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Biomedical subjects

C M Chesney

Publications and source records attributed to C M Chesney.

At least 19 recordsLinked to original sources
PubMed2000

Effect of niacin, warfarin, and antioxidant therapy on coagulation parameters in patients with peripheral arterial disease in the Arterial Disease Multiple Intervention Trial (ADMIT).

BACKGROUND: Patients with peripheral arterial disease (PAD) have high rates of cardiovascular morbidity and mortality, including that caused by associated coronary heart disease and cerebrovascular disease. Previous studies have shown that coagulation parameters are altered in PAD and that altered coagulation may play a critical role in the susceptibility to cardiovascular complications in PAD. It is therefore important to assess the effect of secondary prevention measures on coagulation in patients with PAD. The Arterial Disease Multiple Intervention Trial (ADMIT), a multicenter, randomized, placebo-controlled trial, was conducted to determine the feasibility of a combined lipid-modifying, antioxidant, and antithrombotic treatment regimen in patients with PAD. The objective of this study was to assess the effect of the ADMIT interventions on coagulation. METHODS: ADMIT participants were randomly assigned to low-dose warfarin, niacin, and antioxidant vitamin cocktail or corresponding placebos in a 2 x 2 x 2 factorial design. Specialized coagulation studies were performed in a subset of 80 ADMIT participants at baseline and after 12 months of treatment. RESULTS: Low-dose warfarin (1 to 4 mg/d) resulted in a significant decrease in factor VIIc (P <.001) and in plasma F1.2 (P =.001). Unexpectedly, niacin treatment also resulted in significant decrease in both fibrinogen (48 mg/dL; P <.001) and F1.2 (P =.04). von Willebrand factor increased after antioxidant vitamin treatment (P =.04). CONCLUSIONS: A regimen of low-dose warfarin effectively modifies coagulation in patients with PAD. Niacin also favorably modifies fibrinogen and plasma F1.2. Niacin, in addition to its lipid effects, modifies abnormal coagulation factors that accompany PAD.

Aged↗
PubMed1990

Intravenous desmopressin acetate in children with sickle trait and persistent macroscopic hematuria.

Persistent gross hematuria associated with sickle hemoglobinopathy that fails to respond to conventional supportive therapy represents a difficult management dilemma. Two such patients with protracted, often painful, sickle trait macrohematuria are described. Both patients had normal renal anatomy and vasculature and had failed to respond to bed rest, intravenous hydration, and a trial of oral epsilon-aminocaproic acid. Patient 1 had normal coagulation function. Patient 2 had von Willebrand disease (decreased factor VIII antigen and quantitative ristocetin cofactor activity). Patient 1 responded to intravenous desmopressin acetate at a dose of 0.3 microgram/kg with a 155% increase in factor VIII clotting activity and a 135% increase in ristocetin cofactor and cessation of her macrohematuria within 18 hours after completion of the desmopressin infusion. She remained free of gross hematuria for 5 months with the exception of short-lived trauma-induced hematuria (in three voids) 6 weeks after desmopressin therapy. Patient 2 did not respond to intravenous desmopressin infusion despite a 234% and a 360% increase in factor VIII clotting activity and ristocetin cofactor, respectively. Intravenous desmopressin acetate may be helpful in halting protracted significant macrohematuria associated with sickle trait hemoglobinopathy in some patients when conventional management fails.

Adolescent↗
PubMed1989

Low-dose aspirin in pregnancy.

In a prospective study, we evaluated the effects of low-dose aspirin on maternal and neonatal plasma 6-keto-prostaglandin (PG) F1 alpha concentration, platelet aggregation, platelet thromboxane production, and neonatal transitional circulation. Forty women, at a mean (+/- SD) of 37 +/- 2 weeks' gestation, were randomized to receive (N = 10 each) placebo or 20, 60, or 80 mg of aspirin per day until delivery. Maternal serum 6-keto-PGF1 alpha levels were not affected by these doses of aspirin, whereas thromboxane B2 generated during clotting of maternal blood was decreased significantly by 60 and 80 mg of aspirin by 1 week of therapy. Maternal platelet thromboxane B2 production in response to adenosine diphosphate or collagen was reduced 98% by the 80-mg dose after 1 week of aspirin therapy. The 60-mg dose reduced maternal platelet thromboxane B2 production in response to adenosine diphosphate (50% decrease) or collagen (60% decrease) after 1 week of treatment, a nonsignificant difference. After 2 weeks of treatment with 60 mg of aspirin, platelet thromboxane B2 production induced by both collagen and adenosine diphosphate was inhibited significantly (P less than .01). Neonatal serum levels of 6-keto-PGF1 alpha and thromboxane B2 were not affected by any doses of aspirin. Further, neonatal platelet aggregation in response to platelet stimulation by collagen and adenosine diphosphate was not inhibited. All neonates had echocardiographic evidence of a patent ductus arteriosus, and noninvasive estimates of pulmonary arterial pressure were similar among the groups of infants.(ABSTRACT TRUNCATED AT 250 WORDS)

