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BACKGROUND: Conflicting results on the relationship between the hardness of drinking water and mortality related to ischemic heart disease (IHD) or stroke have been reported. OBJECTIVES: We investigated the possible association between tap water calcium or magnesium concentration and total hardness and IHD mortality or stroke mortality. METHODS: In 1986, a cohort of 120,852 men and women aged 55-69 years provided detailed information on dietary and other lifestyle habits. Follow-up for mortality until 1996 was established by linking data from the Central Bureau of Genealogy and Statistics Netherlands. We calculated tap water hardness for each postal code using information obtained from all pumping stations in the Netherlands. Tap water hardness was categorized as soft [< 1.5 mmol/L calcium carbonate (CaCO3)], medium hard (1.6-2.0 mmol/L CaCO₃), and hard (> 2.0 mmol/L CaCO3). The multivariate case-cohort analysis was based on 1,944 IHD mortality and 779 stroke mortality cases and 4,114 subcohort members. RESULTS: For both men and women, we observed no relationship between tap water hardness and IHD mortality [hard vs. soft water: hazard ratio (HR) = 1.03; 95% confidence interval (CI), 0.85-1.28 for men and HR = 0.93; 95% CI, 0.71-1.21 for women) and stroke mortality (hard vs. soft water HR = 0.90; 95% CI, 0.66-1.21 and HR = 0.86; 95% CI, 0.62-1.20, respectively). For men with the 20% lowest dietary magnesium intake, an inverse association was observed between tap water magnesium intake and stroke mortality (HR per 1 mg/L intake = 0.75; 95% CI, 0.61-0.91), whereas for women with the 20% lowest dietary magnesium intake, the opposite was observed. CONCLUSIONS: We found no evidence for an overall significant association between tap water hardness, magnesium or calcium concentrations, and IHD mortality or stroke mortality. More research is needed to investigate the effect of tap water magnesium on IHD mortality or stroke mortality in subjects with low dietary magnesium intake.

Background: The motives, objectives and design of a multicentre prospective study on job stress, absenteeism and coronary heart disease in Europe (the JACE study) is presented in this paper. Some specific gaps in the reviewed literature are explicitly tapped into by the JACE study. Its objectives are i) to compare the distributions of the Karasek job stress scales for the same broad categories of occupations in different European countries (in males and females), ii) to study the predictive power of the job stress scales and the job strain model for one year of sickness absence (in males and females) and iii) to study the predictive power of the job stress scales and the job strain model for a three year incidence of coronary heart disease (in males only). Methods: In answering these questions, relations are studied controlling for gender, age, level of education, company size, physical work risks and shift work, as well as traditional risk factors for CHD (i.e serum cholesterol, serum HDL cholesterol, smoking habits and blood pressure). The JACE study is a Biomed I concerted action. The JACE group consists of eight participating centres from six countries, i.e. from Belgium and Sweden (two centres), France, Italy, Spain, Sweden and The Netherlands (each one centre). The coordination of the group is in Brussels. The participating centres brought in over 15,000 European workers to test the hypotheses.

Increased plasma factor VII coagulant activity (FVII:C) has been associated with the risk of ischemic heart disease (IHD). Differences in plasma FVII:C among individuals are associated with three common polymorphisms in the FVII gene. Therefore, we investigated FVII polymorphisms in four populations that differ in their risk of developing cardiovascular disease, namely, Europeans, Greenland Inuit, Gujarati Indians, and Afro- caribbeans. We studied (1) the promoter polymorphism, which is the result of a decanucleotide insertion in the FVII promoter at position -323 from the start of translation; (2) the hypervariable region 4 polymorphism (HVR4), which is the result of a variable number of tandem repeats in intron 7; and (3) the RQ353 polymorphism, a guanine-to-adenine substitution in the position of the codon for amino acid 353 resulting in an amino acid replacement of arginine (R) by glutamine (Q) in the FVII protein. The frequencies of these three polymorphisms and their linkage disequilibrium were different in the four populations studied. The frequencies of the alleles associated with higher plasma FVII:C were lower in the Europeans than in the Inuit, a population with a lower incidence of IHD. There was an association between both the promoter polymorphism and the RQ353 polymorphism and the plasma FVII:C in the Europeans, the Inuit, and the Gujarati Indians, and an association only between the RQ353 polymorphism and plasma FVII:C in the Afro-caribbeans. Only in the Inuit was the HVR4 polymorphism associated with plasma FVII:C. In multiple regression analysis, the additional information provided by the promoter polymorphism when the other polymorphisms were already included in the model was the most pronounced, suggesting that the promoter polymorphism may be the functional mutation having the greatest effect on determining plasma FVII:C.

