Showing papers in "Journal of Thrombosis and Thrombolysis in 2002"

Aspirin Resistance and Genetic Polymorphisms

Abstract: Differences in genetic makeup or polymorphisms can affect individual drug response. Detecting genetic variation may help predict how a patient will respond to a drug and could be used as a tool to select optimal therapy, tailor dosage regimens, and improve clinical outcomes. The data are replete relative to the therapeutic efficacy of aspirin (ASA) for the prevention of ischemic events. However, there is a paucity of published data on the relationship between polymorphisms and the clinical effects on ASA. Prothrombotic genetic variations that may contribute to ASA resistance, and increased risk of cardiovascular events may involve: (1) a polymorphism on the cyclooxygenase-1 (COX-1) gene affecting Ser529; (2) overexpression of COX-2 mRNA on platelets and endothelial cells; (3) polymorphism PLA1/A2 of the gene encoding glycoprotein IIIa (GPIIIa); and (4) the homozygous 807T (873A) polymorphism allied with increased density of platelet GP Ia/IIa collagen-receptor gene. Because of the possible increased risk of ischemic vascular events, carriers of these genetic polymorphisms may be resistant to the antithrombotic effects of ASA and should be considered for additional or alternative treatment.

Warfarin dose adjustments based on CYP2C9 genetic polymorphisms.

Abstract: Background: The dose response relationship of warfarin is unpredictable. Polymorphism of the Cytochrome P4502C9 enzyme leads to warfarin hypersensitivity presumably due to decreased metabolism of the S-enantiomer. The purpose of this study was to further characterize the relationship between CYP2C9 genotype and phenotype and to develop a basis for guidelines to interpret CYP2C9 genotype for warfarin dosing. Methods and results: Patients stabilized on warfarin therapy were recruited from an anticoagulation clinic. Patients were genotyped for CYP2C9*2, CYP2C9*3 and CYP2C9*5 alleles by standard methods of polymerase chain reaction amplification and restriction endonuclease digestion. Phenotype was determined by; dose (mg/kg/d) required to maintain anticoagulation, (INR 2.0–3.0), oral plasma S-warfarin clearance, and the plasma S:R-warfarin ratio. In this cohort, no subjects were found to have the CYP2C9*5 allele. The plasma S-warfarin concentration did not differ with age, dose or CYP2C9 genotype. Both CYP2C9*2 and *3 alleles were associated with lower maintenance dosages, lower total and R-warfarin plasma concentrations, decreased oral clearance of S-warfarin, increased plasma S:R-warfarin ratio and extended S-warfarin elimination half-life. Advancing age was found to decrease Warfarin maintenance dose in subjects with the common active CYP2C9*1/*1 genotype but did not influence dose requirement of subjects with one or more variant CYP2C9 alleles. Conclusions: Subjects who have been titrated to a consistent target INR demonstrate comparable plasma S-warfarin concentrations independent of CYP2C9 genotype. The warfarin dose required to maintain a consistent target INR between subjects differs as a function of S-warfarin clearance which is decreased by both CYP2C9*2 and or CYP2C9*3 variant alleles. The variables of CYP2C9 genotype and age can be applied to restrict the dosage range considered for individual patients.

Possible mechanisms of aspirin resistance.

Abstract: Data regarding possible mechanisms of aspirin (ASA) resistance in patients with recurrent myocardial infarction (MI) or vascular ischemia are limited. Five major possible mechanisms of ASA resistance are documented in the primary literature and are discussed in this paper. These mechanisms include: (1) inadequate blockade of erythrocyte-induced platelet activation; (2) biosynthesis of F2-isoprostane 8-iso-prostaglandin (PGF2alpha), a bioactive product of arachidonic acid peroxidation; (3) stimulation of platelet aggregation by cigarette smoking; (4) ASA resistant platelet aggregability by increased levels of norepinephrine, as seen during excessive exercise or periods of mental stress; and (5) increased platelet sensitivity to collagen. Recognizing mechanisms of platelet activation and identifying reversible risk factors such as smoking and mental stress may help decrease the occurrence of ASA resistance and possibly improve patient outcomes. Until more definitive data become available, when prescribing and dosing ASA for the prevention of MI or vascular ischemia, clinicians should identify possible risk factors for ASA resistance. Whether or not patients at risk for ASA resistance are candidates for additive antiplatelet therapy remains to be determined.

The smoker's paradox: insights from the angiographic substudies of the TIMI trials.

