[Prevention of hemorrhage occurring in patients with leukemia].
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Anticoagulants↗
Biomedical subjects
Hideo Wada
Publications and source records attributed to Hideo Wada.
High plasma fibrinogen level is associated with poor clinical outcome in DIC patients.
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 <100 mg/dl of plasma fibrinogen, suggesting that plasma fibrinogen level is not a sensitive marker for DIC. In our analysis of outcome and plasma fibrinogen levels, the rate of death was high in leukemia/lymphoma patients with high fibrinogen concentration, but no significant difference in outcome was observed in relation to plasma fibrinogen concentration in non-leukemia/lymphoma patients with DIC. Among patients with leukemia/lymphoma, the frequency of organ failure was markedly high in patients with high plasma levels of fibrinogen. Among patients without leukemia/lymphoma, the frequency of organ failure increased concomitantly with the increase in plasma fibrinogen levels. The international normalized ratio was significantly increased in leukemia/lymphoma patients with low fibrinogen. FDP levels were slightly increased in patients with low fibrinogen. Platelet count was significantly low in patients without leukemia/lymphoma with high fibrinogen. DIC score increased concomitantly with the reduction in plasma fibrinogen levels. Plasma levels of thrombomodulin and tissue factor were significantly high in patients with high fibrinogen levels. Plasma levels of antiplasmin and plasminogen were significantly decreased in patients with low fibrinogen. Plasma levels of plasmin plasmin-inhibitor complex and tissue type plasminogen activator/plasminogen activator inhibitor-1 complex (PAI-I) were significantly higher in patients with low fibrinogen than in those with high fibrinogen. Plasma levels of PAI-I and IL-6 were significantly higher in patients with high fibrinogen than in those with low fibrinogen. Patients with high fibrinogen levels showed less activation of secondary fibrinolysis, which might explain the occurrence of organ failure and poor outcome.
Adult↗
Comparison of diagnostic criteria for disseminated intravascular coagulation (DIC): diagnostic criteria of the International Society of Thrombosis and Hemostasis and of the Japanese Ministry of Health and Welfare for overt DIC.
We compared the criteria set by the International Society of Thrombosis and Hemostasis (ISTH) for the diagnosis of disseminated intravascular coagulation (DIC) with the criteria of the Japanese Ministry of Health and Welfare (JMHW) set for the diagnosis of overt DIC. We studied 1,284 Japanese patients with DIC. The rate of agreement in the diagnosis of DIC by the two diagnostic systems was 67.4%. In addition, only 2.0% of non-DIC patients by JMHW criteria were diagnosed with overt DIC by ISTH criteria, suggesting that ISTH for overt DIC includes typical cases of DIC. The concordance of diagnosis for DIC by ISTH and JMHW was significantly high in patients with trauma or acute promyelocytic leukemia. About 70% of DIC or overt DIC patients had more than 1 point in the scoring system for prothrombin time, but >50% of those patients had 0 point for plasma fibrinogen level. Abnormal fibrin and fibrinogen degradation product (FDP) levels and platelet counts were observed in >88% of DIC and overt DIC patients but were observed in >50% of non-DIC patients, indicating that these parameters are sensitive markers but not specific markers for the diagnosis of DIC. Considered together, our results suggest that the diagnostic criteria for DIC and overt DIC could be improved by changing the cut-off values of the global coagulation tests.
Blood Coagulation Tests↗
Atherosclerotic and hemostatic abnormalities in patients undergoing hemodialysis.
Vascular events caused by atherosclerosis are the major cause of death in patients undergoing hemodialysis (HD). The relationship between the tests of atherosclerosis and hemostasis in 84 patients with HD was examined. Abnormal test results indicting the occurrence of atherosclerosis were found in 66% by the Fontaine score, in 33% by ankle blood pressures, and in 79% by aortic calcification index (ACI). When HD was prolonged, the mean Fontaine score and ACI were further increased. Particularly, the ACI tended to correlate with HD duration. The ankle-brachial index (ABI) was decreased in patients with HD duration of more than 10 years. Before HD, the plasma levels of fibrinogen, plasmin-plasmin inhibitor complex (PIC), thrombomodulin (TM), and D-dimer were increased, while the plasma levels of protein C (PC), antithrombin (AT), thrombin-antithrombin complex (TAT), and tissue plasminogen activator (tPA)-plasminogen activator inhibitor-I (PAI-I) complex (tPA-PAI-1 complex) were decreased. With prolonged HD, the plasma levels of AT and PC were decreased, while those of D-dimer were increased. The plasma levels of TAT and TPA-PAI-1 complex were significantly increased and those of PIC, soluble fibrin (SF) and D-dimer tended to be high in patients with less than 0.7 of ABI. The plasma levels of D-dimer, TPA-PAI-1 complex, TAT, PIC, and SF tended to be high in patients with more than 0.5 in ABI. These findings suggest that patients undergoing HD have progressive atherosclerosis and that this is associated with some hemostatic abnormalities.
