Biomedical subjects

I Kumabashiri

Publications and source records attributed to I Kumabashiri.

At least 37 records · Page 2Linked to original sources

PubMed1994

Effects of DX-9065a, an orally active, newly synthesized and specific inhibitor of factor Xa, against experimental disseminated intravascular coagulation in rats.

We investigated the protective effects of DX-9065a, an orally active, newly synthesized and specific inhibitor of factor Xa, against two kinds of experimental disseminated intravascular coagulation (DIC) in rats. Endotoxin-induced experimental DIC was induced by a 4-h sustained infusion of endotoxin at a dose of 100 mg/kg. Thromboplastin-induced experimental DIC was induced by a bolus injection of thromboplastin at a dose of 150 mg/kg. The rats were orally administered DX-9065a at 10, 30 or 100 mg/kg 30 min before endotoxin or thromboplastin injection. In both DIC models, DX-9065a showed a protective effect against DIC, at all doses and in all parameters, including fibrin/fibrinogen degradation products (FDP), fibrinogen level, prothrombin time, activated partial thromboplastin time, platelet count and the number of renal glomeruli with fibrin thrombi. When DX-9065a was orally administrated at 100 mg/kg without endotoxin or thromboplastin, no significant changes were seen in hemostatic parameters except PT and APTT, and no fibrin thrombi or abnormal bleeding were seen in renal specimens. These findings suggest that the new oral anti-Xa drug, DX-9065a, has an effect in reducing the severity of DIC. However, further dose-finding and safety studies of this drug have still to be assessed.

Administration, Oral↗

PubMed1994

Plasma levels of lipoprotein(a) are elevated in patients with the antiphospholipid antibody syndrome.

The mechanisms underlying clinical abnormalities associated with the antiphospholipid antibody syndrome (APAS) have not been elucidated. We measured plasma levels of lipoprotein(a) [Lp(a)], the active form of plasminogen activator inhibitor (active PAI), thrombin-antithrombin III complex (TAT) and soluble thrombomodulin (TM), to investigate the relationship of these factors to thrombotic events in APAS. Mean plasma levels of Lp(a), TAT, active PAI and TM were all significantly higher in patients with aPL than in a control group of subjects. Plasma levels of Lp(a) and active PAI were significantly higher in patients with aPL and arterial thromboses than in patients with aPL but only venous thromboses. There was a significant correlation between plasma levels of Lp(a) and active PAI in patients with aPL. These findings suggest that patients with aPL are in hypercoagulable state. High levels of Lp(a) in plasma may impair the fibrinolytic system resulting in thromboses, especially in the arterial system.

Abortion, Habitual↗

PubMed1993

Successful treatment of a patient with idiopathic factor VIII inhibitor with double filtration plasmapheresis and steroid administration.

We report a 74-year-old Japanese woman who had bleeding due to a factor VIII inhibitor in the absence of diseases known to be associated with its development. She abruptly developed a large painful purpura extending from the right hip to the thigh followed by an intramuscular haematoma of her left anterior chest. Examinations revealed a marked depression of factor VIII activity (5%) and the presence of 31 Bethesda units/ml factor VIII inhibiting activity. The phenotypes of these inhibitors were of the IgG-kappa and IgG-lambda types. She was treated with oral prednisolone and double filtration plasmapheresis (DFPP). The inhibitors rapidly disappeared after three sessions of plasmapheresis and her plasma factor VIII activity increased to a normal level. During this treatment, no major adverse effects such as thrombosis and infection were observed and transfusion of fresh frozen plasma (FFP) was not necessary. Heterogeneity of idiopathic factor VIII inhibitors in elderly patients is common and spontaneous disappearance or elimination of such inhibitors by treatment is often difficult to achieve. However, the combination of oral prednisolone and double filtration plasmapheresis is effective and safe for idiopathic factor VIII inhibitors and is a worthwhile approach to treatment.

Aged↗

PubMed1993

Changes in plasma levels of prothrombin fragment F 1 + 2 in cases of disseminated intravascular coagulation.

Plasma levels of prothrombin fragment F 1 + 2 (PTF) and thrombin-antithrombin III complex (TAT) were assayed in 86 cases of disseminated intravascular coagulation (DIC). A significant elevation of both parameters was observed in most cases of DIC, which suggested that the in vivo generation of thrombin is highly accelerated by the cleavage of the prothrombin molecule by factor Xa. On the contrary, no significant elevation of plasma levels of PTF was observed in cases of DIC with severe hepatic failure or fulminant hepatitis in spite of significant elevation of TAT. Plasma levels of PTF were directly proportional to those of TAT in 86 cases of DIC as a whole (r = 0.682, p < 0.001). The measurement of both parameters was considered to be useful to estimate the hemostatic activation in DIC.

