Background: Contradictory results have been published on the effects of T13254C (rs1613662), which distinguishes the two major isoforms of GP6, the gene encoding the platelet receptor glycoprotein... Show moreBackground: Contradictory results have been published on the effects of T13254C (rs1613662), which distinguishes the two major isoforms of GP6, the gene encoding the platelet receptor glycoprotein VI, on platelet function and the risk of cardiovascular disease. Methods: We performed a population-based case-control study, the Study of Myocardial Infarctions in Leiden, among 547 male patients with a first myocardial infarction (MI) and 646 control subjects, as well as a prospective cohort study in which the same MI patients were followed for recurrent events (fatal and non-fatal MI and unstable angina) and mortality (median follow-up of 12 years). P-selectin expression by platelets induced by crosslinked collagen-related peptide (CRP-XL) was measured by whole blood flow cytometry in 274 MI patients. Results: T13254C was not associated with a first MI, but seemed to be associated with a reduced incidence of recurrent events [per-allele hazard ratio 0.77, 95% confidence interval (CI) 0.56-1.06] and mortality (hazard ratio 0.57, 95% CI 0.37-0.89). Pooling with the Heart and Estrogen/Progestin Replacement Study revealed hazard ratios of 0.81 (95% CI 0.66-0.99) and 0.73 (95% CI 0.55-0.96). The minor C-allele was also strongly associated with a reduced percentage of P-selectin-expressing platelets. The reduction per C-allele was 23% (95% CI 18-28%). In an independent study of 219 healthy volunteers, the per-allele reduction of CRP-XL-induced aggregation was 10% (95% CI 2-18%). Conclusion: The minor allele of GP6 T13254C that reduced platelet activation and aggregation also seemed to be associated with a reduced incidence of recurrent cardiovascular events and mortality, but was not associated with first MI. Show less
Snoep, J.D.; Gaussem, P.; Eikenboom, J.C.J.; Emmerich, J.; Zwaginga, J.J.; Holmes, C.E.; ... ; Bom, J.G. van der 2010
BACKGROUND Contradictory results have been published on the effects of T13254C (rs1613662), which distinguishes the two major isoforms of GP6, the gene encoding the platelet receptor glycoprotein... Show moreBACKGROUND Contradictory results have been published on the effects of T13254C (rs1613662), which distinguishes the two major isoforms of GP6, the gene encoding the platelet receptor glycoprotein VI, on platelet function and the risk of cardiovascular disease. METHODS We performed a population-based case-control study, the Study of Myocardial Infarctions in Leiden, among 547 male patients with a first myocardial infarction (MI) and 646 control subjects, as well as a prospective cohort study in which the same MI patients were followed for recurrent events (fatal and non-fatal MI and unstable angina) and mortality (median follow-up of 12 years). P-selectin expression by platelets induced by crosslinked collagen-related peptide (CRP-XL) was measured by whole blood flow cytometry in 274 MI patients. RESULTS T13254C was not associated with a first MI, but seemed to be associated with a reduced incidence of recurrent events [per-allele hazard ratio 0.77, 95% confidence interval (CI) 0.56-1.06] and mortality (hazard ratio 0.57, 95% CI 0.37-0.89). Pooling with the Heart and Estrogen/Progestin Replacement Study revealed hazard ratios of 0.81 (95% CI 0.66-0.99) and 0.73 (95% CI 0.55-0.96). The minor C-allele was also strongly associated with a reduced percentage of P-selectin-expressing platelets. The reduction per C-allele was 23% (95% CI 18-28%). In an independent study of 219 healthy volunteers, the per-allele reduction of CRP-XL-induced aggregation was 10% (95% CI 2-18%). CONCLUSION The minor allele of GP6 T13254C that reduced platelet activation and aggregation also seemed to be associated with a reduced incidence of recurrent cardiovascular events and mortality, but was not associated with first MI. Show less
Middelburg, R.A.; Stein, D. van; Zupanska, B.; Uhrynowska, M.; Gajic, O.; Muniz-Diaz, E.; ... ; Bom, J.G. van der 2010