A high dietary intake of antioxidants ascorbic acid, tocopherol and beta-carotene and 1 or 2 servings of fish per week is associated with a lower risk of coronary heart diseases, but the 'evidence' for a preventive effect still has not been produced. A raised homocysteine level can be lowered with folate, possibly in combination with pyridoxine and cobalamine. Whether this actually decreases the risk of cardiovascular diseases, is still fully in research. Further research should point out the final importance of vitamins and fish fatty acids in the prevention of particularly coronary heart diseases. Chemicals/CAS: cobalamin, 13408-78-1; fish oil, 8016-13-5; folic acid, 59-30-3, 6484-89-5; homocysteine, 454-28-4, 6027-13-0; pyridoxine, 12001-77-3, 58-56-0, 65-23-6, 8059-24-3

De onderste leeftijdsgrens bij het opsporen van hypercholesterolemie in de standaard van het Nederlands Huisartsen Genootschap is 18 jaar.1 De (herziene) cholesterolconsensus uit 1991 geeft geen ondergrens aan.2 Familiaire hypercholesterolemie (FH)3 neemt een speciale plaats in, omdat het cardiovasculaire risico in bepaalde families buitensporig hoog kan zijn (zie het betoog van Bakker in dit nummer, bl. 2548). Veel familieleden van een probandus met FH weten niet dat de cholesterolconcentratie bij hen sterk verhoogd kan zijn. Nu er een werkzaam middel is om de prognose te verbeteren, lijkt opsporing van volwassenen met FH geen punt van discussie meer. Tegen opsporing van FH in de kinderleeftijd, door onderzoek van bloed, zijn echter bedenkingen aan te voeren.

Traffic noise and air pollution have been associated with cardiovascular health effects. Until date, only a limited amount of prospective epidemiological studies is available on long-term effects of road traffic noise and combustion related air pollution. This study investigates the relationship between road traffic noise and air pollution and hospital admissions for ischemic heart disease (IHD: International Classification of Diseases (ICD9) 410-414) or cerebrovascular disease (cerebrovascular event [CVE]: ICD9 430-438). We linked baseline questionnaire data to 13 years of follow-up on hospital admissions and road traffic noise and air pollution exposure, for a large random sample (N = 18,213) of inhabitants of the Eindhoven region, Netherlands. Subjects with cardiovascular event during follow-up on average had higher road traffic noise day, evening, night level (Lden) and air pollution exposure at the home. After adjustment for confounders (age, sex, body mass index, smoking, education, exercise, marital status, alcohol use, work situation, financial difficulties), increased exposure did not exert a significant increased risk of hospital admission for IHD or cerebrovascular disease. Relative risks (RRs) for a 5th to 95th percentile interval increase were 1.03 (0.88-1.20) for Lden; 1.04 (0.90-1.21) for particulate matter (PM10); 1.05 (0.91-1.20) for elemental carbon (EC); and 1.12 (096-1.32) for nitrogen dioxide (NO2) in the full model. While the risk estimate seemed highest for NO2, for a 5th to 95th percentile interval increase, expressed as RRs per 1 μg/m3 increases, hazard ratios seemed highest for EC (RR 1.04 [0.92-1.18]). In the subgroup of study participants with a history of cardiovascular disease, RR estimates seemed highest for noise exposure (1.19 [0.87-1.64] for Lden); in the subgroup of elderly RR seemed highest for air pollution exposure (RR 1.24 [0.93-1.66] for NO2).

Exposure to noise constitutes a health risk. There is sufficient scientific evidence that noise exposure can induce hearing impairment, hypertension and ischemic heart disease, annoyance, sleep disturbance, and decreased school performance. For other effects such as changes in the immune system and birth defects, the evidence is limited. Most public health impacts of noise were already identified in the 1960s and noise abatement is less of a scientific but primarily a policy problem. A subject for further research is the elucidation of the mechanisms underlying noise-induced cardiovascular disorders and the relationship of noise with annoyance and nonacoustical factors modifying health outcomes. A high priority study subject is the effects of noise on children, including cognitive effects and their reversibility. Noise exposure is on the increase, especially in the general living environment, both in industrialized nations and in developing world regions. This implies that in the twenty-first century noise exposure will still be a major public health problem.

