Supplementation of atherogenic diet with B vitamins does not prevent atherosclerosis or vascular dysfunction in monkeys.
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BACKGROUND: Hyperhomocysteinemia is associated with increased risk of atherosclerotic and thrombotic vascular disease. In many patients, hyperhomocysteinemia can be treated or prevented by dietary supplementation with B vitamins, but the clinical benefit of B vitamins for the prevention of vascular disease has not been proven. METHODS AND RESULTS: Using an atherogenic diet that produces both hyperhomocysteinemia and hypercholesterolemia, we tested the hypothesis that dietary supplementation with B vitamins (folic acid, vitamin B(12), and vitamin B(6)) would prevent hyperhomocysteinemia, vascular dysfunction, and atherosclerotic lesions in monkeys. After 17 months, plasma total homocysteine increased from 3.6+/-0.3 to 11.8+/-1.7 micromol/L in monkeys fed an unsupplemented atherogenic diet (P<0.01) but did not increase in monkeys fed an atherogenic diet supplemented with B vitamins (3.8+/-0.3 micromol/L). Serum cholesterol increased from 122+/-7 to 550+/-59 mg/dL in the unsupplemented group (P<0.001) and from 118+/-5 to 492+/-55 mg/dL in the supplemented group (P<0.001). Responses to endothelium-dependent vasodilators, both in resistance vessels in vivo and in the carotid artery ex vivo, were impaired to a similar extent in groups that did and did not receive vitamin supplements. Anticoagulant responses to the infusion of thrombin were also impaired to a similar extent in both groups. Vitamin supplementation failed to prevent intimal thickening in the carotid or iliac arteries. CONCLUSIONS: These findings demonstrate that supplementation with B vitamins prevents hyperhomocysteinemia but is not sufficient to prevent the development of vascular dysfunction or atherosclerotic lesions in monkeys with marked hypercholesterolemia, even in the absence of preexisting atherosclerosis. (+info)
Use of the activated partial thromboplastin time for heparin monitoring.
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The objectives of the present study were to evaluate the relationship between heparin concentration and activated partial thromboplastin time (aPTT) results, define a heparin concentration-derived therapeutic range for each aPTT instrument, compare aPTT- and heparin concentration-guided dosage adjustment decisions, and compare laboratory- and bedside aPTT-guided decisions. In phase 1, 102 blood samples were analyzed for bedside and laboratory aPTTs and heparin concentration (used to establish aPTT therapeutic range). In phase 2, 100 samples were analyzed in the same manner. Correlations for aPTT compared with heparin ranged from 0.36 to 0.82. Dosage adjustment decisions guided by the aPTT agreed with those based on heparin concentration 63% to 80% of the time. Laboratory and bedside aPTT dosage adjustment decisions agreed 59% to 68% of the time. The correlation of aPTT with heparin concentration and agreement between aPTT- and heparin-guided decisions vary with the aPTT instrument. Decisions guided by laboratory aPTT results often disagree with decisions guided by bedside aPTT results. (+info)
Cytomegalovirus pneumonitis, activated prothrombin time prolongation and subacute thyroiditis after unrelated allogeneic bone marrow transplantation.
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A 22-year-old female with acute myeloid leukemia (AML) in complete remission received a conditioning regimen containing antithymocyte globulin for an unrelated bone marrow transplant (BMT). After BMT, the patient suffered from cytomegalovirus (CMV) pneumonitis with markedly high levels of CMV antigenemia, activated prothrombin time (APTT) prolongation, and subacute thyroiditis. Recovery of CD4+ cells was delayed as long as 1 year after BMT. An association between these three episodes and viral infection due to the delayed recovery of CD4+ cells is suggested. (+info)
Endothelial cell protein C receptor plays an important role in protein C activation in vivo.
