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Biomedical subjects

K Kario

Publications and source records attributed to K Kario.

At least 127 records · Page 7Linked to original sources
PubMed1996

Factor VII hyperactivity and endothelial cell damage are found in elderly hypertensives only when concomitant with microalbuminuria.

We studied the relationship among albuminuria, factor VII (FVII) hyperactivity, and endothelial cell damage in 6 elderly hypertensive subjects. The plasma levels of activated FVII (FVIIa), FVII coagulant activity, FVII antigen (FVIIag), von Willebrand factor (vWF), and thrombomodulin were measured to assess FVII hyperactivity and endothelial cell damage, and urinary albumin excretion rate (UAE) was calculated using 12-hour nighttime (7 pm to 7 am) urine collection (mean for 2 consecutive nights). We performed 24-hour ambulatory blood pressure monitoring in all 61 hypertensive patients and classified them into a white-coat hypertension group (n=12) and a sustained hypertension group (n=49). For the levels of FVII, vWF, and thrombomodulin, there were no differences between the white-coat hypertension group and normotensive control subjects (n=25). In the sustained hypertensive group, only the microalbuminuric subgroup (UAE, 15 to 300 microgram/min: n=30) showed significant elevation compared with the normotensive group for the level of FVIIa (mean [95% confidence interval]: 4.0 [3.6 to 4.4] versus 3.0 [2.6 to 3.3] ng/mL, P<.001), the FVIIa/FVIIag ratio (an indicator of activation of FVII zymogen to FVIIa) (1.33 [1.19 to 1.50] versus 1.04 [0.92 to 1.19], P<.01), the level of vWF (188 [165 to 214] % versus 144 [129 to 160] %, P<.01), and thrombomodulin (11.7 [10.3 to 13.3] versus 9.3 [8.5 to 10.3] ng/mL, P<.01). In contrast, none of these levels in the normoalbuminuric hypertensive group (UAE <15 microgram/min, n=19) differed from that in the normotensive control group. These results suggest that among elderly hypertensives, only those with microalbuminuria show enhancement of FVII activation and endothelial cell damage, while patients with white-coat hypertension and normoalbuminuric hypertensives do not show these accompanying abnormalities. Thus, increased levels of FVII activity and markers of endothelial cell damage might account for the higher risk of cardiovascular events in essential hypertension with microalbuminuria.

Aged↗
PubMed1996

'Silent' cerebral infarction is associated with hypercoagulability, endothelial cell damage, and high Lp(a) levels in elderly Japanese.

"Silent" lacunar stroke, often found in the elderly, has been proposed as a predisposing condition for clinically overt stroke. However, the risk factors related to this condition have not been studied thoroughly. We conducted brain magnetic resonance imaging and measured the levels of fibrinogen, molecular markers of coagulation activation [prothrombin fragment 1 + 2 (F1 + 2)] and endothelial cell damage [von Willebrand factor (vWF) and thrombomodulin], and lipid profiles including lipoprotein (a) [Lp(a)] in 178 asymptomatic, high-risk, Japanese subjects aged 44 to 93 years. We also studied 32 symptomatic patients with lacunar stroke (symptomatic lacunar group). The prevalence of silent lacunar stroke increased with age up to 85 years but decreased with age in those 85 years old and older. Of the 160 elderly subjects ( > or = 60 years) 84 (53%) had > or = 1 lacunar infarcts (silent lacunar group) and the remaining 76 were considered as the nonlacunar group. Fibrinogen and F1 + 2 levels in the silent lacunar group were significantly higher than those in the nonlacunar group (P < .01). Mean Lp(a) levels and the prevalence of subjects with an Lp(a) level > 30 mg/dL were significantly higher in the symptomatic lacunar group than the nonlacunar group (P < .05), whereas these levels in the silent lacunar group were intermediate to those of the other two groups. When we further classified the silent lacunar group into three subgroups based on the number of lacunes (few lacunes, 1 or 2; moderate number of lacunes, 3 or 4; and numerous lacunes, > or = 5), levels of Lp(a), F1 + 2, vWF, and thrombomodulin were significantly higher and Lp(a) levels > 30 mg/dL more common in the numerous-lacune than in the few-lacune subgroup. We conclude that silent lacunar stroke is often found in asymptomatic, high-risk, elderly Japanese patients and that silent multiple lacunar stroke is associated with hypercoagulability, endothelial cell damage, and high Lp(a) levels.