A high intake of trans fatty acids (TFAs) has been shown to have an undesirable effect on serum lipid profiles and lipoprotein(a) (Lp(a)) levels and may thereby increase the risk for coronary heart disease (CHD). We performed a study in CHD patients, and measured the TFA concentration of the plasma phospholipid fraction. Comparison was made between a case group with angiographically documented severe CHD (> 80% stenosis in one coronary vessel, n = 83) and a control group of patients who had just minor stenosis on the coronary angiography (< 50% stenosis in all three major vessels, n = 78). All subjects were under 68 years of age and were prestratified on age, gender and smoking habits. The two groups were comparable according to the prestratification criteria, body mass index, blood pressure, number of cigarettes smoked and total fat intake. Controls had higher plasma HDL levels (P < 0.001) and lower, albeit not significantly lower, (P = 0.07) plasma LDL levels. No significant correlations were found between percentages of TFAs in plasma phospholipids and plasma LDL or HDL cholesterol levels. Of the major fatty acid classes, only the percentage of saturated fatty acids was significantly higher in cases (46.2 ± 0.92%) than in controls (45.8 ± 1.07% (means ± S.D.)). The difference in total TFA content between cases and controls (0.32 ± 0.02% versus 0.35 ± 0.02%) was -0.03% (P = 0.2). For the specifrc TFAs C16:1n - 7tr, C18:1n - 9tr and C18:2n - 6tr, just minor differences were found. Adjusted odds ratios for tertiles of TFA percentages were 0.56 (0.25-1.23) and 0.76 (0.36-1.61) for the highest and middle tertile compared to the lowest. These findings do not support an association between TFA intake and risk for coronary heart disease.

Patients with familial hypercholesterolemia (FH) are at an increased risk of premature cardiovascular disease (CVD). The benefits of statin therapy are not well known since no placebo controlled studies have been performed in these patients. The aim of this study was to determine the CVD event and mortality risk in statin-treated patients with FH. A total of 345 FH patients were followed prospectively for 8 years. Mortality from CVD was compared to that of the general population. The absolute risk of CVD in patients without a previous history of CVD was 3% per year for men and 1.6% for women. Mortality from CVD in patients without a previous history was 1.4-fold (95% CI=0.6-3.3) increased and ischaemic heart disease (IHD) mortality was 2.6-fold (95% CI=1.1-6.3) higher compared to the general population. This mortality risk was highest in patients aged 40-59 years. Female FH patients had no increased CVD or IHD mortality risk. Over a period of 8 years the event risk of patients with a history of CVD was almost 30% per year under age 40 years and 15% in patients aged 60 years and over. When compared to the general population, mortality from other causes than CVD was lower for patients with FH, the relative risks not reaching statistical significance. The relative risk of mortality from all causes was 1.5 (P<0.05) for men and 1.0 for women. In conclusion, male patients with FH, treated from middle-age with statins remain at an increased risk of developing CVD. © 2003 Elsevier Ireland Ltd. All rights reserved. Chemicals / CAS: Hydroxymethylglutaryl-CoA Reductase Inhibitors

AIMS: The intention of this study is to investigate the relationship of the demands/control/strain model with hard coronary events in an epidemiological, prospective, multicenter, European study. METHODS AND RESULTS: Six cohorts (Brussels, Ghent, Lille, Barcelona, Göteborg and Malmö) from four European countries (Belgium, France, Spain and Sweden) consisting of 21 111 middle-aged male subjects participated between 1993 and 1996 in the baseline survey of the Job Stress, Absenteeism and Coronary Heart Disease in Europe (JACE) study. The Karasek strain model of psychological demands (five items)/control (nine items) was used. During a mean follow-up of 40 months 185 acute coronary events or coronary deaths were observed. Age-adjusted hazard ratios (HRs) for developing an acute coronary event were 1.46 [CI 95% confidence interval (1.08-1.97)] for high against low psychological demands and 1.53 (95% CI 1.0-2.35) for strained (high demands plus low control) against relaxed (low demands plus high control) groups. After adjustment for standard cardiovascular risk factors the HR for developing a coronary event for those above or equal to the median against those below the median of psychological demands was 1.46 (95% CI 1.08-1.97) whereas the HR for strained against relaxed groups is 1.46 (95% CI 0.96-2.25). Sensitivity analyses confirmed the robustness of the results. CONCLUSION: In this European, multicenter, prospective, epidemiological study the Karasek job strain model was an independent predictor of acute coronary events, with the psychological demands scale emerging as the important component. © 2006 The European Society of Cardiology.

