor response group than in good response group. The changes of PT ratio, fibrinogen, FDP, DIC score, antithrombin, plasmin inhibitor, and protein C were significant in the good response group, but these levels were not significant in the poor response group. The changes in plasma TAT and SFMC levels were significant in the good response group but were not in poor response group. The changes in D-dimer, TM, TF, or TFPI were not significant in both groups. These findings suggest that anticoagulant agents should be administered at levels below TAT 40 ng/mL or SFMC 300 μg/mL in patients with DIC and hematopoietic disorders.

BACKGROUND: Severe deficiency of vWF-cleaving protease (vWF-CPase) activity was recently found in patients with thrombotic thrombocytopenic purpura (TTP). Although the survival of patients with TTP has been dramatically improved with plasma exchange (PE), there are still many patients who are refractory to PE and immunosuppressive therapy. STUDY DESIGN AND METHODS: The activities of vWF-CPase and its inhibitor were measured in 27 patients with nonfamilial TTP and hemolytic-uremic syndrome (HUS) to examine the relationship between the clinical variables and vWF-CPase activity. RESULTS: Eight of nine patients with HUS had more than 40 percent of vWF-CPase activity, whereas one had 28 percent of the normal level at the acute phase. Ten of 12 TTP patients with a good outcome had a severe deficiency of vWF-CPase activity and its inhibitor, whereas four of six patients with a poor outcome had a moderate deficiency of vWF-CPase activity along with a lack of the inhibitor. PE produced normalization of the vWF-CPase activity and neutralization of the inhibitor in TTP patients with a good outcome; however, some TTP patients with vWF-CPase inhibitor had relapsed and required an immunosuppressive therapy. The response to the combination therapy with PE and immunosuppressive treatment was poor in TTP patients without a severe deficiency of vWF-CPase activity. CONCLUSION: Assays of vWF-CPase activity and its inhibitor may be useful for predicting the response to therapy and the outcome of patients with TTP. In some patients, nonfamilial TTP with a poor prognosis may not be caused by a constitutional or acquired deficiency of vWF-CPase with its inhibitor. Although PE and immunosuppressive therapy are effective in patients with nonfamilial TTP and a vWF-CPase inhibitor, other therapeutic modalities may be needed for nonfamilial TTP with unknown etiology.

We measured the plasma levels of thrombin-activatable fibrinolysis inhibitor (TAFI) activity and antigen in patients with disseminated intravascular coagulation (DIC) to examine the relationship between hypofibrinolysis and the pathogenesis of DIC. TAFI activity and antigen levels in the plasma were both significantly low in patients with DIC. TAFI activity in plasma was correlated with TAFI antigen, indicating that activity and antigen correspond well. The decrease of TAFI activity in DIC may be due to enhanced consumption. Since the plasma thrombin-antithrombin III complex (TAT) level was found to be elevated in DIC, increase of thrombomodulin-thrombin complex generation is suggested in this state. TAFI activity and antigen levels were negatively correlated with TAT and D-dimer, suggesting that the plasma levels of TAFI are reduced by thrombin generation. Since TAFI was not correlated with fibrinogen, plasma-alpha(2)plasmin inhibitor complex (PPIC) and tissue type plasminogen activator/plasminogen activator inhibitor-1 (tPA/PAI-1) complex, TAFI might be a secondary modulator of fibrinolysis. 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. In brief, TAFI may play an important role in the pathogenesis of DIC and organ failure.

