PubMed Health⌕ Search

Biomedical subjects

S Barzegar

Publications and source records attributed to S Barzegar.

9 recordsLinked to original sources
PubMed1992

Coagulation activation following estrogen administration to postmenopausal women.

We investigated coagulation system activation following estrogen treatment in 29 healthy postmenopausal women. Study participants received conjugated estrogens at 0.625 and 1.25 mg per day, and placebo for 3-month periods in a randomized crossover protocol. Blood samples were obtained on two consecutive days at the end of each treatment period for immunoassays of F1+2 and fibrinopeptide A (FPA), markers of factor Xa action on prothrombin and thrombin action on fibrinogen in vivo, respectively. Treatment with estrogens at a dose of 0.625 or 1.25 mg resulted in significant increases in mean F1+2 levels of 40 and 98%, respectively, and in mean FPA levels of 37 and 71%, respectively. The measurements of F1+2 were significantly higher in women receiving 1.25 mg of estrogen than 0.625 mg. We also observed significant declines in the levels of antithrombin III and total protein S antigen. Immunologic levels of protein C increased modestly at only the 1.25 mg estrogen dose level. These data indicate that low doses of oral estrogens (< or = 1.25 mg per day) frequently increase the amount of thrombin generated in vivo. Our observations may help to explain the increased thrombotic risk that has been observed with higher doses of this medication (> or = 2.5 mg).

Adult↗
PubMed1992

Gemfibrozil reduces plasma prothrombin fragment F1 + 2 concentration, a marker of coagulability, in patients with coronary heart disease.

The effects of gemfibrozil on several indices of haemostatic activity were explored in male patients with coronary heart disease (CHD). Sixty-three of 71 patients completed a crossover study in which gemfibrozil 1,200 mg/day and matching placebo were each taken in randomised order for 2 months in a double-blind manner, separated by a 2-month washout period. Serum cholesterol decreased by an average (95% confidence interval) of 12 (9 to 15)% and non-fasting triglyceride concentration by 43 (34 to 51)% during active treatment. Plasma prothrombin fragment F1 + 2 concentration, a marker of the in vivo rate of generation of thrombin, was 25 (12 to 37)% lower on average while on gemfibrozil than during the placebo phase. Factor VII coagulant activity (VIIc) and antigen concentration, and fibrinopeptide A concentration were not influenced by gemfibrozil in the group overall. However, the VIIc response appeared to be dependent upon the untreated cholesterol level. Hypercholesterolaemic men (cholesterol greater than 6.5 mmol/l) experienced a significant reduction in VIIc averaging 6% of standard during active therapy. Other effects of gemfibrozil were a 5 (2 to 9)% increase in plasma fibrinogen by a gravimetric method, an 11 (8 to 13)% increase in platelet count, and a 6 (2 to 10)% reduction in white cell count. The reduced incidence of CHD following gemfibrozil therapy in hyperlipidaemic patients may arise in part through a reduction in procoagulant activity and thus the risk of an occlusive coronary thrombosis.

Biomarkers↗
PubMed1992

Monitoring "mini-intensity" anticoagulation with warfarin: comparison of the prothrombin time using a sensitive thromboplastin with prothrombin fragment F1+2 levels.