Adult↗
PubMed1996

Nocturnal fall of blood pressure and silent cerebrovascular damage in elderly hypertensive patients. Advanced silent cerebrovascular damage in extreme dippers.

To study the relation between diurnal blood pressure variations and silent cerebrovascular damage, we performed both 24-hour ambulatory blood pressure monitoring and brain magnetic resonance imaging in 131 elderly asymptomatic hypertensive patients. Silent cerebrovascular damage was identified by the magnetic resonance imaging findings of lacunae (low intensity in T1-weighted images and high intensity in T2-weighted images) and advanced periventricular hyperintense lesions (on T2-weighted images). The frequency of silent cerebrovascular damage in the 100 patients with sustained hypertension was greater than that in the 31 patients with white coat hypertension. We further classified the former group into nondippers (nocturnal reduction of systolic pressure by < 10% of awake systolic pressure; n = 46), dippers (reduction by > or = 10% to < 20%; n = 38), and extreme dippers (reduction by > or = 20%; n = 16). The extent of silent cerebrovascular damage was least severe in the dipper group (P < .05). This J-shaped relation was not found either with the cardiac hypertrophy detected by electrocardiography or with the renal damage assessed by urinary albumin excretion. More than half of the extreme dippers were patients with isolated systolic hypertension, and this prevalence was significantly greater than that in dippers or in nondippers (21% and 30%, respectively). Extreme dippers also had greater variability of pressure (standard deviation of awake systolic pressure) than dippers. Our results indicate that in addition to nondipping, extreme dipping (marked nocturnal fall of blood pressure) should be considered a type of abnormal diurnal blood pressure variation in elderly patients with hypertension who are likely to have advanced silent cerebrovascular damage.

Aged↗
PubMed1995

Lipoprotein(a) levels in the Japanese population: influence of age and sex, and relation to atherosclerotic risk factors. The Jichi Medical School Cohort Study.

The authors studied the distribution of lipoprotein(a) (Lp(a)) levels with stratification for age and sex, as well as the relation between Lp(a) and atherosclerotic risk factors in a large Japanese population between 1992 and 1993. The subjects were 1,235 males and 1,762 females over 30 years old. Lp(a) was measured by an enzyme-linked immunosorbent assay. Lp(a) levels were higher in females than in males. The increase in Lp(a) with age was statistically significant, and the proportion of subjects with Lp(a) levels > 30 mg/dl also increased with age. In the obese subjects (body mass index (BMI) (kg/m2) > 26), Lp(a) levels were lower than in the non-obese subjects (BMI < or = 26) (p < 0.01 in males; p < 0.05 in females). Male alcohol drinkers had lower Lp(a) levels than nondrinkers (p < 0.05). Age, low density lipoprotein subtracting Lp(a) cholesterol [Lp(a) x 0.3], and fibrinogen level were all positively correlated with Lp(a) in both sexes. Alcohol consumption (g/day) and triglycerides were inversely correlated with Lp(a) in males, while total cholesterol subtracting Lp(a) cholesterol [Lp(a) x 0.3], high density lipoprotein, and factor VII were positively correlated in females. Multiple logistic regression analysis showed that triglycerides in males and BMI and fibrinogen in females were significant independent variables. The authors conclude that Lp(a) level is affected by various factors, such as alcohol drinking, BMI, sex, and age, and is not only correlated with lipid levels but also with hemostatic factors such as fibrinogen and factor VII.

Adult↗
PubMed1995

Effect of Thrombin Inhibition on Patients with Peripheral Arterial Obstructive Disease: A Multicenter Clinical Trial of Argatroban.