Abstract: Background: Despite increased risk for coronary artery disease and acute myocardial infarction (AMI), smokers have a paradoxically lower mortality after thrombolysis for AMI than non-smokers. We determined the clinical risk profiles and coronary flow characteristics of patients in the TIMI trials according to smoking status, focusing on microvascular flow. Methods: Among 2,573 patients in the TIMI 4, 10A, 10B and TIMI 14 trials, epicardial flow post-thrombolysis was measured using angiographic TIMI flow grades and the corrected TIMI frame count (CTFC). Microvascular flow was measured by TIMI Myocardial Perfusion Grade (TMPG) and, in TIMI 14, the percentage of ST segment resolution. Results: Clinically, the mean age (54 vs. 62 years), the prevalence of diabetes mellitus (11% vs. 16%) and hypertension (26% vs. 40%), and the 30-day mortality (2.6% vs. 6.2%) were lower among smokers than non-smokers (all p ≤ 0.001). Angiographically, single-vessel disease (48% vs. 40%) and non-left anterior descending infarct arteries (65.4% vs. 60.8%) were more common among smokers (both p ≤ 0.01). Epicardial TIMI grade 3 flow was achieved more often in smokers than non-smokers (61% vs. 56%) and the CTFC was faster (34 vs. 37 frames/sec, both p ≤ 0.01), especially in LAD lesions. However, the frequency of normal microvascular flow (TMPG 3) was similar among smokers and non-smokers (24% vs. 29%, p = 0.16), as was the frequency of complete ST segment resolution (50% vs. 46%, p = 0.29). Conclusions: Smokers have lower mortality after AMI than non-smokers, due in large part to lower clinical risk profiles and faster epicardial flow. Differences in tissue-level perfusion do not appear to contribute to lower mortality in smokers. Abbreviated Abstract. After acute MI, active smokers have lower acute mortality than non-smokers that appears to be largely explained by their healthier risk profiles, less extensive coronary disease, and faster epicardial blood flow after thrombolysis. Microvascular injury does not appear to play a major role in the lower mortality risk among smokers.

Changes in platelet P-selectin and in plasma C-reactive protein in acute atherosclerotic ischemic stroke treated with a loading dose of clopidogrel.

Abstract: Background: The surface expression of P-selectin on platelets contributes to the progression of inflammatory processes and thrombosis in atherothrombosis. In this study, we showed that the combination regimen of clopidogrel with aspirin could downregulate the P-selectin expression on platelets and the plasma concentration of C-reactive protein (CRP) in acute stage of atherosclerotic ischemic stroke.

Decreased platelet reactivity in blood anticoagulated with bivalirudin or enoxaparin compared with unfractionated heparin: implications for coronary intervention.

Abstract: Background: Platelet reactivity predicts complications after percutaneous coronary intervention (PCI). Accordingly, agents that suppress platelet reactivity should decrease adverse events after PCI. This study was designed to determine the effects of therapeutic concentrations of unfractionated heparin (UFH), bivalirudin, or enoxaparin alone or in combination with tirofiban on platelet reactivity.

Platelet glycoprotein Ib alpha receptor polymorphisms and recurrent ischaemic events in acute coronary syndrome patients.

Abstract: Aims: To examine the relationship between polymorphisms in the platelet receptor glycoprotein (GP) Ibα and recurrent ischaemic events, and assess their impact on response to anti-platelet treatment.

The determinants of activated partial thromboplastin time, relation of activated partial thromboplastin time to clinical outcomes, and optimal dosing regimens for heparin treated patients with acute coronary syndromes: a review of GUSTO-IIb.

Abstract: Context: Unfractionated heparin remains widely utilized in the treatment of acute coronary syndromes (ACS). However, limited data exist on optimal dosing and range of activated partial thromboplastin time (aPTT) in this setting. A large trial of thrombolysis for acute myocardial infarction has reported an association between longer aPTTs and adverse outcomes. Objectives: Estimate the optimal heparin-dosing regimen in achieving early therapeutic aPTTs (50 to 75 seconds) and determine the association of aPTT and death, reinfarction, and bleeding in population with ACS. Design: Subgroup analysis within a randomized, controlled trial of 5861 patients given unfractionated heparin who had aPTTs at 6, 12, or 24 hours, with outcome analyses by weight categories. Setting: In 373 hospitals in 13 countries from May 1994 to October 1995. Patients: A total of 12,142 patients admitted for ACS, stratified by the presence (n = 4131) or absence (n = 8011) of ST-segment elevation, and randomized to 72 hours of unfractionated heparin. Results: In a simulated weight-adjusted model, based on retrospective grouping by weight, a simulated dose of 60-U/kg bolus and 12-U/kg/h infusion resulted in the highest proportion of therapeutic aPTTs. After adjustment for baseline variables, longer 12-hour aPTT was associated with the composite of 30-day death or reinfarction in patients not treated with thrombolytic therapy (odds ratio, 1.10; 95% CI, 1.00 to 1.22; P = 0.047). Longer aPTT at 6 hours was associated with increased moderate or severe bleeding for the entire cohort. There was also a significant, nonlinear correlation of the 12-hour aPTT with moderate or severe bleeding in thrombolysis-treated patients. Conclusions: For ACS patients who are treated with heparin, aPTT is highly associated with body weight. Longer aPTT within the first 12 hours is associated with adverse outcomes in ACS. Heparin dosing for ACS should be weight based.