Aged↗
Good or poor responses of hemostatic molecular markers in patients with hematopoietic disorders after treatment of disseminated intravascular coagulation.
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.
Antithrombins↗
Nitric oxide stimulates glucose transport through insulin-independent GLUT4 translocation in 3T3-L1 adipocytes.
OBJECTIVE: It is well known that nitric oxide synthase (NOS) is expressed and that it modulates glucose transport in skeletal muscles. Recent studies have shown that adipose tIssues also express inducible and endothelial nitric oxide synthase (eNOS). In the present study, we investigated whether nitric oxide (NO) induces glucose uptake in adipocytes, and the signaling pathway involved in the NO-stimulated glucose uptake in 3T3-L1 adipocytes. METHODS: First, we determined the expression of eNOS in 3T3-L1 adipocytes, and then these cells were treated with the NO donor sodium nitroprusside (SNP) and/or insulin, and glucose uptake and phosphorylation of insulin receptor substrate (IRS)-1 and Akt were evaluated. Moreover, we examined the effects of a NO scavenger, a guanylate cyclase inhibitor or dexamethasone on SNP-stimulated glucose uptake and GLUT4 translocation. RESULTS: SNP at a concentration of 50 mmol/l increased 2-deoxyglucose uptake (1.8-fold) without phosphorylation of IRS-1 and Akt. Treatment with the NO scavenger or guanylate cyclase inhibitor decreased SNP-stimulated glucose uptake to the basal level. Dexamethasone reduced both insulin- and SNP-stimulated glucose uptake with impairment of GLUT4 translocation. CONCLUSION: NO is capable of stimulating glucose transport through GLUT4 translocation in 3T3-L1 adipocytes, via a mechanism different from the insulin signaling pathway.
3T3 Cells↗
Measurement of tissue factor messenger RNA levels in leukocytes from patients in hypercoagulable state caused by several underlying diseases.
In a preliminary study, we have demonstrated that tissue factor (TF) is immunohistochemically stained in monocytes from patients with disseminated intravascular coagulation (DIC) but not from healthy volunteers, and that leukocytes from DIC patients induce enhanced activated factor X (FXa) generation in the presence of a mixture of FVIIa, FX and Ca(2+). Then, TF mRNA levels in leukocytes were measured to evaluate the role of TF in the pathophysiology of various diseases. TF mRNA levels in leukocytes were low in healthy volunteers but they were significantly increased in various diseases, especially in patients with infectious diseases, solid cancer, and hematopoietic tumors. TF mRNA levels in leukocytes were significantly higher in patients with high levels of C reactive protein (CRP) than in those with low CRP. TF mRNA levels were significantly higher in patients with DIC than in those without DIC. TF mRNA levels were well correlated with TF antigens in plasma and leukocytes. These findings suggest that the expression of TF mRNA in leukocytes is increased in various diseases and that this may play an important role in hypercoagulability or DIC.
Adult↗
Measurement of soluble fibrin monomer-fibrinogen complex in plasmas derived from patients with various underlying clinical situations.