Background: Enhanced thrombin generation has been found in patients with peripheral arterial obstructive disease (PAOD). The objective of this study is to investigate the effect of thrombin inhibition in PAOD patients. Methods: Argatroban (20 mg/day) was infused intravenously over 2 hours for 14-68 days in 27 patients with chronic PAOD of the lower extremities. Plasma thrombin-antithrombin III complex (TAT) levels and clinical signs were assessed. Results: TAT levels before argatroban therapy were significantly higher in the PAOD patients than in age- and gender-matched controls. In the PAOD patients, TAT levels increased stepwise in the presence of rest pain classified as Fontain III and IV. To assess the effect of thrombin inhibition, we divided the patients into a high-TAT group (pretreatment TAT level >/=5 ng/ml, n = 12) and a low-TAT group (pretreatment TAT level <5 ng/ml, n = 15). In the high-TAT group, TAT levels were suppressed in 8 of 12 patients after the administration of argatroban, along with improvement of their clinical symptoms and a decrease in the size of ischemic skin ulcers, indicating that argatroban clearly inhibited thrombin generation in vivo. Even in the low-TAT group, argatroban improved the clinical signs and symptoms, and also reduced the size of ischemic skin ulcers although TAT levels remained within the low range (<5 ng/ml) in 13 of the 15 patients, indicating that PAOD signs and/or symptoms may be related to small amounts of thrombin generated locally at the sites of atherothrombotic stenotic lesion. Conclusions: These results suggest that thrombin generation was enhanced in PAOD and that the amount was related to disease severity. Thrombin inhibition by argatroban may break this vicious cycle and lead to clinical improvement in PAOD.

Journal Article↗
PubMed1995

Gender differences of disturbed hemostasis related to fasting insulin level in healthy very elderly Japanese aged > or = 75 years.

We investigated the relationship between fasting insulin level and various hemostatic factors, including fibrinolytic factors (active plasminogen activator inhibitor-1 (PAI-1), tissue type plasminogen activator (tPA)-PAI-1 complex, plasmin-alpha 2-plasmin inhibitor (PIC), and D-dimer), coagulation factors (activated factor VII, factor VII coagulant activity and antigen, factor VIII, factor X, and fibrinogen), coagulation inhibitors (antithrombin III, heparin cofactor II, and protein C), and an acute phase marker (sialic acid) in 102 healthy individuals aged > or = 75 years (46 men and 56 women). Active PAI-1 levels had a significant negative correlation with PIC levels (r = -0.342, P = 0.0006), indicating that PAI-1 influences in vivo fibrinolytic activity in the very elderly. Gender differences were found in the relationship between insulin and hemostatic abnormalities, with the insulin level being positively correlated with coagulation factors in men (factor VIII activity: r = 0.422, P < 0.01; factor VII activity: r = 0.386, P < 0.01) and with hypofibrinolysis in women (active PAI-1: r = 0.549, P < 0.0001). Insulin levels were positively correlated with the levels of factor VII antigen and factor VII activity in men (P < 0.01), but there was no correlation with activated factor VII levels. The fasting insulin level was also correlated with the levels of heparin cofactor II and sialic acid in men (P < 0.05). However, other hemostatic factors were not related to the insulin level in either sex.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1995

Thrombin inhibition in the acute phase of ischaemic stroke using argatroban.

We studied the effect of argatroban, a new selective thrombin inhibitor, on the haemostatic system in seven patients with acute ischaemic stroke (the argatroban group). Argatroban was infused continuously at 2.5 mg/h for the first 48 h, and then 10 mg of argatroban was infused over 3 h twice a day on days 3-7. The placebo group consisted of six acute ischaemic stroke patients. As a combination therapy, intravenous administration of glycerol was also performed at the same time in five of the seven patients in the argatroban group and in four of the six patients in the placebo group. D-dimer levels were measured by a latex photometric immunoassay that allowed immediate quantitative assessment. The D-dimer levels of our 13 patients with acute ischaemic stroke were raised at the time of admission (day 1) and 69% of the values were above the 97th percentile ( > 500 ng/ml) in healthy subjects. D-dimer levels were significantly reduced in the argatroban group on days 2 and 7 after admission when compared with the placebo group (day 2: P = 0.032; day 7: P = 0.046). Thus, haemostatic activation occurred in acute ischaemic stroke was effectively blocked by argatroban.

