Effects of antiplatelet therapy with indobufen or aspirin-dipyridamole on graft patency one year after coronary artery bypass grafting.

Saphenous vein coronary artery bypass graft patency can be increased by antiplatelet therapy. Aspirin plus dipyridamole are effective but are associated with tolerability problems. Indobufen is a possible alternative antiplatelet agent that may be better tolerated. A prospective, randomized, double-blind, parallel-group study was undertaken to compare the efficacy and safety of indobufen 200 mg twice daily with aspirin 300 mg thrice daily plus dipyridamole 75 mg thrice daily in preventing occlusion of autologous saphenous vein coronary artery bypass grafts. A total of 803 patients were randomized in the study, of whom 552 had a follow-up coronary angiogram approximately 1 year after operation. All anastomoses were patent in 56% of indobufen-treated patients and 59% of aspirin-dipyridamole recipients (p = 0.384). The percentage of all anastomoses patent was 82% in the indobufen group and 83% in the aspirin-dipyridamole group (p = 0.297). Mean postoperative blood loss was significantly less in the indobufen group (p = 0.043). Patients who received indobufen also had significantly fewer adverse events considered to be treatment-related compared with aspirin-dipyridamole recipients (p = 0.02). At the doses tested indobufen was as effective as aspirin plus dipyridamole in preventing occlusion of saphenous vein grafts and was better tolerated. Because indobufen was associated with less postoperative blood loss it may be used before operation in coronary artery bypass grafting.

Response to heparinization in adults and children undergoing cardiac operations.

The activated clotting time is an unreliable index of anticoagulation status during cardiopulmonary bypass procedures. However, modern instrumentation (Hemotec Hepcon HMS) now allows the monitoring of free heparin levels via automated protamine titration. In the present study, the standard procedure of anticoagulation at Killingbeck Hospital, Leeds, was investigated. Twenty-two pediatric patients and 20 adult patients undergoing open heart procedures involving cardiopulmonary bypass were given empirical doses of heparin (3 mg/kg body weight bolus), and activated clotting time was maintained at a level greater than 450 seconds using the Hemochron Timer. Heparin neutralization was performed at the termination of the bypass period using an empirical equivalent (3 mg/kg) of protamine sulfate. Mean free heparin concentration (+/- standard deviation) fell from 2.26 (+/- 0.45) mg/kg to 1.39 (+/- 0.34) mg/kg over the period 10 to 40 minutes on bypass in children. In adults, free heparin level declined from 2.56 (+/- 0.58) mg/kg to 1.81 (+/- 0.58) mg/kg over the same period. The biological half-life for heparin was 60 minutes in adults and 35 minutes in pediatric patients. Empirical protamine dosing resulted in excess protamine administration when compared with Hepcon titrated dose requirements: for children: median (range), 80 (12 to 350) versus 33 (12 to 97) mg, p less than 0.001; and for adults: 350 (200 to 500) versus 130 (61 to 237) mg, p less than 0.001. In conclusion, empirical heparin administration (3 mg/kg) does not result in "steady-state" anticoagulation during cardiopulmonary bypass, and empirical administration of protamine takes no account of interindividual differences in heparin sensitivity and biological half-life, which may be assessed using the Hepcon HMS.

Monitoring of coagulation status using thrombelastography during paediatric open heart surgery.

Thrombelastography (TEG) has proved useful in identifying coagulopathies (via assessment of clot elasticity properties) during hepatic surgery, but its role in cardiac surgery has as yet not been defined. Twenty-two children [11M, 11F, mean age (range) 4.9 (0.1-16) years] undergoing open heart surgery were investigated [1] preoperatively, [2] 15 min post protamine, [3] 2 h and [4] 24 h postoperatively using TEG. Comparisons were made between pre- and postoperative measurements and haematological indices. The values obtained from the TEG were: R phase (indicative of thrombokinase and thrombin formation disorders), K phase (indicative of fibrinogenesis) and MA phase (providing information on clot stability and platelet function). The patients were divided into two groups based upon 24 h blood loss; Group 1 - blood loss less than 0.7 ml/kg/h and Group 2 - blood loss greater than 0.7 ml/kg/h. In Group 2 there was a highly significant correlation between post-protamine MA phase and platelet number (r = 0.93, p less than 0.001) but there was no correlation in Group 1 (p greater than 0.1). Furthermore, in Group 2 elevated postoperative blood loss was associated with a prolonged K phase (mean [SD] 12.0 [6.0] versus 6.3 [2.1] min, p less than 0.05) and diminished MA phase (37 [12.5] versus 56 [4.9] mm, p less than 0.01) relative to preoperative values. In Group 1, K and MA phase did not alter significantly (p greater than 0.5 and p greater than 0.2, respectively). TEG predicted with 100% (8/8) accuracy increased post-operative bleeding. The specificity of TEG prediction of future bleeding was 73% [8/11]. Alterations in TEG parameters merit further evaluation as markers of postoperative haemorrhage.