Antithrombin III↗

PubMed1993

Transient wheeze. Eosinophilic bronchobronchiolitis in acute eosinophilic pneumonia.

The clinicopathologic features of five patients with acute eosinophilic pneumonia who presented with transient wheeze as well as acute onset of high fever, severe hypoxemia, and diffuse pulmonary infiltrates are described. Eosinophilic pneumonia was diagnosed by bronchoalveolar lavage and transbronchial lung biopsy. The illness resolved rapidly with or without corticosteroid therapy. No relapse occurred. To characterize the transient wheeze, a transbronchoscopic bronchial biopsy and pulmonary function tests were performed. Specimens of bronchial wall revealed eosinophil infiltration into the bronchial mucosa. Pulmonary function tests demonstrated reduced diffusing capacity and small airway dysfunction. These findings suggested that eosinophil infiltration into the bronchial mucosa might temporarily cause transient wheeze, different from bronchial asthma, due to small airway dysfunction in acute eosinophilic pneumonia.

Acute Disease↗

PubMed1993

[Plasma exchange failures in two patients with thrombotic thrombocytopenic purpura].

We treated two patients with thrombotic thrombocytopenic purpura (TTP) with multiple plasma exchanges for a short period. Following 6 plasma exchanges during 11 days in patient 1 and the 8 exchanges during 13 days in patient 2, consciousness disturbance and thrombocytopenia improved with a decrease in serum lactate dehydrogenase (LDH) levels in both patients. However, thrombocytopenia rapidly progressed with a rise of serum LDH levels after a few days from cessation of the treatment. They received a few rounds of plasma exchange without beneficial effects and eventually died of massive hemorrhage. The clinical course of these patients indicates that some patients with TTP are refractory to repeated plasma exchanges for a short period. It seems important to determine the target point in blood chemistry values such as the LDH level for plasma exchange at which the treatment could be discontinued without causing relapse of TTP.

Aged↗

PubMed1992

Prothrombin Himi: a compound heterozygote for two dysfunctional prothrombin molecules (Met-337-->Thr and Arg-388-->His).

A congenitally dysfunctional form of prothrombin, Prothrombin Himi, shows reduced fibrinogen clotting activity, although it retains full hydrolytic activity toward synthetic substrates. To elucidate the structural abnormality of the variant prothrombin, we first performed genetic analysis of dysprothrombin. Polymerase chain reaction amplification of the exons 8 through 14 of the proband and her family members' prothrombin genes, which code the thrombin moiety, followed by single-strand conformation polymorphism analysis, identified two variant conformers in exon 10 specific to this family. One variant allele detected in the father was inherited by the proband and one of her sisters, and the other detected in the mother was also inherited by them. This result indicates that the proband has two different base pair changes in the gene. Sequencing showed two novel point mutations in the proband's gene. One is a T to C transition at position 8751, resulting in the substitution of threonine for methionine at codon 337 (Thrombin Himi I). The other is a G to A transition at 8904, resulting in the substitution of histidine for arginine at codon 388 (Thrombin Himi II). By sequencing analysis of her parents, it was determined that Thrombin Himi I was inherited from the father and Thrombin Himi II from the mother. These results confirm that Prothrombin Himi is compound heterozygous for two dysfunctional prothrombin molecules.

Amino Acid Sequence↗

PubMed1992

Increased levels of plasma thrombomodulin in chronic myelogenous leukemia.

Circulating blood plasma contains proteinase-degraded forms of thrombomodulin that are soluble. We quantitatively assayed the plasma levels of thrombomodulin in 15 patients with chronic myelogenous leukemia (CML) in chronic phase by method of an enzyme-linked immunosorbent assay using a monoclonal antibody to protease-degraded products of thrombomodulin. Plasma levels of thrombomodulin in patients with CML at diagnosis were significantly increased (19.5 +/- 6.2 ng/ml: means +/- SD) compared with the levels in normal controls (8.0 +/- 1.9 ng/ml, n = 20) (P less than 0.001). Fibrin degradation products (D-dimer), thrombin-antithrombin III complex, and plasmin alpha 2-antiplasmin complex were almost normal, suggesting that intravascular coagulation or plasmin-mediated fibrinolysis little occurred in these patients. On the other hand, the plasma levels of elastase-alpha 1-proteinase inhibitor (E-alpha 1PI) complex, which was the indicator of released leukocyte elastase, were significantly increased in CML (P less than 0.0001). The plasma levels of thrombomodulin and E-alpha 1PI complex were decreased in parallel with decline of leukocyte counts in 10 patients with CML following anti-leukemic therapy. Furthermore, a statistically significant correlation was observed between the plasma levels of thrombomodulin and E-alpha 1PI complex obtained at 39 time points in 15 patients with CML (r = 0.81, P less than 0.001). These results suggest that the increased plasma levels of thrombomodulin in CML may be partly caused by leukocyte elastase, which may split the surface thrombomodulin and release protease-degraded fragments of it into the circulation.

