Acquired activated protein-C resistance.
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Activated Protein C Resistance↗
Biomedical subjects
C Kluft
Publications and source records attributed to C Kluft.
Statins and C-reactive protein.
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C-Reactive Protein↗
Effect of the stromelysin-1 promoter on efficacy of pravastatin in coronary atherosclerosis and restenosis.
It has proved difficult to identify high-risk patients for atherosclerosis and to determine how they might respond to medication. Recently, a common promoter variant of the human stromelysin-1 gene has been reported, which has been shown to affect the transcription. We investigated whether this polymorphism had any impact on the risk of events, especially restenosis and progression of coronary artery disease and whether the effect was modulated by treatment with pravastatin. The stromelysin-1 genotype was determined for 496 men with coronary artery disease and cholesterol levels between 4.0 and 8.0 mmol/L, participating in the Regression Growth Evaluation Statin Study (REGRESS) study, a clinical trial assessing the effect of the lipid-lowering drug pravastatin on the progression of atherosclerosis. Patients in the placebo group with 5A6A or 6A6A genotypes had more clinical events than patients with the 5A5A genotype (26% and 12%, respectively, p = 0.03). In the pravastatin group, the risk of clinical events in patients with 5A6A or 6A6A genotypes was lower, compared with placebo, whereas it was unchanged in those with a 5A5A genotype (p value for interaction: 0.038). Also, the incidence of repeat angioplasty in the placebo group was greater in patients with the 6A6A or 5A6A genotypes, compared with 5A homozygotes (38% and 40%, respectively, vs 11%, p = 0.09). Again, treatment substantially reduced the incidence in heterozygotes and 6A homozygotes (0% and 15%, respectively), whereas it was unchanged in 5A homozygotes (28%, p for interaction: 0.002). These effects were independent of the effects of pravastatin on the lipid levels. Thus, this study suggests that the stomelysin-1 promoter polymorphism confers a genotype-specific response to medication in determining clinical event-free survival and the risk for symptom-driven repeat angioplasty. This variant may therefore act as a predictor, not only of disease progression, but also of response to therapy and risk of restenosis.
Anticholesteremic Agents↗
The oral bioavailability of pentosan polysulphate sodium in healthy volunteers.
OBJECTIVE: Pentosan polysulphate sodium (PPS), a heparin-like drug, is supposed to be orally applicable. The objective of the present study was to assess the oral bioavailability of PPS. However, since specific assays for PPS do not exist, this was done by using primary and secondary effect parameters. METHODS: The study was carried out using a three-way randomized crossover design with 18 healthy young male volunteers. The subjects received three treatments: PPS i.v. (50 mg), PPS orally (1500 mg) and placebo (orally). Blood sampling was done for activated partial thromboplastin time (APTT), anti-Xa activity, hepatic triglyceride lipase, lipoprotein lipase, tissue plasminogen activator (t-PA) activity, fibrin plate lysis, total triglyceride, total cholesterol, HDL and LDL. RESULTS: Intravenously administered PPS significantly increased APTT, anti-Xa activity, hepatic triglyceride lipase and lipoprotein lipase compared with placebo in a magnitude comparable to other i.v. heparin-like compounds. Orally administered PPS did not significantly influence any of the parameters when compared with placebo. Point estimates for the oral bioavailability of PPS were in the range of 0% with small confidence intervals (CIs). CONCLUSION: The oral bioavailability of PPS is negligible in young healthy males.
Administration, Oral↗
Angiotensin I-converting enzyme and plasminogen activator inhibitor-1 gene variants: risk of mortality and fatal cardiovascular disease in an elderly population-based cohort.