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Endothelial cell protein C receptor (EPCR) augments protein C activation by the thrombin-thrombomodulin complex about 5-fold in vitro. Augmentation is EPCR concentration dependent even when the EPCR concentration is in excess of the thrombomodulin. EPCR is expressed preferentially on large blood vessel endothelium, raising questions about the importance of protein C-EPCR interaction for augmenting systemic protein C activation. In these studies, this question was addressed directly by infusing thrombin into baboons in the presence or absence of a monoclonal antibody to EPCR that blocks protein C binding. Activated protein C levels were then measured directly by capturing the enzyme on a monoclonal antibody and assaying with chromogenic substrate. Blocking protein C-EPCR interaction resulted in about an 88% decrease in circulating activated protein C levels generated in response to thrombin infusion. Leukocyte changes, fibrinogen consumption, fibrin degradation products, and vital signs were similar between the animals infused with thrombin alone and those infused with thrombin and the anti-EPCR antibody. The results indicate that EPCR plays a major role in protein C activation and suggest that defects in the EPCR gene might contribute to increased risk of thrombosis. (+info)
A cohort study of coagulation parameters and the use of blood products in surgery of the thoracic and thoracoabdominal aorta.
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OBJECTIVES: We sought to study the hemostatic profile and the use of blood products in patients undergoing thoracic and thoracoabdominal aortic aneurysm repair. METHODS: This is a cohort study comparing three groups of patients: 7 undergoing elective acute normovolemic hemodilution (ANH); 15 undergoing elective procedures without ANH (non-ANH); and 8 undergoing repair of ruptured thoracoabdominal aneurysms. A control group of 10 patients was used for comparison of preoperative hemostasis. The parameters studied were platelet concentration, partial thromboplastin time (PTT), and international normalized ratio (before and after surgery), packed red blood cells, fresh frozen plasma, platelets, cryoprecipitates, donor exposure, and use of desmopressin and epsilon-aminocaproic acid. Analysis of variance and multiple stepwise regression analysis were used. RESULTS: Before operation the patients with aneurysms had PTTs prolonged compared with control subjects (P <.05). After operation the ANH group had higher platelet counts than the ruptured group (P =.001) and higher platelet counts (P =.05) and lower PTTs (P =.001) than the non-ANH group. The ANH group was transfused fewer platelets than the non-ANH group (P =.001) and less of every blood product than the ruptured group (P =.05); statistically significant differences were not observed for packed red blood cells, fresh frozen plasma, or platelets. The ANH group was exposed to an average of 65 donors fewer than the ruptured group (P <.001) and 34 fewer than the non-ANH group (P <.05). These differences could not be explained by baseline coagulation status or by the intraoperative use of desmopressin or epsilon-aminocaproic acid. CONCLUSIONS: The coagulation abnormality identified before surgery is that of higher PTT values, suggesting a disturbance of the extrinsic coagulation pathway. Blood losses, donor exposure, and platelet use were highest in the ruptured group and lowest in the ANH group. After surgery the ruptured group exhibited the worst coagulation parameters, and the ANH group exhibited the best with higher platelet count and lower PTT values than the other groups. The ANH technique appears to be an useful adjunct in the anesthetic management of these patients. (+info)
Preparation and characterization of monoclonal antibody against recombinant human tissue factor pathway inhibitor.
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OBJECTIVE: To prepare and identify monoclonal antibody (McAb) against recombinant human tissue factor pathway inhibitor (rhTFPI) and to use it for measurement of TFPI by ELISA, and to evaluate the effects of the McAb on dilute prothrombin time (PT) and activated partial thromboplastin time (APTT). METHODS: After intrasplenic immunization of Balb/c mouse with TFPI, hybridoma technique was used to raise monoclonal antibody against rhTFPI. The McAb was well-characterized and labelled with horseradish peroxidase (HRP) by using assay of TFPI in ELISA. Furthermore, the McAb was added to normal and factor IX deficient plasma for observation of dilute PT and APTT. RESULTS: Two hybridomas (4F4, 4F8) secreting McAb against TFPI were established. The Ig class and subclass of the McAb purified from 4F8 was IgG1. Immunoblotting results indicated that the McAb4F8 only recognized a single band of TFPI with molecular weight of 34.8 KD. The results of Sandwich enzyme-linked immunosorbent assay (ELISA) by using the HRP labelled McAb4F8 showed that the mean of TFPI in normal human plasma is 103.2 +/- 11.5 micrograms/L. The McAb 4F8 was also proved to shorten markedly dilute prothrombin time of factor IX deficient plasma and normal plasma. CONCLUSIONS: We established two hybridomas cell lines (4F4, 4F8) and obtained the McAb4F8 against TFPI and reported the levels of TFPI in healthy adult human plasma by Sandwich ELISA with HRP labelled McAb4F8 in Chinese. (+info)
Enoxaparin in experimental stroke: neuroprotection and therapeutic window of opportunity.
