effects of dipyridamole and acetylsalicylic acid on platelet functions in patients with aortic...

Effects of dipyridamole and acetylsalicylic acid on platelet functions in patients with aortic ball-valve prostheses

Jon Dale, M.D. Erik Myhre, M.D. Kjell Rootwelt, M.D. Oslo, Norway

Arterial thromboembolic complications fre- quently occur in patients with heart ball-valve prostheses.l-* The thrombi characteristically form on the valve itself,1,5s6 and resulting emboli are often localized in cerebral arteries,*~*~’ repre- senting a major threat to the patients.

Since the thrombi develop in the arterial system, the platelets play an important role in their formation.8Traditional anticoagulant therapy can, therefore, not be expected to totally pre- vent systemic thromboembolism, and embolic episodes occur in spite of strict anticoagulation,‘s5sg although the frequency is considerably reduced.2,7This focuses the interest on substances known to modify the function of blood platelets.‘O

The purpose of this investigation was to study the effects of ingested dipyridamole and acetylsalicylic acid (ASA) on platelet function in patients with prosthetic ball valves.

Material and methods

Five male patients with Starr-Edwards aortic ball-valve prostheses, implanted one to four years previously, were selected for the study. They were between 49 and 58 years of age, and all received digitoxin and warfarin therapy. Cerebral embolic episodes had occurred in two of them; one (AH) was fully restituted, while the other (PO) suffered from slight residual pareses. This patient had a valve of the older series 1,200 with a Silastic ball and cloth-covered cage; in the

From the Institute for Thrombosis Research, Medical Department B, and Section of Nuclear Medicine, University Hospital, Rikshospitalet, Oslo, Norway.

Received for publication June 28, 1974.

Reprint requests: Dr. J. Dale, Institute for Thrombosis Research, Rikshospitalet, Oslo 1, Norway.

May, 1975, Vol. 89, No. 5, pp. 613-618

others valves of series 2,300 with a hollow Stellite ball and cloth-covered cage were used

The two drugs were administered for three separate periods of 21 days with intermissions of at least two weeks, and all patients received the drugs in the same dosage and sequence. First, dipyridamole was ingested in a daily dose of 150 + 75 + 150 mg. Second, 1 Gm. of ASA was taken twice a day, and third, a combination of 150 + 75 mg. of dipyridamole and 0.5 4 0.5 Cm. of ASA was used

The bleeding time was measured from two in- cisions by Borchgrevink and Waaler’sn modification of Ivy’s method. Platelets were counted in a hemacytometer by a modification of Nygaard’s method,12 and platelet adhesiveness was determined in native blood according to the modified glass-bead filter method of Hellem.13 Platelet aggregation was estimated with the turbidimetric method described by Borr~,‘~using the Unigalvo EEL-titrator (Evans Electroselenium Ltd., Essex, England). Platelet-rich plasma @RPI for the test was obtained by centrifugation of titrated blood at 300 X g for 15 minutes. Aggregation was initiated with collagen, ADP, and adrenalin in final concentrations of 2.1 w per miRiliter, 0.7 PM, and 3.64 PM, respectively. The response was estimated from the maximal rate of collagen- and ADP-induced aggregation and calculated as the per cent of the mean value in normal subjects at the actual platelet count (Dale and Stormorken, to be published). Whether adrenalin induced the secondary irreversible phase of aggregation was evaluated from the shape of the curves. Platelet survival was determined according to Abraham- sen’s15 method by preparing autokrgous platelets which were labeled with 81Cr04-- and reinjected

American Heart Journal 613

Dale, Myhre, and Rootwelt

Table I. Lactate dehydrogenase (LDH), hematocrit, bleeding-time, platelet count, and platelet adhesiveness in patients with aortic ball-valve prostheses before drug ingestion. The normal range (mean f 2 S.D.) is given

Patient

HF PO AH KJ JL

Mean

Normal range

LDH Hematocrit W/L. 1 (per cent)