Aged↗
PubMed1995

Suppression of plasma-activated factor VII levels by warfarin therapy.

To investigate the effect of warfarin treatment on the early phase of tissue factor-induced coagulation, we measured plasma-activated factor VII (factor VIIa) levels by a direct fluorogenic assay in 74 cardiovascular disease patients on long-term oral anticoagulation. We divided the patients into three groups based on the international normalized ratio (INR). In the patients with INR ranges of < 1.7 and 1.7 to 2.5, factor VIIa levels were 42% and 61% lower, respectively, than in age- and sex-matched controls. Factor VII coagulant activity (factor VIIc), factor VII antigen (factor VIIag), protein C, and factor X levels were also reduced to a similar extent in both groups. However, in patients with an INR > 2.5, the factor VIIa level was not decreased compared with that at an INR of 1.7 to 2.5, although the factor VIIc, factor VIIag, factor X, and protein C levels were all decreased further. Although the precise relation between the reduction of factor VIIa levels and the increase of INR requires appropriately designed long-term clinical trials, our data suggest that an INR range of 1.7 to 2.5 is sufficient for the suppression of factor VIIa. During the long-term follow-up of three patients with congenital antithrombin III or protein C deficiency, the factor VIIa level was more responsive to changes in the warfarin dose than the INR, and there were generally no corresponding changes of the thrombin-antithrombin III complex (TAT) level. However, one patient showed a transient marked increase of factor VIIa during the discontinuation of warfarin that was accompanied by an increase in TAT. Based on these findings, factor VIIa could be useful for monitoring both hypercoagulable and hypocoagulable states.

Adult↗
PubMed1995

Activation of tissue factor-induced coagulation and endothelial cell dysfunction in non-insulin-dependent diabetic patients with microalbuminuria.

We studied the relationships between albuminuria, tissue factor-induced coagulation, and endothelial cell dysfunction in 67 patients with non-insulin-dependent diabetes mellitus (NIDDM) who were divided into three groups on the basis of their urinary albumin excretion rate (AER). To assess the early phase of tissue factor-induced coagulation, activated factor VII (FVIIa) levels in plasma were measured by a direct fluorogenic assay. As markers of endothelial cell dysfunction, levels of von Willebrand factor (vWF), tissue-type plasminogen activator-plasminogen activator inhibitor-1 (TPA-PAI-1) complex, PAI-1, and tissue factor pathway inhibitor (TFPI) were measured. FVIIa levels were increased in normoalbuminuric NIDDM patients (AER < 15 micrograms/min) when compared with normal control subjects. This FVIIa increase was accompanied by an increase in thrombin-antithrombin III complex (TAT) levels, indicating increased activation of coagulation even in normoalbuminuric patients. In NIDDM patients with microalbuminuria (AER = 15-200 micrograms/min), the FVIIa level, the FVIIa-FVII antigen (Ag) ratio (an indicator of activation of FVII zymogen to FVIIa), and the TAT level were further increased. This group also had higher levels of endothelial cell-derived factors (vWF, TPA-PAI-1 complex, and PAI-1) than the control group. The levels of endothelial cell-derived factors (including TFPI) were highest in the NIDDM patients with overt albuminuria (AER > 200 micrograms/min). In all 67 diabetic patients, AER showed a strong positive correlation with FVIIa (r = .574, P < .0001) and a weakly but still significant correlation with FVIIa-FVII:Ag (r = .365, P = .01), vWF (r = .315, P < .01), and TAT (r = .323, P < .01).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

Marked increase of activated factor VII in uremic patients.