Plasma vitronectin levels in patients with coronary atherosclerosis are increased and correlate with extent of disease.

Abstract: Background: Acute thrombosis after atherosclerotic plaques disruption is a major complication of primary atherosclerosis, leading to acute ischemic syndromes and atherosclerotic proression. Vitronectin (VN) is multifunctional glycoprotein in blood and in the extracellular matrix. It binds glycosaminoglycans, collagen, plasminogen and urokinase receptor. VN stabilizes the inhibitory confirmation of plasminogen activation inhibitor-1 (PAI-1). Vitronectin may control the clerance of vascular thrombi by binding and stabilizing PAI-1, a key regulator of fibrinolysis. Therefore, VN is generally regarded as a cofactor for PAI-1 activity. On the other hand vitronectin binds to platelet glycoproteins may mediate platelet adhesion and aggregation at sites of vascular injury. Previous studies showed that anti-VN antibodies inhibit platelet aggregation in vitro, suggesting that vitronectin contributes to platelet accumulation at sites of vascular injury. In this study; we investigated the levels of plasma vitronectin in patients with Coronary Artery Disease (CAD) and control group. Methods: The patient group was divided into four subgroups: patients with no, single, double and triple vessel disease according to their angiography results. ELISA procedure (Technoclone) was used to determine the plasma vitronectin levels. Results: Plasma vitronectin levels in patient with CAD (% 125.87 ± 58.38) were found to be significantly higher than control group (% 89.47 ± 25.3) (p:0.000). In addition, in patients with double vessel disease (% 146.03 ± 71.69) plasma vitronectin levels were significantly higher than no vessel disease (% 87.84 ± 22.30) and control group, triple vessel disease (% 160.81 ± 57.02) significantly higher as compare with no, single vessel disease (% 111.68 ± 45.34) and control group (p < 0.05). There was no correlation between vitronectin and lipid parameters. Conclusion: These findings suggested that vitronectin is a marker of CAD. Elevated levels may indicate its role in the genesis and/or progression of CAD or may be the results of a compensatory mechanism.

Pharmacological intervention at disparate sites in the coagulation cascade: comparison of anti-thrombotic efficacy vs bleeding propensity in a rat model of acute arterial thrombosis.

Abstract: The Tissue Factor/Factor VIIa (TF/FVIIa) complex is an attractive target for pharmacological interruption of thrombin generation and hence blood coagulation, as this complex is the initiation point of the extrinsic pathway of coagulation. TF is a cell membrane-associated protein that interacts with soluble FVIIa to activate factors IX and X resulting in a cascade of events that leads to thrombin generation and eventual fibrin deposition. The goal of this non-randomized study was to evaluate XK1, a specific protein inhibitor of TF/FVIIa, and compare antithrombotic efficacy and bleeding propensity to a previously described Factor Xa (FXa) inhibitor (SC-83157/SN429) and a direct-acting thrombin inhibitor (SC-79407/L-374087) in an acute rat model of arterial thrombosis. All saline-treated animals experienced occlusion of the carotid artery due to acute thrombus formation within 20 minutes. Rats treated with XK1 exhibited a dose-dependent inhibition of thrombus formation with full antithrombotic efficacy and no change in bleeding time or total blood loss at a dose of 4.5 mg/kg, i.v. administered over a 60 minute period. FXa inhibition with SC-83157 resulted in complete inhibition of thrombus formation at a dose of 1.2 mg/kg, i.v.; however, this effect was associated with substantial blood loss. Thrombin inhibition with SC-79407 also afforded complete protection from thrombus formation and occlusion at a dose of 2.58 mg/kg, i.v., and like SC-83157, was associated with substantial blood loss. These data imply that TF/FVIIa inhibition confers protection from acute thrombosis without concomitant changes in bleeding, indicating that this target (TF/FVIIa) may provide improved separation of efficacy vs. bleeding side-effects than interruption of coagulation by directly inhibiting either FXa or thrombin.