198 41 238 48 432 42

1,050 41 1,665 35

716 41.4

80-160 40-54

Adhesive Bleeding time Platelet platelets

(min.) (no.) (per cent)

7.5 219,000 28 6.5 214,000 79

12 256,000 40 11 200,000 19 13 226,000 5 10.8 223,000 34.2

3-11 150,000-350,000 50-100

Table II. Maximal rate of platelet aggregation in per cent of normal (collagen and ADP) and appearance of secondary phase of aggregation (adrenalin), platelet half-life, and platelet consumption in patients with prosthetic aortic ball valves before drug ingestion

Patients

HF PO AH KJ JL

Mean

Normal response

Platelet aggregation induced by

Collagen ADP Adrenalin (per cent) (per cent) (sec. phase)

57 81 + 106 91 + 70 85 +

125 76 + 84 76 +

88.4 81.8

60-140 60-140 +

Platelet half-life kl!nys)

3.5 3.6 3.0 3.4 4.1 3.52

3.77*

Plutelet consumption (pl.l~llday)

31,200 29,700 42,700 29,400 27,600 32,160

30,660*

*Mean values estimated from Foss-Abrahamaeb’s studies.”

intravenously. Blood samples were collected daily for eight days and the radioactivity was counted The platelet half-life was estimated and the consumption calculated in platelets per microliter blood per 24 hours. l6 For estimation of the degree of intravascular hemolysis, serum lactate dehydrogenase activity (LDH) was determined as described earlier.16

The assays were performed four times in each patient, before administration of the drugs and during the three periods of treatment. In each period, the tests were done when the drugs had been ingested for 11 days, except the survival studies which started after two weeks.

Student’s t-test for paired comparisons was used for statistical analysis.

Drugs: Dipyridamole: “Persantin” was obtained from Boehringer, Ingelheim, West Ger- many, and acetylsalicylic acid: “Colfarit” was obtained from Bayer, Leverkusen, West Germany.

Results

The degree of hemolysis differed widely between the five patients with aortic ball valves as judged from their lactic dehydrogenase (LDH) levels (Table I), the upper normal value being 160 U. per liter. The patient with the most pro- nounced red cell breakdown (JL) was anemic in spite of earlier blood transfusions and iron therapy. Before drug ingestion, the bleeding time was in the upper normal range in the three patients with the highest serum LDH. The platelet adhesiveness was considerably reduced in four patients as compared to a mean normal retention of 75 per cent (SD. = 12.8 per cent),13 most markedly in the two patients with the strongest hemolysis (Table I). The studies on platelet aggregation revealed no obvious abnormalities before treatment (Table II). The expected half- life of platelets in normal subjects at the same age would be 3.77 days, as calculated from

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Effects of dipyridamole and acetylsalicylic acid

Table III. LDH, bleeding time, platelet number, and platelet adhesiveness before and after 11 days of treatment with dipyridamole, acetylsalicylic acid (ASA), and both drugs combined

!lkeatment

Before drugs Dipyridamole ASA Combined

LDH UJIL.) meun

716 128 729 745

Bleediw time (min.) Platelet number

Mean S.D. Mean SD.

10.8 2.85 223,000 21,000 9.7 2.97 215,800 46,100

>20 231,300 28,600 so 238,700 32,600

Adhesive platelets (per cent)

mean

34.2 35.2 32.3 33.0

Table IV. Effects of dipyridamole and ASA on platelet aggregation. The maximal rate of aggregation induced by collagen and ADP is calculated in per cent of normal, and the number of patients showing secondary aggregation by adrenalin is listed.

Maximal rate of aggregation (per cent)

Collagen ADP Secondary qgregation by adrenalin,

!hatment Mean S.D. Mean SD. (No. of patients)

Before drugs 88.4 27.3 81.8 6.4 5 Dipyridamole 79.0 16.2 88.0 9.9 5 ASA 21.0 14.2 89.4 10.3 0 Combined 15.4 16.9 70.4 23.6 0

Abrahamsen’s results.16 Compared to this, the mean platelet half-life in our patients was slightly shorter, 3.52 days, but neither this difference nor the slight increase in platelet consumption was statistically significant in this small material.