OBJECTIVES: We studied the contribution of putative risk genotypes at the angiotensin I-converting enzyme inhibitor (ACE D/D) and plasminogen activator inhibitor-1 (PAI-1 4G/4G) loci to all-cause and cardiovascular mortality in a population-based cohort. BACKGROUND: The ACE D/D and PAI-1 4G/4G genotypes have been consistently associated with elevated plasma activities of the gene products. Their role in cardiovascular disease, although explored intensively, is still equivocal. METHODS: The ACE and PAI-1 genotypes were determined in 648 subjects > or =85 years old. In a cross-sectional analysis, the genotype distributions in a subset of 356 elderly subjects who were born in Leiden, The Netherlands, were compared with those in 250 young subjects whose families originated from the same geographic region. In addition, the complete cohort of elderly subjects was followed over 10 years for all-cause and cardiovascular mortality and was stratified according to genotype. RESULTS: In the cross-sectional analysis, the ACE and PAI-1 genotype distributions were similar in elderly and young subjects. In the prospective follow-up study, however, the age-adjusted risk of fatal ischemic heart disease was increased threefold (95% confidence interval [CI] 1.2 to 7.6) in elderly men carrying the PAI-1 4G/4G genotype. The risk of all-cause mortality was not increased among elderly subjects carrying the PAI-1 4G/4G (relative risk [RR] 0.9, 95% CI 0.7 to 1.1) or the ACE D/D genotype (RR 0.9, 95% CI 0.7 to 1.1), nor did we observe elevated risks of death from all cardiovascular diseases combined. There was no interaction between the genotypes. CONCLUSIONS: The PAI 4G/4G genotype may be a risk factor for fatal ischemic heart disease in elderly men. The impact of moderately increased ACE and PAI-1 activities associated with the ACE D/D and PAI-1 4G/4G genotypes is too small to affect mortality in the general population.
Aged↗
Inflammatory status as a main determinant of outcome in patients with unstable angina, independent of coagulation activation and endothelial cell function.
AIMS: Inflammation, endothelial cell function and the coagulation system have been demonstrated to be involved in the onset and course of unstable angina. Whether a proinflammatory state independently determines outcome is unknown and has not been determined yet in a clinically well defined study population of consecutive patients admitted with unstable angina. METHODS AND RESULTS: Markers of inflammation, coagulation activation and endothelial cell function were determined on admission in blood of 211 consecutive patients with severe unstable angina and were related to the in-hospital course. Refractory unstable angina occurred in 76 patients (36%) during their hospital stay. In a univariate analysis, C-reactive protein (P = 0.03), fibrinogen (P < 0.001) and erythrocyte sedimentation rate (P = 0.001) levels were significantly higher in patients with refractory unstable angina, when compared with patients who had an uneventful clinical course. The odds ratios (95% CI) adjusted for age, sex, body mass index, smoking behaviour and cholesterol levels of the occurrence of refractory unstable angina for patients in the highest quartile compared with patients in the lowest quartile of inflammatory markers were 2.19 (0.94-5.11) for C-reactive protein, 2.83 (1.13-7.10) for fibrinogen and 4.72 (1.70-13.09) for the erythrocyte sedimentation rate. The findings were not affected by the presence or absence of myocardial necrosis or the interval between onset of angina and blood collection. No association was found between markers of coagulation activation or markers of endothelial cell function, and in-hospital outcome. CONCLUSION: We found that in a clinically well-defined study population of patients with severe unstable angina, a proinflammatory state is an important and independent determinant of short-term outcome. The data strengthen the importance of inflammation in this syndrome.
Adult↗
Postprandial response of activated factor VII in elderly women depends on the R353Q polymorphism.