Treatment with warfarin using a target International Normalized Ratio (INR) range of 1.7 to 2.5 is efficacious for many clinical indications, but the minimal intensity of anticoagulation required for antithrombotic protection has yet to be determined. To evaluate whether patients could be reliably monitored with a less intense regimen, we anticoagulated patients with warfarin for several months using a target INR range of 1.3 to 1.6 as determined by prothrombin time (PT) using a sensitive thromboplastin (Dade IS, International Sensitivity Index [ISI] = 1.3). Plasma measurements of F1+2, a marker of factor Xa action on prothrombin in vivo, were also obtained to determine the suppressive effect of warfarin on hemostatic system activity. Overall, 20 of 21 patients with a history of cerebrovascular events (mean age, 61 years) could be reliably regulated with warfarin in the target INR range. F1+2 levels were significantly suppressed from baseline in all patients, with a mean reduction of 49% (range, 28% to 78%). We found a significant relationship between the extent of suppression of prothrombin activation levels and the baseline measurements. A mean reduction of 65% was observed for those patients with baseline F1+2 greater than or equal to 1.5 nmol/L, but only 38% for baseline F1+2 less than or equal to 0.5 nmol/L. Overall, 68% of plasma samples obtained during stable anticoagulation were within the target INR range. PTs were also determined on all plasma samples with two thromboplastins of lower sensitivity (C+, ISI = 2.09; and automated simplastin, ISI = 2.10). Only 47% and 35% of PT determinations, respectively, were within the target range with these reagents. We conclude that prothrombin activation can be significantly suppressed in vivo with use of warfarin in an INR range of 1.3 to 1.6. This level of anticoagulation can be reliably achieved by monitoring PTs with a thromboplastin of high sensitivity.

Blood Coagulation↗
PubMed1992

Factor IXa-factor VIIIa-cell surface complex does not contribute to the basal activation of the coagulation mechanism in vivo.

We have infused recombinant factor VIIa into patients with hereditary factor VII deficiency with marked reductions in plasma concentrations of factor IX activation peptide (FIXP), factor X activation peptide (FXP), and prothrombin activation fragment F1+2. These investigations show substantial elevations in these markers of coagulation activation and thereby demonstrate that the factor VII-tissue factor pathway is largely responsible for the activation of factor IX as well as factor X in the basal state (ie, the absence of thrombosis or provocative stimuli). We have administered a monoclonal antibody purified factor IX concentrate to individuals with hemophilia B. These studies show an increase in the plasma levels of FIXP that were initially greatly decreased, but no change in FXP or F1+2. We have also infused highly purified factor VIII concentrate into patients with hemophilia A. The data demonstrate no significant changes in the plasma concentrations of FXP and F1+2. The above observations indicate that factor IXa generated by the factor VII-tissue factor pathway is unable to activate factor X under basal conditions. Based upon the above findings, we outline a model of blood coagulation system function under basal conditions, and suggest a process by which the generation of factor Xa and thrombin might be accelerated during normal hemostasis and in the setting of thrombotic disorders.

Adolescent↗
PubMed1991

Influence of anticoagulants used for blood collection on plasma prothrombin fragment F1 + 2 measurements.

The levels of prothrombin fragment F1 + 2 were measured by a double antibody radioimmunoassay in blood samples collected into different anticoagulant solutions. We evaluated healthy males between the ages of 42 and 77, asymptomatic patients with hereditary deficiencies of protein C or protein S, and persons receiving tumor necrosis factor infusions. The results in specimens collected in an anticoagulant containing ACD, EDTA, adenosine, and 25 U/ml of heparin (a) were highly correlated with those collected in an anticoagulant containing a synthetic thrombin inhibitor, EDTA, and aprotinin (b). However, in asymptomatic patients with congenital antithrombin III deficiency, we found that the plasma levels of F1 + 2 in blood collected in anticoagulant (a) were usually substantially higher than those collected in anticoagulant (b). We determined that this phenomenon was not attributable to the venipuncture procedure itself, but rather appears to be due to the action of low concentrations of heparin in the presence of reduced blood levels of antithrombin III. Our data show that the previously documented elevations in plasma F1 + 2 levels in patients with congenital antithrombin III deficiency appear to be caused by the above in vitro anticoagulant effect, and that this population does not exhibit evidence of a prethrombotic state as defined by the F1 + 2 assay.

Adult↗
PubMed1991

No activation of the common pathway of the coagulation cascade after a highly purified factor IX concentrate.