High dose of tranexamic acid for treatment of severe menorrhagia in patients with von Willebrand disease.

Abstract: Menorrhagia is one of the most important and frequent complications in women with congenital von Willebrand disease (vWD). Three cases of menorrhagia with vWD (type 1; 1 case, type 2A; 2 cases) were successfully treated with tranexamic acid at dose of 3 grams daily in four divided doses for the first 5 days of the menstrual cycle. All patients had severe menorrhagia lasted for more than 10 days with iron deficiency anemia of hemoglobin levels of 6.5-8.4 g/dl. Common dosage of tranexamic acid of 1 gram daily in 4 divided doses on days 1-5 of their menstrual cycles did not correct their menorrhagia. The treatment was then changed to the daily dose of 3 grams in 4 divided doses on days 1-5 of their menstrual cycles. Thereafter, their menorrhagia became well-controlled with improvement of their anemia up to hemoglobin of 11.5-12.4 g/dl. High dose of tranexamic acid has been administered safely in all patients for 3-5 years without significant complications. Oral high-dose administration of tranexamic acid is very convenient and useful for treatment of menorrhagia in the patients with vWD.

Interleukin-1 receptor antagonist: a sensitive marker of instability in patients with coronary artery disease.

Abstract: Background: Increased plasma levels of acute phase reactants are correlated with acute coronary syndromes and increased risk of in-hospital events. Interleukin-1 receptor antagonist (IL-1Ra) modulates the activity of IL-1, a cytokine associated with inflammatory response; we have prospectively investigated whether detection of increased levels of IL-1Ra in patients may be useful in the characterization of coronary syndromes. Methods: Plasma levels of IL-1Ra were measured in 118 consecutive patients undergoing coronary angiography with a clinical diagnosis of recent unstable angina (N = 57), chronic stable angina (N = 49) or atypical chest pain (N = 12). Results: Angiography showed significant coronary disease in the first two groups and was normal in the latter group. Patients with unstable angina had significantly higher levels of IL-1Ra than stable patients [158 (110–224) vs 108 (95–154) pg/ml, P = 0.002] and individuals with chest pain and normal coronary angiogram [110 (97–123) pg/ml, P: = 0.038]. In contrast, while C-reactive protein levels were significantly higher in patients with stable and unstable angina vs those without coronary disease (0.29 vs 0.06 mg/dl, P: = 0.022), they did not discriminate between stable and unstable angina patients (0.22 vs 0.32 mg/dl, P: = 0.66). Conclusions: These results indicate that IL-1Ra may be a sensitive marker of clinical instability in patients with coronary artery disease.

Critical pathways for patients with acute chest pain at low risk.

Abstract: Critical pathways are predefined protocols that define the crucial steps in evaluating and treating a clinical problem to improve quality of patient care, reduce variability and enhance efficiency. Critical pathways have proliferated for a variety of diagnoses, including evaluation of patients with chest pain, a common and costly complaint. This review will outline the development, implementation, and assessment of critical pathways using as a paradigm our experience with a pathway for patients presenting to the Emergency Department with acute chest pain who are at low risk of myocardial ischemia. The goals of the pathway were to expedite evaluation of low-risk patients and reduce admission rates among these patients and in the cohort overall without compromising outcomes. The pathway was developed by a multidisciplinary team in an iterative process that considered published literature, as well as the experience and consensus of local opinion leaders. Patients at least 30 years old presenting to the Emergency Department of an urban teaching hospital who were pain-free without heart failure or ischemic changes on EKG, but who were not considered appropriate for discharge by the treating physician, were eligible for the critical pathway. The pathway involved one set of creatine kinase-MB enzymes drawn at least 4 hours after pain, a 6 hour observation period after the last episode of pain and exercise testing. Outcomes during evaluation and admission rates were assessed. Clinical outcomes at 7 days and 6 months after evaluation and patient satisfaction at 7 days were also measured. Of 1363 patient visits, 145 (10.6%) were triaged by the pathway: 131 (90.3%) were discharged, 14 (9.7%) were admitted. The overall admission rate decreased from 63% (2898/4595) to 60% (819/1363) [p < 0.05] in comparison to a cohort studied prior to pathway implementation. Pathway patients reported low rates of subsequent cardiac procedures. No deaths or myocardial infarctions were recorded. At 7 days, only 2 respondents (2%) reported going to an Emergency Department since their evaluation. Most respondents (83%) rated their care as very good or excellent. Critical pathways designed to enhance efficiency, reduce variability, and improve the quality of care are becoming increasingly common. Our pathway for evaluation of patients with chest pain at low risk of myocardial ischemia was feasible and safe and was associated with a decline in absolute admission rates. Because of the possibility of concomitant secular trends and the effects of a changing medical environment, further rigorous research on the efficacy of individual pathways is needed.