BACKGROUND: Although quantitative evidence is lacking, it is generally believed that the majority of cases of transfusion-related acute lung injury (TRALI) are caused by female blood donors. We... Show moreBACKGROUND: Although quantitative evidence is lacking, it is generally believed that the majority of cases of transfusion-related acute lung injury (TRALI) are caused by female blood donors. We aimed to examine the relation between female donors and the occurrence of TRALI. STUDY DESIGN AND METHODS: We performed an international, multicenter case-referent study. TRALI patients who were diagnosed clinically, independent of serology or donor sex, and had received transfusions either only from male donors or only from female donors (unisex cases) were selected The observed sex distribution among the donors of these TRALI patients was compared to the expected sex distribution, based on the relevant donor populations. RESULTS: Eighty-three clinical TRALI cases were included; 67 cases received only red blood cells (RBCs), 13 only plasma-rich products, and three both. Among RBC recipients the relative risk (RR) of TRALI after a transfusion from a female donor was 1.2 (95% confidence interval [Cl], 0.69-2.1) and among plasma-rich product recipients the RR was 19 (95% Cl, 1.9-191). The p value for the difference between RBCs and plasma was 0.023. CONCLUSION: Our data support the notion that plasma from female donors is associated with an increased risk of TRALI, while RBCs from female donors are not. Show less
Atary, J.Z.; Borleffs, C.J.W.; Bom, J.G. van der; Trines, S.A.I.P.; Bootsma, M.; Zeppenfeld, K.; ... ; Schalij, M.J. 2010
Myocardial excitability is known (amongst other reasons) to be related to the degree of ischaemia, contractile dysfunction and heart failure. It was hypothesized that the right ventricular (RV)... Show moreMyocardial excitability is known (amongst other reasons) to be related to the degree of ischaemia, contractile dysfunction and heart failure. It was hypothesized that the right ventricular (RV) stimulation threshold has prognostic value with respect to the occurrence of ventricular arrhythmias (VAs) and patient survival in recipients of an implantable cardioverter defibrillator (ICD). Ischaemic heart disease patients receiving an ICD at Leiden University Medical Center as primary prevention for sudden cardiac death were included in this study. Right ventricular thresholds were determined at ICD implant. Data were collected on VAs triggering ICD therapy and on all-cause mortality. A total of 689 consecutive patients were included (87% male, age 63 +/- 11 years, left ventricular ejection fraction (LVEF) 29 +/- 11%) and followed for a median of 28 months. Post-implant RV-threshold was 0.7 +/- 0.5 volt (V) at 0.5 ms pulse duration. Best dichotomous separation was reached at a cut-off of 1 V. During follow-up, 167 (24%) patients received appropriate ICD therapy, 88 (13%) had appropriate shocks and 134 (19%) died. Cumulative appropriate shock incidence for patients with RV threshold >= 1 V (n = 166) was 16% at 1 year, 24% at 3 years and 34% at 5 years compared with 4, 11 and 17% for patients with an RV-threshold < 1 V (n = 523). Adjusted hazard ratio of RV threshold >= 1 V was 2.0 (95% CI: 1.4-2.9) for appropriate therapy, 3.3 (95% CI: 2.0-5.4) for appropriate shocks and 1.6 (95% CI: 1.1-2.5) for mortality. The RV stimulation threshold at ICD implant has a strong independent prognostic value for the occurrence of VAs triggering appropriate ICD therapy, appropriate shocks and mortality. Show less
BACKGROUND: A problem when studying adverse events of blood transfusions is that patients have usually received transfusions from several donors while only one of these donors is the actual cause.... Show moreBACKGROUND: A problem when studying adverse events of blood transfusions is that patients have usually received transfusions from several donors while only one of these donors is the actual cause. This will result in underestimation of the effect of donor-related risk factors if not adequately corrected for. We encountered this problem when studying transfusion-related acute lung injury (TRALI) and describe four methods to overcome this problem. STUDY DESIGN AND METHODS: Simulated data are used to illustrate the results of six different approaches: not correcting for the number of donors, using standard correction methods, and four newly proposed methods. Donor sex is used throughout as an example. The first two new methods apply restriction of the study to cases who have received a transfusion from a single donor or from donors who are all of the same sex. In