Several hemostatic and vascular endothelial cell markers were measured in 39 patients with thrombotic thrombocytopenic purpura (TTP)/hemolytic uremic syndrome (HUS) and in 20 healthy volunteers to examine the relationship between the occurrence of hemostatic abnormality or vascular endothelial cell injury and patient outcome. The plasma levels of von Willebrand factor, tissue plasminogen activator (TPA), plasminogen activator inhibitor (PAI-1), and the TPA-PAI-1 complex were significantly increased in TTP/HUS patients; however, the levels of these markers were not significantly different between TTP/HUS patients who survived and those who died, suggesting that these markers might not be directly related to outcome. The plasma levels of soluble granule membrane protein (GMP)-140 were significantly higher in TTP/ HUS patients than in healthy volunteers, suggesting that platelets and vascular endothelial cells are activated or injured in TTP/HUS. There was no significant difference in GMP-140 levels between TTP/HUS patients with good and poor prognoses ; this may be owing to the release of GMP-140 from platelets. The plasma thrombomodulin (TM) levels in TTP/ HUS patients were significantly higher than in healthy volunteers; the plasma TM levels were significantly higher in patients who died than in patients who survived. These findings showed that TM levels reflect the outcome and that the outcome of TTP/HUS depends on the presence vascular endothelial cell injury. The plasma protein C and antithrombin levels were markedly reduced in TTP/HUS patients who died compared with those who survived. These findings suggest that reduced plasma antithrombin and protein C may be useful markers of systemic vascular endothelial injury. In conclusion, the results of this study showed that the outcome of TTP/HUS is related to vascular endothelial cell injury and that plasma TM, antithrombin, and protein C levels may be useful markers of systemic vascular endothelial cell injury.

Plasma levels of tissue factor pathway inhibitor (TFPI)-activated factor Xa (FXa) complex were measured in patients with disseminated intravascular coagulation (DIC), pre-DIC, and DIC. Plasma levels of plasmin-plasmin inhibitor complex (PPIC), D-dimer, and soluble fibrin monomer (SFM) were significantly higher in patients with DIC than in those with pre-DIC or non-DIC; the levels of these hemostatic markers were significantly higher in patients with pre-DIC than in those with non-DIC. Plasma levels of thrombin-antithrombin complex (TAT) were significantly higher in patients with DIC or pre-DIC than in those with non-DIC. Plasma levels of tissue factor (TF), total TFPI, free TFPI, and TFPI-Xa complex were significantly higher in patients with DIC than in those with non-DIC. Plasma levels of TFPI-Xa complex were significantly increased in patients with pre-DIC as compared to those with non-DIC; however, plasma free TFPI levels were significantly decreased in patients with pre-DIC as compared to those with non-DIC. These findings suggest that free TFPI might be consumed in the pre-DIC state, thereby confirming the activation of the extrinsic pathway. Plasma levels of TFPI-Xa complex were significantly correlated with TF, free TFPI, and total TFPI. Increased plasma TFPI-Xa complex levels might be useful for the diagnosis of DIC or pre-DIC, particularly that occurring by activation of the extrinsic pathway of blood coagulation.

To evaluate the relationship between the tissue factor (TF) pathway and lupus anticoagulant (LA), in the pres ent study, we measured the plasma levels of TF antigen and TF pathway inhibitor (TFPI) antigen in patients positive for LA. Plasma TF and TFPI levels in LA-positive patients were sig nificantly higher than levels in healthy volunteers (p < 0.01). In LA-positive patients, there were no significant differences in plasma TF and TFPI levels between patients with and without thrombosis. In patients with thrombosis, there was no signifi cant difference in the plasma TF level between LA-positive and LA-negative patients; however, the plasma TFPI level in LA- positive patients was significantly lower than that in LA- negative patients (p < 0.01). We also examined the TF pathway in human umbilical venous endothelial cells (HUVEC) incu bated with plasma of LA-positive patients, LA-negative pa tients, and healthy volunteers. TF activity was significantly higher (p < .05) in HUVECs incubated with the plasma of LA-positive patients than in cells incubated with the plasma of the other two groups (p < .01). However, there was no signifi cant difference in TFPI antigen levels among the media of HUVECs incubated with the plasma of all groups. The viability of HUVEC incubated with the plasma of LA-positive patients with thromboses, LA-positive patients without thromboses, and LA-negative patients with thromboses were significantly lower than that of HUVECs incubated with the plasma of healthy volunteers (p < .01). These findings suggest that abnormalities of the TF pathway plays an important role in the mechanism of hypercoagulability in LA-positive patients. LA may affect vas cular endothelial cells causing thrombogenesis. Key Words: Lupus anticoagulant—Tissue factor—Tissue factor pathway inhibitor—Vascular endothelial cell—MTT assay.