The Association of Mondor's Disease with Protein S Deficiency: Case Report and Review of Literature

Abstract: The authors present a case of superficial thrombophlebitis of the left anterolateral chest wall in a man whose diagnostic investigation culminated in the characterization of the vasculopathy denominated as Mondor's disease associated with protein S deficiency. We performed an analysis of the disease's main etiologic components and preponderant clinical aspects and determined all appropriate therapeutic measures for the pathology at issue.

Methodologic and clinical validation of the TIMI myocardial perfusion grade in acute myocardial infarction.

Abstract: Improved microvascular perfusion using the TIMI myocardial perfusion grade (TMPG) has been related to reduced in hospital, 30-day and 2-year mortality following thrombolytic administration. We sought to validate this measure using the more quantitative technique of digital subtraction angiography (DSA) and to correlate TMPG with ST segment resolution. DSA was used to analyze films from the LIMIT AMI acute myocardial infarction trial of front loaded r-tPA and rhuMAb CD18. Dye kinetics were also characterized using DSA in 88 arteries from patients without acute coronary syndromes in the absence of an obstructive lesion. Compared to normal patients, microvascular perfusion was reduced in acute myocardial infarction patients on DSA as demonstrated by a reduction in peak Gray (brightness) (p < 0.0001), the rate of rise in Gray/sec (p < 0.0001), the blush circumference (p < 0.0001), and the rate of growth in circumference (cm/sec) (p < 0.0001). However, while DSA perfusion was impaired overall in the setting of acute myocardial infarction, TMPG grade 3 in the setting of acute myocardial infarction did not differ from that in normal patients when studied quantitatively as shown by similar rates of growth in brightness and circumference (p = NS). ST resolution and the TMPG were significantly associated (p = 0.04). Compared to normal patients, acute myocardial infarction reduces the peak brightness of the myocardium, the rate of rise in brightness, the circumference of blush and the rate of growth in circumference as assessed using digital subtraction angiography. However, acute myocardial infarction patients with TMPG 3 had rates of growth in brightness and circumference that were nearly identical to normal patients. Thus, DSA validates that TMPG 3 is associated with normal kinetics of myocardial perfusion, and this likely accounts for the low (0.7%) 30 day mortality observed among those patients with TFG 3 and TMPG 3.

Use of thrombolytic therapy for acute myocardial infarction: effects of gender and age on treatment rates.

Abstract: Background: Although there have been efforts to increase the utilization of thrombolytic therapy, there are still many patients who might benefit from this treatment who do not receive it. Women and the elderly have been particularly undertreated, despite evidence that their survival can be improved with thrombolysis. This study was undertaken to determine the relative rates of treatment of women vs. men and the elderly vs. younger subjects and to examine factors that might explain differences in treatment frequency. Methods and Results: This is a retrospective study of patients who presented to the Emergency Departments of four local hospitals in 1993 and 1994 with evidence for acute ST-elevation myocardial infarction. Demographic data, past medical history, information on co-morbid illnesses, and times to hospital arrival, first electrocardiogram, physician notification, and thrombolytic therapy were recorded as was survival to hospital discharge. Data for patients who did or did not receive thrombolytic therapy were compared. Men were treated more frequently in both tertiary and community hospitals. Women were older, but within each age bracket, men were treated more often. The time of arrival was similar for men and women, but men who arrived within 6 hours or 6–12 hours after pain onset were treated at a higher rate than women. For patients without contraindications, treatment was not affected by gender or age. However, treatment rates decreased with increased prevalence of exclusionary factors, and since both women and the elderly tended to have more such factors, elderly women were treated at a markedly lower rate. The single clinical factor that increased thrombolytic usage in women compared to men was a history of prior myocardial infarction. Conclusion: Despite convincing evidence that thrombolytic therapy is beneficial in women and the elderly, these groups have been relatively neglected unless attention is called to clinical risk, for example, by history of prior myocardial infarction.

