Altered Platelet Function in Patients
with Prosthetic Mitral Valves
Effects of Sulfinpyrazone Therapy
By HUGH S. WEILY, M.D.,
AND
EDWARD GENTroN, M.D.
Downloaded from http://circ.ahajournals.org/ by guest on June 15, 2017
SUMMARY
Platelet survival time and platelet adhesiveness and aggregation were examined in
16 patients with prosthetic mitral valves. Subsequently, nine patients were treated with
sulfinpyrazone in doses of 400 mg and 800 mg/day, and the studies were repeated
after a treatment period of 5 to 8 weeks. 51Chromium survival time was shortened in
15 of 16 patients, and the mean value for the entire group was 5.49 + 0.23 days (normal, 6.73 + 0.21 days; P < 0.001). Mean platelet adhesiveness in glass bead columns
53 + 5% (normal, 30 to 60%). Platelet aggregation (turbidometric technic of Born)
normal. Treatment with 400 mg of sulfinpyrazone daily reduced platelet adhesiveto 40 5% (P < 0.05), but effected no change in platelet survival time or platelet
aggregation. Therapy with 800 mg of sulfinpyrazone daily corrected platelet survival
time to normal, 6.68 + 0.57 days (P < 0.01), but it produced no further decrease in
adhesiveness and no change in aggregation. It is concluded that platelet abnormalities
regularly occur in patients with prosthetic mitral valves and may contribute to thromboembolism in this group. Platelet survival time is a more sensitive measure of altered
platelet kinetics than platelet adhesiveness or platelet aggregation. Therapy with 800
mg of sulfinpyrazone per day corrects demonstrated abnormalities and may be useful
for prevention of thromboembolism in patients with prosthetic mitral valves.
was
was
ness
Additional Indexing Words:
Thromboembolism
Platelet aggregation
Platelet adhesiveness
best, only partial protection in patients with
prostbietic mitral valves.1 2 This failure
sugge sts that factors involved in thrombosis,
which are unaffected by conventional anticoagulaint therapy, may be important. Demonstratic)n that platelets play a key role in
initiatting thrombosis20 and that they are not
affect ed by inhibition of the coagulation
mechcanism2' has led to much recent interest
in eva luating platelet function in patients with
throm boembolism or with conditions predisposinEg to thromboembolic disease. Studies of
this n iature have demonstrated that postoperative patients and patients with recurrent
venouis thrombosis or pulmonary embolism
have increased platelet adhesiveness22 23 and
sugge st that platelets are important in
thromibogenesis in many clinical situations.
S YSTEMIC emboli remain the major cause
of late morbidity and mortality in
patients with prosthetic cardiac valves.'-'3
Newer designs and modifications of previously
employed valves appear to be associated with
a lower risk of thromboembolism,14-19 but
they have not eliminated this complication.
Although anticoagulants have reduced the
incidence of embolic episodes in patients with
aortic valve prostheses, they have provided, at
From the Division of Cardiology, Department of
Medicine, University of Colorado Medical Center,
Denver, Colorado.
Supported in part by Grant HE 05390 from the
National Institutes of Health, Bethesda, Maryland,
and the Colorado Heart Association.
Received June 8, 1970; revision accepted for
publication July 23, 1970.
Circulation, Volume XLII, November 1970
Platelet survival time
967
WEILY, GENTON
968
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That the platelet may be important in the
pathogenesis of thromboembolism in patients
with cardiac valve prostheses is suggested by
the demonstration of decreased platelet
survival time in this group.24' 25 Several
compounds are known to alter platelet
activity,2636 and there is evidence to suggest
that they may be useful in the prevention of
emboli in patients with prosthetic cardiac
valves.25 3 Sullivan and associates37 have
shown a decrease in the number of embolic
episodes in such patients treated with
dipyridamole in addition to warfarin, when
compared to a control group treated with
warfarin alone. Recently, Harker25 demonstrated that shortened platelet survival time in
patients with heart valve prostheses can be
partially corrected with acetylsalicylic acid
and completely corrected with dipyridamole.
