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Publications (18)64.84 Total impact

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    ABSTRACT: 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 microgram/mL in patients with DIC and hematopoietic disorders.
    Clinical and Applied Thrombosis/Hemostasis 02/2003; 9(1):71-7. · 1.02 Impact Factor
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    ABSTRACT: 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.
    American Journal of Hematology 12/2000; 65(3):210-4. · 4.00 Impact Factor
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    ABSTRACT: Before hemodialysis (HD), plasma levels of tissue factor (TF), free-TF pathway inhibitor (TFPI) and thrombomodulin (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 complex (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 complications 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 parameters, with the exception of TF and PC. Hemostatic abnormalities existed in patients with HD; especially, increased TF and decreased PC might cause thrombotic complications.
    Clinical and Applied Thrombosis/Hemostasis 05/2000; 6(2):100-3. · 1.02 Impact Factor
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    ABSTRACT: To evaluate that the relationship between the truncated form of tissue factor pathway inhibitor (TFPI) and the stage of disseminated intravascular coagulation (DIC), we measured the plasma levels of tissue factor (TF) antigen and the intact and truncated forms of TFPI antigens in 41 patients with DIC, 12 with pre-DIC, and 20 with non-DIC. The plasma TF and total TFPI antigen levels were significantly higher in patients with DIC than in non-DIC patients. Plasma levels of intact TFPI antigen in the pre-DIC groups were significantly lower than in the non-DIC and DIC groups. The truncated form of TFPI antigen levels in DIC patients were significantly increased compared with those in non-DIC and pre-DIC patients. The fact that the intact form of TFPI was decreased in pre-DIC patients compared with that in non-DIC patients, suggests that it is consumed in the pre-DIC state and that hypercoagulability occurs in pre-DIC patients. The increased level of the truncated form of TFPI in DIC patients may be attributed to proteolysis of the intact form of TFPI in these patients. The increased level of the truncated form of TFPI may be a useful index for the diagnosis of DIC.
    American Journal of Hematology 03/1999; 60(2):94-8. · 4.00 Impact Factor
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    ABSTRACT: Several studies indicated that activation of the clotting system may promote the growth and the invasive behavior of tumor cells. In the present study, we evaluated the migratory response of various melanoma cell lines to several clotting factors and prothrombin derivatives (thrombin, fragment 1, fragment 2 and kringle 1 fragment). Prothrombin, thrombin and fragment 1 stimulated chemotaxis of the murine (K-1735 M2, X21) and human A375 (SM) melanoma cell lines. Prothrombin and prothrombin fragment 1 showed their maximal chemotactic activity at 0.5 approximately 1 microM. Chemotaxis induced by thrombin was inhibited by hirudin, but not that induced by prothrombin or fragment 1. Other clotting proteins and the fragment 2 and kringle 1 fragment of prothrombin did not elicit chemotactic activity. Checkerboard analysis indicated that motility was directional with a significant chemokinetic component. The K-1735 M2 cells also migrated in a concentration-dependent manner to substratum-bound insoluble prothrombin, thrombin or fragment 1. Ligand binding assays showed that both prothrombin and fragment 1 bound to K-1735 M2 cells with apparent Kds of 0.5 microM. This binding was inhibited by an excess concentration of unlabeled prothrombin and fragment 1 but not by similar concentrations of other prothrombin fragments. These findings suggest that prothrombin and its fragment 1 exert chemotactic activity on melanoma cells by different mechanisms and different binding sites from that induced by thrombin.
    Thrombosis and Haemostasis 10/1998; 80(3):407-12. · 6.09 Impact Factor
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    ABSTRACT: The aim of this study was to evaluate the inhibitory activity of adenosine on tumor necrosis factor-alpha (TNF), thrombin-, or phorbol 12-myristate 13-acetate (PMA)-induced tissue factor (TF) expression on human umbilical vein endothelial cells (HUVECs). This inhibitory effect of adenosine was found to be counteracted by the non-selective adenosine receptor (AR) antagonist, 8-(p-sulfophenyl) theophylline. To clarify the role of ARs (A1, A2a, A2b, and A3) in this regulation, we evaluated the effect of several agonists and antagonists specific for AR-subclass on TF expression. The selective A2aAR agonist, 2-p-(2-carboxyethyl) phenethylamino-5'-N-ethylcarboxamido adenosine hydrochloride (CGS 21680), the A3AR agonist, N6-2-(4-aminophenyl) ethyladenosine (APNEA), and the A1AR antagonist, 1,3-dipropyl-8-(2-amino-4-chlorophenyl) xanthine (PACPX) each inhibited TF activity expression induced by TNF, thrombin, or PMA on HUVECs. In contrast, the selective A1AR agonist, chloro-N6-cyclopentyladenosine (CCPA) and the A2AR antagonist, 3,7-dimethyl-1-propargylxanthine (DMPX) enhanced each stimulant-induced TF activity expression. All agonist or antagonist alone did not alter the basal TF expression on HUVECs. Our results suggest that stimulation of A2aAR and A3AR down-regulates and that of A1AR up-regulates the endothelial cell TF expression induced by TNF, PMA, or thrombin. Thus, it appears that adenosine itself may exert anticoagulant activity on vascular endothelial cells via its A2a and A3 receptors, particularly during ischemic or atherosclerotic processes which are known to be associated with local increased levels of adenosine.