The association between inherited thrombophilia, antiphospholipid antibodies and lipoprotein A levels with obstetrical complications in pregnancy

Abstract: Objectives: To evaluate the association between obstetrical complications in pregnancy and thrombophilic factors. Study Design: 75 pregnant women with obstetrical complications and 66 controls with live births without obstetrical complications were tested for thrombophilia. All subjects were negative for thromboembolic disease. Results: The obstetrical complications in the study group were unexplained oligohydramnios = 16 (21%), IUGR = 17 (23%), preeclampsia <32 weeks = 15 (20%), recurrent abortions = 42 (56%), fetal demise = 14 (19%), abruption = 8 (11%). Comparing women with obstetrical complications versus controls, factor V Leiden mutation was present in 7 (10%) versus 1 (2%) P = .064, odds ratio (OR) = 7, 95%, CI = 0.8–58.5, antiphospholipid antibody syndrome in 14 (19%) versus 2 (3%) P = .003, OR = 7, 95% CI = 1.7–35, high lipoprotein A levels 13 (30%) versus 6 (10%) P = .019, OR = 3.8, 95% CI = 1.3–11. In the study group, there was a case each of prothrombin gene mutation, elevated homocysteine level, antithrombin III, protein S&C deficiencies. Major thrombophilia diagnosis was present in 24 (32%) versus 3 (5%) of controls p = .001, OR = 9.8. No association was found with the methylenetetrahydrofolate reductase gene mutation. In 22 women who subsequently became pregnant, prophylactic anticoagulant therapy compared to pretreatment control pregnancies showed 22 versus 11 live births P = .001, 95% CI = 0.3–0.7 and obstetrical complications of 2 (9%) versus 22 (100%) P = .001, OR = 11, 95% CI = 2.9–41.2. Conclusion: An association is suggested between non-thromboembolic pregnancy complications and hypercoagulable disorders. Prophylactic anticoagulant therapy may be associated with improved pregnancy outcome.

Which approach to anticoagulation management is best? Illustration of an interactive mathematical model to support informed decision making.

Abstract: Background: Among patients with atrial fibrillation or mechanical heart valves, determining the best approach to oral anticoagulation largely depends on comparing the costs of anticoagulation management with the costs of events (thromboembolism and bleeding) averted. The Anticoagulation Management Event/Cost Model (ACME) is an interactive mathematical model intended to help clarify these trade-offs.

Quantitative comparison of coronary artery flow and myocardial perfusion in patients with acute myocardial infarction in the presence and absence of recent cocaine use.

Abstract: Background: Numerous factors have been im- plicated in the pathogenesis of cocaine associated my- ocardial infarction (CAMI). However, the relative con- tributions each of these mechanisms provide to the pathogenesis of CAMI have not been well defined. We hy- pothesized that significant angiographic differences ex- ist between CAMI patients vs thrombotic AMI patients (TAMI) and normal controls. Methods: The TIMI Flow Grade, corrected TIMI Frame Count (CTFC), TIMI Myocardial Perfusion Grade (TMPG), presence of triple-vessel disease, stenosis severity, and presence of angiographically apparent thrombus were compared in patients who sustained CAMI to TAMI patients and normal controls. Results: 2,495 angiograms were analyzed (CAMI = 57, TAMI = 2,403, Controls = 35). Impairment in both epi- cardial and microvascular flow in patients with CAMI was intermediate between TAMI and controls. Com- pared to TAMI patients, CAMI patients were less likely to have 3 vessel disease (8.9% vs. 19.1%; p < 0.05), epicardial stenosis was less severe (14.9+/−30.2 vs. 72.6+/−18.6; p < 0.0001), less thrombus was present (6.5% vs. 33.1%; p < 0.001) and TIMI grade 3 flow was observed more frequently (76% vs. 59%). Normal TMPG 3 perfusion was significantly impaired in both CAMI and TAMI patients when compared to controls with- out AMI (TMPG 3 was 40% and 26.6% vs. 100% re- spectively; p < 0.001 for both). The majority of patients in both AMI groups had diminished or absent tissue level perfusion (TMPG 0 flow, CAMI 53.9 vs. TAMI 56.8%). Conclusions: Both epicardial and microvascular flow is impaired in CAMI. While epicardial flow among CAMI patients is slightly better than TAMI patients, the incidence of little or severely impaired tissue level perfusion is nearly identical. Condensed abstract. Compared to TAMI patients, CAMI patients were less likely to have 3 vessel disease, stenosis, and thrombus. The majority of patients in both AMI groups had diminished or absent tissue level perfusion. While epicardial flow among CAMI patients is slightly better than TAMI patients, the incidence

