Thrombosis Journal - Latest Articles

Plasma TF activity predicts cardiovascular mortality in patients with acute myocardial infarction

Birgit Steppich — 2009-07-02T00:00:00Z

Objectives and Background: Tissue factor (TF) contributes to thrombosis following plaque disruption in acute coronary syndromes (ACS). Aim of the study was to investigate the impact of plasma TF activity on prognosis in patients with ACS.Methods and Results: 174 patients with unstable Angina pectoris (uAP) and 112 patients with acute myocardial infarction (AMI) were included with a mean follow up time of 3.26 years. On admission, plasma TF activity was assessed. Patients were categorized into 2 groups: a high-TF activity group with TF >24 pmol/L and low TF activity group with TF <24pmol/L. Fifteen cardiovascular deaths occurred in the uAP group and 16 in the AMI group. In AMI TF activity was 24,9+2,78 pmol/l (mean+SEM) in survivors and 40,9+7,96 pmol/l in nonsurvivors (P=0.024). In uAP no differences were observed (25.0+8.04 pmol/L nonsurvivors vs. 25.7+2.14 pmol/L survivors; P=0.586). Kaplan-Meier estimates of survival at 3.26 years regarding TF activity in AMI were 81.3% and 92.2% with an hazard ratio of 3.02 (95% CI[1.05-8.79], P =0.03). The Cox proportional hazards model adjusting for correlates of age and risk factors showed that plasma TF activity was an independent correlate of survival (hazard ratio 9.27, 95% CI [1.24-69.12], P =0.03). In an additional group of patients with uAP and AMI, we identified circulating microparticles as the prevailing reservoir of plasma TF activity in acute coronary syndromes. Conclusion: Systemic TF activity in AMI has an unfavorable prognostic value and as a marker for dysregulated coagulation might add to predict the atherothrombotic risk.

Plasma fibrinolysis is related to the degree of organ dysfunction but not to the concentration of von Willebrand Factor in critically ill patients

Karim Zouaoui Boudjeltia — 2009-06-19T00:00:00Z

Background: Endothelial cell dysfunction, by promoting fibrin deposition, has been implicated in the development of multiple organ failure. Altered fibrinolysis during inflammation may participate in microvascular alterations. We sought to determine whether plasma fibrinolysis was related to the severity of organ dysfunction and/or to the levels of von Willebrand factor (vWF antigen), as a marker of endothelium dysfunction, in critically ill patients. Methods: Forty-nine consecutive patients admitted to an adult medico-surgical intensive care unit (ICU) with (18) or without sepsis (31) were included. C-reactive protein and vWF levels were measured on ICU admission and plasma fibrinolysis was assessed by the Euglobulin Clot Lysis Time (ECLT). The sequential organ failure assessment (SOFA) score and the simplified acute physiology score (SAPS) II were calculated on admission. Results: ECLT was significantly longer in septic than in non-septic patients [1033 min (871-1372) versus 665 min (551-862), p = 0.001]. There were significant correlations between ECLT and C-reactive protein (CRP) concentrations (r=0.78, p<0.001) and the Sequential Organ Failure Assessment (SOFA) score (r= 0.39, p= 0.006). The level of vWF was not correlated with the ECLT (r= -0.06, p= 0.65) or the SOFA score (r= -0.02, p= 0.88). Conclusions: ECLT measurement at admission could be a marker of organ dysfunction and a prognostic indicator in critically ill patients.

Thrombotic genetic risk factors and warfarin pharmacogenetic variants in Sao Miguel's healthy population (Azores)

Claudia Branco — 2009-06-18T00:00:00Z

Background: The Azorean population presents the highest standardized mortality rate for cardiovascular diseases (CVD) when compared to mainland Portugal and other populations. Since thrombosis is a common cause of CVD, we assessed four polymorphisms in three thrombotic risk genes - F5 (G1691A), F2 (G20210A) and MTHFR (C677T, A1298C), in 469 healthy blood donors from Sao Miguel Island (Azores). We also analysed the CYP2C9 (C430T, A1075C) and VKORC1 (G1639A) variants in fifty-eight individuals with predisposition to thrombosis (possessing at least one variation in F5 or F2 genes and one in MTHFR) to evaluate their warfarin drug response genetic profiles. Results: Among the 469 individuals, the data showed that thrombotic risk allele frequencies - 1691A (4.9%), 20210A (1.8%), 677T (41.7%) and 1298C (24.8%) - were similar to other Caucasians, but significantly different from mainland Portuguese (chi-square, p<0.001). The combined analysis of these variants identified twenty-two different genetic profiles (genotype order: F5, F2, MTHFR C677T and A1298C). Complete homozygosity for all wild-type alleles (GG GG CC AA) was present in 11.7%, being GG GG CT AA (22.4%) the most frequent profile. The results also demonstrated that 12.4% (58 out of 469) of Sao Miguel islanders have increased genetic predisposition to thrombosis. Subsequently, we evaluated these individuals for their warfarin response genetic profiles. The data showed that seven out of fifty-eight individuals are poor metabolizers (two with CYP2C9*2/*2 and five with CYP2C9*2/*3 genotypes). VKORC1 polymorphism analysis identified twelve individuals (20.7%) with AA genotype, who probably will require lower doses of warfarin. The joint analysis of CYP2C9 and VKORC1 revealed that 79.3% (46 out of 58) of the individuals carry at least one polymorphism in these genes. Within these, twenty-five individuals (43.1%) need intermediate and/or low doses of warfarin, if treatment is started. Conclusion: The present study demonstrated, for the first time, that Sao Miguel, and possibly the Azores population, shows significant differences on allele frequencies of thrombotic risk factors when compared to mainland Portugal. This research constitutes a primary approach for future studies on CVD, as well as for the implementation of warfarin dosing protocols using the patient's genotypic information.