Antineoplastic Agents↗

PubMed1992

Role of endothelin in disseminated intravascular coagulation.

We examined the changes in plasma levels of endothelin-1 (ET-1), a potent vasoconstrictor peptide, in 47 cases of disseminated intravascular coagulation (DIC) to investigate the role of ET-1 in DIC and its relation to multiple organ failure (MOF). A significant elevation of plasma levels of ET-1 was observed in some cases of DIC, especially in patients with sepsis, blastic crisis of chronic myelogenous leukemia, and cancer. However, no such significant elevation was observed in patients with acute promyelocytic leukemia (APL), acute leukemias except for APL, or non-Hodgkin lymphoma. Plasma levels of ET-1 were higher in patients with DIC with MOF than in those without MOF. Although the levels of ET-1 were decreased or remained low with clinical improvement in most DIC patients, the levels were further increased or remained high in patients who showed no improvement in DIC. It is suggested that ET-1 must play an important role in further progression of MOF with the vasoconstriction and microcirculatory disorders.

Disseminated Intravascular Coagulation↗

PubMed1992

Prothrombin fragment F1 + 2 and thrombin-antithrombin III complex are useful markers of the hypercoagulable state in atrial fibrillation.

It is well known that atrial fibrillation (AF) is one of the most important diseases that predispose patients to thrombosis. We have attempted to identify patients with AF in the hypercoagulable state by measuring molecular markers such as thrombin-antithrombin III complex (TAT) and prothrombin fragment 1 + 2 (PTF) and determining the effect of antithrombotic therapy on these markers; 83 patients with AF were studied. Increased levels of plasma TAT and PTF were more frequently observed in patients with AF and associated mitral stenosis than in patients with AF alone. In cases of AF without mitral stenosis, plasma levels of TAT and PTF were significantly lower in those patients receiving antithrombotic agents (aspirin or warfarin) than in those receiving no antithrombotic agents. Furthermore, plasma levels of PTF were significantly lower in patients given warfarin than in those receiving aspirin. These results suggest that (1) patients with AF and mitral stenosis who are not given warfarin are in an extremely hypercoagulable state and (2) some patients with AF without mitral stenosis who are not given antithrombotic agents are also moderately hypercoagulable. In vivo activation of blood coagulation was more effectively controlled in patients receiving warfarin than in those taking aspirin.

Aged↗

PubMed1991

Prothrombin Himi; an abnormal prothrombin characterized by a defective thrombin activity.

An abnormal prothrombin has been detected in a 26-year-old female, who had no history of excessive bleeding. Prothrombin activity was approximately 10% when measured using either the classical one-stage assay or the assay with Echis carinatus venom, whereas prothrombin antigen level was normal. In keeping with current nomenclature practices, the abnormal prothrombin was designated "Prothrombin Himi". The electrophoretic behavior and calcium binding properties of Prothrombin Himi did not differ significantly from normal. Prothrombin Himi was isolated by chromatography on Q-Sepharose. Electrophoretic migration of the purified abnormal prothrombin on SDS-PAGE was normal. Upon prothrombin activation by Echis carinatus venom, the clotting activity produced from Prothrombin Himi was only 37% of the normal level after 90 minutes of the activation time, where as the amidolytic activity was almost the same as normal. The cleavage patterns of Prothrombin Himi by factor Xa or Echis carinatus venom investigated by SDS-PAGE, were found to be normal. These results indicate that Prothrombin Himi was characterized by a defective thrombin enzymatic activity.

Adult↗

PubMed1991

Changes in plasma levels of tissue-plasminogen activator/inhibitor complex and active plasminogen activator inhibitor in patients with disseminated intravascular coagulation.

