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Biomedical subjects

G Davì

Publications and source records attributed to G Davì.

At least 37 records · Page 2Linked to original sources
PubMed2000

Oxidant stress and aspirin-insensitive thromboxane biosynthesis in severe unstable angina.

BACKGROUND: Unstable angina is associated with enhanced lipid peroxidation and reduced antioxidant defenses. We have previously reported aspirin failure in the suppression of enhanced thromboxane (TX) biosynthesis in a subset of episodes of platelet activation in this setting. We tested the hypothesis that the in vivo formation of the F(2)-isoprostane 8-iso-prostaglandin (PG)F(2alpha), a bioactive product of arachidonic acid peroxidation, is enhanced in unstable angina and contributes to aspirin-insensitive TX biosynthesis. METHODS AND RESULTS: Urine samples were obtained from patients with unstable angina (n=32), stable angina (n=32), or variant angina (n=4) and from 40 healthy subjects for the measurement of immunoreactive 8-iso-PGF(2alpha) and 11-dehydro-TXB(2). 8-Iso-PGF(2alpha) excretion was significantly higher in patients with unstable angina (339+/-122 pg/mg creatinine) than in matched patients with stable angina (236+/-83 pg/mg creatinine, P:=0.001) and control subjects (192+/-71 pg/mg creatinine, P:<0.0001). In patients with unstable angina, 8-iso-PGF(2alpha) was linearly correlated with 11-dehydro-TXB(2) excretion (rho=0.721, P:<0.0001) and inversely correlated with plasma vitamin E (rho=-0.710, P:=0. 004). Spontaneous myocardial ischemia in patients with variant angina or ischemia elicited by a stress test in patients with stable angina was not accompanied by any change in 8-iso-PGF(2alpha) excretion, thus excluding a role of ischemia per se in the induction of increased F(2)-isoprostane production. CONCLUSIONS: These findings establish a putative biochemical link between increased oxidant stress and aspirin-insensitive TX biosynthesis in patients with unstable angina and provide a rationale for dose-finding studies of antioxidants in this setting.

Angina, Unstable↗
PubMed2000

Effects of vitamin E supplementation on F(2)-isoprostane and thromboxane biosynthesis in healthy cigarette smokers.

BACKGROUND: Increased formation of 8-iso-prostaglandin (PG) F(2alpha) and thromboxane (TX) A(2), potent agonists of platelet and vascular thromboxane (TH)/PGH(2) receptors, has been detected in cigarette smokers. We performed a randomized, double-blind, placebo-controlled study of the effects of vitamin E (300, 600, and 1200 mg/d, each dose for 3 consecutive weeks) on 8-iso-PGF(2alpha) and TXA(2) biosynthesis in 46 moderate cigarette smokers. METHODS AND RESULTS: Urinary immunoreactive 8-iso-PGF(2alpha) and 11-dehydro-TXB(2), plasma vitamin E, and serum TXB(2) were measured by previously validated techniques. Baseline urinary 8-iso-PGF(2alpha) and 11-dehydro-TXB(2) excretion averaged 241+/-78 and 430+/-293 pg/mg creatinine, respectively. Urinary 8-iso-PGF(2alpha) was significantly correlated with 11-dehydro-TXB(2) (r=0.360, n=138, P<0.0001). Baseline plasma vitamin E levels averaged 20.6+/-4.9 micromol/L and were inversely correlated with urinary 11-dehydro-TXB(2) (r=-0.304, P=0.039) but not with 8-iso-PGF(2alpha) (r=-0.227, P=0.129). Vitamin E supplementation caused a dose-dependent increase in its plasma levels that reached a plateau at 600 mg (42.3+/-11.2 micromol/L, P<0. 001). This was not associated with any statistically significant change in urinary 8-iso-PGF(2alpha) or 11-dehydro-TXB(2) excretion. CONCLUSIONS: Supplementation with pharmacological doses of vitamin E has no detectable effects on lipid peroxidation and thromboxane biosynthesis in vivo in healthy subjects with a mild degree of oxidant stress. These findings are consistent with the hypothesis that the basal rate of lipid peroxidation is a major determinant of the response to vitamin E supplementation and have implications for the use of vitamin E in healthy subjects as well as for the design and interpretation of clinical trials of antioxidant intervention.