We previously reported a monoclonal antibody named IF-43 that specifically recognizes thrombin-modified fibrinogen (desAA- and desAABB- fibrin monomer) bound with fibrinogen or other D(1) domain-containing plasmic fragments such as fragments X,Y, and D(1), but not intact fibrinogen or cross-linked fibrin degradation products (XDP). Here, we tentatively named such complexes, soluble fibrin monomer (FM) -fibrinogen complex. By utilizing IF-43, we have developed a kit to measure soluble FM-fibrinogen complex and compared the profiles with those of two established molecular markers for thrombo-embolic disorders: i.e. the thrombin-antithrombin complex (TAT) and the D-dimer in plasma of patients who underwent surgery without any thrombo-embolic complications. The result indicated that soluble FM-fibrinogen complex is a distinct entity from the two established molecular markers. We have also attempted to observe their profiles in patients with the disseminated intravascular coagulation syndrome (DIC). Although the pro-files of soluble FM-fibrinogen complex in individual patients appeared to vary from one patient to the other, the plasma level of soluble FM-fibrinogen complex was found to be increased at the initial phase of disseminated intravascular coagulation syndrome. Thus, the soluble FM-fibrinogen complex may serve as an independent molecular marker for the detection of thrombin generation and the diagnosis of thrombosis. The soluble FM-fibrinogen complex may also serve as a risk factor for thrombosis, because it may precipitate as insoluble complexes beyond its threshold in plasma, or when it is modified by thrombin.
Antithrombin III↗
[Clinical evaluation of a test for plasma fibrin/fibrinogen degradation products (FDP) based on monoclonal anti-FDP antibody technology: an application for the scoring system of the disseminated intravascular coagulation (DIC) diagnostic criteria].
Fibrin/fibrinogen degradation products(FDP) have been measured using serum samples which were specially prepared for the FDP test because of the usage of anti-human fibrinogen antibody for the assay. Since diagnostic criteria for DIC were established by the study group on thrombosis and hemostasis which is supported by the Japanese Ministry of Health and Welfare(JMHW), serum FDP assay have been used as standard methods to diagnose DIC in Japan. Recently, a reagent using an anti-human FDP monoclonal antibody was developed and this has enabled the use of plasma samples for FDP measurement. The comparability, especially of the DIC score, of a new assay, Latex test BL-2 P-FDP, using plasma samples with a conventional assay for serum was investigated. Two sets of DIC scores based on data from the two tests were compared and the correlation was high with 97.5% of the patients being diagnosed with the same DIC status. In four disease groups--DIC, thrombosis, leukemia and solid cancer--high comparability between the two tests was also shown and no significant difference was observed in the correlation coefficient and the slope coefficient between serum and plasma samples. To conclude, it is suggested that "Latex test BL-2 P-FDP" is applicable to the diagnostic criteria for DIC from JMHW without any difficulty.
Antibodies, Monoclonal↗
Molecular characterization of coagulation factor XII deficiency in a Japanese family.
We report the identification in a Japanese family of a novel homozygous W486C mutation in the protease domain of coagulation factor XII (FXII), which was associated with the reduction of plasma FXII activity and antigen level to less than 5% of normal. Sequences of each exon for FXII gene was analysed in family members by polymerase chain reaction (PCR) amplification followed by a direct sequencing method. Sequence analysis showed a homozygous substitution of G to C at nucleotide position 10587 (cDNA position 1458) in proband's FXII gene, resulting in a Trp to Cys substitution in the catalytic domain of FXII. PCR-fragment length polymorphism analysis of 55 healthy volunteers showed no such mutation. Transient expression of FXII in HK-293T cells and analysis of FXII antigen in culture media and cell lysates showed reduced secretion of mutant protein by more than 84% relative to that of wild type protein although the intracellular contents were similar. Our results suggest that the reduced secretion of FXII protein was due to incorrect folding caused by the introduction of Cys486. We designated this mutation as FXII Mie-1.
Amino Acid Substitution↗
A comparison of supercritical carbon dioxide and organic solvents for the intercalation of 4-phenylazoaniline into a pillared clay mineral.
The intercalation of 4-phenylazoaniline (PAA) in supercritical carbon dioxide (SC-CO(2)) into montmorillonite (TMA-Mnt) pillared with tetramethylammonium ions at 313 K and 15 MPa was investigated. The adsorption rate and equilibrium PAA uptake were compared with those in n-hexane, CCl(4) and benzene solutions at 313 K. The XRD and N(2) adsorption/desorption analyses showed that TMA-Mnt after adsorption of PAA in SC-CO(2) had the same pore structure as after adsorption of PAA in normal solvents. SC-CO(2) was found to be a good medium for PAA adsorption owing to its having a relatively high adsorption rate and the highest adsorptivity at the same PAA concentration. The properties of PAA adsorption on TMA-Mnt could be well elucidated by the difference in solubility parameters between liquid and solid phases.