both restriction designs the sex of the causal donors is known and can be compared to the expected value from a reference population. The other two new methods apply statistical correction for the number of donors, either by standardization or by maximum likelihood methods. RESULTS: If not corrected for, or if corrected for by standard methods, increasing numbers of donors per patient result in decreasing estimates of the effect of risk factors. All four newly proposed methods yield valid estimates. CONCLUSIONS: It is clear that the problem of multiple transfusions requires specialized correction methods. All four newly proposed methods yield on average good estimates of the underlying true value. Show less
Background: von Willebrand Disease (VWD) is the most frequent inherited bleeding disorder. It is unknown how this disorder affects quality of life. Objectives: This nationwide multicenter cross... Show moreBackground: von Willebrand Disease (VWD) is the most frequent inherited bleeding disorder. It is unknown how this disorder affects quality of life. Objectives: This nationwide multicenter cross-sectional study determined health-related quality of life (HR-QoL) in adult patients with moderate or severe VWD, and assessed whether bleeding severity and type of VWD are associated with HR-QoL. Methods: HR-QoL was assessed using the Short Form (SF)-36, and bleeding severity was measured using the Bleeding Score (BS). Results: Five hundred and nine patients participated; 192 males and 317 females, median age and range 45 (16-87) and 47 (16-84) years, respectively. Compared with the general population, HR-QoL in VWD patients was lower in the vitality domain (61 vs. 66 P < 0.001 for females, 67 vs. 72 P < 0.001 for males). Patients with the most severe bleeding phenotype (highest quartile BS, BS > 17) had a lower HR-QoL in eight domains than patients with a less severe bleeding type (lowest quartile BS, BS < 7) in the univariate analysis. After adjustment for age, gender, co-morbidity and employment/educational status, a more severe bleeding phenotype was associated with lower scores on the domains of physical functioning, role limitations due to physical functioning, bodily pain, general health, social functioning and physical component summary. Conclusions: HR-QoL is lower in VWD patients compared with the general population. HR-QoL is strongly associated with bleeding phenotype. Show less
To compare the long-term efficacy and safety of sirolimus-eluting stents (SES) to those of bare-metal stents (BMS) for ST-segment elevation myocardial infarction, outcomes were assessed in 310... Show moreTo compare the long-term efficacy and safety of sirolimus-eluting stents (SES) to those of bare-metal stents (BMS) for ST-segment elevation myocardial infarction, outcomes were assessed in 310 patients (mean age age 59 +/- 11 years, 78% men) included in the randomized MISSION! Intervention Study: A Prospective Randomised Controlled Trial to Evaluate the Efficacy of Drug-Eluting Stents Versus Bare-Metal Stents for the Treatment of Acute Myocardial Infarction after a median follow-up period of 38 months. All patients were treated with aspirin (lifelong) and clopidogrel for 1 year after stent implantation. Except for a significant difference between reference vessel diameters (SES 2.76 mm vs BMS 2.92 mm, p = 0.02), there were no significant differences in baseline and angiographic characteristics between the treatment groups (158 SES, 152 BMS). A significant difference between SES and BMS patients for all revascularization end points was found after the first year of follow-up. However, at 3 years of follow-up, although there was still a trend toward better clinical outcomes in SES-treated patients, differences were no longer significant (death 4.4% vs 6.6%, p = 0.41; target vessel related myocardial infarction 2.5% vs 4.6%, p = 0.32; target vessel revascularization 8.9% vs 15.8%, p = 0.06), target lesion revascularization 6.3% vs 12.5%, p = 0.06; and target vessel failure 12.0% vs 19.7%, p = 0.06). Three cases of very late (definite) stent thrombosis were observed in the SES group (1.9%) versus none in the BMS group (p = 0.14). In conclusion, the significant SES benefit (compared to BMS) in patients with ST-segment elevation myocardial infarctions at 1-year follow-up in terms of target vessel revascularizations decreased to some extent because of more similar target vessel revascularization rates during the 2 subsequent years. Rates of death and nonfatal recurrent MI remained comparable. (C) 2010 Elsevier Inc. All rights reserved. (Am J Cardiol 2010;106:4-12) Show less