Adult↗
PubMed2000

In vivo lipid peroxidation and platelet activation in cystic fibrosis.

F(2)-isoprostanes are bioactive peroxidation products of arachidonic acid whose urinary excretion provides an index of lipid peroxidation in vivo. We tested the hypothesis that formation of F(2)-isoprostanes is altered in patients with cystic fibrosis and contributes to platelet activation and pulmonary dysfunction in this setting. The urinary excretion of immunoreactive 8-iso-prostaglandin F(2alpha) (PGF(2alpha)) was significantly (p = 0.0001) higher in 36 patients with cystic fibrosis than in 36 age-matched healthy subjects: 618 +/- 406 versus 168 +/- 48 pg/mg creatinine. The urinary excretion of immunoreactive 11-dehydro-thromboxane B(2) (TXB(2)), an index of in vivo platelet activation, was also significantly (p = 0.0001) higher in patients than in control subjects: 2,440 +/- 1,453 versus 325 +/- 184 pg/mg creatinine. The excretion rate of 8-iso-PGF(2alpha) was correlated with that of 11-dehydro-TXB(2) (rho = 0.51; p = 0.0026) and inversely related to FEV(1) (rho = -0.40; p = 0.0195). Urinary 8-iso-PGF(2alpha) excretion was largely unaffected during cyclooxygenase inhibition with low-dose aspirin, nimesulide, or ibuprofen, consistent with a noncyclooxygenase mechanism of F(2)-isoprostane formation in cystic fibrosis. Increased vitamin E supplementation (from 200 to 600 mg/d) was associated with statistically significant (p = 0.005) reductions in urinary 8-iso-PGF(2alpha) and 11-dehydro-TXB(2) excretion, by 42% and 29%, respectively. We conclude that enhanced lipid peroxidation is an important feature of cystic fibrosis and may contribute to persistent platelet activation and pulmonary dysfunction via generation of bioactive isoeicosanoids. Our results provide a rationale for reassessing the adequacy of vitamin E supplementation in this setting.

Adolescent↗
PubMed2000

Fluvastatin reduces soluble P-selectin and ICAM-1 levels in hypercholesterolemic patients: role of nitric oxide.

BACKGROUND: Lipid-lowering therapy with 3-hydroxy-3-methylglutaryl-coenzymeA (HMG-CoA) reductase inhibitors reduces the incidence of atherosclerosis-related cardiovascular events. Adhesion molecules, regulating interactions between vascular and circulating cells, may play a central role in the pathogenesis of atherosclerosis and related complications. In the present report we examined the impact of the HMG-CoA reductase inhibitor fluvastatin on plasma levels of P-selectin and ICAM-1. METHODS: Plasma levels of P-selectin and ICAM-1 were determined using an enzyme immunoassay in 26 patients with type IIa hypercholesterolemia randomized to treatment with either fluvastatin (80 mg/d) or placebo in a double blind fashion for 12 weeks. RESULTS: Fluvastatin administration reduced either P-selectin (118 +/- 63 vs 81 +/- 36 ng/mL [-31%], P = 0.0015) or ICAM-1 (264 +/- 75 vs 228 +/- 68 ng/mL [-13.7%], P = 0.0033) levels. Fluvastatin also lowered urinary 11-dehydro-TXB2 (1396 +/- 536 vs 1009 +/- 378 pg/mg creatinine [-27%], P = 0.0015) and von Willebrand Factor levels (1456 +/- 716 vs 1203 +/- 527 U/L [-17.4%], P = 0.0275), and a direct correlation was observed between P-selectin and 11-dehydro-TXB2 levels (r = 0.588, P = 0.0033). Patients treated with fluvastatin displayed an increase in nitric oxide (NO) generation, evaluated with measurements of serum NO2-/NO3-, (4.7 +/- 1 vs 8.9 +/- 3.1) mumol/L [98%], P = 0.0046). Moreover, an inverse correlation was observed between NO2-/NO3- and P-selectin (r = -0.420; P = 0.0343), 11-dehydro-TXB2 (r = -0.511; P = 0.0106), or LDL (r = -0.742; P = 0.0002) levels. CONCLUSIONS: These results may provide novel biochemical basis for the beneficial clinical effects of HMG-CoA reductase inhibitors in hypercholesterolemia.