Journal Article↗
Evaluation of tissue factor antigen level in human seminal plasma.
We measured the seminal plasma levels of tissue factor (TF) and interleukin-6 (IL-6) in men and examined their relationship with sperm concentration and motility. The study comprised 71 patients in three groups: an infertile group with ( n=11) and without ( n=50) leukocytospermia and a fertile group ( n=10). The seminal plasma levels of TF were significantly higher in the infertile patients than in the fertile ones. The seminal plasma levels of both TF and IL-6 were significantly higher in the infertile patients with leukocytospermia than in those without leukocytospermia. In 54 nonazoopermic cases the seminal plasma levels of TF were significantly correlated with the sperm concentration and sperm motility. Further studies are necessary to clarify the role of TF in human fertilization.
Adult↗
Expression of tissue factor and vascular endothelial growth factor is associated with angiogenesis in colorectal cancer.
We examined the expression of tissue factor (TF) and vascular endothelial growth factor (VEGF) and the microvessel density (MVD) in 100 patients with colorectal cancer, and we investigated the relationship of the expression of TF or VEGF with angiogenesis. TF antigen was positive in 57.0% of all specimens. Incidence of TF expression was 41.2%, 45.5%, 52.6%, 84.6%, and 81.3% in tumors from patients in clinical stages I, II, IIIA, IIIB, and IV, respectively. TF expression was correlated with the Dukes' classification (P = 0.01) and the clinical stage of colorectal cancer (P = 0.02). VEGF antigen was positive in 64.0% of all specimens. Incidence of VEGF expression was 41.2%, 57.6%, 73.7%, 84.6%, and 75.0% in tumors from patients in clinical stages I, II, IIIA, IIIB, and IV, respectively. VEGF expression was correlated with the Dukes' classification (P = 0.01) but showed a weak association with the clinical stage (P = 0.08). MVD was significantly associated with the depth of invasion (P = 0.01), lymph node metastasis (P = 0.001), and liver metastasis (P = 0.02). The mean values of MVD were 7.5 +/- 2.8, 10.1 +/- 5.7, 14.6 +/- 5.8, 13.5 +/- 3.9, and 15.9 +/- 4.2 in tumors from patients in clinical stages I, II, IIIA, IIIB, and IV, respectively. A close relationship between VEGF and MVD (P < 0.001) and a significant correlation between TF expression and MVD were observed (P = 0.02). TF-positive carcinomas presented high MVD and VEGF expression (P < 0.001) more frequently than did TF-negative tumors. These results suggest that involvement of TF in the process of metastasis and progression of colorectal cancer may depend on increased angiogenesis.
Adult↗
Predicting response to plasma exchange in patients with thrombotic thrombocytopenic purpura with measurement of vWF-cleaving protease activity.
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.
ADAM Proteins↗
Hemostatic abnormalities following bone marrow transplantation.
Hemostatic abnormalities in 26 patients following bone marrow transplantation (BMT) were examined. In the event-free survival group, the plasma levels of antithrombin (AT) and protein C (PC) were significantly decreased 1 and 2 weeks after BMT, and the plasma levels of thrombomodulin (TM) and tissue plasminogen activator-plasminogen activator inhibitor-1 complex (tPA-PAI-I complex) were significantly increased from 4 weeks to 13 weeks after BMT. Excepting AT, there was no significant difference in hemostatic parameters before BMT among the event-free survival, 6-month survival, and death within 6 months groups. On day 0 following BMT, only plasma AT levels were significantly lower in the 6-month survival group than in the death within 6 months group. From 1 to 3 weeks after BMT, plasma levels of AT or PC were significantly lower in the death within 6 months group than in the 6-month survival group. From 1 to 5 weeks after BMT, the plasma levels of TM and tissue type plasminogen activator-plasminogen activator inhibitor-I complex (tPA-PAI-I complex) were significantly higher in the 6-month survival group than in the death within 6 months group. From 1 to 13 weeks after BMT, the plasma levels of D-dimer or soluble fibrin monomer (SFM) were significantly higher in the death within 6 months group than in the 6-month survival group. There was no remarkable difference in plasma levels of thrombin-antithrombin comlex or plasmin-plasmin inhibitor complex following BMT between these groups of patients. These findings suggest that the decrease in the plasma AT or PC level reflects early occurrence of complications of prognostic significance and that the increase in vascular endothelial cell markers such as plasma levels of TM or tPA-PAI-I complex reflects occurrence of complications during the middle course of BMT. Plasma levels of D-dimer and SFM may be useful markers for predicting complications associated with poor prognosis after BMT.