Middelburg, R.A.; Watering, L.M.G. van de; Bom, J.G. van der 2010
SUMMARY BACKGROUND Platelets are involved in the occlusion of coronary arteries after rupture of an atherosclerotic plaque. Furthermore, activated platelets release large quantities of growth... Show moreSUMMARY BACKGROUND Platelets are involved in the occlusion of coronary arteries after rupture of an atherosclerotic plaque. Furthermore, activated platelets release large quantities of growth factors, chemokines and interleukins that regulate inflammatory reactions. Therefore, we hypothesized that high basal platelet reactivity may contribute to an increased risk of myocardial infarction (MI) in premenopausal women. METHODS We assessed the relation between high platelet reactivity and MI in a population-based case-control study among premenopausal women (aged < 50 years). We used multivariable logistic regression to quantify the effect of high platelet reactivity, adjusted for potential confounders. Platelet reactivity was estimated by plasma levels of neutrophil activating peptide 2 (NAP-2), CXC chemokine ligand (CXCL)4, soluble glycoprotein 1b (sGPIb) and soluble P-selectin. RESULTS High platelet reactivity (i.e. levels >or= 90th percentile control subjects) was associated with a 2- to 3-fold increased incidence of MI: the adjusted odds ratios (ORs) were 3.0 [95% confidence interval (CI) 1.4-6.4] for NAP-2, 2.2 (0.9-5.1) for CXCL4, 1.9 (0.7-4.6) for sP-selectin and 2.5 (1.1-5.7) for sGPIb. The incidence of MI dose-dependently increased when more markers were elevated. High platelet reactivity according to both NAP-2 and sGPIb was associated with an up to tenfold increased incidence (9.9, 95% confidence interval 2.0-48.3). CONCLUSIONS High basal platelet reactivity was associated with a 2- to 3-fold higher incidence of MI compared with normal platelet reactivity in premenopausal women. Our results suggest that high basal platelet reactivity may contribute to a higher risk of MI. Show less
Snoep, J.D.; Roest, M.; Barendrecht, A.D.; Groot, P.G. de; Rosendaal, F.R.; Bom, J.G. van der 2010
Background: Platelets are involved in the occlusion of coronary arteries after rupture of an atherosclerotic plaque. Furthermore, activated platelets release large quantities of growth factors,... Show moreBackground: Platelets are involved in the occlusion of coronary arteries after rupture of an atherosclerotic plaque. Furthermore, activated platelets release large quantities of growth factors, chemokines and interleukines that regulate inflammatory reactions. Therefore, we hypothesized that high basal platelet reactivity may contribute to an increased risk of myocardial infarction (MI) in premenopausal women. Methods: We assessed the relation between high platelet reactivity and MI in a population-based case-control study among premenopausal women (aged < 50 years). We used multivariable logistic regression to quantify the effect of high platelet reactivity, adjusted for potential confounders. Platelet reactivity was estimated by plasma levels of neutrophil activating peptide 2 (NAP-2), CXC chemokine ligand (CXCL)4, soluble glycoprotein 1b (sGPIb) and soluble P-selectin. Results: High platelet reactivity (i.e. levels >= 90th percentile control subjects) was associated with a 2- to 3-fold increased incidence of MI: the adjusted odds ratios (ORs) were 3.0 [95% confidence interval (CI) 1.4-6.4] for NAP-2, 2.2 (0.9-5.1) for CXCL4, 1.9 (0.7-4.6) for sP-selectin and 2.5 (1.1-5.7) for sGPIb. The incidence of MI dose-dependently increased when more markers were elevated. High platelet reactivity according to both NAP-2 and sGPIb was associated with an up to tenfold increased incidence (9.9, 95% confidence interval 2.0-48.3). Conclusions: High basal platelet reactivity was associated with a 2- to 3-fold higher incidence of MI compared with normal platelet reactivity in premenopausal women. Our results suggest that high basal platelet reactivity may contribute to a higher risk of MI. Show less