Adult↗
PubMed1999

In vivo formation of 8-iso-prostaglandin f2alpha and platelet activation in diabetes mellitus: effects of improved metabolic control and vitamin E supplementation.

BACKGROUND: Diabetes mellitus (DM) is associated with enhanced lipid peroxidation and persistent platelet activation. We tested the hypothesis that the in vivo formation of the F2-isoprostane 8-iso-prostaglandin (PG)F2alpha, a bioactive product of arachidonic acid peroxidation, is enhanced in DM and contributes to platelet activation. METHODS AND RESULTS: Urine samples were obtained from 85 diabetic patients and 85 age- and sex-matched healthy subjects for measurement of immunoreactive 8-iso-PGF2alpha and 11-dehydro-thromboxane B2 (TXM), an in vivo index of platelet activation. Sixty-two had non-insulin-dependent (NID)DM, and 23 had insulin-dependent (ID) DM. Vitamin E supplementation, metabolic control, and cyclooxygenase inhibitors were used to investigate the mechanisms of formation of 8-iso-PGF2alpha in this setting. Urinary 8-iso-PGF2alpha excretion was significantly higher (P=0.0001) in NIDDM patients (419+/-208 pg/mg creatinine; range 160 to 1014) than in age-matched control subjects (208+/-92; 41 to 433). Urinary 8-iso-PGF2alpha was linearly correlated with blood glucose and urinary TXM. 8-iso-PGF2alpha excretion was also significantly (P=0. 0001) higher in IDDM patients (400+/-146; 183 to 702) than in control subjects (197+/-69; 95 to 353). Vitamin E supplementation (600 mg/d for 14 days) was associated with a statistically significant reduction in both urinary 8-iso-PGF2alpha (by 37%) and TXM (by 43%) in 10 NIDDM patients. Improved metabolic control was associated with a significant (P=0.0001) reduction in 8-iso-PGF2alpha and TXM excretion by 32% and 41%, respectively, in 21 NIDDM patients. 8-iso-PGF2alpha was unchanged after 2-week dosing with aspirin and indobufen despite profound suppression of TXM excretion. CONCLUSIONS: We conclude that DM is associated with increased formation of F2-isoprostanes, as a correlate of impaired glycemic control and enhanced lipid peroxidation. This may provide an important biochemical link between impaired glycemic control and persistent platelet activation. These results provide a rationale for dose-finding studies of antioxidant treatment in diabetes.

Adult↗
PubMed1999

Determinants of enhanced thromboxane biosynthesis in patients with systemic lupus erythematosus.

OBJECTIVE: To evaluate the rate of thromboxane biosynthesis in patients with systemic lupus erythematosus (SLE), exploring the interplay between antiphospholipid antibodies (aPL) and 2 markers of endothelial perturbation: thrombin generation and platelet activation. METHODS: A comparison of 11-dehydrothromboxane B2 (TXB2) excretion, which is a marker of in vivo platelet activation, aPL, von Willebrand factor (vWF) and tissue plasminogen activator (tPA), which are 2 circulating markers of endothelial perturbation, and plasma levels of the prothrombin fragment F1+2, which is a marker of thrombin generation, was performed in 40 SLE patients and 40 healthy subjects. Thromboxane metabolite excretion was also measured in 8 SLE patients before and after treatment with low-dose aspirin. RESULTS: SLE patients had significantly higher 11-dehydro-TXB2 excretion, plasma F1+2, vWF, and tPA levels than controls. A statistically significant correlation was found between plasma levels of vWF and tPA and excretion of thromboxane metabolite. Moreover, significantly higher 11-dehydro-TXB2 was found in patients with aPL positivity and endothelial perturbation. Low-dose aspirin suppressed 11-dehydro-TXB2 by 80%, suggesting a predominant platelet source of enhanced thromboxane biosynthesis. After a median followup of 48 months, all SLE patients who experienced major cardiovascular events had thromboxane metabolite excretion, aPL positivity, and signs of endothelial perturbation. CONCLUSION: We have characterized a sensitive marker of platelet activation, which is abnormal in SLE patients who were positive for aPL and endothelial perturbation. This analytical approach may help identify those patients at increased risk of thrombosis as potential candidates for antiplatelet therapy.