BACKGROUND: Activated factor VII (FVIIa) is a very potent coagulant and may be a key determinant of the outcome of a cardiovascular event. The main determinants of FVIIa are the R353Q polymorphism and dietary fat intake, which may have an interactive effect. OBJECTIVE: The objective was to investigate whether the response of FVIIa to a fat-rich breakfast varies across genotypes of the R353Q polymorphism. DESIGN: Ninety-one apparently healthy elderly women (>60 y of age), 56 with the RR genotype and 35 with the RQ or QQ genotype, participated in a randomized, controlled crossover study. Subjects received 5 breakfasts, each on a separate day: 1 low-fat control breakfast and 4 high-fat test breakfasts. Blood samples were taken for measurement of FVIIa at 0800 before each breakfast (fasting) and at 1300 and 1500. RESULTS: The mean (+/-SD) fasting FVIIa concentration was 93.3 +/- 26.7 U/L in women with the RR genotype, 49.3 +/- 19.1 U/L in those with the RQ genotype and 39.5 +/- 17.2 U/L in those with the QQ genotype. The mean absolute response to all 4 test breakfasts was 37.0 U/L in those with the RR genotype and 16. 1 U/L in those carrying the Q allele (P < 0.001 for difference). Likewise, the FVIIa response relative to fasting FVIIa was significantly higher in women homozygous for the R allele. CONCLUSION: This observation may indicate a considerable difference in cardiovascular risk between genotype groups as a result of an increase in FVIIa after a fat-rich diet.
Aged↗
Specific determination of plasmin inhibitor activity in plasma: documentation of specificity of manual and automated procedures.
Recently, a chromogenic kit for determination of plasmin inhibitor activity, Coamatic Plasmin Inhibitor, has been developed with the aim to increase specificity and to allow application to a wide range of automates. The highly sensitive plasmin substrate S-2403 is used and, to further improve specificity, a low level of plasmin and a short incubation time is utilized as well as the incorporation of methylamine to quench alpha2-macroglobulin activity. The Coamatic Plasmin Inhibitor kit has been evaluated regarding specificity and compared with six commercially available plasmin inhibitor (also denoted alpha2-antiplasmin) kits and with the manual Immediate Plasmin Inhibition Test (IPIT) method, the reference method within the framework of the European Concerted Action against Thrombosis and Disabilities. Analysis of plasmin inhibitor deficient plasma with Coamatic Plasmin Inhibitor resulted in activities below 5% for all instrument applications, whereas all other commercial kits displayed unexpectedly higher values for this plasma (16-35%). There was a good agreement between the Coamatic Plasmin Inhibitor method and the IPIT method for all tested instrument applications; slope =0.80-1.02 and r = 0.92-0.97. No interference was detected from alpha2-macroglobulin, lysine, unfractionated and low-molecular weight heparin, and epsilon-amino caproic acid or from the non-plasminogen binding form of plasmin inhibitor.
Adult↗
Both raloxifene and estrogen reduce major cardiovascular risk factors in healthy postmenopausal women: A 2-year, placebo-controlled study.
Currently raloxifene, a selective estrogen receptor modulator, is being investigated as a potential alternative for postmenopausal hormone replacement to prevent osteoporosis and cardiovascular disease. We compared the 2-year effects of raloxifene on a wide range of cardiovascular risk factors with those of placebo and conjugated equine estrogens (CEEs). Analyses were based on 56 hysterectomized but otherwise healthy postmenopausal women aged 54. 8+/-3.5 (mean+/-SD) years who entered this double-blind study and who were randomly assigned to raloxifene hydrochloride 60 mg/d (n=15) or 150 mg/d (n=13), placebo (n=13), or CEEs 0.625 mg/d (n=15). At baseline and after 6, 12, and 24 months of treatment, we assessed serum lipids, blood pressure, glucose metabolism, C-reactive protein, and various hemostatic parameters. Compared with placebo, both raloxifene and CEEs lowered the level of low density lipoprotein cholesterol by 0.53 to 0.79 mmol/L (all P<0.04) and lowered, at 24 months, the level of fibrinogen by 0.71 to 0.86 g/L (all P<0.05). The effects of raloxifene and CEEs did not differ significantly. In contrast to raloxifene, from 6 months on CEEs increased high density lipoprotein cholesterol by 0.25 to 0.29 mmol/L and reduced plasminogen activator inhibitor-1 antigen by 30.6 to 48.6 ng/mL (all P<0.02 versus both placebo and raloxifene). CEEs transiently increased C-reactive protein by 1.0 mg/L at 6 months (P<0.05 versus placebo) and prothrombin-derived fragment F1+2 by 0. 79 nmol/L at 12 months (P<0.001 versus placebo). Finally, from 12 months on, CEEs increased triglycerides by 0.33 to 0.56 mmol/L (all P<0.05 versus both placebo and raloxifene). Our findings suggest that in healthy postmenopausal women, raloxifene and estrogen monotherapy have similar beneficial effects on low density lipoprotein cholesterol and fibrinogen levels. These treatments differ, however, in their effects on high density lipoprotein cholesterol, triglycerides, and plasminogen activator inhibitor-1 and possibly in their effects on prothrombin fragment F1+2 and C-reactive protein.