Ingestion of dipyridamole in daily doses of 375 mg. did not cause significant changes in any of the parameters of platelet function (Tables III, IV, and V). The mean platelet half-life rose to 3.72 days, but this was entirely due to the pro- longation from 3.0 to 4.2 days in one patient (AH) as was the moderate reduction in mean platelet consumption.

After administration of 2 Gm. of ASA daily, the platelet aggregation was considerably changed. The aggregating response to collagen particles was markedly reduced in all subjects, with a lowering of the mean value from 88.4 to 21.0 per cent of normal (Table IV). The difference is statistically highly significant (p (0.001). The secondary phase of aggregation, induced by adrenalin, disappeared in all subjects after ASA. The concentration of ADP used was too low to induce secondary aggregation at any time during the study, and the response observed reflects the

Table V. Effects of dipyridamole and ASA on platelet survival and platelet consumption in patients with aortic ball-valve prostheses

Before drugs 3.52 0.40 32,160 6,050 Dipyridamole 3.72 0.37 28,840 5,730 ASA 3.72 0.41 31,370 4,000 Combined 4.00 0.91 30,720 5,670

first phase of aggregation which remained un- altered by the medication. ASA prolonged the bleeding time considerably in all patients, to 12.5 minutes in one subject (PO) and to more than 20 minutes in the others. As mentioned, they all received anticoagulant therapy throughout the study.

In the third period of medication, with a combination of the two drugs in lower doses, the effects observed were essentially the same as after ASA alone (Tables III, IV, and V). The mean platelet half-life increased from 3.72 after ASA to 4.0 days, which was again attributable to


Dale, Myhre, and Rootwelt

the change in one patient (PO), and none of the differences observed between the four series was significant (Table IV). The bleeding time and platelet aggregation were influenced to the same marked extent by the combined treatment as by 2 Gm. of ASA alone.

The degree of hemolysis, as reflected by the LDH values,17 was not affected by the drugs (Ta- ble III).

Discussion

The mechanisms behind the disturbed platelet function in patients with prosthetic ball valves, as reflected by decreased adhesiveness and shortened platelet life-span6J8 or increased consumption,19 are probably complex. The intravascular hemolysis regularly found in such patients20 might be of importance, since ADP is liberated from red cells. Even if ADP is rapidly removed from plasma,21p22 the concentrations near the valve may be high enough to cause aggregation of platelets, an early step in the formation of arterial thrombi, and also to induce platelet refrac- toriness toward ADP.23,24Adhesive platelets might be consumed by thrombus formation, and the increased platelet consumption could be caused by direct damage of the platelets by the impact of the ba11.26 Finally, the effects on the platelets may be due to a combination of these mechanisms. A more extensive discussion on platelet function in patients with aortic ball valves is given elsewherea2”

Arterial thrombi are characteristically com- posed of aggregated platelets and fibrin strands.8,27 Adhesion of platelets to suben- dothelial structures and platelet aggregation are early steps in thrombus formation.28*29ADP probably plays an important role in the thrombotic mechanism, it is responsible for platelet adhesion to foreign surfaces,12 it induces primary platelet aggregation30 and in higher concentrations it induces the release reaction, whereby large amounts of ADP are liberated, causing massive, irreversible platelet aggregation.31 Inhibition of release is associated with diminished aggregation by collagen, and impaired secondary aggregation by ADP and adrenalin.10v32-34 Experimental data further indicate the role of ADP in thrombosis. Thus, application of ADP outside the wall of venules36 and intravenous injection36*37 provoked formation of platelet thrombi. Consequently, ADP liberated from red cells during continuous

intravascular hemolysis may, at least in part, be responsible for the strong tendency to arterial thromboembolism in patients with prosthetic valves. In addition, the disturbance of blood flow by the valve will favor deposition of platelet ag- gregates on the foreign surface represented by the valve itself or endothelial tissue exposed by the operation.