Adult↗
PubMed1998

Increased levels of soluble P-selectin in hypercholesterolemic patients.

BACKGROUND: Hypercholesterolemia is considered a major risk factor for the development of atherosclerosis. Enhanced lipid peroxidation and persistent platelet activation can be observed in vivo in hypercholesterolemic patients and may have pathophysiological implications in the occurrence of cardiovascular events. P-selectin may play an important role in the pathogenesis of multicellular events, including atherosclerosis. We studied the impact of hypercholesterolemia and oxidative stress on plasma levels of P-selectin. METHODS AND RESULTS: Plasma levels of P-selectin were measured by means of an enzyme immunoassay in 20 hypercholesterolemic patients with no clinical evidence of cardiovascular disease and in 20 sex- and age-matched normocholesterolemic subjects. Hypercholesterolemic patients had higher levels of P-selectin compared with that of control subjects (98+/-61 versus 56+/-14 ng/mL; P=.001). They also displayed increased von Willebrand Factor (vWF) levels (176+/-22 versus 119+/-12%; P=.0001). A direct correlation was observed between P-selectin and LDL cholesterol levels (p=.453). Administration of vitamin E (600 mg/d for 2 weeks) to hypercholesterolemic patients significantly reduced plasma P-selectin (40%), and an inverse correlation was observed between vitamin E and P-selectin plasma levels (p=-.446). CONCLUSIONS: Hypercholesterolemia is associated with elevated plasmatic P-selectin. Altered oxidative processes leading to endothelial dysfunction and persistent platelet activation may contribute to increased soluble P-selectin levels. P-selectin may be proposed as a marker of endothelial dysfunction in hypercholesterolemic patients.

Cholesterol, LDL↗
PubMed1998

Long-term treatment with the dual antithromboxane agent picotamide decreases microalbuminuria in normotensive type 2 diabetic patients.

Picotamide both inhibits thromboxane synthetase and acts as a thromboxane antagonist at the receptor level. We investigated the long-term effect of picotamide on urinary albumin excretion (UAE) at rest and induced by exercise in 30 type 2 diabetic patients who were normotensive and had microalbuminuria while at rest. The subjects of our study had a mean age of 52.5 +/- 1.6 years, BMI of 28.5 +/- 0.7 kg/m2, diabetes duration of 9.1 +/- 1.8 years, and HbA1c of 7.0 +/- 0.8%. The study was a randomized double-blind placebo-controlled trial. The patients were randomly allocated to receive for 1 year either picotamide, 300 mg, 3 tablets/day, or placebo, 3 tablets/day. The patients were asked to visit our outpatient clinic after 1, 3, 6, 9, and 12 months of treatment. At all times, blood pressure, microalbuminuria at rest, blood glucose, serum creatinine, serum picotamide, and creatinine clearance were measured; at baseline and after 6 and 12 months, all patients underwent submaximal physical exercise. After 6 months of picotamide, baseline and exercise-induced microalbuminuria were significantly decreased (up to one-third) as compared with the baseline and placebo level, with no further drops at month 12 of picotamide treatment. On placebo treatment, UAE at rest and after exercise was slightly increased compared with baseline values. The effects of picotamide occurred without significant side effects or changes in either blood pressure levels or glycometabolic control. Our study is the first long-term intervention trial in type 2 diabetes showing that an antithromboxane agent is able to decrease microalbuminuria, which in this disease is a dual marker of macro- and microangiopathy. Our findings suggest an important role for thromboxane in the pathophysiology of microalbuminuria in diabetes; moreover, we hypothesize that antithromboxane agents may have a place in the treatment/prevention of both macro- and microvascular complications in type 2 diabetic patients.

Administration, Oral↗
PubMed1998

Increased thromboxane metabolites excretion in liver cirrhosis.