Alprostadil↗
PubMed1987

Oral contraceptive steroid induced platelet coagulant hyperactivity: dissociation of in vivo and in vitro effects.

The use of oral contraceptives (OC) has been associated with an increased risk of thromboembolic events in a subset of women. Factors predisposing to this problem are still not clearly defined although an increased platelet coagulant activity (CA) has been reported. This study was designed to evaluate the CA of platelets from asymptomatic current OC users compared with control subjects. The asymptomatic OC users were found to have evidence of hypercoagulability in the form of increased availability of platelet CA. These findings were present in both collagen stimulated and unstimulated platelets. In order to understand the mechanism we examined the in vitro effects of estradiol and/or progesterone on platelets. Platelets from normal males were incubated for one hour with estrogen and/or progesterone. There was no significant difference in CA of hormone treated platelets compared with control platelets from the same donor. CA was analyzed in platelets exposed to epinephrine, adenosine diphosphate, and collagen in the platelet aggregometer. Although a dose dependent effect was observed on CA of platelets exposed to the range of aggregating agents, the results show no significant difference between CA of the hormone treated and control platelets (p greater than 0.05). Likewise, platelet aggregation and release of nucleotide were not different between hormone treated and control platelets. Thus a direct effect of the hormones on platelets is an unlikely mechanism causing the increased CA seen in OC users.

Adult↗
PubMed1987

Triazolobenzodiazepines competitively inhibit the binding of platelet activating factor (PAF) to human platelets.

PAF causes dose dependent platelet aggregation of human platelet rich plasma or gel filtered platelets (GFP). The benzodiazepines alprazolam and triazolam, but not diazepam (1-10 microM), inhibit PAF induced aggregation but have no effect on aggregation induced by other platelet agonists such as ADP, epinephrine and collagen. The IC50 for aggregation by PAF (4 nM) in GFP is 1 microM for both alprazolam and triazolam. The mechanism for this inhibition was explored by studying the binding of 3H-PAF(0.08 nM) to GFP in Tyrodes buffer containing albumin (0.35%), Mg++ (1mM) and Ca++ (0.5mM). GFP was incubated with different doses of the drug for 5 min prior to addition of 3H-PAF. Incubation was then carried out for 60 min at 25 degrees C to achieve binding equilibrium, as previously established. Alprazolam and triazolam, but not diazepam, caused competitive displacement of 3H-PAF from specific binding sites of GFP. The IC50 of alprazolam was 3.8 microM while that of triazolam was 0.82 microM. Lineweaver-Burk plots of 3H-PAF binding in the presence of inhibitor were also consistent with competitive inhibition. These results are consistent with the interpretation that the specific inhibition of PAF induced platelet aggregation by alprazolam and triazolam, respectively, is due to competitive inhibition of binding of PAF to its receptor.

Alprazolam↗
PubMed1987

Involvement of von Willebrand factor in thrombosis following asparaginase-prednisone-vincristine therapy for leukemia.

To determine if factor VIII-von Willebrand factor (vWF) complex is involved in the thrombosis associated with asparaginase-prednisone-vincristine induction therapy for acute lymphoblastic leukemia, plasma vWF was analyzed by sodium dodecyl sulfate-agarose gel electrophoresis and crossed immunoelectrophoresis. Five patients with cerebral thrombosis were studied; all had a decreased platelet count following the complication. Sequential studies of three patients disclosed changes in plasma vWF multimer pattern. One patient who was studied serially from 2 days before to 1 day after the event, had an increase in unusually large plasma vWF multimers that disappeared after the complication. The other two patients who were studied at presentation subsequently showed a decrease in plasma large vWF multimers, especially remarkable in the patient having the sharpest decrease in platelet count. No appreciable difference in vWF multimer pattern, when compared to normal pooled plasma, was found in the remaining two patients who were only studied at presentation, or in the seven controls who received the same treatment but did not develop thrombosis. Crossed immunoelectrophoretic analyses of two patients tested disclosed a right shift of immunoprecipitin line in one and a left shift in the other. Our findings suggest that the thrombotic complications resulted from platelet agglutination by plasma vWF.