Plasma levels of tissue-plasminogen activator.plasminogen activator inhibitor (t-PA.PAI) complex and active PAI were assayed in 58 cases of disseminated intravascular coagulation (DIC). A significant elevation of both parameters was observed in most cases of DIC, especially in patients with non-Hodgkin lymphoma, sepsis, or some patients with acute leukemia, but no such elevation was observed in patients with acute promyelocytic leukemia (APL). The levels of both parameters were higher in cases of DIC with multiple organ failure (MOF) than in those without MOF. Since no elevation of t-PA.PAI complex was observed in most cases of APL, t-PA did not seem to play an important role in the activation of fibrinolytic system in APL. Active PAI, which reflects the inhibitory regulation in fibrinolytic system, was considered to play a role in the progression of MOF. Plasma levels of active PAI were low in the cases of APL, which had no complication of MOF.

Disseminated Intravascular Coagulation↗

PubMed1991

Plasma levels of soluble thrombomodulin increase in cases of disseminated intravascular coagulation with organ failure.

We examined the changes in plasma levels of soluble thrombomodulin in 66 cases of disseminated intravascular coagulation (DIC), to investigate the damage to vascular endothelial cells and its relationship to multiple organ failure. A significant elevation of plasma levels of soluble thrombomodulin was observed in most cases of DIC, especially in patients with sepsis. However, no such significant elevation was observed in patients with acute promyelocytic leukemia. Plasma levels of both soluble thrombomodulin and active plasminogen activator inhibitor were higher in the cases of DIC with multiple organ failure than in those without multiple organ failure. The levels of soluble thrombomodulin were decreased with the clinical improvement in most cases of DIC but were further increased or remained at high levels in patients who showed no improvement of DIC. It was suggested that an increase in soluble thrombomodulin indicates the damage to the vascular endothelial cells in cases of DIC and that the damage to vascular endothelial cells plays some role in further progression of multiple organ failure.

Disseminated Intravascular Coagulation↗

PubMed1991

The course of disseminated intravascular coagulation is predicted by changes in thrombin-antithrombin III complex levels--is there any difference between treatment with standard heparin or low-molecular-weight heparin?

Changes in thrombin-antithrombin III complex (TAT) over a one week period studied in 42 cases of disseminated intravascular coagulation (DIC); 19 treated with standard (or unfractionated) heparin (UFH) and 23 treated with low-molecular-weight heparin (LMWH). Closer examination of short term changes in TAT (determined 2, 6, 12, 24, 48, and 72 h after starting anticoagulant therapy) was performed in ten cases of DIC; six treated with UFH and four treated with LMWH. In twelve of the 19 cases of DIC treated with UFH and 19 of the 23 cases treated with LMWH, plasma levels of TAT decreased one day after starting anticoagulant therapy, and no exacerbation of DIC was observed for the following week. In the other cases, these levels further increased and most patients had persistently high levels of TAT for the next week. Plasma levels of TAT were significantly lower in patients treated with LMWH than in those treated with UFH, which may suggest that LMWH is more beneficial in DIC. A transient increase in plasma levels of TAT was observed 6 h after the start of anticoagulant therapy in two of the six cases treated with UFH and one of the four cases treated with LMWH. From these results we conclude that fluctuation of TAT was not influenced by the type of heparin (UFH or LMWH), and that the course of DIC for the following week can be predicted by the changes in plasma TAT levels one day after starting anticoagulant therapy.

Antithrombin III↗

PubMed1991

Fibrinogen Kanazawa: a congenital dysfibrinogenaemia with delayed polymerization having a replacement of proline-18 by leucine in the A alpha-chain.

Congenital dysfibrinogenaemia was found in a 39-year-old female and her two children. The proposita, apparently heterozygous for this abnormality, had no episode of bleeding or thrombosis. The abnormal fibrinogen showed normal release of fibrinopeptides A and B but impaired polymerization of the fibrin monomer. Amino acid sequence analysis of the whole A alpha-chain isolated from fibrinogen Kanazawa showed a substitution of Leu for Pro at position 18 in the A alpha-chain. This substitution was corroborated by the analysis of the amino acid sequence which demonstrated the lysyl endopeptidase peptides derived from the A alpha-chain of fibrinogen Kanazawa. The minimal genetic exchange responsible for this substitution was a C----T transition in the middle position of the Pro codon. We conclude that Pro-18 in the A alpha-chain is crucial for the polymerization of the fibrin monomer.

Adult↗

PubMed1990

Role of D dimer in patients with elevated fibrinogen degradation products in serum: further study in chronic myelogenous leukemia.