Biomarkers↗
Increased thromboxane biosynthesis is associated with poststroke dementia.
BACKGROUND AND PURPOSE: It has been suggested that daily intake of aspirin is associated with a reduction of cognitive decline, both in normal and in demented subjects, but the mechanism is unclear. We have therefore studied the relationship between thromboxane (TX) A(2) biosynthesis, as reflected by the urinary excretion of 11-dehydro-TXB(2), and the presence of dementia in patients after acute stroke. METHODS: Patients from the Rotterdam Stroke Databank were screened for dementia between 3 and 9 months after stroke. Patients had a full neurological examination, neuropsychological screening, and, if indicated, extensive neuropsychological examination. Criteria used for the diagnosis of dementia were from the Diagnostic and Statistical Manual of Mental Disorders, Third Edition (Revised). Urine samples were taken at the time of screening. Urinary 11-dehydro-TXB(2) was measured by means of a previously validated radioimmunoassay. RESULTS: Dementia was diagnosed in 71 patients, and urine samples were available for 62. Median value (range) of 11-dehydro-TXB(2) was 399 (89 to 2105) pmol/mmol creatinine for demented patients versus 273 (80 to 1957) for 69 controls with stroke but without dementia (P=0.013). No difference was found between 44 patients with vascular dementia, 404 (89 to 2105) pmol/mmol creatinine, and 18 patients with Alzheimer's disease plus cerebrovascular disease, 399 (96 to 1467) pmol/mmol creatinine (P=0.68). In a stepwise logistic regression analysis, in which possible confounders such as use of antiplatelet medication, cardiovascular risk factors, and type of stroke were taken into account, increased urinary excretion of 11-dehydro-TXB(2) remained independently related to the presence of dementia (OR 1.12, 95% CI 1.03 to 1.22 per 100 pmol/mmol creatinine). The difference in metabolite excretion rates between demented and nondemented patients was most prominent within the subgroup of ischemic stroke patients who received aspirin (P<0.01). CONCLUSIONS: Increased thromboxane biosynthesis in the chronic phase after stroke is associated with the presence of but not the type of poststroke dementia. It is particularly apparent in patients on aspirin, thereby suggesting the involvement of extraplatelet sources of TXA(2) production in this setting.
Aged↗
A comparative study of the effects of gestodene 60 microg/ethinylestradiol 15 microg and desogestrel 150 microg/ethinylestradiol 20 microg on hemostatic balance, blood lipid levels and carbohydrate metabolism.
OBJECTIVES: This multicenter, randomized, parallel-group, open-label study was conducted to compare the effects of gestodene (GTD) 60 microg/ethinylestradiol (EE) 15 microg and desogestrel (DSG) 150 microg/EE 20 microg (Mercilon) on selected metabolic measurements during six cycles in 124 healthy women. METHODS: GTD/EE subjects received a single pill once daily from days 1 to 24 of a 28-day cycle, followed by placebo pills daily for the last 4 days of the cycle. DSG/EE subjects received a single pill daily from days 1 to 21 of a 28-day cycle, followed by a 7-day pill-free interval. Safety was assessed from changes in hemostatic measurements, lipid profile, glucose tolerance and adverse events. RESULTS: Both GTD/EE and DSG/EE groups exhibited minimal effects on the lipid profile. An increased glucose response was noted with both treatments and an increased insulin response was noted with GTD/EE. Hemostatic activity was increased in both groups but a counteracting increase in fibrinolytic activity occurred together with an increase in coagulatory activity. The incidence of adverse events was comparable between groups, and no significant differences in cycle control were observed between groups. No pregnancies occurred in either group. CONCLUSIONS: The 24-day GTD 60 microg/EE 15 microg formulation and DSG/EE produced similar effects on hemostatic balance, lipid metabolism and glucose tolerance, and exhibited comparable efficacy and tolerability.