Polyethylene Glycol Diisocyanate Decreases Platelet Deposition After Balloon Injury of Rabbit Femoral Arteries

Abstract: Background: Platelet deposition after angioplasty remains problematic and may contribute to intimal hyperplasia and restenosis. We proposed that polyethylene glycol diisocyanate (PEG-DISO), a polymer that rapidly forms covalent linkages with amine residues on proteins, could mask thrombogenic vascular wall proteins from platelets, thereby abrogating acute platelet deposition. Methods and Results: To test this hypothesis, we isolated the femoral arteries of 10 New Zealand White rabbits and injured them with 3 passes of a 2F Fogarty catheter which was inserted through a distal arteriotomy. Immediately after balloon injury, 111indium-labeled autologous platelets were infused peripherally and the injured femoral arteries were randomly treated for 1 minute with a PEG-DISO solution in one artery and a control solution of the phosphate buffered saline vehicle in the contralateral artery. Following treatment, reflow was initiated. The vessels were harvested after 1 hour and radioactivity was quantified in a gamma counter. Platelet counts were standardized by weight and expressed as platelets/mg (mean ± SEM). Platelet deposition onto arteries treated with PEG-DISO was (1.2 ± 0.5) × 106 platelets/mg compared to (5.6 ± 4.2) × 106 platelets/mg onto the contralateral control arteries treated with vehicle (P < 0.005). Scanning electron micrographs of the injured vessel segment confirmed qualitatively less platelet deposition on the treated segments than on the control segments. Conclusion: Treatment with PEG-DISO significantly inhibited platelet deposition after vascular injury. These data support the hypothesis that treatment with PEG-DISO masks surface adhesive proteins from platelet receptors in vivo and that the resulting molecular barrier significantly reduces platelet deposition onto the damaged vessel wall for at least one hour. The formation of a molecularly thin barrier to platelet deposition may thus be a novel and effective treatment to abrogate acute intravascular thrombosis and may have value in the treatment of restenosis.

Reliability, validity and ease of use of a portable point-of-care coagulation device in a pharmacist-managed anticoagulation clinic.

Abstract: In a pharmacist-managed anticoagulation clinic, portable point-of-care coagulation devices may facilitate patient monitoring by providing rapid INR measurement. Few studies, however, have validated this type of device.

Pharmacologic reperfusion therapy for acute myocardial infarction.

Abstract: Acute myocardial infarction (MI) remains a significant problem in terms of morbidity, mortality and healthcare costs. Pharmacologic reperfusion therapies for MI are becoming increasingly complex. This review therefore places contemporary pharmacologic MI developments into perspective. An historical overview of pharmacologic reperfusion therapy for MI is provided, followed by an analysis of current limitations, treatment options, and present and likely future pharmacologic therapies. Adjunctive percutaneous and other treatments are also discussed, to clarify what is becoming a rapidly changing field.

Effects of different thrombolytic treatment regimen with abciximab and tirofiban on platelet aggregation and platelet-leukocyte interactions: a subgroup analysis from the GUSTO V and FASTER trials.

Abstract: Background: Due to considerably high rates of reocclusion under standard thrombolytic therapy GP IIb/IIIa inhibitors have been combined with thrombolytics to improve therapeutic outcomes. Potential reasons for arterial reocclusion may be increased platelet activation, interaction of platelets with other cell types such as leukocytes and inadequate drug dosing due to lack of ideal platelet monitoring. We compared combination therapy regimens consisting of GP IIb/IIIa inhibitors and thrombolytics with respect to platelet inhibition and platelet-leukocyte interactions.

Congenital Thrombophilia Associated to Obstetric Complications

Abstract: During pregnancy there are hemostatic changes that result in a hypercoagulable state and can have thrombotic consequences. This condition can be aggravated in women who are carriers of congenital thrombophilic factors. This thrombotic tendency can manifest as thrombotic lesions in the placenta with compromise of utero-placental circulation, which are common characteristics present in obstetric complications, such as preeclampsia/eclampsia, miscarriage, fetal loss, intrauterine growth retardation, and abruptio placentae. In this paper we review data concerning about the association of congenital thrombophilia in pregnancy with obstetric complications, mainly preeclampsia and fetal loss, focusing in factor V Leiden and its related activated protein C resistance, prothrombin mutation G20210A and hyperhomocysteinemia related with C677T mutation of methylenetetrahydrofolate reductase. Although factor V Leiden has been the thrombophilic factor most studied, all three thrombophilic mutations have been related with obstetric complications; however, contradictory results about the specific association of each mutation with each type of obstetric complication are described. These discrepancies could obey to the ethnic difference of the studied groups, or to the fact that some studies were performed in closed populations with few migratory movement, where the genetic pool is relatively homogeneous, as well as the different inclusion and exclusion criteria. Even though this variability is present, the significance of recognizing true associations between these thrombophilic mutations and obstetric complications is essential in order to determine the likelihood of routinely screening for these conditions in pregnant women with risk factors for thrombosis and for carrying out specific prophylactic measures.

