Showing papers by "Jaap W. Deckers published in 2008"

Frequency of the von Willebrand factor Tyr1584Cys polymorphism in arterial thrombosis.

Abstract: A recent review on von Willebrand factor (VWF) proteolysis (Bowen & Collins, 2006) extensively discussed the Tyr1584Cys polymorphism. The Tyr1584Cys polymorphism, located in exon 28 of the VWF gene (VWF), is associated with an increased proteolysis of VWF by ADAMTS13. A strongly increased frequency of this polymorphism was first reported in Canadian patients with Von Willebrand Disease type 1 (O’Brien et al, 2003). A functional study then reported an increased proteolysis of VWF in heterozygotes (Bowen et al, 2005). As VWF is essential in clot formation it is expected that decreased proteolysis of VWF would increase the risk of thrombosis. Upon endothelial activation, ultra large VWF is released from Weibel-Palade bodies into the circulation, where it binds platelets, which can then form aggregates. In the circulation VWF is vulnerable to proteolysis by ADAMTS13. The proteolysis cleaves the ultra large multimers in smaller, less active multimers, resulting in decreased platelet aggregation and thereby in a decreased thrombus growth. In coronary heart disease high levels of VWF are associated with an increased risk of arterial thrombosis (Jansson et al, 1991). We recently confirmed the association between levels of VWF antigen and activity and risk for ischemic stroke (Bongers et al, 2006). It has not yet been studied whether the Tyr1584Cys polymorphism is associated with the risk of arterial thrombosis. Therefore we investigated the Tyr1584Cys polymorphism in two different case-control studies in patients with well-documented arterial thrombosis. The first study, the COCOS-study, has been described in detail previously (Leebeek et al, 2005). Briefly, this study comprised 124 patients with a first-ever ischemic stroke and 125 controls without a history of stroke with an age range between 18–75 years. The second study, the ATTAC-study, was a case-control study that comprised 374 young patients (males £ 45 years and females £ 55 years) with a first-ever arterial thrombotic event, including unstable angina pectoris, acute myocardial infarction, transient ischemic attack, ischemic stroke or peripheral arterial disease and 332 young population controls without a cardiovascular event (unpublished observations). The Tyr1584Cys polymorphism in VWF results from an A/G Single Nucleotide Polymorphism at 24/1282 (rs1800386). The relevant region of exon 28 was amplified by polymerase chain reaction (PCR), using the forward primers: 5-’AAGCCGGATTAGAACC-’3 and reverse primer: 5’-AACTCCATGGTTGTGGAT-’3. The primers contain three mismatches to avoid amplifying the VWF pseudogene. The PCR comprised 95 C for 4 min followed by 35 cycles of 94 C for 30 s, 65 C for 1 min, 72 C for 1 min and finally 72 C for 4 min. The PCR product (682bp) was digested with Kpn1, which cleaves the A-allele in two fragments of 276 and 406, while the G-allele was not cleaved. The fragments were separated using 2% agarose gels and visualized using ultra violet light. The COCOS study (mean age 56 years ± 12 SD) showed similar carrier frequencies of 1584Cys carriers in cases and controls, [one patient (0.8%) and four (3.2%) controls were heterozygote, P = 0.48]. No homozygotes for the 1584Cys allele were present. In the ATTAC population (mean age 43 ± 7 years,) we observed no differences in 1584Cys carrier frequency between patients and controls [two patients (0.5%)

Abstract 5066: The Treatment Effect of Perindopril is Consistent in All Patients with Vascular Disease or High Risk of Vascular Disease: A Combined Analysis of Three Perindopril Trials

Abstract: The beneficial effect of the ACE-inhibitor perindopril has been demonstrated in large placebo-controlled clinical trials consisting of patients with stable CAD without overt heart failure (EUROPA),...