Aminaphtone in the control of Schamberg's Disease

Jose Maria Pereira de Godoy — 2009-06-11T00:00:00Z

The aim of this case report is to describe control of Schamberg's disease using aminaphtone. We report on the case of a 28-year-old patient who presented with multiple purpuric lesions of the lower extremities which had appeared spontaneously. A biopsy of the skin was performed that showed a perivascular T-cell lymphocytic infiltrate centered on the small superficial blood vessels of the skin and so a diagnosis of Schamberg's disease was reached. The patient was prescribed corticoids and the lesions disappeared however on suspension of the medication the lesions re-emerged within three to seven days. This treatment was unsuccessfully continued for more than one year. Thus another therapeutic option was attempted: 75 mg of aminaphtone was prescribed twice daily for one month and the purpuric lesions disappeared within about one week. One year after suspending the medication no relapse of the purpura was observed.

Delayed formation of pulmonary artery stump thrombus: a case report and review of the literature

Monika Joshi — 2009-06-10T00:00:00Z

Pulmonary artery stump thrombosis is a recognized complication after pneumonectomy. However, to our knowledge, there is only one case report of delayed development of this complication. We report the case of a 68 year-old man who presented with chest pain nearly ten years after undergoing a right pneumonectomy for lung cancer. Workup identified a pulmonary artery stump thrombosis. Due to the acute onset of his symptoms, the patient was anticoagulated, and his chest pain resolved. While the literature suggests that anticoagulation is not generally required for stump thromboses, we highlight features of this case that may indicate an increased risk of clinically important sequelae. Taking previous reports into account, we argue that a specific subset of patients with stump thrombosis may benefit from systemic anticoagulation.

Clopidogrel resistance "Live" - the risk of stent thrombosis should be evaluated before procedures

Zuzana Motovska — 2009-05-19T00:00:00Z

Every year, millions of people undergo percutaneous coronary intervention (PCI) with intracoronary stent implantation. A patient from the PRAGUE-8 trial (Optimal pre-PCI clopidogrel loading: 600 mg before every coronary angiography vs. 600 mg in the cath-lab only for PCI patients) is described who suffered from acute stent thrombosis. This patient did not have any relevant inhibition of platelet activation even after the 600 mg dose of clopidogrel. Dose uptitration would have been ineffective. New P2Y12 receptor inhibitors are desperately needed. In the light of recently published data, the use of prasugrel may be considered as an alternative.

Acute myocardial infarction and pulmonary embolism in a young man with pernicious anemia-induced severe hyperhomocysteinemia

Ayyash Melhem — 2009-05-13T00:00:00Z

A 27 year-old man who presented to the hospital with progressive lower extremity weakness, developed an acute ST elevation myocardial infarction on his second hospital day. Primary angioplasty to the left anterior descending coronary artery was performed. Due to persistent dyspnea, the patient underwent a diagnostic chest computed tomography which confirmed multiple small pulmonary emboli. Laboratory analysis revealed a megaloblastic anemia with a reduced vitamin B12 level and positive titers for antibodies against intrinsic factor, establishing a diagnosis of pernicious anemia. Screening for hypercoaguable markers documented an isolated severely elevated homocysteine levels (105 μmol/l). No other significant risk factors for coronary artery disease including a family history of premature atherosclerosis were identified. This case illustrates the importance of testing for hyperhomocysteinemia as part of a workup for atherothrombotic disease, especially in patients without other significant risk factors. The severity of hyperhomocysteinemia found in our patient is unusual for patients with vitamin B12 malabsorption and raises the question of whether the widely practiced folic acid fortification in the United States may mask or even worsen vitamin B12 deficiency over time, leading to more severe cases of vitamin B12 deficiency and hyperhomocysteinemia than seen in the past.