An augmented systemic production of thromboxane (TX) A2, as assessed by urinary excretion of the thromboxane metabolites, has been described in severe liver cirrhosis. However, the significance of this finding remains unclear since in liver cirrhosis a number of phenomena i.e. altered hepatic TXA2 metabolism, increased intrasplenic platelet destruction, may affect TXA2 entry into systemic circulation as well as its metabolism. In order to further clarify this, we measured both major enzymatic metabolites of TXB2 in the urine of 44 patients affected by liver cirrhosis, subdivided in three classes on the basis of Child-Pugh criteria. Urinary 11-dehydro-TXB2 and 2,3-dinor-TXB2 were assayed with previously validated RIA techniques. The urinary excretion rate of 11-dehydro-TXB2 was significantly (p = 0.0001) increased in the cirrhotic patients (673.5 pg/mg cr, median) in comparison with the controls (275 pg/mg cr, median) but no significant difference could be demonstrated among the excretion rates of the three patient subgroups. The excretion rate of 2,3 dinor-TXB2 was also significantly (p = 0.0001) increased in the patients (824 pg/mg cr, median) in comparison with controls (175 pg/mg cr, median), with a significant (p < 0.05) increase from class A (381 pg/mg cr) to class C (1337 pg/mg cr). The sum of the two enzymatic metabolites was significantly (p = 0.0001 ) increased in the cirrhotic patients in comparison to controls, with a progressive increase from class A (1003 pg/mg cr, median) to class C (2240 pg/mg cr, median). The urinary excretion of 2,3 dinor-TXB2 was significantly (p = 0.008) related to plasma prothrombin fragment 1+2 (F1+2). This study provides further evidence of increased thromboxane biosynthesis in liver cirrhosis. Moreover, we demonstrate intraliver shift of thromboxane metabolic disposition, due to progressive liver decompensation, because only the fraction undergoing beta-oxidation to 2,3-dinor-TXB2 was progressively increased with the degree of liver failure. We, also, find a significant correlation between urinary excretion of 2,3-dinor-TXB2 and plasma F1+2, suggesting that clotting activation could partly account for in vivo platelet activation.

Adult↗
PubMed1997

Diabetes mellitus, hypercholesterolemia, and hypertension but not vascular disease per se are associated with persistent platelet activation in vivo. Evidence derived from the study of peripheral arterial disease.

BACKGROUND: Previous studies relating increased thromboxane (TX) biosynthesis to cardiovascular risk factors do not answer the question whether platelet activation is merely a consequence of more prevalent atherosclerotic lesions or reflects the influence of metabolic and hemodynamic disturbances on platelet biochemistry and function. METHODS AND RESULTS: We examined 64 patients with large-vessel peripheral arterial disease and 64 age- and sex-matched control subjects. TXA2 biosynthesis was investigated in relation to cardiovascular risk factors by repeated measurements of the urinary excretion of its major enzymatic metabolite, 11-dehydro-TXB2, by radioimmunoassay. Urinary 11-dehydro-TXB2 was significantly (P = .0001) higher in patients with peripheral arterial disease (57 +/- 26 ng/h) than in control subjects (26 +/- 7 ng/h). Seventy percent of patients had metabolite excretion > 2 SD above the normal mean. However, 11-dehydro-TXB2 excretion was enhanced only in association with cardiovascular risk factors. Multivariate analysis showed that diabetes, hypercholesterolemia, and hypertension were independently related to 11-dehydro-TXB2 excretion. During a median follow-up of 48 months, 8 patients experienced major vascular events. These patients had significantly (P = .001) higher 11-dehydro-TXB2 excretion at baseline than patients who remained event free. CONCLUSIONS: The occurrence of large-vessel peripheral arterial disease per se is not a trigger of platelet activation in vivo. Rather, the rate of TXA2 biosynthesis appears to reflect the influence of coexisting disorders such as diabetes mellitus, hypercholesterolemia, and hypertension on platelet biochemistry and function. Enhanced TXA2 biosynthesis may represent a common link between such diverse risk factors and the thrombotic complications of peripheral arterial disease.

Adult↗
PubMed1997

Enhanced thromboxane biosynthesis in patients with chronic obstructive pulmonary disease. The Chronic Obstructive Bronchitis and Haemostasis Study Group.

