Patients with a high plasma level of factor VIII have an increased risk of recurrent venous thromboembolism.

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SummaryAnti-platelet drug therapy is currently performed without monitoring, because the established method of platelet aggregometry is cumbersome. The recently developed platelet function analyzer PFA-100® measures shear stress dependent, collagen epinephrine (CEPI) and collagen adenosine diphosphate (CADP) induced platelet plug formation. As the PFA-100 provides a valuable tool to detect patients with platelet dysfunction more efficiently and cost-effectively than aggregometry, we investigated its potential to monitor the efficacy of aspirin treatment.All healthy volunteers (n = 10) received a fractionated infusion of L-aspirin to establish individual dose-response curves. Further, in a randomized, double-blind, placebo controlled two-way cross over study the same volunteers received either 50 or 100 mg aspirin/day p.o. for a period of 11 days to determine the day-to-day variability CEPI induced closure time (CT) under constant intake of low dose aspirin, and to compare the efficacy of those two doses.Intra- and intersubject variability of CEPI-CT averaged 9% and 22%, respectively. Seven volunteers exceeded the maximum of CEPI-CT (>300 s) already after infusion of 100 mg L-aspirin. Intake of 100 mg of aspirin elicited a more rapid onset of effect than 50 mg, which was only significant on days 3 and 4 of aspirin intake. The aspirin induced CEPI-CT prolongation correlated positively with basal CEPI-CT values (r = 0.86; p = 0.001) and were strongly dependent on von Willebrand Factor levels (r = -0.9; p = 0.001).Thus, the PFA-100 system appears suitable to demonstrate an aspirin-induced platelet effect in a longitudinal study, and may be adequate to monitor a patient’s compliance. However, prospective trials have to be conducted to demonstrate whether the EPI-CT achieved under ASA-intake has predictive value for cardiovascular outcome.

Background-Lipopolysaccharide (LPS) is a major trigger of sepsis-induced disseminated intravascular coagulation (DIC) via the tissue factor (TF)/factor VIIa-dependent pathway of coagulation. Experimental endotoxemia has been used repeatedly to explore this complex pathophysiology, but little is known about the effects of clinically used anticoagulants in this setting. Therefore, we compared with placebo the effects of unfractionated heparin (UFH) and low-molecular-weight heparin (LMWH) on LPS-induced coagulation. Methods and Results-In a randomized, double-blind, placebo-controlled trial, 30 healthy male volunteers received LPS 2 ng/kg IV followed by a bolus-primed continuous infusion of UFH, LMWH, or placebo. In the placebo group, activation of coagulation caused marked increases in plasma levels of prothrombin fragment F 1ϩ2 (PϽ0.01) and polymerized soluble fibrin, termed thrombus precursor protein (TpP; PϽ0.01); TF-positive monocytes doubled in response to LPS, whereas levels of activated factor VII slightly decreased and levels of TF pathway inhibitor remained unchanged. UFH and LMWH markedly decreased activation of coagulation caused by LPS, as F 1ϩ2 and TpP levels only slightly increased; TF expression on monocytes was also markedly reduced by UFH. TF pathway inhibitor values increased after either heparin infusion (PϽ0.01). Concomitantly, factor VIIa levels dropped by Ͼ50% at 50 minutes after initiation of either heparin infusion (PϽ0.01). Conclusions-This

Abstract-Leptin, a protein encoded by the obese gene, is produced by adipocytes and released into the bloodstream. In obese humans, serum leptin levels are increased and correlate with the individual's body mass index and blood pressure. Elevated serum concentrations of endothelin-1 (ET-1), a potent vasoconstrictor and mitogen, were also observed in obese subjects. The pathomechanisms underlying this ET-1 increase in obesity are poorly understood. In the present study, we investigated the influence of the ob gene product leptin on the expression of ET-1 in human umbilical vein endothelial cells (HUVECs). Binding studies using 125 I-radiolabeled leptin revealed high-and low-affinity leptin binding sites on HUVECs (Kd1ϭ13.1Ϯ3.1 nmol/L and Kd2ϭ1390Ϯ198 nmol/L, respectively), mediating a time-and dose-dependent increase of ET-1 mRNA expression and protein secretion after incubation of HUVECs with leptin. This leptin-induced ET-1 expression was inhibited by preincubation of HUVECs with 0.75 mol/L antisense phosphorothioate oligonucleotides directed against the leptin receptor Ob-Rb. Furthermore, after incubation with leptin, increased nuclear staining of c-fos and c-jun, the major components of the transcription factor AP-1, and increased AP-1 DNA binding were observed. Transient transfection studies with ET-1 promoter constructs showed that leptin-induced promoter activity was abolished in the absence of AP-1 binding sites or by cotransfection with a plasmid overexpressing a mutated jun, which is able to bind c-fos but not DNA. Thus, leptin upregulates ET-1 production in HUVECs via a mechanism potentially involving jun binding members of the bZIP family. Key Words: endothelin Ⅲ obesity Ⅲ hypertension Ⅲ vasculature A lthough the association of obesity and hypertension is well established, 1 there is, however, scarce information about the underlying pathomechanisms. Recently, the adipocyte gained more attention, serving not only as a passive energy storage pool but also as an important source of endocrine-active peptides, thus leading to a novel concept of adipocyte function.One of the adipocyte-derived peptides involved in the control of body weight is the recently identified hormone leptin, 2 a protein encoded by the obese (ob) gene modulating lipid metabolism, 3 hematopoiesis, 4 pancreatic ␤-cell function, 5 and angiogenesis. 6,7 Mutation of the ob gene causes severe obesity in ob/ob mice, which can be reversed through administration of exogenous leptin. 8 -10 In contrast, serum leptin levels in obese humans are increased and correlate with their body mass index, 11 suggesting that obese subjects are resistant to endogenous leptin.Several alternate spliced isoforms of the leptin receptor (Ob-R) have been cloned (reviewed in Tartaglia 12 ) containing a single transmembrane domain and an extracellular domain homologous to the class I cytokine receptor family, but differing in the length of their cytoplasmic tail. The receptor with the full-length cytoplasmic domain (Ob-Rb, 302 amino acids) is predominantly expressed...

Abstract-A genetic variation in the prothrombin gene, the G3 A transition at nucleotide 20210, is a risk factor for venous thrombosis in heterozygotes and is associated with increased prothrombin activity. The homozygous phenotype and the extent of thrombin generation in heterozygous and homozygous subjects are unknown. We investigated a family that included 2 homozygous and 5 heterozygous carriers of the 20210 A allele. The homozygous propositus and his presumably heterozygous father suffered from deep-vein thrombosis. His presumably heterozygous mother and his homozygous sister had recurrent phlebitis at a young age. The remaining 5 affected family members are still asymptomatic. We studied thrombin generation in the family and in 22 unrelated carriers of the 20210 A allele by measuring (1) prothrombin fragment F1ϩ2 (F1ϩ2) as an index of ongoing thrombin generation and (2) the endogenous thrombin potential (ETP) as an index of the possible thrombin-forming capacity. Their F1ϩ2 levels were not different from those of age-matched controls, and thus, ongoing hemostatic system activation was not detectable. A significantly increased ETP was found in the heterozygous carriers of the 20210A allele compared with the controls (527.8Ϯ114.9 versus 387Ϯ50

Our data suggest that the diurnal changes in the plasma levels of activators and inhibitors of coagulation and fibrinolysis lead to corresponding changes in the activity state of these systems, leading to morning hypercoagulability and hypofibrinolysis.

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