A. Strano

Thromboxane Biosynthesis and Platelet Function in Type II Diabetes Mellitus

It has been suggested that platelet hyperreactivity in patients with diabetes mellitus is associated with increased platelet production of thromboxane. We therefore compared the excretion of a thromboxane metabolite and platelet function in 50 patients with Type II diabetes mellitus who had normal renal function and clinical evidence of macrovascular disease and in 32 healthy controls. The mean (+/- SD) excretion rate of urinary 11-dehydro-thromboxane B2 was significantly higher in the patients than in the controls (5.94 +/- 3.68 vs. 1.50 +/- 0.79 nmol per day; P less than 0.001), irrespective of the type of macrovascular complication. Tight metabolic control achieved with insulin therapy reduced the levels of 11-dehydro-thromboxane B2 by approximately 50 percent. The fractional conversion of exogenous thromboxane B2 (infused at a rate of 4.5, 45.3, or 226.4 fmol per kilogram of body weight per second) to urinary 11-dehydro-thromboxane B2 was assessed in four patients, in whom it averaged 5.4 +/- 0.1 percent; this value did not differ from that measured in healthy subjects. Aspirin in low doses (50 mg per day for seven days) reduced urinary excretion of the metabolite by approximately 80 percent in four patients. The fact that thromboxane biosynthesis recovered over the following 10 days was consistent with a platelet origin of the urinary metabolite.(ABSTRACT TRUNCATED AT 250 WORDS)

Double-Blind, Crossover Study of the Clinical Efficacy and the Hemorheological Effects of Pentoxifylline in Patients With Occlusive Arterial Disease of the Lower Limbs

The effect of a 3 month daily administration of 800 mg pentoxifylline (Trental 400 bds) or placebo was assessed under double blind crossover design in 18 patients (12 males and 6 females) with peripheral occlusive arterial disease in respect of painfree walking distance and various hemorheological and hemostasiological variables, platelet aggregation, serum cholesterol and triglycerides. In first treatment period walking distance significantly increased with pentoxifylline by 46% from baseline 121 ± 15 m and by 4% with placebo from baseline 134 ± 18 m. Pentoxifylline administration furthermore yielded significant decrease in whole blood and plasma viscosity and significant increase in erythrocyte deformability. This was paralleled by distinct reduction of fibrinogen, platelet aggregation and euglobuline lysis time, also plethysmographic variables showed positive changes pointing to improvement of limb perfusion. The results of the study suggest that treatment of peripheral occlusive vascular disease by a drug improving blood fluidity through correction of hemorheological and hemostasiological factors turns especially promising and beneficial since the action centers finally on the languishing microcirculation in the ischemic tissue.

Thromboxane B2 formation and platelet sensitivity to prostacyclin in insulin-dependent and insulin-independent diabetics.

TxB2 formation in PRP after thrombin stimulus, serum TxB2 and platelet sensitivity to prostacyclin and the correlation with ambient fasting plasma glucose and lipoproteins were determined in 20 insulin-independent diabetics (IID) with macroangiopathy, 10 insulin-dependent diabetics (IDD) with microangiopathy and 30 matched controls. Platelets obtained from insulin-independent diabetics synthetize significantly higher amounts of TxB2 than those of insulin-dependent diabetics and matched controls. IDD and IID patients required significantly higher concentrations of prostacyclin (p less than 0.001) for a similar degree of platelet aggregation inhibition. The amount of prostacyclin required for 50% platelet aggregation inhibition was correlated with fasting plasma glucose (r = 0.64, p less than 0.001) and HbA1% (r = 0.48, p less than 0.01) in all diabetic subjects. We conclude that: 1) only PRP, obtained from some insulin-independent diabetics with a concomitant macroangiopathy, shows an increased synthesis of TxB2; 2) platelet sensitivity to prostacyclin is highly dependent on the fasting ambient plasma glucose.