Thrombotic complications of pulmonary circulation occur in patients with chronic obstructive pulmonary disease (COPD). In the present study, we sought to evaluate in vivo platelet activation through the measurement of 11/dehydro-thromboxane (Tx) B2 TxA2 major metabolite in the urine, in 29 patients with COPD, compared with 29 sex- and age-matched healthy subjects. The urinary excretion of 11-dehydro-TxB2 was significantly higher in patients with COPD than in control subjects: median (range), 753 (277-4,409) and 275 (129-612) pg/mg creatinine, respectively; p < 0.0001). Moreover, 11-dehydro-TxB2 excretion was inversely related with arterial oxygen tension (rho = -0.46; p = 0.0145). In five of the 29 patients a short-term therapeutic course with oxygen supplementation induced a significant decrease of urinary 11-dehydro-TxB2 excretion: median range, 941 (452-2,640) to 445 (166-1,560) pg/mg creatinine. Moreover, selective inhibition of platelet cyclooxygenase activity by low-dose aspirin was associated with more than 90% inhibition of thromboxane metabolite excretion, demonstrating its being of platelet origin. Plasma levels of prothrombin fragment F1 + 2 were higher in patients than in control subjects (2.6 +/- 1.5 versus 0.9 +/- 0.4 nM, p = 0.0001). No relation between 11-dehydro-TxB2 excretion and plasma F1 + 2 levels was found. We conclude that platelet TxA2 biosynthesis is enhanced in patients with COPD and may be influenced by arterial oxygen tension changes.

Aged↗
PubMed1997

Platelet activation markers in patients with peripheral arterial disease--a prospective comparison of different platelet function tests.

Peripheral vascular disease (PVD) is an indicator of diffuse atherosclerosis and is associated with a greatly increased incidence of coronary heart and cerebrovascular disease. Although several studies have assessed whether in vivo platelet activation takes place in patients with PVD, no data are available comparing different platelet function tests in this patient population. We have compared prospectively four tests for the measurement of in vivo platelet activation (plasma betaTG, plasma PF4, intraplatelet betaTG and urinary excretion of 11-dehydro-TXB2) and one in vitro platelet function test (ADP-induced platelet aggregation) in 63 well-characterized patients with intermittent claudication and in 18 age- and sex-matched healthy volunteers. No statistically significant difference was found between patients and controls for plasma betaTG (20.0 +/- 11.8 vs. 18.8 +/- 9.0 ng/ml, respectively), plasma PF4 (5.2 +/- 2.9 vs. 6.3 +/- 3.5 ng/ml), betaTG/PF4 ratio (4.0 +/- 2.9 vs. 3.6 +/- 1.8), intraplatelet betaTG (4503 +/- 1482 vs. 4059 +/- 1065 ng/ml), and threshold aggregatory concentration of ADP (1.7 +/- 0.72 vs. 1.45 +/- 0.56 microM). Urinary 11-dehydro-TXB2 was instead significantly higher in the PVD group (55.4 +/- 27.5 vs. 26.7 +/- 7.0 ng/h, p <0.001). Our study shows that urinary 11-dehydro-TXB2 is a more sensitive index of in vivo platelet activation than the measurement of either platelet specific proteins or of in vitro platelet aggregation in patients with PVD.

Adenosine Diphosphate↗
PubMed1996

Influence of metabolic control on thromboxane biosynthesis and plasma plasminogen activator inhibitor type-1 in non-insulin-dependent diabetes mellitus.

We have previously shown that tight metabolic control by insulin therapy reduced thromboxane-dependent platelet activation in non-insulin-dependent diabetes mellitus (NIDDM) patients. The present study was undertaken to determine whether a similar effect could be obtained without switching diabetics in secondary failure to insulin treatment. For this purpose, we gave strict diet and exercise advise program and adjusted on a weekly basis the oral antidiabetic therapy (glipizide) that 26 patients with NIDDM had been given over the previous months. Basal measurements of urinary 11-dehydro-TXB2 and PAI-1 confirmed previous findings of enhanced levels of these parameters in NIDDM patients with macrovascular disease in comparison to age- and sex-matched controls. After 2-6 weeks, 16 patients achieved tight metabolic control associated with significant reduction of both thromboxane biosynthesis and PAI-1 levels; 10 patients remained in poor control and no significant decrease of both parameters was observed. We conclude that reduction of in-vivo platelet activation and PAI-1 antigen levels after metabolic improvement obtained by frequent reassessment of sulphonylurea therapy together with strict diet and exercise programs may have beneficial effects on the progression of diabetic micro- and macrovascular disease.