Plasma eicosanoids, platelet function and cold sensitivity.

As abnormal eicosanoid (prostaglandin) metabolism has been suggested as a factor in the aetiology of vasospastic diseases we have measured levels of stable eicosanoid metabolites using a radioimmunoassay in 30 normal subjects and 31 patients with Raynaud's phenomenon. There were 13 patients with primary Raynaud's, ten with Raynaud's secondary to scleroderma and eight men with vibration white finger (VWF) disease. We have also measured platelet aggregation to adenosine diphosphate (ADP), collagen and adrenaline in 19 normal subjects, 22 patients with primary Raynaud's, 12 with Raynaud's secondary to scleroderma and 14 men with VWF. When compared with our normal subjects, patients with VWF have an elevated thromboxane B2 level, with a normal 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) level. Their platelets are less sensitive to ADP and collagen. Patients with primary and secondary Raynaud's have elevated thromboxane B2 levels but this is much more marked in the secondary group. Patients with primary Raynaud's have a normal 6-keto-PGF1 alpha level but in patients with secondary Raynaud's the 6-keto-PGF1 alpha level is markedly raised. The platelets from both groups are more sensitive to ADP and collagen and this is more marked in the secondary group. Whether these phenomena are a cause or an effect of vasospasm remains unknown.

Effect of preclotting on the porosity and thrombogenicity of knitted Dacron grafts.

The effects of single- and four-stage preclotting methods on graft porosity and thrombogenicity were compared in two types of Dacron prosthesis. The single-stage method significantly reduced leakage of blood (P less than 0.001), but did not seal the grafts. The four-stage method rendered the grafts impermeable at the second step. Thrombogenicity was compared by perfusing preclotted grafts with fresh heparinized blood (containing 111In-labelled platelets) in an artificial circulation. Platelet deposition and consumption were significantly less in the four-stage method whilst platelet function remained unchanged during perfusion. We conclude that the four-stage technique is superior to standard preclotting methods by rendering knitted Dacron grafts impermeable and hypothrombogenic.

The effect of indobufen on the thrombogenic potential of a Dacron prosthesis in an artificial circulation.

We have evaluated the effect of indobufen on the potential thrombogenicity of a Dacron vascular prosthesis in an artificial circulation. In a randomised double blind crossover study, ten healthy volunteers received indobufen 200 mg or placebo twice daily for one week. The artificial circulation, incorporating a 15 cm length of 8 mm Dacron graft was perfused for 60 mins with volunteer blood containing autologous 111In labelled platelets. Graft thrombogenicity was assessed by changes in platelet function, isotope labelled platelet studies and scanning electron microscopy. Platelet count fell significantly during graft perfusion (P less than 0.05) and aggregation was significantly inhibited by treatment with indobufen pre perfusion compared with the placebo group (P less than 0.02). While deposition of labelled platelets was not statistically significant, consumption of these platelets was greater in the placebo group (P less than 0.01). Field counts of adherent platelets made from scanning electron micrographs of the indobufen treated group were significantly lower (P less than 0.01) compared with the placebo group. We conclude that indobufen can reduce the thrombogenic potential of Dacron vascular grafts and suggest that it may be an effective antiplatelet agent for use following Dacron bypass surgery.

Acetylsalicylic acid and dipyridamole improve the early patency of aorta-coronary bypass grafts. A double-blind, placebo-controlled, randomized trial.