Adult↗
Fibrinolytic activity in peripheral atherosclerosis in the elderly.
Increased concentrations of plasminogen activator inhibitor type 1 (PAI-1) and of D-dimer have jointly been found in subjects with cardiovascular disease. To understand this apparent paradox of increased inhibition of fibrinolysis (high PAI-1) combined with increased fibrinolytic activity (high D-dimer), we examined the relation between D-dimer, PAI-1 and the activator of fibrinolysis, tissue type plasminogen activator (t-PA) in subjects with varying severity of peripheral atherosclerosis. In 325 subjects selected from the Rotterdam Study, a cohort of 7983 men and women aged 55 years and over, the ankle to brachial systolic blood pressure ratio, t-PA antigen and activity, PAI-1 antigen and D-dimer were measured. T-PA antigen and t-PA activity were, independent from each other, increased with degree of atherosclerosis; t-PA antigen increased with 3.5 ng/ml (SE 1.7, p = 0.04) and t-PA activity with 0.46 IU/ml (0.20, p = 0.02) per unit decrease in ankle to brachial pressure ratio (i.e. increase in atherosclerosis). PAI-1 antigen was not related to atherosclerosis. More marked atherosclerosis was associated with increased D-dimer, mainly in subgroups with PAI-1 antigen below 50 ng/ml, t-PA antigen below 10 ng/ml, or t-PA activity above 1.5 IU/ml. In contrast to current beliefs, we found that only a fraction of the variation of t-PA antigen was due to the variation in circulating PAI-1 antigen. A slight positive association was observed between t-PA antigen and D-dimer. PAI-1 and t-PA activity were not associated with D-dimer concentration. In conclusion, in subjects with peripheral atherosclerosis PAI-1 antigen is not increased, but low PAI-1 levels (and possibly also low levels of t-PA antigen and high levels of t-PA activity) appear to be required to increase circulating D-dimer. This suggests that increased D-dimer levels in subjects with atherosclerosis do not reflect increased inhibition, but rather reflect increased fibrinolysis.
Aged↗
Genetic research stimulates development of individual treatment.
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Adult↗
DNA-polymorphisms and plasma levels of vascular disease risk factors in Greenland Inuit--is there a relation with the low risk of cardiovascular disease in the Inuit?