Background: Long working hours might increase the risk of cardiovascular disease, but prospective evidence is scarce, imprecise, and mostly limited to coronary heart disease. We aimed to assess long working hours as a risk factor for incident coronary heart disease and stroke. Methods: We identified published studies through a systematic review of PubMed and Embase from inception to Aug 20, 2014. We obtained unpublished data for 20 cohort studies from the Individual-Participant-Data Meta-analysis in Working Populations (IPD-Work) Consortium and open-access data archives. We used cumulative random-effects meta-analysis to combine effect estimates from published and unpublished data. Findings: We included 25 studies from 24 cohorts in Europe, the USA, and Australia. The meta-analysis of coronary heart disease comprised data for 603 838 men and women who were free from coronary heart disease at baseline; the meta-analysis of stroke comprised data for 528 908 men and women who were free from stroke at baseline. Follow-up for coronary heart disease was 5·1 million person-years (mean 8·5 years), in which 4768 events were recorded, and for stroke was 3·8 million person-years (mean 7·2 years), in which 1722 events were recorded. In cumulative meta-analysis adjusted for age, sex, and socioeconomic status, compared with standard hours (35-40 h per week), working long hours (≥55 h per week) was associated with an increase in risk of incident coronary heart disease (relative risk [RR] 1·13, 95% CI 1·02-1·26; p=0·02) and incident stroke (1·33, 1·11-1·61; p=0·002). The excess risk of stroke remained unchanged in analyses that addressed reverse causation, multivariable adjustments for other risk factors, and different methods of stroke ascertainment (range of RR estimates 1·30-1·42). We recorded a dose-response association for stroke, with RR estimates of 1·10 (95% CI 0·94-1·28; p=0·24) for 41-48 working hours, 1·27 (1·03-1·56; p=0·03) for 49-54 working hours, and 1·33 (1·11-1·61; p=0·002) for 55 working hours or more per week compared with standard working hours (ptrend<0·0001). Interpretation: Employees who work long hours have a higher risk of stroke than those working standard hours; the association with coronary heart disease is weaker. These findings suggest that more attention should be paid to the management of vascular risk factors in individuals who work long hours.

Fibrinogen is a large heterogeneous family of closely related molecules consisting of three pairs of non-identical polypeptide chains: two Aα-, two Bβ- and two γ-chains, held together by disulphide bridges. The heterogeneity of fibrinogen is due to heterogeneities in all three chains. Four main types of assay are used to determine fibrinogen:clotting rate (Clauss), clottable protein, precipitation and immunological assays. Heterogenities may differ from person to person and may affect the apparent fibrinogen concentrations in different assays. A further complicating factor was, until recently, the lack of an international fibrinogen standard. The ratio of Clauss:enzyme immunoassay (EIA) for high + low molecular weight fibrinogen decreases during therapy for acute myocardial infarction and increases again after thrombolytic therapy to above normal values. Furthermore, high molecular weight fibrinogen tends to clot more easily than low molecular weight fibrinogen. This suggests that high molecular weight fibrinogen might be associated with increased thrombolytic risk. Fibrinogen assessed by a functional assay (Clauss) alone is strongly associated with ischaemic heart disease. Although not proven, it is conceivable that a fibrinogen with a Clauss:EIA ratio of > 1 has an even stronger association in epidemiological studies. Chemicals/CAS: disulfide, 16734-12-6; fibrinogen, 9001-32-5; Fibrinogen, 9001-32-5

Chemicals / CAS: lipoprotein lipase, 83137-80-8, 9004-02-8; APOA5 protein, human; Apolipoproteins A; Apolipoproteins; Triglycerides

Personalized medicine - defined as customized medical care for each patient's unique condition - in the broader context of personalized health, will make significant strides forward when a systems approach is implemented to achieve the ultimate in disease phenotyping and to create novel therapeutics that address system-wide molecular perturbations caused by disease processes. Combination drug therapies with individualized optimization are likely to become a major focus. Metabolomics incorporates the most advanced approaches to molecular phenotype system readout and provides the ideal theranostic technology platform for the discovery of biomarker patterns associated with healthy and diseased states, for use in personalized health monitoring programs and for the design of individualized interventions. © 2006 Future Medicine Ltd.