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BACKGROUND AND PURPOSE: Heparin and heparinoids have long been proposed for stroke treatment. This study investigates the effect of enoxaparin (Lovenox, Clexane), a low-molecular-weight heparin, on functional outcome (neuroscore) and lesion size in stroke models with reversible and irreversible cerebral ischemia using middle cerebral artery occlusion (MCAO) in the rat. METHODS: Ischemia was induced in rats by transient occlusion for 2 hours or by permanent electrocoagulation of the left MCA. Forty-eight hours after ischemia, neurological deficit was evaluated by scoring sensorimotor functions and ischemic damage was quantified by histological evaluation of lesion volumes. RESULTS: After transient MCAO, enoxaparin at 2x1.5 mg/kg IV (2 and 24 hours after insult) significantly reduced lesion size by 30% (P<0.05) and improved neuroscore (P<0.01). This significant effect on lesion size and neuroscore was still evident when treatment was started 5 hours after insult. Administered under the same protocol with a 5 hours delay post permanent MCAO, enoxaparin reduced lesion size by 49% (P<0.05) and improved neuroscore (P<0.01). CONCLUSIONS: This study indicates that standard nonhemorrhagic doses of enoxaparin reduce ischemic damage with a wide therapeutic window. In addition to its anticoagulant properties, other properties of enoxaparin could act in synergy to explain its neuroprotective profile in ischemia. Thus clinical application of enoxaparin treatment in stroke warrants serious consideration. (+info)
Antiplatelet agents in tissue factor-induced blood coagulation.
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Several platelet inhibitors were examined in a tissue factor (TF)-initiated model of whole blood coagulation. In vitro coagulation of human blood from normal donors was initiated by 25 pM TF while contact pathway coagulation was suppressed using corn trypsin inhibitor. Products of the reaction were analyzed by immunoassay. Preactivation of platelets with the thrombin receptor activation peptide did not influence significantly the clotting time or thrombin-antithrombin III complex (TAT) formation. Addition of prostaglandin E(1) (5 microM) caused a significant delay in clotting (10.0 minutes) versus control (4.3 minutes). The prolonged clotting time is correlated with delays in platelet activation, formation of TAT, and fibrinopeptide A (FPA) release. In blood from subjects receiving acetylsalicylic acid (ASA or aspirin), none of the measured products of coagulation were significantly affected. Similarly, no significant effect was observed when 5 microM dipyridamole (Persantine) was added to the blood. Antagonists of the platelet integrin receptor glycoprotein (gp) IIb/IIIa had intermediate effects on the reaction. A 1- to 2-minute delay in clot time and FPA formation was observed with addition of the antibodies 7E3 and Reopro (abciximab) (10 microg/mL), accompanied by a 40% to 70% reduction in the maximal rate of TAT formation and delay in platelet activation. The cyclic heptapetide, Integrilin (eptifibatide), at 5 microM concentration slightly prolonged clot time and significantly attenuated the maximum rate of TAT formation. The disruption of the gpIIb/IIIa-ligand interaction not only affects platelet aggregation, but also decreases the rate of TF-initiated thrombin generation in whole blood, demonstrating a potent antithrombotic effect superimposed on the antiaggregation characteristics. (+info)