Comparative effects of unfractionated heparin and low molecular weight heparin on vascular endothelial cell tissue factor pathway inhibitor release: a model for assessing intrinsic thromboresistance.

Abstract: Objectives: The purpose of our study was to characterize tissue factor pathway inhibitor (TFPI) release from human vascular endothelial cells following daily exposure to varying concentrations of unfractionated heparin (UFH) and low molecular weight heparin (LMWH).

Feasibility and Timing of Prehospital Administration of Reteplase in Patients with Acute Myocardial Infarction

Abstract: Background: In myocardial infarction patients undergoing thrombolysis, treatment delays negatively impact outcomes. This pilot study was conducted to determine the feasibility and timing of field administration of intravenous double bolus reteplase in patients with ST-elevation myocardial infarction. Methods: Sixty three patients with symptoms and EKG changes consistent with acute myocardial infarction of less than six hours duration received the first bolus of reteplase before arriving at the emergency department. A second bolus of reteplase was given in the emergency department. Subsequent resolution of ST-segment elevation was measured. Mean time from symptom onset to paramedic dispatch, and paramedic arrivals to first bolus of reteplase were measured. The mean time from the first bolus of reteplase to heparin bolus in an emergency department was also measured. All patients with evidence of ST-elevation and suspected acute myocardial infarction gave consent for the thrombolytic therapy. There were no refusals of therapy among those candidates eligible for thrombolysis. Results: The mean times from the first bolus of reteplase to heparin bolus in the emergency department was substantially longer than the in-field times. Resolution of ST-segment elevation was recorded in 52 of the 63 patients and the times of resolution ranged from five minutes after the first bolus dose to 190 minutes after the second bolus of reteplase. Resolution of ST-segment elevation and relief of pain occurred almost simultaneously. Conclusions: These results demonstrated that in-field administration of thrombolytic therapy is a viable option to reduce the delay from symptom onset to initiation of thrombolysis. They demonstrated that satisfactory resolution of ST-segment elevation can be recorded in the field. The reduction in mortality observed in this study is comparable to previously published studies on inpatients.

Lack of α2-antiplasmin enhances ADP induced platelet micro-aggregation through the presence of excess active plasmin in mice

Abstract: Background: The role of α2-antiplasmin (α2-AP) on platelet aggregation was investigated using mice deficient in α2-AP (α2-AP−/−) or using wild type mice (α2-AP+/+).

Prothrombotic response to coronary angioplasty in patients with unstable angina and raised C-reactive protein.

Abstract: Background: To better understand the mechanisms linking C reactive protein (CRP) to the risk of coronary thrombosis, we investigated the relation between inflammatory state and hemostatic response to coronary angioplasty in patients with either stable or unstable angina

An automated strategy for bedside aPTT determination and unfractionated heparin infusion adjustment in acute coronary syndromes: insights from PARAGON A.

Abstract: Background: Intravenous unfractionated heparin remains a cornerstone of anticoagulation therapy for patients with acute coronary syndromes, but regulation to a target aPTT is challenging. We assessed unfractionated heparin infusion regulation by bedside, whole-blood aPTT testing and computerized, algorithmic infusion adjustment, and further evaluated the relationship of achieving the target aPTT with clinical outcomes.

Fatal pulmonary artery embolism in a sickle cell patient: case report and literature review.

Abstract: This article reports a rare case of fatal saddle embolism to the pulmonary artery presenting as an Acute Chest Syndrome (ACS) in a Sickle Cell patient. We present a review of the etiology, pathophysiology, clinical manifestation and management of ACS. Clinicians should be aware of the fact that a sickle cell crisis admission may represent a life-threatening process. Such awareness will help physicians to act promptly and execute proper therapeutic interventions. It is important for clinicians to be expectant of impending clinical deterioration and likewise be aware that ACS can develop in patients hospitalized for other medical or surgical conditions.