Sulfinpyrazone alters platelet reactivity and
has been shown capable of decreasing platelet
adhesiveness, decreasing the response of
platelets exposed to collagen when large doses
are given acutely and increasing platelet
survival time with several weeks of therapy.33-36 Studies of its effect on platelet
activity in patients with prosthetic cardiac
valves, however, are lacking. It was the
purpose of this study to examine platelet
survival and platelet adhesiveness and
aggregation in a group of patients with
prosthetic mitral valves and to determine the
response of these parameters to treatment
with sulfinpyrazone.
Methods
Platelet Survival Time
Platelet survival time
was determined by using
autologous 51chromium (51Cr) -labeled platelets
according to the technic of Aster and Jandl.38
Platelet Adhesiveness
Platelet adhesiveness in glass bead columns
determined by employing a modification of
the technic of Salzman.39 Using a two-syringe
technic, 2 ml of blood was drawn into a plastic
heparinized syringe and immediately passed
through a standardized glass bead column in
exactly 1 min.
was
Platelet Aggregation
Platelet aggregation
was
determined by using
a
modification of the turbidometric technic of
Born.40 An Aminco fluoromicrophotometer was
adapted to measure light transmission through
platelet-rich plasma maintained at 37C, with
constant agitation provided by a magnetic stir
bar. Adenosine diphosphate (ADP) in a final
concentration of 2 to 20 4g/ml of plasma or twofold dilutions of a collagen suspension* were
added and the resulting aggregation observed.
Sulfinpyrazone Levels
Plasma levels of sulfipyrazone were determined
a method previously described.41 42 In most
cases, the samples were drawn at random. In two
patients, levels were determined serially 1, 2, 4,
and 6 hours following the usual oral dose of 200
by
mg.
Analysis of Data
For testing of platelet survival data, the
Wilcoxon matched pair, signed-rank test, and the
rank-sum test were employed. In addition, the
slope of the regression line, from which the halflife of 51Cr was determined, and a pooled Pvalue for change in slope were calculated. Platelet
adhesiveness data were tested using the Wilcoxon
matched pairs, signed-rank test.
Subjects
Studies of platelet adhesiveness, aggregation,
and survival time were performed in 16 patients
with prosthetic mitral valves. The patient group
included 11 men and five women, aged 33 to 63
years, who had mitral valve prostheses placed 6
mo to 6 years prior to entry into the study. Of
these, 13 had Starr-Edwards ball valves, and
three had Kay-Shiley disc prostheses. With the
exception of one patient who had valve
replacement as a result of severe papillary muscle
dysfunction, all had underlying rheumatic heart
disease. Following completion of initial studies,
nine of these patients, eight with Starr-Edwards
prostheses and one with a Kay-Shiley valve, were
treated with sulfinpyrazone. Therapy was
initiated with 400 mg per day in six and with 800
mg per day in three patients. After 5 to 8 weeks
of treatment, platelet survival studies were repeated. During therapy, measurements of platelet
adhesiveness and aggregation and sulfinpyrazone
plasma levels were made weekly when possible
or at the time of repeat platelet survival
study. Following the second study, the dose, for
those patients initially given 400 mg/day, was
increased to 800 mg/day, and after an additional
treatment period of 5 to 8 weeks, studies were
repeated as described above.
*Sigma C-9879-Collagen from bovine Achilles
tendon.
Circulation, Volume XLII, November 1 970
PLATELETS AND PROSTHETIC MITRAL VALVES
Table 1
Results of Platelet Survival Studies in Patients
with Prosthetic Mitral Valves Prior to and
Following Sulfinpyrazone Therapy
Platelet survival time (days)
Sulfinpyrazone
400 mg/day
800 mg/day
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Prosthetic
valve
patient
Untreated
T.T.
P.J.
R.K.
M.K.
C.S.
D.C.
W.C.*
R.S.
B.M.
N.B.*
H.B.
A.B.*
C.R.
B.T.
S.M.