Although coagulation is triggered by platelet release and aggregation,* the primary participa- tion of platelets in arterial thrombosis explains the relative insufficiency of oral anticoagulation, and theoretically this type of thrombosis could better be prevented by substances that modify platelet function. Dipyridamole added to PRP is a rather weak inhibitor of aggregation initiated by collagen Loveland ADP,34*38 and of serotonin release induced by collagen and adrenalin.‘O These in vitro effects on aggregation have not been found to appear after intravenous administration of the drug in rabbits.39 Harker and Slichter18 found no effect on platelet aggregation or bleeding time of 400 mg. of dipyridamole ingested daily in their patients with prosthetic heart ball valves but, surprisingly, the considerably shortened platelet survival times were completely normalized. In the present study, no effects of dipyridamole on platelet adhesiveness, aggregation, or bleeding time could be demonstrated. On this treatment, the mean platelet half-life was close to the expected normal value, but since the pretreatment survival was only slightly shortened and full normalization was the best that could be expected, statistically significant differences could not possibly be achieved by any of the drugs.

ASA inhibits the platelet release reaction in vitro as well as after ingestion.10,18,33,40-43 Platelet aggregation induced by collagen and the release- dependent secondary aggregation initiated by ADP or adrenalin are abolished18~32,33~43-46 ASA prolongs the bleeding-time,18~43,47 possibly by in- hibiting release, and the effect of a single dose on platelet aggregation& and bleeding time48 lasts for four to seven days. According to Stuart,46 the collagen-induced aggregation is reduced to the same extent 15 minutes after ingestion of 0.3 Gm. of ASA as after one month’s treatment, and the effect is the same as after a larger dose. The similar effects observed on bleeding time and aggregation after the combined treatment with only 1 Gm. of ASA daily and dipyridamole as after ingestion of 2 Cm. of ASA can, therefore, be

616 May, 1975, Vol. 89, No. 5

Effects of dipyridamole and acetylsalicylic acid

explained by the action of this drug alone. The apparent normalization of the mean platelet half-life by ingestion of each drug and slight pro- longation by the combined administration did not allow any conclusions. Harker and SlichterlB found no effect of ASA, as opposed to dipyridamole, on platelet survival. It is difficult to explain why ingestion of dipyridamole, in contrast to ASA, should affect platelet survival without in- fluencing platelet adhesiveness or aggregation. It can hardly be due to membrane stabilization, since the degree of hemolysis was constant in our patients.

4 days by the combined treatment. None of the differences was, however, statistically significant. A clinical study with ASA has been started in a larger series of patients to evaluate the effect on arterial thromboembolism.

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Since platelets play an important role in arterial thrombus formation, agents modifying their function may be effective in preventing this type of thrombosis. In a double-blind study, Sullivan, Harken, and Gorlin4g reported that dipyridamole, in a daily dose of 400 mg., sign% cantly reduced the number of thromboembolic complications in patients with prosthetic cardiac valves. Since ASA reduced collagen-induced aggregation considerably and inhibited the secondary irreversible aggregation in all our patients, this drug might be superior to dipyridamole as an antithrombotic agent. Thus, Dragojevic, Hetzer, and Corterierso found that ASA, in contrast to dipyridamole and warfarin, effectively inhibited thrombus formation on Teflon strips implanted in dog hearts.

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Summary 13.

The effects of dipyridamole and ASA on platelet functions were studied in patients with aortic ball-valve prostheses. Before ingestion, platelet adhesiveness was markedly reduced and platelet survival time slightly, but insignificantly shortened. ASA prolonged the bleeding time, reduced collagen-induced platelet aggregation, and inhibited secondary aggregation initiated by adrenalin. Similar effects were obtained with 2 Gm. of ASA alone as with 1 Gm. daily in combination with 225 mg. of dipyridamole. Platelet adhesiveness remained low. Dipyridamole alone, 375 mg. daily, did not influence any of these parameters. The mean platelet half-life was prolonged from 3.52 to 3.72 days by each drug and to

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effects of dipyridamole and acetylsalicylic acid on platelet functions in patients with aortic...

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