    Thrombosis Research 08/1998; 91(2):57-64. · 3.13 Impact Factor
  • Thrombosis Research 07/1998; 91(2). · 3.13 Impact Factor
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    ABSTRACT: Dilazep, an antiplatelet agent, is generally used as an antithrombotic drug in clinical practice. Dilazep is also known to exert cytoprotective and antioxidant effects on endothelial cells. However, its effect on the endothelial or monocyte procoagulant activity is unknown. In the current study, the effect of dilazep on the expression of tissue factor (TF) in human umbilical vein endothelial cells (HUVECs) after the stimulation with tumor necrosis factor-alpha (TNF), thrombin, or phorbol 12-myristate 13-acetate (PMA) was evaluated. We also evaluated the effect of dilazep on TNF (1,000 U/mL)-induced TF expression on monocytes. Dilazep inhibited TF activity induced on HUVECs by each stimulant, TNF (1000 U/mL), thrombin (25 nmol/L), or PMA (5 nmol/L) in a dose-dependent fashion (1 to 100 microg/mL). TF activity decreased to approximately 10% after treating with 100 microg/mL of dilazep. Dilazep also blocked the expression of TF antigen induced by each stimulant on the surface of HUVECs as determined by flow cytometric analysis. In addition, in HUVECs, it significantly decreased the expression of TF mRNA and the total TF antigen induced by thrombin or PMA, but not those induced by TNF, suggesting that dilazep blocks the TF expression induced by PMA or thrombin at a transcriptional level and that induced by TNF at a posttranscriptional level. Western blot analysis showed that dilazep reduces the accumulation of native TF but increases that in lower molecular weight TF derivatives. The adenosine receptor antagonist, 8-(p-sulfophenyl) theophylline, partially counteracted the anticoagulant activity of dilazep on HUVECs, thereby suggesting that the inhibitory effect of dilazep on TF expression in HUVECs depends, at least in part, on its adenosine potentiating activity. Dilazep also inhibited TNF-induced TF expression on monocytes in a dose-dependent fashion (0.1 to 100 microg/mL). In brief, the current study showed for the first time that dilazep, a commonly used antiplatelet drug, strongly inhibits the TF expression in HUVECs and monocytes. Dilazep may have a potent therapeutic value in patients with hypercoagulable state for its inhibitory property on the procoagulant activity of endothelial cells and monocytes.
    Blood 10/1997; 90(6):2345-56. · 9.06 Impact Factor
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    ABSTRACT: beta2-Glycoprotein I (beta2GPI), a plasma glycoprotein with phospholipid-binding property, is known to be the actual target antigen for autoimmune type anticardiolipin antibodies (aCLs). Certain groups of aCLs (anti-beta2GPI antibodies) exert lupus anticoagulant (LA) activity and perturb the function of vascular endothelial cells. This investigation aimed at highlighting some insights into the molecular basis by which aCLs exert their biological effects by using anti-beta2GPI mAbs with well-characterized epitopes from mice and from patients with antiphospholipid syndrome. Anti-beta2GPI mAbs directed against the third domain (Cof-20 and Cof-22) and fourth domain (Cof-21, EY1C8, and EY2C9) of beta2GPI inhibited the thrombin generation induced by Russell's viper venom in diluted plasma and that induced by the prothrombinase complex reconstituted with purified clotting factors. This anticoagulant activity was abrogated in the presence of an excess amount of phospholipids, thus resembling the LA activity. In stark contrast, anti-beta2GPI mAbs directed against the fifth domain and the carboxy-terminal region of the fourth domain showed no LA-like activity. These findings suggest that the LA activity of anti-beta2GPI antibodies depends on their epitope specificity. Experiments carried out to clarify the mechanism of the LA activity showed that anti-beta2GPI mAbs with LA-like activity, but not those without this effect, enhance the beta2GPI binding to phospholipids. In addition, the F(ab')2 fragment, but not the Fab' fragment, of the anti-beta2GPI mAbs was found to enhance the LA activity and the beta2GPI binding to phospholipids, suggesting that anti-beta2GPI antibodies induce formation of multiple complexes of beta2GPI on the surface of phospholipids because of their bivalent property. This clustering of beta2GPI molecules induced by anti-beta2GPI antibodies, probably because of their multivalent property and epitope specificity, might hinder the lateral mobility and activation of clotting factors on the surface of phospholipids and thus exert LA activity. Clustering of beta2GPI molecules may also explain the molecular mechanism by which anti-beta2GPI antibodies alter the function of leukocytes and endothelial cells. The well-documented heterogeneous LA activity of aCLs (anti-beta2GPI antibodies) may also be explained by their epitope specificity.