Greenland Inuit are a population with a low risk of cardiovascular disease. Recently, we stated that frequencies of potentially high risk alleles of the apolipoproteins, fibrinogen, factor V, glycoprotein IIIa and factor VII (FVII) genes have different allele frequencies in the Inuit when compared with Caucasian populations. We have extended this study and evaluated whether or not this was also true for the genetic polymorphisms of tissue-type plasminogen activator (t-PA), plasminogen activator inhibitor-1 (PAI-1), angiotensin-converting enzyme (ACE) and angiotensinogen in a group of 133 Greenland Inuit, aged 30-34 gamma. In addition, we compared the plasma levels of these factors and those of C-reactive protein (CRP) and D-Dimer in Inuit and in Danes, comparable for age and gender. Frequencies (f) were assessed of the alleles that are known as the potential high risk alleles in Caucasians. In the Inuit, the f(insertion allele) of the t-PA intron8ins311 polymorphism was 0.37 (CI 0.32-0.43), the f(4G allele) of the PAI-1 promoter polymorphism was 0.88 (CI 0.83-0.91), the f(deletion allele) of the ACE intron16ins287 polymorphism was 0.40 (CI 0.33-0.47) and the f(M-allele) of the angiotensinogen M/T353 polymorphism was 0.30(CI 0.25-0.38). As for fibrinogen and FVII polymorphisms, these frequencies are all significantly different from what is reported for Caucasian populations. In the Inuit, plasma levels of fibrinogen and D-Dimer were higher than in the Danes, the PAI-1 levels were lower and FVII, t-PA and CRP levels were comparable. The observed allele frequencies of the polymorphisms of t-PA, fibrinogen, FVII, ACE, angiotensinogen and the plasma levels of PAI-1 and D-Dimer were in accordance with the low CVD risk in the Inuit, considering the observed associations between these measures and CVD risk in Caucasian populations, but for other measures this was not the case (allele frequencies of the PAI-1 polymorphism, and plasma levels of fibrinogen, FVII and t-PA). In conclusion there are clear differences in genetic background and plasma levels of risk factors in Greenland Inuit compared with Caucasian populations, and these differences were sometimes, but not always, in accordance with the observed low cardiovascular disease risk of the Inuit population.
Adult↗
Plasma homocysteine is weakly correlated with plasma endothelin and von Willebrand factor but not with endothelium-dependent vasodilatation in healthy postmenopausal women.
BACKGROUND: Hyperhomocysteinemia is an independent cardiovascular risk factor, possibly through the induction of endothelial dysfunction. The postmenopausal state is associated with increased plasma homocysteine. We examined whether increased homocysteine is associated with impaired endothelial function. METHODS: Sixty-three hysterectomized but otherwise healthy postmenopausal women (54.8 +/- 3.5 years) participated in this study. Fasting total plasma homocysteine (tHcy) was measured as free plus protein-bound homocysteine. Endothelial function was assessed by measuring plasma concentrations of the endothelium-derived proteins endothelin (ET), von Willebrand factor (vWF), and plasminogen activator inhibitor type 1 (PAI-1) as well as brachial artery flow-mediated, endothelium-dependent vasodilatation (FMD). RESULTS: Plasma tHcy was 9.6 +/- 2.5 micromol/L. After adjustment for possible confounders, a 1 micromol/L increase in tHcy was associated with an increase in ET of 0.08 ng/L (P = 0.045) and an increase in vWF of 4.2% (P = 0.05). No statistically significant association was present between tHcy and PAI-1 or FMD. CONCLUSIONS: Increased fasting homocysteine in postmenopausal women may impair some aspects of endothelial function. It is of clinical interest to study whether homocysteine lowering can improve endothelial function and thus cardiovascular morbidity and mortality in postmenopausal women.
Adult↗
Polymorphisms in the coagulation factor VII gene and the risk of myocardial infarction.
BACKGROUND: High blood levels of coagulation factor VII are associated with a risk of ischemic vascular disease. Although factor VII levels may be genetically determined, the relation between genetic polymorphisms of factor VII, factor VII blood levels, and the risk of myocardial infarction has not been established. METHODS: We performed a case-control study of 165 patients with familial myocardial infarction (mean [+/-SD] age, 55+/-9 years) and 225 controls without a personal or family history of cardiovascular disease (mean age, 56+/-8 years). The polymorphisms involving R353Q and hypervariable region 4 of the factor VII gene were studied. Factor VII clotting activity and antigen levels were also measured. RESULTS: Patients with the QQ or H7H7 genotype had a decreased risk of myocardial infarction (odds ratios, 0.08 [95 percent confidence interval, 0.01 to 0.9] and 0.22 [95 percent confidence interval, 0.08 to 0.63], respectively). For the R353Q polymorphism, the RR genotype was associated with the highest risk, followed by the RQ genotype and then by the QQ genotype (P<0.001). For the polymorphism involving hypervariable region 4, the combined H7H5 and H6H5 genotypes were associated with the highest risk, followed in descending order by the H6H6, H6H7, and H7H7 genotypes (P<0.001). Patients with the QQ or H7H7 genotype had lower levels of both factor VII antigen and factor VII clotting activity than those with the RR or H6H6 genotype. Patients with the lowest level of factor VII clotting activity had a lower risk of myocardial infarction than those with the highest level (odds ratio, 0.13; 95 percent confidence interval, 0.05 to 0.34). CONCLUSIONS: Our findings suggest that certain polymorphisms of the factor VII gene may influence the risk of myocardial infarction. It is possible that this effect may be mediated by alterations in factor VII levels.