We investigated plasma activated factor VII (FVIIa) levels in uremic patients (nondialysis group: n = 38; dialysis group: n = 36) and healthy controls (n = 32). We also measured the plasma levels of thrombomodulin (an indicator of endothelial cell injury) and tissue factor. Plasma FVIIa showed a marked increase in the nondialysis group (mean [95% confidence interval]: 4.6 [4.1-5.1] ng/ml, p < 0.0001) with the progressive impairment of renal function, as indicated by the serum creatinine level, when compared with the 32 controls (2.8 [2.5-3.1] ng/ml), and was further increased in the dialysis group (6.1 [5.5-6.8] ng/ml, p < 0.001 vs. nondialysis group). Plasma levels of thrombomodulin and tissue factor were also higher in the nondialysis group than the control group, and were further increased in the dialysis group. Plasma tissue factor levels did not show any correlation with FVIIa or thrombomodulin in both the nondialysis and dialysis groups. Thus, circulating tissue factor appears to be released by a different mechanism from thrombomodulin and may not contribute to the direct activation of factor VII in uremic patients. On the other hand, the plasma level of thrombomodulin was positively correlated with that of FVIIa in the nondialysis group, and this correlation was independent of renal function. Thus, enhanced conversion of factor VII zymogen to FVIIa, probably related to endothelial cell injury, may be a risk factor for cardiovascular events in uremic patients.

Aged↗
PubMed1995

Genetic determinants of plasma factor VII activity in the Japanese.

We investigated the frequency of the factor VII Gln353 (FVII Gln353) allele in Japan, where coronary artery disease is much less common and factor VII coagulant activity (FVIIc) is lower than in Western countries. Japanese males (n = 144) aged 40-59 years living in 2 different districts were studied, and the FVIIc and activated factor VII (FVIIa) levels were measured with human (FVIIa Hum) and bovine soluble tissue factor (FVIIa Bov). The frequency of the FVII Gln353 allele in the 2 districts was 0.026 and 0.052 (combined: 0.034), which was about one third of that in a European population. Thus, the lower FVIIc level in Japanese is not due to the effect of FVII Gln353 allele. Ten individuals with the Gln353 allele showed a 39% decrease of FVIIa Hum levels and a 29% decrease of the FVIIa Bov level compared with 134 individuals homozygous for the FVII Arg353 allele. These decreases of FVIIa were greater than the decrease of FVIIc (17%), suggesting that FVII Gln353 may be difficult to activate in vivo. The marked decrease of FVIIa levels in individuals with the FVII Gln353 allele suggests that they are genetically protected against cardiovascular disease irrespective of ethnic background, by virtue of their decreased FVIIa level.

Adult↗
PubMed1995

Effect of the angiotensinogen gene Met235-->Thr variant on blood pressure and other cardiovascular risk factors in two Japanese populations.

OBJECTIVE: To investigate the gene frequency of the T235 allele and its relationship with hypertension in two Japanese populations. METHODS: T235 was investigated by restriction fragment length polymorphism using the polymerase chain reaction technique in 213 Japanese males aged 40-59 years, who were randomly selected from participants in the Jichi Medical School Cohort Study (Awaji-Hokudan population, n = 157; Niigata-Yamato population, n = 56). RESULTS: The gene frequency of the T235 allele in the two populations was very similar (Awaji-Hokudan 0.65, Niigata-Yamato 0.62; mean 0.64). The T235 frequency was 0.60 in normotensive males, approximately 1.2- to 1.7-fold that in Caucasians. Hypertension, in particular that associated with a positive family history of hypertension, was more common in individuals homozygous for the T235 allele. The levels of total cholesterol, blood glucose and fibrinogen showed a weak and non-significant relationship with the angiotensinogen genotype. CONCLUSION: The T235 angiotensinogen allele was more common in Japanese than in Caucasians, and was a predisposing factor for hypertension.

Adult↗
PubMed1995

The strong positive correlation between factor VII clotting activity using bovine thromboplastin and the activated factor VII level.