Acute Disease↗
PubMed1986

Lack of pathogenetic role of proteins C and S in thrombosis associated with asparaginase-prednisone-vincristine therapy for leukaemia.

Plasma levels of protein C and protein S antigens were measured in eight children who developed thrombosis following asparaginase-prednisone-vincristine treatment for acute lymphoblastic leukaemia and in nine similarly treated children without this complication. Protein C antigen levels were below normal in three of the eight patients with thrombosis and in three of the nine patients without the complication (P = 0.38). Low protein S antigen levels were found in five of six patients with thrombosis and in two of seven patients without thrombosis (P = 0.10). Plasma factor IX and factor X antigen levels, other vitamin K dependent factors, were also measured in the two groups of patients. In general, reduced levels of protein C, protein S or both antigens (anticoagulant vitamin K dependent proteins) were associated with reduced levels of factor IX, factor X, or both of these factors (procoagulant vitamin K dependent clotting proteins). The ratios of protein C and protein S antigens to each other and to factor IX and factor X antigens did not differ between the two groups. Thus, there is no clear evidence that reduced levels of protein C and (or) protein S cause thrombosis in leukaemia patients treated with this drug combination.

Adolescent↗
PubMed1986

Mitral valve prolapse in women with oral contraceptive-related cerebrovascular insufficiency. Associated persistent hypercoagulable state.

We examined a group of former oral contraceptive (OC) users, who had experienced cerebrovascular insufficiency, for the presence of hypercoagulable states. We found hypercoagulability in this group in the form of decreased plasma antithrombin III activity, increased platelet coagulant activity, and elevated plasma beta-thromboglobulin level. Certain characteristics (cigarette smoking, vascular headache, hyperlipidemia, and mitral valve prolapse) were encountered with increased frequency among former OC users who had experienced cerebrovascular insufficiency. The association of mitral valve prolapse with OC-related cerebrovascular insufficiency was particularly striking. We propose that preexisting hypercoagulable states, such as may exist in a subset of individuals with mitral valve prolapse, will magnify the risk of OC-related cerebrovascular morbidity.

Adult↗
PubMed1985

Desensitization of human platelets by platelet activating factor.

Human platelets are less responsive to PAF at 37 degrees than at 25 degrees. They can be desensitized to the effects of PAF by pre-exposure to small concentrations. In both cases desensitization appears to be accompanied by a decreased affinity of the high affinity site for PAF rather than loss of binding sites. Alteration of a metabolic step subsequent to binding cannot be excluded, but platelets show normal response to a variety of other agents under the conditions resulting in desensitization of platelets to PAF.

Adenosine Diphosphate↗
PubMed1985

Perturbation of protease inhibitors and substrates in inflammatory arthritis.

Defective systemic fibrinolysis and articular persistence of fibrinlike material are well recognized in RA. Perturbation of the major plasma protease inhibitors, A1AT, A2MG, and AT III, was explored in RA, psoriatic arthritis, and Reiter's syndrome. Experimental evidence is presented and assessed with respect to the potential role of serine esterases and their inhibitors in the pathophysiology of inflammatory arthritis.

Adult↗
PubMed1985

Platelet and plasma vasopressin in dog during hydration and vasopressin infusion.

Dog platelets contain a substance immunologically similar to arginine vasopressin. In conscious and anesthetized dogs under basal conditions, platelet immunoreactive vasopressin accounts for approximately 40% of the total circulating immunoreactive vasopressin. When the plasma vasopressin concentration in the anesthetized dog was lowered 75% by intravenous infusion of isotonic dextrose solution for 2 h, the platelets failed to discharge a significant quantity of immunoreactive vasopressin. Subsequently, when the plasma vasopressin concentration was elevated to a level 10-fold greater than the initial levels by intravenous infusion of arginine vasopressin, there was no statistically significant increase in the estimated platelet vasopressin content measured 1 and 2 h after the start of the infusion, although there was the suggestion that the platelets had indeed taken up some vasopressin after 2 h of vasopressin infusion. Thus immunoreactive vasopressin in dog platelets does not appear to exchange readily with plasma vasopressin. The physiological role of platelet immunoreactive vasopressin remains to be determined.

Animals↗
PubMed1985

Altered von Willebrand factor molecule in children with thrombosis following asparaginase-prednisone-vincristine therapy for leukemia.