Analysis of Variance↗
The Dutch Vascular Factors in Dementia Study: rationale and design.
Dementia is a rapidly increasing health problem in the industrialized countries. With the ageing of the population the number of demented persons increases both in relative and absolute terms. Obviously, there is a need for prevention and intervention strategies. We describe the methods and baseline findings of a large study aimed at identifying potentially modifiable vascular, thrombogenic, and metabolic determinants of dementia. The study population consists of subjects 55 years of age or older. Since the vascular wall of the cerebral vessels is different from that of the coronary or peripheral vessels, we formed three subgroups in which vascular risk factors for dementia are studied. Subjects with stroke were distinguished from subjects with coronary or peripheral artery disease, and from subjects without stroke or coronary or peripheral artery disease. To obtain a large enough number of subjects with stroke, cases and controls from a stroke registry were combined with cases and controls of a population-based study from the same region. For the diagnosis of dementia the DSM-III-R criteria were used. Extensive information on cardiovascular risk factors was collected, including indicators of atherosclerosis. Blood and urine were sampled to study platelet function and thrombogenic and metabolic factors. The study population consists of 7,466 subjects, of whom 300 were recruited from a hospital-based stroke registry. Coronary or peripheral artery disease was present in 956 subjects and stroke in 617. Dementia was present in 434 (5.8%) of all subjects. The prevalence of dementia was 3.0, 24.0, and 4.4% in subjects with a history of coronary or peripheral artery disease, a history of stroke, and subjects without a history of coronary or peripheral artery disease or stroke, respectively. The study will allow us to investigate the role of vascular factors in dementia, irrespective of its cause.
Adult↗
Effects of liver blood flow on the pharmacokinetics of tissue-type plasminogen activator (alteplase) during thrombolysis in patients with acute myocardial infarction.
BACKGROUND: The removal of recombinant tissue-type plasminogen activator (rt-PA; alteplase) by the liver is so rapid that liver blood flow becomes rate determining for its clearance. In patients with myocardial infarction changes in liver blood flow may result from impaired cardiac performance or drug treatment. OBJECTIVE: To estimate the effect of variations in liver blood flow on t-PA plasma concentrations during thrombolytic therapy. METHODS: Fifteen patients with acute myocardial infarction were investigated in an open single-center study at the coronary care unit of University Hospital Leiden. Patients received thrombolytic treatment with 100 mg rt-PA over 3 hours. Liver blood flow was estimated by indocyanine green clearance and by Doppler echocardiography. Concentrations of t-PA antigen, t-PA activity, indocyanine green, alpha 2-antiplasmin, fibrinogen, and fibrin and fibrinogen degradation products were measured. RESULTS: Indocyanine green clearance and clearance of both t-PA antigen (r = 0.78; p < 0:01) and t-PA activity (r = 0.54; p < 0.05) were significantly related. Significant associations between t-PA antigen and fibrin and fibrinogen degradation products and between t-PA antigen and alpha 2-antiplasmin were also found. CONCLUSIONS: The liver blood flow of patients with myocardial infarction is inversely correlated with plasma concentrations of t-PA. In patients with severely impaired liver blood flow and heart failure, high t-PA plasma concentrations may occur if standard doses are given. This finding could contribute to optimization of the dosage of t-PA in certain patient groups.
Aged↗