Adult↗
PubMed1995

Inhibition of thromboxane biosynthesis and platelet function by simvastatin in type IIa hypercholesterolemia.

Thromboxane A2 (TXA2) biosynthesis is enhanced in the majority of patients with type IIa hypercholesterolemia. Because simvastatin (a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor) was previously shown to reduce platelet aggregation and TXB2 production ex vivo, we investigated TXA2 biosynthesis and platelet function in 24 patients with type IIa hypercholesterolemia randomized to receive in a double-blind fashion simvastatin (20 mg/d) or placebo for 3 months. The urinary excretion of 11-dehydro-TXB2, largely a reflection of platelet TXA2 production in vivo, was measured by a previously validated radioimmunoassay technique. Blood lipid levels and urinary 11-dehydro-TXB2 excretion were significantly (P < .001) reduced by simvastatin. In contrast, placebo-treated patients did not show any statistically significant changes in either blood lipids or 11-dehydro-TXB2 excretion. The reduction in 11-dehydro-TXB2 associated with simvastatin was correlated with the reduction in total cholesterol (r = .81, P < .0001), LDL cholesterol (r = .79, P < .0001), and apolipoprotein B (r = .76, P < .0001) levels. Platelets from patients with type IIa hypercholesterolemia required significantly (P < .01) more collagen and ADP to aggregate and synthesized less TXB2 in response to both agonists after simvastatin therapy. Bleeding time, platelet sensitivity to Iloprost, and blood lipoprotein(a) and HDL cholesterol levels were not significantly affected by either treatment. We conclude that enhanced TXA2 biosynthesis in type IIa hypercholesterolemia is, at least in part, dependent on abnormal cholesterol levels and/or other simvastatin-sensitive mechanisms affecting platelet function.

Adult↗
PubMed1995

Thromboxane biosynthesis, neutrophil and coagulative activation in type IIa hypercholesterolemia.

Thromboxane (Tx) A2 biosynthesis is enhanced in the majority of patients with type IIa hypercholesterolemia. Because blood clotting activation is an important component of the inflammatory response, involved in the initiation and progression of atherosclerotic plaques, we have investigated TxA2 biosynthesis, neutrophil activation and thrombin generation in 24 patients with type IIa hypercholesterolemia. Urinary 11-dehydro-TxB2, was significantly higher (p = 0.0001) in patients than in 24 sex- and age matched healthy subjects. Similarly, prothrombin fragment 1 + 2 (F1 + 2), thrombin-antithrombin III complexes and plasma elastase were significantly higher in patients than in controls. Urinary 11-dehydro-TxB2 excretion was correlated with plasma elastase (r = 0.758; p = 0.0001), and prothrombin fragment 1 + 2 (r = 0.804; p = 0.001). The enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor simvastatin (20 mg/day for 2 months) significantly reduced cholesterol levels, urinary 11-dehydro-TxB2 excretion, plasma elastase and plasma F1 + 2 in 8 patients. We conclude that type IIa hypercholesterolemia is associated with biochemical evidence of platelet, neutrophil and blood clotting activation. The relationship between these events remains to be investigated.

Adult↗
PubMed1995

Demonstration of Rickettsia Conorii-induced coagulative and platelet activation in vivo in patients with Mediterranean spotted fever.

Endothelial injury in vivo induced by Rickettsia Conorii, the etiologic agent of Mediterranean Spotted Fever (MSF) has been recently demonstrated. We sought to determine whether platelet and/or coagulative activation in vivo can be demonstrated in the acute phase of MSF, through measurements of a major metabolite of thromboxane (TX) in the urine (11-dehydro-TXB2) and of plasma prothrombin fragment 1 + 2, whose levels reflect activation of prothrombin to thrombin. Moreover, we measured plasma endothelin-1 as marker of endothelial dysfunction. Our results provide biochemical evidence for the occurrence of TXA2-dependent platelet activation and thrombin generation in vivo, together with endothelial dysfunction. These phenomena could account for clinical manifestations of MSF, such as vasculitis and focal microthrombus formation. These results could also provide a rationale for testing the efficacy of aspirin or heparin in reducing the prothrombotic status of Rickettsiae diseases.

Acute Disease↗