E.B.
Mean
6.38
6.26
5.74
6.40, 6.00
3.60
4.58
5.42
5.68
5.80
5.56
3.96, 3.52
5.34
5.86
6.00
6.80
6.08
5.49
6.10
3.30
5.86
4.33
7.60
5.66
8.04
6.72
5.76
9.95
5.06
6.72
7.74
6.10
4.10
5.47
6.68
*Kay-Shiley prosthesis.
Results
Platelet Survival Time (Table 1)
Mean platelet survival time in seven normal
controls was 6.73 ± 0.21 days (standard error
of the mean). Platelet survival time was
shortened in 15 of 16 patients with prosthetic
mitral valves, and the mean for the entire
8
969
group, 5.49 + 0.23 days, was significantly
shorter than normal (P < 0.001; fig. 1). In the
two patients on whom two control studies
were performed, results varied by 6% and 11%.
Platelet survival time averaged 5.51 + 0.27
days in patients with Starr-Edwards prostheses and 5.44 + 0.06 days in those with KayShiley valves. The difference in these values is
not statistically significant (P > 0.50). The
mean platelet survival time before treatment
was 5.58 ± 0.27 days in those patients
subsequently treated with sulfinpyrazone.
There was no significant difference between
this value and that found in the patients with
prosthetic valves who were not treated
(P > 0.50). Treatment with 400 mg of
sulfinpyrazone per day resulted in no
significant change in platelet survival time.
However, treatment with 800 mg of sulfinpyrazone was associated with an increase
in platelet survival time in seven of nine
patients, to a mean survival time of
6.68 + 0.57 days (fig. 2). This was a
statistically significant increase (P < 0.01),
but the resulting mean survival time did not
differ significantly from that of the normal
group (P > 0.50).
Platelet. Adhesiveness (Table 2)
The normal range for platelet adhesiveness
in this laboratory is 30% to 60%. In the nine
patients subsequently treated with sulfinpyrazine, pretreatment platelet adhesiveness averaged 53 + 5%. Following therapy with 400 mg
Table 2
Platelet Adhesiveness in Patients with Prosthetic
Mitral Valves Prior to and Following Sulfinpyrazone Therapy
7
-E
a-
5
N
7N=1
Normal
Co n trol
Prosthetic
Valve
P a tie n t s
Figure 1
Platelet survival time in normal controls and in patients with prosthetic mitral valves (mean + SEM).
Circulation, Volume XLII, November 1970
Av. platelet adhesiveness (%)
valveti
patient
Untreated
T.T.
P.J.
R.K.
M.K.
C.S.
W.C.
R.S.
B.M.
Mean
38
45
62
43
81
36
47
62
53
Sulfinpyrazone
400 mg/day
800 mg/day
36
60
43
36
25
40
46
45
38
32
40
45
40
41
38
WEILY, GENTON
970
or the degree of maximal aggregation. No
change in these parameters occurred following
treatment with sulfinpyrazone.
Sulfinpyrazone Levels
!E
During chronic therapy, plasma levels of
sulfinpyrazone ranged between 10 and 25
mg/L in all subjects. In two patients,
determination of levels 1, 2, 4, and 6 hours
after oral administration of 200 mg revealed
that the sulfinpyrazone plasma concentration
remained relatively constant, that is, between
15 and 20 mg/L.
7
6
5
800mg/day
400mg/day
Un t r,ta
Downloaded from http://circ.ahajournals.org/ by guest on June 15, 2017
Figure 2
Platelet survival time: Effect of sufinpyrazone therapy
(mean
±
SEM).
of sulfinpyrazone per day, this decreased to
40+5% (P<0.05; fig. 3). When the dose of
sulfinpyrazone was increased to 800 mg/ day,
mean platelet adhesiveness decreased further
to 38 ± 2.5%, but this was not significantly
different from that found with the lower
dose.