Objective: Moderate alcohol consumption has been proposed to be anti-atherogenic and protect against coronary heart disease. Arterial stiffness provides a summary measure of atherosclerotic arterial damage and cardiovascular risk. A vascular protective effect of moderate alcohol consumption would be reflected in an inverse association between alcohol intake and aortic stiffness. Design: A cross-sectional study. Setting: The male population of Utrecht. Participants: Of 370 men, aged 40-80 years, alcohol intake was calculated from a standardized questionnaire and aortic stiffness was non-invasively assessed by pulse-wave velocity (PWV) measurement of the aorta. Results: There were no non-drinkers; therefore the group consuming 0-3 glasses of alcoholic beverage per week was chosen as the reference group in the analyses. Those drinking 4-10, 11-21 and 22-58 glasses of alcoholic beverage per week had a -0.77 m/s (95% confidence interval, -1.26 to -0.28), -0.57 m/s (95% confidence interval, -1.07 to -0.08) and -0.14 m/s (95% confidence interval, -0.65 to 0.36) difference in mean PWV compared with those drinking 0-3 glasses per week. Adjustment for factors that correlated with PWV or alcohol consumption did not change the strength of the association. Conclusion Among men aged 40-80 years there is a J-shaped association between alcohol consumption and PWV. This further supports a decreased risk of cardiovascular disease with moderate alcohol consumption. © 2004 Lippincott Williams & Wilkins.

Moderate alcohol consumption is associated with a reduced risk of coronary heart disease. Part of this inverse association may be explained by its effects on HDL. Paraoxonase, an HDL-associated enzyme, has been suggested to protect against LDL oxidation. We examined the effects of moderate consumption of red wine, beer and spirits in comparison with mineral water on paraoxonase activity in serum. In this diet-controlled, randomised, cross-over study 11 healthy middle-aged men consumed each of the beverages with evening dinner for 3 weeks. At the end of each 3 week period, blood samples were collected pre- and postprandially and after an overnight fast. Fasting paraoxonase activity was higher after intake of wine (P<0.001), beer (P<0.001), and spirits (P<0.001) than after water consumption (149.4±111.1, 152.6±113.1, 152.8±116.5 and 143.1±107.9 U/l serum), but did not differ significantly between the 3 alcoholic beverages. Similar effects were observed pre- and postprandially. The increases in paraoxonase activity were strongly correlated with coincident increases in concentrations of HDL-C and apo A-I (r=0.60, P<0.05 and r=0.70, P<0.05). These data suggest that increased serum paraoxonase may be one of the biological mechanisms underlying the reduced coronary heart disease risk in moderate alcohol consumers Copyright (C) 1999 Elsevier Science Ireland Ltd.

Chemicals / CAS: 2 methylpropanethioic acid s [2 [1 (2 ethylbutyl)cyclohexylcarboxamido]phenyl] ester, 211513-37-0; atorvastatin, 134523-00-5, 134523-03-8; nicotinic acid, 54-86-4, 59-67-6; torcetrapib, 262352-17-0; Carrier Proteins; CETP protein, human; Cholesterol Ester Transfer Proteins; Cholesterol Esters; Cholesterol, HDL; Glycoproteins; Lipoproteins, HDL