To assess survival and to construct a baseline mortality risk score in primary prevention implantable cardioverter defibrillator (ICD) patients with non-ischaemic or ischaemic heart disease. Since... Show moreTo assess survival and to construct a baseline mortality risk score in primary prevention implantable cardioverter defibrillator (ICD) patients with non-ischaemic or ischaemic heart disease. Since 1996, data of all consecutive patients who received an ICD system in the Leiden University Medical Center were collected and assessed at implantation. For the current study, all 1036 patients [age 63 (SD 11) years, 81% male] with a primary indication for defibrillator implantation were evaluated and followed for 873 (SD 677) days. During follow-up, 138 patients (13%) died. Non-ischaemic and ischaemic patients demonstrated similar survival but exhibited different factors that influence risk for mortality. A risk score, consisting of simple baseline variables could stratify patients in low, intermediate, and high risk for mortality. In non-ischaemic patients, annual mortality was 0.4% (95% CI 0.0-2.2%) in low risk and 9.4% (95% CI 6.6-13.1%) in high risk patients. In ischaemic patients, mortality was 1.0% (95% CI 0.2-3.0%) in low risk and 17.8% (95% CI 13.6-22.9%) in high risk patients. Utilization of an easily applicable baseline risk score can create an individual patient-tailored estimation on mortality risk to aid clinicians in daily practice. Show less
Gouw, S.C.; Berg, H.M. van den; Bom, J.G. van der; PedNet Rodin Study Grp 2010
The aim of our study was to assess the cumulative incidence and severity ('burden') of late effects in a single-centre cohort of childhood haematopoietic stem cell transplantation (HSCT) survivors,... Show moreThe aim of our study was to assess the cumulative incidence and severity ('burden') of late effects in a single-centre cohort of childhood haematopoietic stem cell transplantation (HSCT) survivors, at least 2 years after transplantation. The presence and severity of late effects in each survivor was documented according to the Common Terminology Criteria for Adverse Events (version 3.0). The burden of late effects was graded from mild to disabling/life-threatening. Risk factors for a high burden of late effects were assessed by univariate and multivariate logistic regression analyses. Among 162 survivors of HSCT seen in our late effects outpatient clinic, cumulative incidence of late effects was 93.2% after a median follow-up time of 7.2 years (range 2.0-21.0 years) after HSCT. The burden of late effects was mild, moderate, severe and disabling in 28, 41, 24 and 1% of survivors respectively. Risk factors for a severe or disabling burden of late effects were older age at HSCT (P for trend <0.001) and a conditioning regimen including irradiation OR 2.2, 95% CI 1.1-4.7, P = 0.03). In conclusion, a high burden of late effects is found in childhood HSCT survivors after a median follow-up of only 7 years. Bone Marrow Transplantation (2010) 45, 79-85; doi: 10.1038/bmt.2009.92; published online 4 May 2009 Show less
The aim of our study was to assess the cumulative incidence and severity ('burden') of late effects in a single-centre cohort of childhood haematopoietic stem cell transplantation (HSCT) survivors,... Show moreThe aim of our study was to assess the cumulative incidence and severity ('burden') of late effects in a single-centre cohort of childhood haematopoietic stem cell transplantation (HSCT) survivors, at least 2 years after transplantation. The presence and severity of late effects in each survivor was documented according to the Common Terminology Criteria for Adverse Events (version 3.0). The burden of late effects was graded from mild to disabling/life-threatening. Risk factors for a high burden of late effects were assessed by univariate and multivariate logistic regression analyses. Among 162 survivors of HSCT seen in our late effects outpatient clinic, cumulative incidence of late effects was 93.2% after a median follow-up time of 7.2 years (range 2.0-21.0 years) after HSCT. The burden of late effects was mild, moderate, severe and disabling in 28, 41, 24 and 1% of survivors respectively. Risk factors for a severe or disabling burden of late effects were older age at HSCT (P for trend <0.001) and a conditioning regimen including irradiation OR 2.2, 95% CI 1.1-4.7, P=0.03). In conclusion, a high burden of late effects is found in childhood HSCT survivors after a median follow-up of only 7 years. Show less