Platelet Aggregation
In this group of patients, values for collagen
and ADP-induced aggregation closely paralleled each other, and when compared with
normal, no abnormalities were demonstrated
in terms of the amount of aggregation
produced by a given concentration of ADP or
collagen, the slope of the dose-response curve,
70
a
60
1Iel
a0
<a-
50
40
ffi
N=9
4u
16
2
NO-
Untreated
The results of this study confirm the
observation that platelet survival is shortened
in patients with prosthetic cardiac valves. The
cause for this remains unclear, but it may
result from mechanical trauma to the platelet
similar to that which produces chronic red cell
damage in these patients.43-4 Alternatively,
chronic red cell destruction with concommitant ADP release may result in concentrations
of ADP in the area of the valve sufficient to
produce formation of platelet aggregates on
the prosthesis. Finally, it is possible that the
shortened survival time is a result of continued
formation of platelet aggregates in response to
the presence of a large foreign object, the
prosthetic valve. Whatever the cause, the fact
that platelet survival time is shortened in patients with prosthetic heart valves supports the
view that platelets are important in the
pathogenesis of thromboemboli in this group.
Although a significant decrease in mean
platelet adhesiveness occurred with sulfinpyrazone therapy, only three of nine patients
had abnormally high initial values, and mean
adhesiveness before treatment was within
normal limits. Similarly, no abnormalities in
collagen or ADP-induced aggregation were
demonstrated prior to therapy. These results
suggest that platelet survival time may be a
more sensitive indicator of altered platelet
function than studies of either platelet
adhesiveness or platelet aggregation.
With regard to platelet aggregation, it has
previously been shown that in rabbits,
intravenous infusion of sulfinpyrazone in doses
IXI<L~~~~~~~~~~~~
401
in
Discussion
0
400 mg/Day
-8
00 m
Da Y
111-
Figure 3
Platelet adhesiveness: Effect of sulfinpyrazone therapy
(mean ±- SEM).
Circulation, Volume XLII, November 1970
PLATELETS AND PROSTHETIC MITRAL VALVES
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ranging from 25 to 150 mg/kg blocks the
aggregating action of collagen on platelets.35
In those studies, suppression of aggregation
was noted with a dose of 50 mg/kg and a
corresponding plasma level of 200 mg/L. No
change in collagen-induced aggregation was
noted in the present study, but much smaller
doses of sulfinpyrazone, given orally, were
used, and plasma levels ranged from 10 to 25
mg/L.
This group of patients was not large enough
nor the observation period long enough to
allow conclusions regarding (1) the effectiveness of sulfinpyrazone in preventing thromboembolism, or (2) the usefulness of the platelet
survival time in predicting the likelihood of
systemic emboli. However, four of the patients
studied had embolic episodes following
placement of the prosthetic valve and prior to
entry into the study. All of these patients had
shortened platelet survival times. While on
therapy, one patient continued to have
cerebral emboli associated with evidence of
severe valvular dysfunction requiring additional surgery. This patient (C.S.) had a very
short platelet survival time and an incomplete
response to therapy. At surgery, thrombus
formation on the valve was found to be
extensive. No other patients had evidence of
systemic emboli while being treated with
sulfinpyrazone. These observations are in
agreement with the promising results of others
who have used drugs which alter platelet
function in the treatrnent of patients with
prosthetic heart valves.24' 36 Further investigations in this area, including a controlled study
employing the methods used in our study,
seem indicated.
2.
3.
4.
5.
6.
7.
8.
9.
10.
1 1.
12.
Acknowledgment
The advice and assistance of Philip Archer, Ph.D.
in the analysis of data are gratefully acknowledged.
The authors also wish to express their appreciation to
Miss Brenda Walton and Miss Ann Wissenberg for
technical assistance and to Miss Jean Finlayson for
preparation of the manuscript.
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Circulation, Volume XLII, November 1970
Altered Platelet Function in Patients with Prosthetic Mitral Valves Effects of
Sulfinpyrazone Therapy
HUGH S. WEILY and EDWARD GENTON
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Circulation. 1970;42:967-972
doi: 10.1161/01.CIR.42.5.967
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