Enhanced Platelet Release Reaction in Insulin-Dependent and Insulin-Independent Diabetic Patients

Plasma beta thromboglobulin (BTG) and platelet factor 4 (PF4) levels were measured and correlated with plasma lipid and lipoprotein patterns in 20 insulin-independent diabetics, in 10 insulin-dependent diabetics and in 30 healthy controls matched to patients as to age, sex and weight. Increased plasma BTG and PF4 levels both in insulin-dependent and in insulin-independent diabetics indicate enhanced in vivo platelet activation and release reaction in these patients. No difference in BTG and PF4 values between these two groups of diabetic patients was observed in our study. A marked correlation between plasma PF4 values and plasma glucose levels was shown in insulin-dependent diabetics only whereas a significant positive correlation with plasma triglycerides and plasma triglyceride VLDL and a negative correlation with cholesterol-HDL was shown in insulin-independent diabetics.

Clinical Evaluation of Short-Term Defibrotide Treatment of Patients with Atherosclerosis obliterans of the Lower Limbs

Ten patients with atherosclerosis obliterans of the lower limbs (Fontaine stage IV) were studied under basal conditions during and after short-term administration of defibrotide (800 mg/day intravenously from day 1 to 10 and then 400 mg/day intramuscularly from day 11 to 30). The clinical effectiveness of defibrotide was evaluated not only clinically (subjective and objective symptomatology) but also by Doppler velocimetry (Windsors Index (WI] and primary antiplasmin activity. Seven patients (70%) showed improvement in subjective and objective symptomatology. There were increases in WI at the end of intravenous treatment in 6 patients (60%). In the remaining 40%, WI did not change from basal values. All patients showed normalization of primary antiplasmin activity versus basal values (55.62%, 17.75 SD) at the end of both intravenous and intramuscular treatment (101.37%, 15.71 SD and 102.5%, 13.86 SD, respectively). Therefore, we think that defibrotide may be useful for therapy of atherosclerosis obliterans of the lower limbs.

Platelet Function Changes in Acute Myocardial Infarction

Whether the thrombotic component of myocardial infarction is primary or secondary in a given patient, platelet function alterations can influence many mechanisms — operating at the microenvi-ronmental level — from which it depends if the thrombotic lesion grows or sends platelet emboli to the smaller myocardial vessels.

Platelet Activity and Blood Lipid Changes in Diabetes Mellitus

An altered platelet function can often be found in diabetes mellitus (2, 3, 4, 10, 13, 16, 17, 23, 24). Several studies have pointed towards an increased sensitivity of platelets to ADP induced aggregation (3, 6, 23) in diabetic patients; this phenomenon can also be found in diabetics without apparent vasculopathy and in subjects with altered glucose tolerance (3, 23).

PLATELET THROMBOXANE SYNTHESIS IN TREATED CHILDHOOD DIABETES MELLITUS

TXB2 formation in PRP after thrombin or arachidonic acid stimulation was determined in 23 young compensated insulin-dependent diabetic patients, and in 10 control subjects of equivalent age. No significant difference in TXB2 synthesis during the times sampled was observed. Six out of 23 diabetics had circulating immune complexes (CIC) in their sera as detected by the C1q-SP; after the addition of arachidonic acid and thrombin the amount of TXB2 in PRP from CIC-positive patients was significantly higher than in PRP from CIC-negative patients. The increased synthesis of PG endoperoxides in CIC-positive patients could be a direct effect of antigen-antibody complexes on platelets.

Platelet Aggregation, Coagulation and Fibrinolysis at Rest and after Bicycle Ergometer Test in CHD

Several observers have suggested that a dysfunction of dynamic balance between platelet aggregation, coagulation and fibrinolysis may be a factor in the pathogenesis of atherosclerosis. This dysfunction, presumably, is correlated with the atherosclerotic vascular lesions, that could reduce the parietal synthesis of heparan-sulphase, prostacyclin and plas minogen activator.

Hemostatic Alterations in Peripheral Arteriopathies

The most common cause of obliterative disease in limb arteries is slowly progressive arteriosclerosis which is eventually superimposed by thrombosis.