598 Abstracts

J. Hirsh, W. G. van Aken, A. S. Gallus, 0. T. Dollery and J. Oade (McMaster University Medical Centre, 1200 Main St. W., Hamilton, Canada): Heparin l{inetics in Venous Thrombosis and Pulmonary Embolism. (298)

Patients with venous thromboembolism differ considerably in their heparin response and requirements. We have investigated the mechanism for, and practical consequence of this variation in 20 patients with proven venous thromboembolism (VTE). A standard i/v heparin dose 70 Ujkg bolus followed 90 min later by 400 U/kg/24 hrs. by continuous infusion was given. Blood was drawn pre heparin and 15, 45 and 90 min post bolus and then during maintenance infusion for the following tests : heparin tolerance, activated partial thromboplastin time (APTT), heparin level. In addition heparin recovery and clearance were calculated. There were large inter-individual variations in the anticoagulant response to heparin which was due in part to differences in rates of heparin inactivation and clearance and in part to marked differences in the APTT response to heparin. For example, the heparin level at 15 min post bolus varied from 0.2 U to 0.9 U and during maintenance from 0.0 U to 0.5 U. The APTT varied from 45 to 200 sees. at 15 min and 38 to 96 sees during maintenance infusion. In addition the APTT prolongation over the pre­treatment APTT varied up to 9 fold between patients for a given heparin concentration. There was a marked and significant difference in heparin half life between patients with venous thrombosis (70±17 min) and pulmonary embolism (PE) (38±1 min) p < 0.005. This rapid clearance in PE may be due to release of antiheparin activity from platelets which interact with thrombin onto the surface of the embolus. The results suggest that the heparin dose should be individualized in VTE and that larger doses should be initially given to patients with PE.

J. T. Robertson, M. Dugdale, N. Balky and H. Robinson (University of Tennessee College of Medicine, 858 Madison Avenue, Room 231, Memphis, Te. 38163, U.S.A.): The Effect of a Platelet Inhibiting Dmg (Sulfinpyrazone) in the Therapy of Patients with Transient Ischemic Attacks (Tia's) and Minor Strokes. (299)

A prospective double blind randomized trial of sulfinpyrazone and placebo is described in patients with TIA'S and minor strokes. The criteria for entry into the Study were patients with at least two transient ischemic attacks within a two-week period or patients with a minor fixed neurological deficit resulting from cerebrovascular occlusive disease. All patients had routine laboratory, special p latelet aggregation studies, and cerebral arteriography. Several had initial and subsequent platelet survival studies. To insure equivalence of the two groups, patients were randomly assigned to categories reflecting their risk factors and age. Patients were followed every three months with appropriate laboratory and platelet studies. Interval follow-up occured when side effects or additional symptoms appeared.

When patients failed on sulfinpyrazone, they were placed on sulfinpyrazone and Couma­din. Patients who failed on placebo were placed on sulfinpyrazone followed by sulfin­pyrazone and Coumadin if subsequent failure occured. Failure was defined as two transient ischemic attacks within a two-week period or an additional stroke syndrome.

New patients will be enrolled for three years, and all patients will be followed for five years . All data is incorporated into computer files .

Preliminary results relating to the first sixty patients will be presented.

Leon Michaels, P . A. Galbmith and J. R. Ledwich (Manitoba Clinic, Winnipeg, Manitoba, Canada): A Clinical Trial of Antiplatelet 'l'herapy in Patients with Coronary Arterial Disease. (300)

Patients who had received long-term anticoagulants for acute coronary insufficiency or myocardial infarction were followed for 16 weeks after stopping treatment. There was a 37% thromboembolic relapse rate among 82 subjects who had angina during the last 3 treatment months and/or symptomatic occlusive extra-cardiac arterial disease. 13

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Abstracts 599

additional patients with one or both of these features were then selected for an anti­platelet therapy trial; having received warfarin for 1 to 2 years, they were switched to a IG-week course of entrophen 300 mg and sulfinpyrazone 200 mg, 4 times daily. Treatment was monitored by platelet adhesiveness, template bleeding time and serum salicylate measurements. There were no hemorrhagic complications. In 3 patients, intolerance compelled dosage reduction or stopping one drug; 10 adhered to protocol. 4 of the 13 suffered a thromboembolism while taking both drugs according to protocol. This 31% incidence is almost identical to that seen when no treatment followed warfarin with­drawal. The study is continuing, but t he results to-date suggest that entrophen-sulfin­pyrazone is not a practical or effective treatment for coronary disease. They do not preclude possible effectiveness of this combination in other vascular disease or oth er antiplatelet drugs in coronary disease.

A. L. Bloom, J. 0. Giddings and S. A. M. Shearn (University Hospital of Wales, Cardiff, U.K.): Immunohistological Studies of Coagulation Factors in Normal Blood Vessels and Platelets. (301)

Rabbit antisera to factors II, V , VIII (related protein), X, XI, fibrinogen and fragment D have been used to localise these factors in normal blood vessels and platelets by an indirect fluorescent antiglobulin technique. Localisation of factors V and VIII (RP) confined to the endothelium of normal blood vessels was confirmed but the presence of fibrinogen and fragment D at this site was variable and t h ese latter antigens were also demonstrated in the sub-intima and media. There was no evidence for the presence of prothrombin and factor X in normal blood vessels. Platelets, separated by albumin­gradient centrifugation were washed up to 12 times in buffer with and without Ca++. Factor VIII (RP) and factor V were present in platelets and resisted removal by repeated washings. Initial studies indicated that factor XI is not present in platelets or is easily removed. Weakly positive reactions were obtained for prothrombin with four-times washed platelets but the reaction was enhanced by repeated washings . Factor X (or Xa) was removed from platelets by Ca-free buffer but not by Ca - containing buffer. The results indicate the selective presence of coagulation factors in vascular endothelial cells and platelets and are consistent with the finding of a Ca.-dependent link between phospholipid and factor Xa which was also demonstrated in conventional chromatographic studies.

E . J . W. Bowie, V. Fu.ster, 0. A . Owen, Jr. and A. L. Brown (Mayo Clinic, Rochester, MN. 55901 U .S.A.) : Resistance to the Development of Spontaneous Atherosclerosis in Pigs with von Willebrand's Disease. (302)

The thoracic and abdominal aortas of 26 pigs with von W illebrand's disease were examined for atherosclerosis by gross inspection. In 6 of these pigs, older than one year, a detailed histological study was made from tissue taken from areas most likely to develop atherosclerosis in the pig i.e. the distal part of the lesser curvature of the aortic arch and t he posterior descending thoracic aorta at t h e level of the fifth intercostal artery. Six normal pigs were matched with the 6 von \iVillebrand pigs by breed, a.ge, sex, and heart weight and a similar gross and histologic study of their aortas was performed. The aortas of 5 of the 6 normal pigs showed atherosclerotic lesions consistent with the known high frequency of atherosclerosis in normal pigs about one year of a.ge. Only one of the bleeder pigs showed an atherosclerotic lesion; this was a fatty streak at the origin of the innominate artery. These preliminary observations suggest that pigs with von Willebrand's disease are more resistant than normal pigs to t he development of a therosclerosis. This may be related to the impaired platelet function in von Willebrand's disease . vVe are extending these observations by means of prospective controlled dietary studies .

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