    Journal of Clinical Investigation 06/1997; 99(9):2260-8. · 12.81 Impact Factor
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    ABSTRACT: We examined plasma levels of activated factor VII (F VIla) in 50 patients positive for lupus anticoagulant (LA), in 83 patients negative for LA, and in 10 healthy volunteers as controls. Plasma F VIIa was present in healthy volunteers; its level was significantly increased, compared to the level in the controls, in patients with thrombosis, collagen diseases, and disseminated intravascular coagulation (DIC), suggesting that it reflected a thrombotic state. Plasma F VIIa was correlated with thrombin-antithrombin complex (TAT) in patients negative for LA but showed no such correlation in those positive for LA. Plasma F VIIa was negatively correlated with activated partial thromboplastin time (APTT) in patients positive for LA, but not in those negative for LA, suggesting that LA could inhibit the F VIIa assay system. Plasma F VIIa level was significantly increased in patients with thrombotic diseases; however, in patients positive for LA, it is possible that increased plasma F VIIa level may not be correlated with thrombogenicity.
    American Journal of Hematology 06/1997; 55(1):9-14. · 4.00 Impact Factor
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    ABSTRACT: The kringle 2 domain of prothrombin has been shown to interact with factor Va during the activation of prothrombin by the prothrombinase complex composed of factor Xa, factor Va, negatively charged phospholipids and Ca2+ ions. However, contradictory results have been reported about the role of the kringle 1 domain of prothrombin during the assembly of the prothrombinase complex. In an attempt to clarify the role of the kringle 1 domain of prothrombin, its effect on the activation of prothrombin by the prothrombinase complex and its direct binding to human factor Va were assessed. Comparative evaluation with the effects caused by other prothrombin structural components [a fragment 1 (gamma-carboxyglutamic acid and kringle 1 domains), a kringle 2 domain and a catalytic protease domain] was also performed. In the presence of factor Va, each kringle 1 and kringle 2 fragment significantly inhibited the factor Xa-catalysed prothrombin activation in the absence of phospholipids. However, in the absence of both factor Va and phospholipids, kringle 2 fragment, but not kringle 1 fragment, inhibited prothrombin activation. Evaluation of the molecular interaction of the kringle domains with factor Va in assays with solid-phase phospholipid vesicles showed that each kringle 1 and kringle 2 fragment inhibited the prothrombinase complex activity. Assessment of the direct binding of prothrombin and each kringle domain of prothrombin with factor Va by fluorescence polarization showed that prothrombin, kringle 1 and kringle 2 fragments bind directly to factor Va with dissociation constants of 1.9+/-0.1, 2.3+/-0.1 and 2.0+/-0.4 microM (means+/-S.D.) respectively. These findings suggest that both kringle 1 and 2 domains of prothrombin interact with factor Va during the assembly of the prothrombinase complex.
    Biochemical Journal 03/1997; 321 ( Pt 3):729-35. · 4.65 Impact Factor
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    ABSTRACT: The prevalence of activated protein C (APC) resistance and the antigen levels of factor V were assessed in 37 patients with lupus anticoagulant (LA), 12 with essential thrombocythemia (ET), 17 with idiopathic thrombocytopenic purpura (ITP), and in 27 cases of thrombotic complications associated with diabetes mellitus and collagen vascular disease. Blood samples taken from 30 healthy normal subjects were also available for comparison. The mean APC ratio of patients with LA (2.9 ± 1.5), ET (2.7 ± 1.2), and secondary thrombosis (2.6 ± 0.9) were significantly lower than that of the healthy control group (3.5 ± 1.0). The APC ratio of ET patients with thrombosis (2.3 ± 0.6) was significantly lower than that measured in ET cases without thrombotic complication (3.9 ± 1.9). Patients positive for LA and with thrombotic complication (1.8 ± 1.4) presented lower APC ratios than those without thrombosis (3.3 ± 1.4). Among all patients, an APC ratio lower than 2 was found in 24 cases, of which 16 had thrombotic disease, but none of them presented the factor V:R506Q mutation. The antigen levels of factor V correlated significantly with APC ratio in all patients. The results of this investigation suggest that an acquired poor anticoagulant response to APC might explain, at least in part, the thrombophilia of patients with LA and ET and that associated with diabetes mellitus or collagen disease. Key Words: APC resistance—Lupus anticoagulant—Essential thrombocythemia.
