Ticlopidine, Alka-Seltzer, or a combination of citric acid with aspirin: effects on platelet aggregation in individuals with an insufficient response to aspirin alone.

Aspirin (ASA) does not effectively lower platelet aggregation in all people. The platelet aggregation (PA) score is an easily used clinical method for measuring the effect in individuals of antiplatelet medications. Fifteen apparently healthy subjects (2 men and 13 women), selected for their resistance to ASA's antiaggregation effect, completed a sequential trial of ticlopidine, Alka-Seltzer, and ASA + citric acid (CTA). Ticlopidine was the strongest aggregation inhibitor and the ASA + CTA combination was more inhibitory than Alka-Seltzer. It was determined that measuring antiaggregation effects of a particular agent in an individual prior to usage would optimize treatment. The PA score methodology provides a means for testing patients prior to antiplatelet therapy for prevention and treatment of the thrombotic complications of vascular disease.

Platelet aggregometry can accurately predict failure of externally supported knitted Dacron femoropopliteal bypass grafts.

PURPOSE: Our purpose was to evaluate whether a method for quantification of platelet aggregability will predict failure of knitted Dacron femoropopliteal bypass grafts. METHODS: A numerically derived platelet aggregation (PA) score, based on the aggregation pattern and platelet count, was determined in the 40 patients available for platelet analysis who underwent 53 femoropopliteal bypass grafts with preclotted, 6 mm, externally supported knitted Dacron grafts from 1981 to 1991 (mean follow-up 50 months). The preoperative score was found to remain stable after surgery, enabling the use of postoperative values when preoperative values were not available. The PA score was available in 19 patients (23 grafts) before surgery and 23 patients (30 grafts) after surgery. The following factors were analyzed for predicting graft failure by the Cox proportional hazards regression model: PA score, age, gender, history of smoking, coronary artery disease, hypertension, hyperlipidemia, cerebrovascular disease, diabetes, claudication versus limb salvage, site of the distal anastomosis, previous ipsilateral bypass, and state of the runoff as determined by preoperative angiography. RESULTS: Of the studied risk factors, the value of the PA score was the most significant predictor of graft closure (p < 0.0001). An increase of 10 units was associated with an increased relative risk of 2.02. Throughout the follow-up period, 15 of 16 grafts remained patent in patients with a PA score of 15 or less, but only 2 grafts out of 17 remained patent in patients with a PA score of 30 or greater. CONCLUSIONS: These data suggest that the PA score is a potential risk factor for failure of femoropopliteal bypass with externally supported knitted Dacron grafts.

A new combination therapy for selective and prolonged antiplatelet effect: results in the dog.

This study characterizes the effect of dazmegrel, a thromboxane synthetase inhibitor, on platelet function in the dog and introduces its potential use in combination with aspirin therapy. Ex vivo testing of dazmegrel alone was performed with three dosages and three administration regimens. Platelet aggregation response, malondialdehyde formation and prostaglandin metabolites generation were evaluated. To maintain complete thromboxane A2 inhibition, dazmegrel had to be given 3 times per day at dosages of not less than 6 mg/kg. The same result was achieved with a single daily administration of combined dazmegrel and aspirin in equal dosages of 3 mg/kg. Dazmegrel, both alone and with aspirin, increased and sustained heightened levels of prostacyclin, unlike the simultaneous inhibition of both prostaglandin metabolites seen with aspirin therapy alone. Because the combination of dazmegrel and aspirin effectively blocks thromboxane A2 formation and also enhances prostacyclin formation, the synergistic action of these agents increases their combined antiplatelet effect to a level not attainable by either agent alone. The significance of this combined therapy warrants further experimental study and may soon merit clinical trial for the prevention of stroke and other major thrombotic complications.

The effect of predetermined thrombotic potential of the recipient on small-caliber graft performance.

This study was designed to establish the influence of the recipient's thrombotic potential on the patency of small-caliber prostheses and to evaluate the subsequent improvement of graft performance by medicinally altering the prostaglandin balance in subjects predisposed to graft occlusion. Mongrel dogs were pretested and classified as low and high responders according to their thrombotic potential, measured as prostaglandin metabolite balance and platelet aggregability. High responders were randomly divided into two groups. Those assigned to serve as the medicated subjects were pretreated 1 week before surgery with a single oral daily administration of combined dazmegrel (UK-38,485) and aspirin in equal dosages of 3 mg/kg. Medication was continued throughout the experiment. Dacron grafts were implanted bilaterally in the carotid artery site in all subjects. Following a 3-week implantation period, the patency rate for the group with low thrombotic potential was 100%. In the animals with high thrombotic potential the patency rate was 10% for nonmedicated subjects and 100% for medicated subjects. These data support the concept that the thrombotic potential largely determines the capacity of the recipient's blood to thrombose small-caliber prostheses. Effective medicinal alteration of prostaglandin balance results in exceptionally increased patency of synthetic grafts.

Glutaraldehyde preparation of coronary artery bypass bioprostheses.

A method for glutaraldehyde (GA) fixation of canine carotid arteries has been developed for the preparation of small caliber biologic prostheses for coronary artery bypass. The biologic grafts were preserved by a static inflation technique that proved to be more advantageous than the standard stenting method. The most suitable static inflation pressure was found to be 120 mm Hg. By means of colorimetric measurements the minimal tanning time and the amount of GA required for complete fixation for canine vascular tissue were established. Stabilization of the vessel collagen and confirmation of GA-collagen cross-linking were verified by evaluation of the elastic properties and shrinkage temperature of the grafts. Stress-strain measurements were evaluated to determine the number of cross-links introduced in the vascular tissue by GA. This number was shown to be proportional to the inflation pressure. Ethyl alcohol was chosen as the storage solution because it maintained the best physical, chemical, and histologic characteristics of the grafts. Biological evaluations were performed with carotid implants that were examined following acute low flow studies and implantations up to 112 days. All implantations have yielded 100% patencies.

Aspirin therapy in small-caliber arterial prostheses: long-term experimental observations.

To study the therapeutic effects of 3 mg/kg aspirin given at the time of surgery and postoperatively, Dacron carotid grafts with an internal diameter of 4 mm and a length of 6 cm were implanted bilaterally in mongrel dogs. Sixteen control grafts in eight subjects and 20 grafts in 10 subjects treated with aspirin were followed by serial angiograms until consecutive studies showed stable patency rates in both groups. Platelet aggregations, malondialdehyde production, serum salicylate levels, and thromboxane A2 and prostacyclin secretion (measured as thromboxane B2 and 6-keto-prostaglandin F1 alpha) were monitored prior to and throughout the experiment. Surface mapping, indium-111 uptake, factor VIII-related antigen staining, and scanning and transmission electron microscopy were performed on the grafts at sacrifice. This study demonstrates a protective effect on the early patency of small-caliber prostheses in the canine model with daily oral aspirin administration. The degree and duration of this effect depends on the preoperative baseline ratio of thromboxane to prostacyclin in each subject.