Background: Flow mediated dilatation (FMD) of the brachial artery and soluble intercellular adhesion molecule 1 (sICAM-1) are measures of distinct functions of the endothelium, reflecting nitric oxide (NO)-mediated and pro-inflammatory status, respectively. The comparative value of the two measures in relation to cardiovascular risk is unknown. Objective: To study and quantify the relation between these two measures, and their relative value in relation to the risk of coronary heart disease as estimated by the Framingham risk function. Methods: We performed a single centre population-based study of 85 men and 81 women, aged 18-73 years. Endothelial function was assessed biochemically by sICAM-1 and functionally by FMD. In addition traditional cardiovascular risk factors, CRP, leukocyte count, homocysteine and fibrinogen were determined. Analyses were performed with multivariate linear regression, adjusted for age, gender, and CRP. Results: Median sICAM-1 levels were 217.0 μg/l (interquartile range: 174.0-348.5). Mean FMD was 4.5% (S.D.: 3.9). The regression coefficient for the association between sICAM-1 and FMD was -3.3 μg/l (95% CI: -6.0;-0.6) per percentage rise in FMD, after adjustment for age, gender, smoking, oral contraceptives (OC) use, classical risk factors and CRP. After adjustment for CRP and sICAM-1, the estimated risk of coronary heart disease in the next 10 years varied from 1.55% (95%CI: 0.89; 2.70) in the highest quintile of FMD to 3.92% (95% CI: 2.23; 6.92) in the lowest quintile. For sICAM-1, estimated risk, adjusted for FMD and CRP varied from 1.50% (95%CI: 0.85; 2.64) in the lowest quintile of sICAM-1 to 4.15% (95%CI: 2.35; 7.34) in the highest quintile. P-values for trends were 0.02 and 0.01 for quintiles of FMD and quintiles of sICAM-1, respectively. Conclusion: These findings indicate that sICAM-1 and FMD are related in healthy individuals, independently of cardiovascular risk factors and CRP, and that they are both related to the estimated risk of coronary heart disease, independently of each other. © 2003 Elsevier Ireland Ltd. All rights reserved.

Background: The development of global tests for the fibrinolytic capacity in blood is hampered by the low base-line fibrinolytic activity in blood, by the involvement of both plasmatic components and blood cells in the fibrinolytic system and by the loss of fibrinolytic activity as a result of the action of plasminogen activator inhibitor-1 (PAI-1). Objective: To develop a new test for the global fibrinolytic capacity (GFC) of whole blood samples. Methods and results: Collection of blood in thrombin increased the subsequent generation of fibrin degradation products. This was ascribed to rapid clot formation and concomitant reduction of in vitro neutralization of tissue-type plasminogen activator (tPA) by PAI-1. On the basis of this observation, the following test was designed: blood samples were collected in thrombin with and without aprotinin and clots were incubated for 3h at 37°C. The GFC was assessed from the difference between the fibrin degradation products in the two sera. The assay was applied to blood samples from patients and healthy subjects. Other hemostasis parameters were determined in plasma samples taken simultaneously. The GFC varied considerably (normal range 0.13-13.6 μg mL-1); physical exercise strongly increased the GFC. Statistically significant correlations were found with tPA activity, PAI-1 activity and fibrinogen level. A mixture of antibodies against tPA and urokinase-type plasminogen activator (uPA) completely inhibited the GFC. An inhibitor of activated thrombin-activatable fibrinolysis inhibitor (TAFI) accelerated fibrinolysis 8-fold. Conclusion: The new test represents a global assessment of the main fibrinolytic factors in plasma and potentially those associated with blood cells. © 2007 International Society on Thrombosis and Haemostasis.

Differences in genetic influence on death from CHD between males and females have been reported. Haemostatic factors have consistently been associated with risk for coronary heart disease (CHD), but sex differences in genetic architecture have not been studied. This study in middle-aged twins investigates whether there are sex differences in means and in genetic and/or environmental variance components of haemostatic risk factors for CHD. A total of 93 monozygotic twin pairs (44 male and 49 female) and 116 dizygotic twin pairs (36 male, 40 female and 40 opposite sex) were available for this study. Structural equation modelling was used to estimate the relative influence of genetic and environmental factors on variation in levels of fibrinogen, tissue plasminogen activator (tPA) antigen and von Willebrand factor (vWF). Mean levels of tPA vWF increased with age. Oral contraceptive pill (OCP) and menopause had significant influences on levels of fibrinogen and tPA. Genetic influences explained 39, 66 and 72% of the variation in levels of fibrinogen, tPA and vWF, respectively. No quantitative or qualitative differences of genetic influences on haemostatic levels were seen between males and females. Haemostatic factor may account for a significant part of the genetic risk for cardiovascular disease. No difference in genetic architecture for levels of fibrinogen, tPA or vWF was observed between males and females. © 2006 Schattauer GmbH, Stuttgart. Chemicals / CAS: fibrinogen, 9001-32-5; tissue plasminogen activator, 105913-11-9; von Willebrand factor, 109319-16-6; Biological Markers; Fibrinogen, 9001-32-5; Tissue Plasminogen Activator, EC 3.4.21.68; von Willebrand Factor