Eleven consecutive leukemia patients with thrombosis induced by asparaginase-prednisone-vincristine therapy were studied to gain insight into the pathogenesis of this complication. Measurement of anti-thrombin III, plasminogen, factor V, and fibrin degradation products as well as platelet aggregation sensitivity to adenosine diphosphate disclosed no consistent abnormalities that would explain pathologic thrombus formation. A decrease in platelet counts observed in nine of 11 patients, prompted us to investigate the possible involvement of factor VIII in this disorder. Levels of factor VIII procoagulant activity, von Willebrand factor (vWF) and ristocetin cofactor were similar to findings for an identically treated comparison group who remained free of thrombotic complications. However, qualitative examination of vWF by crossed immunoelectrophoresis (CIE) revealed a distinct right shift of the immunoprecipitin lines in each of three thrombotic patients tested, whereas a normal profile was found in three similarly treated patients without the complication. This altered pattern had reverted to normal when CIE was repeated 2 to 7 months later. We postulate that the abnormal vWF is related to the development of thrombosis.

Adolescent↗
PubMed1985

Subcellular localization of vasopressin-like material in platelets.

It has recently been reported that 90% of circulating vasopressin in humans appears to be in platelets. We have confirmed these results and studied the subcellular localization and secretion of vasopressin from human platelets. Sucrose density gradient analysis showed highest relative specific activity for vasopressin in the membrane fractions. Stirring of platelet-rich plasma with a number of different platelet-aggregating agents including epinephrine, norepinephrine, arachidonic acid, collagen, adenosine diphosphate, A23187, and platelet-activating factor failed to release significant amounts of immunoreactive vasopressin, despite the expected aggregation and secretion of platelet factor 4 by these agents. Thus vasopressin appears to be primarily a platelet membrane component and is not secreted in the usual way by agents modulating platelet function.

Adenosine Diphosphate↗
PubMed1983

The role of platelet factor V in prothrombin conversion.

The contribution of platelet factor V to prothrombin conversion was studied in a purified two-stage system designed to measure the ability of factor V to accelerate prothrombin conversion. When unstimulated gel-filtered platelets (GFP) were substituted for both factor V and phospholipid, thrombin evolution was linear following a long lag time. Gel filtration resulted in considerable phospholipid availability with minimal factor V release. Incubating platelets with collagen in increasing concentrations resulted in marked shortening of the lag time, an increase in the initial rate of thrombin formation, and release of platelet factor V. The inhibition of thrombin formation by preincubation of the platelets with metabolic inhibitors is consistent with previous observations that factor V is released from alpha-granules by collagen in a process requiring metabolic energy. Released platelet factor V added to metabolically inhibited platelets reproduces the acceleration of prothrombin conversion demonstrated in GFP incubated with collagen. Furthermore no acceleration of the clotting time at collagen concentrations used in this study was demonstrated in an assay designed to measure available platelet phospholipid in the presence of excess factor V. The rate of increased thrombin generation produced by collagen stimulation is primarily due to released platelet factor V in the system employed.

Animals↗
PubMed1983

Reevaluation of the role of the polar groups of collagen in the platelet-collagen interaction.

Chemical modification of collagen is a tool for exploring the platelet-collagen interaction. Since collagen must polymerize prior to the initiation of platelet aggregation and secretion, modification must be shown to affect platelet-collagen interaction and not collagen-collagen interaction. To address this point, the authors carried out the following chemical modifications on soluble monomeric collagen and preformed fibrillar collagen in parallel: 1) N-and O-acetylation, 2) esterification of the carboxyl groups, 3) succinylation of the free amino groups, 4) esterification of succinylated collagen. Intrinsic viscosity studies of the modified soluble collagens were consistent with normal triple helix conformation. Electron microscopy revealed all modified fibrillar collagen to maintain a fibrillar structure. Platelet aggregation and secretion of 14C-serotonin and platelet factor 4 by soluble and fibrillar collagen, respectively, were studied in human platelet-rich plasma. Neutralization of polar groups by 1) totally abolished aggregation and secretion by both collagens, while blocking acidic groups 2) resulted in enhanced aggregation and secretion by both soluble and fibrillar collagen. Blockage of amino groups by 3) abolished aggregation and secretion by both collagens. Esterified succinylated collagen 4) caused aggregation and secretion at relatively high collagen concentrations. These data support the theory that positive groups of collagen are important in platelet-collagen interaction.

Acetylation↗