Comparison of VerifyNow-P2Y12 test and Flow Cytometry for monitoring individual platelet response to clopidogrel. What is the cut-off value for identifying patients who are low responders to clopidogrel therapy?

Cosmo Godino — 2009-05-06T00:00:00Z

Background: Dual anti-platelet therapy with aspirin and a thienopyridine (DAT) is used to prevent stent thrombosis after percutaneous coronary intervention (PCI). Low response to clopidogrel therapy (LR) occurs, but laboratory tests have a controversial role in the identification of this condition. Methods: We studied LR in patients with stable angina undergoing elective PCI, all on DAT for at least 7 days, by comparing: 1) Flow cytometry (FC) to measure platelet membrane expression of P-selectin (CD62P) and PAC-1 binding following double stimulation with ADP and collagen type I either in the presence of prostaglandin (PG) E1; 2) VerifyNow-P2Y12 test, in which results are reported as absolute P2Y12-Reaction-Units (PRU) or % of inhibition (% inhibition). Results: Thirty controls and 52 patients were analyzed. The median percentage of platelets exhibiting CD62P expression and PAC-1 binding by FC evaluation after stimulation in the presence of PG E1 was 25.4% (IQR: 21.4–33.1%) and 3.5% (1.7–9.4%), respectively. Only 6 patients receiving DAT (11.5%) had both values above the 1st quartile of controls, and were defined as LR. Evaluation of the same patients with the VerifyNow-P2Y12 test revealed that the area under the receiver-operating-characteristic (ROC) curve was 0.94 (95% CI: 0.84–0.98, p < 0.0001) for % inhibition and 0.85 (0.72–0.93, p < 0.005) for PRU. Cut-off values of ≤ 15% inhibition or > 213 PRU gave the maximum accuracy for the detection of patients defined as having LR by FC. Conclusion: In conclusion our findings show that a cut-off value of ≤ 15% inhibition or > 213 PRU in the VerifyNow-P2Y12 test may provide the best accuracy for the identification of patients with LR.

Editorial on hypothesis and objectives in clinical trials: superiority, equivalence and non-inferiority

Claudio Gonzalez — 2009-03-21T00:00:00Z

Randomized clinical trial is often considered as the Gold Standard method for comparing treatment effects. In practice, taking into consideration their main objectives, the majority of clinical trials are aimed to establish the superiority of an intervention regarding to an active control or placebo. But neither equivalence nor non-inferiority should be from definitively concluded from superiority trials exhibiting non-significant results.To evaluate equivalence or non-inferiority between treatments, specific trials should be designed. These designs have strengths and weaknesses dicussed in this Editorial. In spite of the limitations in the doctrine that supports the classification of the clinical experiments as "superiority", "equivalence" and "non-inferiority" trials, this methodological approach allowed for a improved production and understanding of the medical evidence when compared with the traditional view. Further epistemological refinements of this theory are granted.

Mild hypothermia does not attenuate platelet aggregation and may even increase ADP-stimulated platelet aggregation after clopidogrel treatment

Carl Hogberg — 2009-02-23T00:00:00Z

Background: Mild hypothermia is currently standard of care for cardiac arrest patients in many hospitals and a common belief is that hypothermia attenuates platelet aggregation. We wanted to examine the effects of clopidogrel on platelet aggregation during hypothermia. Methods: Platelet reactivity at 37°C and 33°C was evaluated by light transmission aggregometry and vasodilator-stimulated phosphoprotein (VASP) in blood from healthy volunteers before, and 24 hours after, a 600 mg loading dose of clopidogrel. Results: Collagen, 5-HT, epinephrine, U46619 and ADP-induced platelet aggregation was unaltered or even increased by hypothermia. After clopidogrel, there was a significant increase in platelet aggregation for 5 and 20 μM ADP at 33°C compared to 37°C (46 ± 5 vs. 34 ± 5% and 58 ± 4 vs. 47 ± 4%, p < 0.001, n = 8). Hypothermia also increased ADP-induced aggregation after pretreatment with the P2Y1 antagonist MRS2500. The decreased responsiveness to clopidogrel during hypothermia could be overcome by addition of the reversible P2Y12 antagonist AZD6140. ADP-induced inhibition of VASP-phosphorylation was unaffected by hypothermia both in the presence and absence of clopidogrel. A dose-response curve for ADP-induced platelet aggregation revealed increased potency for ADP during hypothermia with no difference in efficacy. Conclusion: Mild hypothermia did not attenuate platelet aggregation, instead it even increased ADP-stimulated platelet aggregation after clopidogrel treatment. Dual platelet inhibition with aspirin and a P2Y12 receptor antagonist is probably needed for patients with acute coronary syndromes treated with mild hypothermia, and it is possible that future ADP blockers could be of benefit.