Early diagnosis is necessary for the treatment of disseminated intravascular coagulation (DIC), but criteria for the stage preceding the diagnosis of DIC (pre-DIC) have not yet been established. To clarify hemostatic abnormalities that occur before the onset of DIC, we performed hemostatic studies in 117 patients within at least a week before the onset of DIC (pre-DIC), in 237 patients with DIC, and in 50 patients without DIC or pre-DIC (non-DIC). Levels of FDP, PT, and fibrinogen, and platelet counts were significantly abnormal after the onset of DIC, but not before. Thrombin-antithrombin III complex (TAT), plasmin-alpha 2 plasmin inhibitor complex (PIC), and FDP-D-dimer levels were significantly higher before the onset of DIC compared to the non-DIC patients. Hemostatic abnormalities were observed within a week before the onset of DIC. Monitoring the plasma levels of TAT, PIC, and FDP-D-dimer might be useful for the diagnosis of a pre-DIC condition.

The fibrinolysis in 6 patients with lupus anticoagulant was studied. The intrinsic fibrinolytic activity by kaolin activated euglobulin with plasminogen free fibrin plate was low level in all patients. Although we could not obtain common results in fibrinolytic factors-plasminogen, α1-AT, α2-M, α2-PI and Cl-inactivator with immunodiffusion method, and in fibrinolytic activity by euglobulin from plasma with ELT and plasminogen rich fibrin plate.In two patients with Budd-Chiari syndrome, the IgG fraction of plasma through Sephadex G 200 had the inhibitory activity of fibrino (geno) lysis on the fibrin plate method and the immunoelectrophoresis, as well as high lupus anticoagulant activity.Those findings suggest that fibrinolysis plays a role on formation of thrombus in patient with lupus anticoagulant.

We experienced 6 patients with graft versus host disease (GVHD) after blood transfusion. Their age were 65, 70, 68, 65, 57 and 67 years old. There were 4 males and 2 females. GVHD was occured in 5 cases of cardio-vascular surgery and 1 case of orthopedic surgery. Although fresh blood was transfused to 5 patients, one patient was associated with GVHD after only stored red blood cells transfusion.In most cases, high fever and skin rush began within about 10 days after operation, and liver function abnormalities and bone marrow supression began within about 15-20 days after operation. In some cases, renal failure, gastrointestinal bleeding or disseminated intravascular coagulation was observed. They died of acute complications of the disease within 30-40 days, although they were complications of the disease within 30-40 days, although they were treated with streoid, methotrexate or antilymphocyte globulin.Blood transfusion should be carefully, and blood produce irradiation and auto-blood transfusion was recommended for prevention of posttransfusion GVHD.

Blood coagulation was studied in patients with idiopathic thrombocytopenic purpura (ITP), essential thrombocythemia (ET), polycythemia (PC), myelodysplastic syndrome (MDS), and aplastic anemia (AA), and prolongation of APTT was observed in ITP, ET, MDS and PC with thrombocythemia, but shortening of APTT was seen in AA. Circulating anticoagulant was detected in only 4 ITP patients by cross mixing experiment and the effect of high-dose platelin on kaolin clotting time. The prolongation of APTT was statistically improved after treatment of ITP with steroid and high-dose gammaglobulin therapy (HDGT). In ITP patients with prolonged APTT, megakaryocytes were increased, serological tests were more positive and weight of spleen was increased compared with patients with normal APTT. In terms of effectiveness on therapy, steroid therapy and HDGT were more effective in patients with prolonged APTT than in patients with normal APTT. Homogenate of more than 4×105/μl platelets prolonged APTT, PTT and recalcification time but shortened kaolin clotting time. Phospholipids (phosphatidylcholine, phosphatidylserine, phosphatidylinositol, phosphatidylethanolamine, sphingomyelin, phosphatidic acid) also prolonged APTT at high concentration.In ITP and MDS, phospholipids from destroyed platelets might be increased and prolong APTT, and it was suspected that increased platelets also prolonged APTT in ET and PC. In these diseases, APTT might reflect the function of reticuloendothelium system and the number of destroyed platelets.

This is a report of a case of coronary and cerebral embolism occurred in a patient with mitral steno-insufficiency. Clinical diagnosis of coronary and cerebral embolism was made by evidences of left hemiplegia and myocardial infarction shown by electrocardiogram. Clinical diagnosis was confirmed at autopsy and postmortem coronary angiography disclosed the location of the coronary embolus.