Purer factor IX concentrates, containing very little or no factor II or X, have been developed in an attempt to avoid the thromboembolic complications that occur with prothrombin complex concentrates (PCC), which also contain factors II and X and variable amounts of factor VII. To evaluate ex vivo the thrombogenic potential of one of these purer concentrates, we studied whether large single doses produced signs of activation of the coagulation cascade in patients with haemophilia B, and compared the results with those obtained after infusion of a PCC. Seven patients were infused with 50 IU/kg of factor IX concentrate and seven additional patients were subsequently infused with 100 IU/kg of the same concentrate. After the infusions, factor IX levels rose in proportion to the administered dose while the concentrations of factor II and factor X did not rise at all. At both doses of concentrate, we did not observe significant post-infusion increments in the levels of the factor X activation peptide (a measure of the activity of the factor VIIa-tissue factor complex and/or the factor IXa-VIIIa-activated surface complex), prothrombin fragment 1 + 2 (a measure of factor Xa activity), and fibrinopeptide A (a measure of thrombin activity). We also infused 10 patients with a PCC (50 IU/kg). After the infusions, significant rises in the concentrations of the factor X activation peptide and prothrombin fragment were observed. Therefore, it appears that the infusion of a PCC to patients with haemophilia B can augment factor X activation and subsequently thrombin generation in vivo and that this process can be abrogated by the administration of more pure factor IX concentrate.

Adolescent↗
PubMed1990

Thrombin generation is not increased in the blood of hemophilia B patients after the infusion of a purified factor IX concentrate.

Prothrombin complex concentrates (PCC), licensed for the treatment of hemophilia B, are known to carry a significant risk of thromboembolic complications. Although the reasons for thrombogenicity are not completely understood, several manufacturers have developed purified factor IX concentrates that contain negligible amounts of the other vitamin K-dependent factors. To evaluate whether or not the infusion of such a factor IX concentrate is followed by lesser activation of the hemostatic system than by the infusion of a PCC, we performed a series of coagulation assays on 11 hemophilia B patients before and after the administration of these two types of concentrate using a randomized cross-over design. The levels of prothrombin fragment F1 + 2, a sensitive measure of the in vivo cleavage of prothrombin by factor Xa, was significantly increased in plasma after PCC, but not after factor IX concentrate. Plasma fibrinopeptide A, a sensitive index of the enzymatic activity of thrombin on fibrinogen, also increased significantly after PCC but not after factor IX concentrate. The fragment B beta 15-42, a sensitive index of the enzymatic action of plasmin on fibrin II, did not change after either concentrate. There were also no differences in less sensitive coagulation measurements, such as plasma fibrinogen, antithrombin III, and fibrin monomers, nor in indices of platelet activation, such as beta-thromboglobulin and platelet factor 4. These findings show that the infusion of a purified factor IX concentrate can result in substantially less activation of the coagulation cascade than may be seen with PCC.

Adolescent↗
PubMed1989

Tumor necrosis factor infusions have a procoagulant effect on the hemostatic mechanism of humans.

Several investigators have reported that tumor necrosis factor (TNF) can alter the hemostatic properties of vascular endothelial cells in vitro. We have examined the in vivo effects on the hemostatic mechanism of recombinant human TNF administered as a continuous intravenous infusion to 23 cancer patients with active disease. A battery of sensitive and specific immunochemical techniques were used to monitor changes in blood coagulability. Serial determinations of F1 + 2, the protein C activation peptide (PCP), and fibrinopeptide A (FPA) were obtained prior to the initiation of the TNF infusions and at three and 24 hours after the start of therapy in 12 individuals who received greater than 3 x 10(5) U/m2/24h. The mean levels of F1 + 2, PCP, and FPA were significantly elevated at both time points as compared to the baseline values. The metabolic behavior of 125I-F1 + 2 in an animal model was not affected by infusions of the cytokine. We therefore conclude that the observed elevations in the concentration of this marker in humans receiving TNF result from hemostatic system hyperactivity. In 11 subjects infused with 1 x 10(5) to 2.4 x 10(5) U/m2/24 h of the cytokine, the mean levels of F1 + 2, PCP, and FPA were not significantly greater at 24 hours as compared with the baseline values, indicating that there is a threshold dose at which the cytokine can exert a biochemical effect on the coagulation system. Our studies demonstrate that TNF is able to provide a substantial net procoagulant stimulus to the hemostatic mechanism, and suggest that this cytokine may be a mediator of certain hypercoagulable states in humans.

Blood Coagulation Tests↗