A total of 125 patients undergoing aorta-coronary bypass grafting for disabling angina were randomized to receive either 330 mg of acetylsalicylic acid (aspirin) plus 75 mg of dipyridamole three times daily or a placebo for 6 months postoperatively. In addition, all patients were given warfarin for 3 months. Repeat angiography was performed at 6 months in 103 patients. In the treatment group 95 grafts were implanted in 48 patients, of which 87 were patent (91.6% patency rate). This figure compares with 88 grafts patent out of 118 implanted in 55 patients in the placebo group (74.6% patency rate) (p less than 0.01). We conclude that antiplatelet therapy improves the early patency of saphenous vein aorta-coronary bypass grafts.

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.

HLA antigens in relationship to duodenal ulceration, gastric acid secretion and the clinical result following vagotomy.

The distribution of 20 HLA antigens was measured in 100 patients with a duodenal ulcer. An increase (P less than 0.05) in the incidence of the HLA-BW35 antigen was identified which conferred an increased risk factor of developing a duodenal ulcer of 2.7. The preoperative acid output in patients who had the BW35 antigen was significantly lower than that found in all other patients prior to surgery. The clinical outcome from definitive surgical treatment did not appear to be influenced by the HLA status of the patients.

Steroid-responsive nephrotic syndrome and allergy: immunological studies.

Immunological studies were performed on 84 children with steroid-sensitive nephrotic syndrome as part of an investigation of the relationship between steroid-responsive nephrotic syndrome and allergy. Serum total IgE levels tended to be raised, particularly in children who had frequent relapses of nephrotic syndrome. Ten children had extremely high levels (greater than 1500 IU/ml) and several of them had neither a history of atopy nor any other identifiable cause. 25% of the children had at least one positive test for specific IgE antibody. IgE was not detected by immunofluorescence in renal biopsy tissue from 25 children, regardless of whether the child was in remission or relapse at the time of biopsy. Serum IgG and IgA levels were depressed particularly at the time of a relapse. Serum IgM tended to be raised and to remain so, even in children who had been in remission for more than a year. No clinically useful relationship was found between the frequency of HLA antigens and the occurrence or course of the syndrome, whether or not accompanied by atopy. Clinical and immunological features of atopy are more common in children with idiopathic nephrotic syndrome. This may be a causal or non-causal association. Pollen sensitivity is a rare cause of nephrotic syndrome; careful search for provocative agents may show other causes.

Arterial graft maturation: the duration of thrombotic activity in Dacron aortobifemoral grafts measured by platelet and fibrinogen kinetics.

Dacron is thrombogenic, hence small arterial grafts of this material frequently thrombose in the period prior to graft maturation. Anti-thrombotic therapy may therefore be indicated to preserve patency during this risk period. To evaluate the thrombogencity of immature Dacron grafts, platelet and fibrinogen kinetics using 51Cr and 125I respectively were measured before operation and at 3, 6 and 9 months in 10 patients following aortobifemoral bypass and in 6 age-matched volunteers. Platelet survival was reduced from 8.8 +/- 0.2 d before surgery to 7.4 +/- 0.24 d at 3 months. This was accompanied by an increase in platelet turnover from 39 +/- 2.4 X 10(9)l-1d-1 to 46.9 +/- 2.9 X 10(9)l-1d-1. Fibrinogen t1/2 fell from 3.72 +/- 0.13 d preoperatively to 3.36 +/- 0.11 d at 3 months, while fibrinogen fractional catabolic rate rose from 0.27 +/- 0.014 to 0.34 +/- 0.014. These changes were all significant (P less than 0.01). Fibrinogen consumption had returned to normal by 6 months following surgery but platelet kinetics only equated to preoperative levels at 9 months. We suggest that Dacron grafts are thrombogenically active for about 9 months. When anti-thrombotic therapy is indicated it should be continued throughout this period.

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.

Seronegative pauciarticular arthritis and HLA B27.

Twenty-six patients with a pauciarticular arthritis have been studied clinically, radiologically and with histocompatibility typing. An increased frequency of HLA B27 was found (p = 1.87 x 10(-12)). Low back and buttock pain, Achilles tendinitis and dactylitis of the toes were more frequent in HLA-B27 positive patients. It is suggested that histocompatibility testing may be of some value in diagnosis and in the investigation of the possible 'reactive' nature of this type of arthritis.