Adult↗
Plasma levels of heparin cofactor II (HCII) and thrombin-HCII complex in patients with disseminated intravascular coagulation.
Plasma levels of heparin cofactor II (HCII), thrombin-HCII complex (THC), antithrombin (AT), and thrombin-AT complex (TAT) were evaluated in patients with disseminated intravascular coagulation (DIC) associated with several underlying diseases. Plasma levels of AT were significantly reduced in almost all underlying diseases associated with DIC, but the plasma levels of HCII and HCII/AT ratio were significantly reduced only in patients with infections. While the plasma level of TAT was significantly increased in patients with all underlying diseases associated with DIC, the increase of THC was not significant. Plasma levels of AT were significantly reduced in DIC and pre-DIC associated with almost all underlying diseases, but those of HCII were significantly reduced only in DIC and pre-DIC patients with inflammatory diseases. The plasma levels of TAT were significantly increased in DIC, pre-DIC, and non-DIC patients with all underlying diseases, and those of THC were significantly increased in DIC and pre-DIC patients with inflammatory diseases. The plasma levels of THC were not significantly increased in non-DIC patients of any disease group. The decrease of AT may be caused by thrombin generation or inflammatory reaction that occurs in DIC associated with underlying diseases, while the decrease of HCII might be caused by both thrombin generation and inflammatory reaction. Finally, AT inhibits thrombin more strongly than HCII in several underlying diseases associated with DIC except for inflammatory diseases. In inflammatory diseases, HCII might play an important role in preventing the onset of DIC.
Antithrombin III↗
[Criteria for diagnosing DIC].
The differences between reagents of prothrombin time (PT), fibrinogen and fibrin and fibrinogen degradation products(FDP) were examined in patients with disseminated intravascular coagulation (DIC) and without DIC. The sensitivity of the PT ratio for DIC is lowered by the PT reagent with a high international sensitivity index, and the difference between PT reagents was marked. The sensitivity of PT-international normalized ratio (INR) for DIC was higher than that of the PT ratio and the difference between reagents in PT-INR was low. Though the difference between reagents for fibrinogen is slight, the usefulness in diagnosing DIC is also slight. Though the sensitivity of FDP for DIC was good, the difference between FDP reagents was marked. Therefore, standardization of PT and FDP seems to be necessary. Concordance of overt-DIC diagnostic criteria by the International Society of Thrombosis and Haemostasis (ISTH) and DIC diagnostic criteria of Japanese Ministry of Health and Welfare (JMHW) was about 70%, and overt-DIC diagnostic criteria of ISTH seemed to diagnose the typical type of DIC diagnosed by JMHW criteria. Finally, the diagnostic criteria of non-overt DIC are expected to become increasingly important.
Algorithms↗
[Hemostatic abnormalities in DIC].
There are global coagulation tests and hemostatic molecular markers in the diagnosis of disseminated intravascular coagulation (DIC). In the global coagulation tests, the sensitivity of prothrombin time ratio and fibrinogen for the diagnosis of DIC is low, but their specificity is high. In platelet count and FDP, the sensitivity for the diagnosis of DIC is good, but the specificity is low. Fibrinogen may be unsuitable for the diagnosis of DIC, because it increases of the inflammatory reaction. It is possible to theoretically diagnose DIC by increased tissue factor production. It is currently considered that hemostatic molecular marker should be utilized to diagnose DIC. Thrombin-antithrombin complex and soluble fibrin are reflected to hypercoagulable state, thrombomodulin to vascular endothelial cell injuries, and plasminogen activator inhibitor-I to hypofibrinolytic state. In leukemia with DIC, hyperfibrinolysis and marked bleeding symptoms are often observed. In septicemia with DIC, hypofibrinolysis and severe organ failure often occur. Early diagnosis and treatment of DIC are important to improve the prognosis, and hemostatic molecular markers should be useful for that purpose.
Blood Coagulation Tests↗