    Clinical and Applied Thrombosis-hemostasis - CLIN APPL THROMB-HEMOST. 01/1997; 3(2):119-123.
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    ABSTRACT: Enhanced activation of the clotting system has been recently implicated in the pathogenesis of vascular complications in patients with diabetes mellitus. Abnormalities of the anticoagulant system may constitute a potential trigger factor for the haemostatic activation observed in diabetic subjects. The current study aimed to evaluate anticoagulant activity in diabetic patients by assessing the plasma levels of activated protein C-protein C inhibitor complex; and by measuring the anticoagulant response to exogenous thrombomodulin. This study comprised 61 patients (34 men, 27 women) with non-insulin-dependent diabetes mellitus (NIDDM) of whom 22 showed microalbuminuria and 39 normoalbuminuria. Data obtained in 31 non-obese and non-diabetic subjects were available for comparison. The plasma levels of fibrinogen (p < 0.02), prothrombin fragment 1 + 2 (p < 0.05), fibrin monomer (p < 0.0001), protein C antigen (p < 0.005), total protein S antigen (p < 0.02), soluble thrombomodulin (p < 0.005) and soluble E-selectin (p < 0.005) were significantly higher in diabetic patients than in healthy subjects. The plasma level of activated protein C-protein C inhibitor complex (7.4 +/- 3.8 vs 3.0 +/- 0.4 pmol/l) was significantly higher (p < 0.0001) and the anticoagulant response to exogenous thrombomodulin (23.4 +/- 2.6 vs 35.3 +/- 3.0 ng/ml) was markedly lower (p = 0.005) in all diabetic patients than in healthy subjects. Cases with microalbuminuria presented low plasma levels of activated protein C-protein C inhibitor complex (5.5 +/- 0.6 vs 8.6 +/- 0.7 pmol/l, p < 0.05) and significantly decreased values of the anticoagulant response to exogenous thrombomodulin (16.5 +/- 2.9 vs 23.4 +/- 2.6%, p = 0.03) as compared to those with normoalbuminuria. The present study suggests that the hyper-coagulable state in NIDDM is associated with an increased activation of protein C but with a poor plasma reactivity to the anticoagulant effect of thrombomodulin.
    Diabetologia 12/1996; 39(12):1455-61. · 6.49 Impact Factor
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    ABSTRACT: 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.
    American Journal of Hematology 05/1996; 51(4):255-60. · 4.00 Impact Factor
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    ABSTRACT: The Plasma level of soluble fibrin monomer (sFM) was measured in 218 patients with a hematopoietic malignancy. Of them, 198 were diagnosed with disseminates intravascular coagulation (DIC), 20 with Pre-DIC, and 20 with Non-DIC. Pre-DIC was retrospectively defined as the condition at least 1 week before the onset of DIC. The plasma levels of sFM, thrombin-anti-thrombin III complex (TAT), plasmin alpha 2-antiplasmin inhibitor complex (PIC), and FDP-D-dimer were significantly higher in patients with DIC than in those with Non-DIC. These levels were significantly higher in patients with Pre-DIC than in those with Non-DIC. Among these hemostatic parameters, the plasma sFM showed the highest sensitivity and specificity for DIC or Pre-DIC. These findings suggests that sFM is the most valuable marker hemostatic for the diagnosis of DIC and Pre-DIC.
    Rinsho byori. The Japanese journal of clinical pathology 02/1996; 44(1):57-60.
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    ABSTRACT: Octreotide acetate, a long-acting somatostatin analogue, is effective in controlling and markedly reducing the symptoms of carcinoid crisis. We report a patient with carcinoid syndrome with prolonged survival for 4.5 years with high dose octreotide therapy and survived for 7.5 years after the first flushing, in spite of episodes of severe carcinoid crisis. Dose escalation was required in order to control carcinoid symptoms, and the final dosage was 5,950 micrograms/day. Although administration of such a high dosage of octreotide has never been reported before, we found that octreotide could be used at this dosage safely without inducing serious side effects, and probably prolonged the patient's survival. Our experience with this case indicates that octreotide acetate is an effective drug in controlling carcinoid crisis and prolonging survival without serious side effects.
    Internal Medicine 03/1994; 33(2):100-2. · 0.97 Impact Factor
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    ABSTRACT: Within the framework of a multicenter clinical study of the recombinant human factor VIII preparation BAY w 6240, we studied the pharmacokinetics of this factor in blood by using the preparation during tooth extraction in a patient with hemophilia A. The results allowed us to conclude that this preparation exerts a hemostatic effect comparable to that of human-derived concentrated factor VIII preparation and that it can be safely used in patients with hemophilia A who undergo tooth extraction.
    Current Therapeutic Research 10/1993; 54(4):389–394. · 0.45 Impact Factor
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