We compared factor VII clotting activity (FVIIc) assays using different thromboplastins to determine which is the most sensitive for activated FVII (FVIIa) or for FVII antigen (FVIIag). FVIIc levels were measured using thromboplastins derived from bovine brain (FVIIc Bov), human placenta (FVIIc Hum), and rabbit brain (FVIIc Rab). FVIIa levels were measured by fluorogenic assays using human soluble tissue factor (rsTF) or bovine rsTF. We also measured FVII activity by an amidolytic assay (FVIIc:am Hum) using human thromboplastin and a chromogenic substrate for thrombin. FVIIag levels were determined by ELISA. In the FVIIa assay, the reaction time obtained from using bovine rsTF was shorter than that with human rsTF, suggesting that the interaction of plasma FVIIa with bovine rsTF was stronger than with human rsTF. The plasma FVIIa levels measured using human rsTF and bovine rsTF were almost the same (r = 0.947, p < 0.0001). Among the three FVIIc assays, FVIIc Bov had the strongest positive correlation with the plasma FVIIa level (r = 0.886, p < 0.0001), but had no correlation with FVIIag. An increase of 1 ng/ml in the plasma FVIIa level yielded a 27.9% increase of FVIIc Bov. Plasma FVIIc Hum and FVIIc:am Hum showed moderate correlations with both FVIIa (r = 0.520, p < 0.02 and r = 0.569, p < 0.01, respectively) and FVIIag (r = 0.438, p < 0.05 and r = 0.468, p < 0.05, respectively). FVIIc Rab had the lowest correlation with FVIIa (r = 0.367, p < 0.1), but had a moderate correlation with FVIIag (r = 0.436, p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

High lipoprotein (a) levels in chronic hemodialysis patients are closely related to the acute phase reaction.

To study the mechanism underlying the high lipoprotein (a) [Lp(a)] level in uremic patients on chronic hemodialysis, we investigated the levels of Lp(a), acute phase reactants (C-reactive protein and sialic acid), and interleukin-6 (IL-6) in 54 dialysis patients. The mean [95% CI] Lp(a) level was increased in the hemodialysis patients compared with the 30 controls (30 [25-36] vs. 18 [14-23] mg/dl, p < 0.005). Among dialysis patients, 46% had an Lp(a) level > 30 mg/dl, which was significantly higher than the percentage in the control group (17%). The levels of C-reactive protein, sialic acid, and IL-6 were also increased in dialysis subjects compared with controls (200 [134-299] vs. 37 [24-58] micrograms/dl, p < 0.0001; 63 [59-66] vs. 54 [52-56] mg/dl, p < 0.002; and 9.2 [7.8-11] vs. 5.5 [5.0-6.1] pg/ml, p < 0.0005, respectively). The Lp(a) level was positively correlated with that of C-reactive protein (r = 0.415, p < 0.002), sialic acid (r = 0.426, p < 0.002), and IL-6 (r = 0.298, p < 0.05) in the hemodialysis patients, but not in the controls or non-dialysis uremic patients. The Lp(a) level in the dialysis patients was also positively correlated with activation markers of coagulation (thrombin-antithrombin III complex and plasmin-alpha 2-plasmin inhibitor complex, p < 0.005). These results indicate that the Lp(a) level is closely related to the acute phase reaction and hypercoagulability in chronic hemodialysis patients.

Acute-Phase Reaction↗
PubMed1995

Decreased plasma tissue factor pathway inhibitor activity in ischemic stroke patients.

Although tissue factor pathway inhibitor (TFPI) plays an essential role in the regulation of blood coagulation, the quantitative changes in its levels in thrombotic disease are still undefined. We compared TFPI activity in ischemic stroke patients and control subjects matched for age and cholesterol level to determine whether TFPI activity is changed in the disease. TFPI activity was significantly lower in the stroke patients (1.01 +/- 0.24 U/ml) than in the control subjects (1.10 +/- 0.16 U/ml). In relation to clinical subtypes of stroke, TFPI activity in atherothrombotic infarction (0.93 +/- 0.19 U/ml) and lacunar infarction (0.99 +/- 0.23 U/ml) was significantly lower than in the control subjects, whereas the level in cardioembolic infarction (1.16 +/- 0.31 U/ml) was not. No relationship could be established between TFPI activity and other haemostatic parameters reflecting the production of thrombin/fibrin and the activation of fibrinolysis. These results may suggest that the moderately lower TFPI activity in stroke patients could be due to atherosclerotic changes rather than to consumptive coagulopathy.

Age Factors↗