We quantitatively assayed the levels of cross-linked fibrin degradation products (D dimer) in plasma at 73 points in time in 32 patients with elevated fibrin/fibrinogen degradation products (FDP) in serum. The assay of FDP was performed on serum samples prepared in test tubes containing 5 U/ml thrombin (final concentration) by a method based on latex agglutination using antifibrinogen antibodies, and the levels of D dimer in plasma were determined by a newly developed latex immunoassay using monoclonal antibodies which do not cross-react with fibrinogen. 5 patients with chronic myelogenous leukemia (CML) had highly elevated FDP levels with normal levels of D dimer. Plasma samples from such patients with CML were treated with various concentrations of thrombin (2-10 U/ml) and after the removal of fibrin clots the levels of FDP in supernatants were assayed by the FDP assay procedure described above. The levels of FDP were normalized when plasma were treated with 10 U/ml thrombin. In 2 patients with CML who had elevated levels of FDP in serum, it was impossible to remove fibrinogen completely by addition of 5 U/ml thrombin. However, FDP levels in the sera treated with 5 U/ml thrombin were almost normal in normal controls and patients with other diseases than CML. From these results it is concluded that residual fibrinogen reacted in the assay procedure as markedly increased FDP in supernatants and elevated FDP levels in serum reflected fibrinogen-related materials, which may not completely polymerize in the presence of lower concentrations of thrombin in some patients with CML. The assay of D dimer in plasma using monoclonal antibodies is recommended in cases of CML to rule out disseminated intravascular coagulation.

Adult↗

PubMed1990

Effects of aerosol administration of a thromboxane synthetase inhibitor (OKY-046) on bronchial responsiveness to acetylcholine in asthmatic subjects.

Bronchial hyperresponsiveness is one of the major clinical features of bronchial asthma. We previously reported that oral administration of a selective thromboxane synthetase inhibitor, OKY-046, reduced bronchial hyperresponsiveness to acetylcholine in asthmatic subjects. In this study, the effect of aerosol administration of OKY-046 on bronchial hyperresponsiveness was evaluated in ten inpatients with intrinsic asthma. Acetylcholine inhalation tests were performed before and after four days of inhalation of OKY-046 (100 mg/day). The provocative concentration of acetylcholine producing a 20 percent fall in forced expiratory volume in 1 s (PC20-FEV1) and that causing a 35 percent fall in respiratory conductance (PC35-Grs) were measured as indexes of bronchial responsiveness. There was a significant increase in PC20-FEV1 (p less than 0.001) and PC35-Grs (p less than 0.02) after inhalation of OKY-046 from 0.79 (GSEM, 1.41) Mg/ml and 0.96 (GSEM, 1.35) mg/ml to 1.20 (GSEM, 1.41) mg/ml and 1.74 (GSEM, 1.32) mg/ml, respectively. There was no significant difference in forced vital capacity (FVC), FEV1, or respiratory resistance (Rrs) baseline values before and after inhalation of OKY-046. Platelet aggregation was not inhibited by the treatment in other five inpatients. Thus, prophylactic administration of aerosol OKY-046 may be available for treatment of asthma by reduction of bronchial hyperresponsiveness. Further studies are needed to determine the optimum dose.

Acetylcholine↗

PubMed1990

[Tissue-type plasminogen activator and its inhibitor (PAI-1) in plasma in cases of non-insulin-dependent diabetes mellitus (NIDDM)].

Parameters of fibrinolysis, including plasminogen, alpha 2 plasmin-inhibitor (alpha 2 PI), tissue-type plasminogen activator (t-PA) and plasminogen activator inhibitor-1 (PAI-1) antigens, and fibrinogen were assayed in 53 patients (28 women and 27 men; mean age: 64 years, age range: 32-87 years) with non-insulin-dependent diabetes mellitus (NIDDM). The control group was similarly aged (mean age: 60.4 years, age range: 38-81). The levels of t-PA and t-PA/PAI-1 ratio of the diabetic group (mean +/- SD; 9.8 +/- 4.3 ng/ml, 0.94 +/- 0.47, respectively) were significantly higher than that of the control group (5.5 +/- 2.5 ng/ml, 0.51 +/- 0.23, respectively). The increased levels of t-PA antigen and t-PA/PAI-1 ratio in diabetics mean that free t-PA has been released. However, there was no significant difference in the level of PAI-1 between the diabetic group (12.9 +/- 6.4 ng/ml) and the control group (12.1 +/- 5.6 ng/ml). Levels of fibrinogen, plasminogen and alpha 2 PI in plasma were not different in the two groups. Duration of the disease, levels of glycosylated hemoglobin, differences in treatment and presense of diabetic nephropathy or retinopathy did not affect the fibrinolytic parameters. The levels of fibrinogen was higher in those with nephropathy than in the diabetics without nephropathy and retinopathy (p less than 0.05). There were no significant differences in the levels of t-PA, t-PA/PAI-1 ratio and PAI-1 between younger (less than 65 years) and older (65 years or more) subjects, in either the control or diabetic groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