Microthrombus formation on hemodialysis membranes: a placebo controlled randomized trail of two doses of Indobufen.

The role of Indobufen in preventing the formation of microthrombi on hemodialysis membranes has been investigated in 18 patients in a placebo controlled randomized double-blind cross-over study. All patients had been on regular maintenance hemodialysis for at least 3 months. Indobufen was given as 100 mg b.d. and 200 mg b.d. each for a 7 day period with a 7 day wash-out period between the treatments. Both Indobufen regimens prevented the fall in platelet count, reduced the increase in plasma BTg levels during dialysis, increased the post dialysis plasma heparin levels (p less than 0.05) and inhibited pre-dialysis platelet aggregation with collagen (p less than 0.05), when compared with placebo treatment. Scanning electron microscopy demonstrated minimal fibrin and reduced platelet deposition following Indobufen treatment. There was no difference in the effect of 100 mg b.d. and 200 mg b.d. Indobufen doses. The drug was well tolerated, despite the relatively high levels measured, only one patient withdrew because of side effects. This study indicates that Indobufen when added to a routine hemodialysis treatment schedule, can significantly reduce platelet activation and the thrombus formation on the hemodialysis membranes.

Comparison of the thrombogenicity of four types of knitted Dacron arterial graft in an artificial circulation.

The thrombogenicity of four types of knitted Dacron arterial graft was compared by measuring the effect of each prosthetic graft on human platelet function in an artificial circulation. The grafts examined were plain knitted (Meadox 'Cooley'), knitted double velour (Meadox 'Microvel'), filamentous external velour (U.S.C.I. 'Sauvage Filamentous') and a plain knitted graft with a pyrolytic carbon coating (Meadox 'Carboknit'). Platelet count, adhesion and percentage aggregation were all decreased during perfusion. The greatest changes in these parameters were produced by the filamentous velour graft and the least by the carbon coated graft. Electron microscopy demonstrated significantly more platelets adherent to the filamentous graft (rho less than 0.01) with changes in platelet morphology indicating activation. These results suggest that the filamentous graft is more thrombogenic than the other grafts.

Prevention of platelet deposition and thrombus formation on hemodialysis membranes: a double-blind randomized trial of aspirin and dipyridamole.

A double-blind crossover study comparing low-dose aspirin (ASA) and dipyridamole (DPM) (100 mg ASA + 75 mg DPM, t.d.s.), high-dose ASA and DPM (300 mg ASA + 75 mg DPM, t.d.s.), and placebo on platelet deposition and thrombus formation on hemodialysis membranes was undertaken in 17 long-term dialysis patients. The high-dose combination significantly reduced the fall in platelet count during dialysis and also significantly increased postdialysis heparin concentrations. Scanning electron microscopy of the Cuprophan membranes showed a reduction in platelet deposition and fibrin formation during both treatment schedules, but this was most marked with the high-dose combination. The results of this study indicate that there is a graded response to combined ASA-DPM treatment and that this can significantly reduce platelet consumption and contact activation of fibrin during hemodialysis with Cuprophan membranes.

Antithrombotic therapy for vascular prosthesis: an experimental model testing platelet inhibitory drugs.

Although Dacron vascular grafts are widely used, they are thrombogenic and rapid blood flow maintains patency. When blood flow is suboptimal, antithrombotic therapy may prevent early occlusion. We evaluated the effect of three platelet inhibitory drugs: acetylsalicylic acid (ASA), dipyridamole (DPM), sulphinpyrazone (SPZ), and a combination of ASA plus DPM on platelet adherence to woven Dacron in an artificial circulation. Heparinized blood from 18 volunteers was divided equally for test and control circuits, and to the test each drug was added in therapeutic concentration. The experiment was repeated ex vivo using blood donated by six volunteers after each had taken, separately for 1 week: (1) no drug; (2) ASA, 300 mg, three times a day; (3) DPM, 100 mg, four times a day; (4) SPZ, 200 mg, four times a day; (5) ASA, 300 mg, plus DPM, 75 mg, combined, three times a day. Platelet count, adhesion and aggregation were measured during the 60-minute perfusion, and scanning electron miscroscopy of the graft's luminal surface was performed. ASA was the most effective single agent, significantly impairing platelet function and reducing consumption of platelets by the graft. DPM reduced platelet adherence only in the ex vivo experiment, and its addition to ASA imparted no further influence. Sulphinpyrazone had little effect in either experiment. Antithrombotic therapy with ASA and DPM requires clinical evaluation.

The interaction of varying doses of dipyridamole and acetyl salicylic acid on the inhibition of platelet functions and their effect on bleeding time.

1 In normal volunteers maximum reductions in platelet functions, collagen aggregation, adhesion and PF4 availability, were achieved using combined doses of 50 mg three times daily dipyridamole + 180 mg ASA or 75 mg three times daily dipyridamole + 120 mg ASA daily. 2 These doses did not prolong the bleeding time. 3 A synergistic effect has been demonstrated with 25 mg dipyridamole three times daily and 60 mg ASA. 4 At higher doses the effects on platelet functions were additive up to the maximal response. 5 The effect of low doses of ASA on platelet function was cumulative. 6 As lower doses of ASA in the combination studied inhibit platelet functions maximally without altering the bleeding time and probably without inhibiting prostacyclin, we suggest that these combinations of dipyridamole and ASA merit consideration in future clinical trials.

Heparin administration during extracorporeal circulation: heparin rebound and postoperative bleeding.

The individual variations in heparin dose response and heparin activity decay have indicated limitations of the protocols based on body surface area and weight of the patients. In the present study the heparin levels and simpler clotting tests were monitored in a consecutive series of 71 patients undergoing standard cardiac operations. The clotting tests used were the Celite activated clotting time (Celite ACT) and the whole blood activated recalcification time (BART). Forty-four patients received a loading dose of heparin, 3 mg. per kilogram, a maintenance dose of heparin, 1.5 mg. per kilogram per hour, and 6 mg. of protamine sulfate per kilogram at the termination of extracorporeal circulation (ECC) (Protocol I). Twenty-seven patients received a similar initial dose, but the maintenance dose of heparin and the dosage of protamine sulfate were administered according to the measured heparin levels (Protocol II). A significant difference was seen in the measured heparin levels (p less than 0.01, Celite ACT (p less than 0.01), and BART (p less than 0.01) in patients on Protocols I and II. Ten of the 24 patients on Protocol I and none on Protocol II showed heparin rebound phenomenon, and blood loss in patients on Protocol I was significantly greater than that in patients on Protocol II. The study clearly demonstrates that our protocol of heparin administration and control with simpler tests ensures safe hypocoagulation during ECC and efficient reversal at the end, with minimal postoperative blood loss.

Evaluation of the thrombogenic potential of three types of arterial graft studied in an artificial circulation.

The thrombogenic potential of woven Dacron, expanded polytetrafluoroethylene (Gore-Tex) and gluteraldehyde-treated human femoral artery (HFA) grafts was evaluated using an artificial circulation. The differences in the platelet parameters (platelet count, adhesion and aggregation) and scanning electron microscopy (SEM) appearances before and after perfusion were used as indices of thrombogenicity. Platelet counts fell significantly with woven Dacron, moderately with HFA and no fall was observed with Gore-Tex. Platelet aggregation was unaffected by any graft, but platelet retention was significantly marked in woven dacron. SEM studies revealed minimal adherence of platelets to Gore-Tex and HFA endothelium, but marked adherences to woven Dacron, accompanied by morphological changes of the adhered platelets. In an artificial circulation, of the three types of arterial graft, woven Dacron has the greatest influence on platelet function, indicating significant thrombogenicity, whereas HFA is intermediate in its effect and Gore-Tex appears to have the lowest thrombogenic potential.

The effect of dipyridamole on platelet function: correlation with blood levels in man.

1 The effect on platelet functions of dipyridamole (a pyrimido-pyrimidine compound) was compared with a control group of patients taking warfarin. 2 Adhesion, aggregation and platelet factor 4 availability showed a significant decrease in the dypyridamole group. 3 Aggregation and platelet factor 4 showed a significant correlation with blood dipyridamole level. 4 Adhesion, aggregation and platelet factor 4 were reduced below the lower limit of normal at blood dipyridamole levels above 3.5 micronmol/1.