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A comparison of thromboelastogram and template bleeding time in the evaluation of platelet function after aspirin ingestion
A Comparison of Thromboelastogram and Template Bleeding Time in the Evaluation of Platelet Function after Aspirin Ingestion Mark J. Trentalange, MD,* Leonard F. Walts, MD_F Department
Study
of Anesthesiology,
Oljective:
togruphy (TEG)
UCLA
School
of Medicine,
Los Angeles,
To compare templute bleeding time (TBT)
CA.
with thromboelus-
in human subjects qfter uspirin ingestion.
Health! volunteers whre gizlen a single 650 mg dose qf aspirin or u dose
Design:
qf 650 mg of uspzrin on three successive days. TBT and TEG studies were PeTformed prior to uspirin ingestion and 4, 24, 72, and 168 hours after iqestion.
Setting: Inpatient operating room support urea at the UCLA Center,for Health Sciences. Volunteers:
Residents and nurses who were in good generul heulth, had not taken
aspirin fvr 2 weeks, had normul platelet counts, and hud no exjidence of bleeding or cougulution disorders. Intervention: TBT and TEG studies were performed
prior to and qfter the
ingestion of uspirin. J. Clin. Anesth.
3:377-381,
1991
Measurements and Main Results: TBT studies were significantly prolonged ut 4,24, and 72 hours compared with controls. Muximum bleeding time prolongution occurred 24 hours ufter aspirin iqestion.
Bleeding time returned to control values
“Resident
by the end of‘ 168 hours (1 week). No TEG pammeter
tProfessor
by aspirin ingestion. &clusion: TEG results muy not ider$ty patients who huve an increased bleeding
Address reprint requests to Dr. Waits at the Department ot‘ Anesthesiology, UCLA School of Medicine, Los Angeles, CA 900241778, USA. Received f’or publication April 24, 1990; revised manuscript accepted for publication January 3 I, I99 I.
0 I991 Butterworth-Heinemann
was sign$icuntly
changed
time us u result qf uspirin ingestion.
Keywords: Thromboelastography; tests; aspirin.
bleeding time; platelet function
Introduction Aspirin prolongs bleeding time. For this reason, anesthesiologists itant
to perform
regional
nerve
blocks
J. Clin. Anesth.,
in patients
who
have
vol. 3, September/October
are hes-
recently
1991
in-
377
gested aspirin. It is a poliq at L:(LA 10 test these patients for prolonged bleeding using the template bleeding time (-I‘B’I‘). If the bleeding time falls withregional anesthesia may be in the normal range, elected. TBT tests are labor-intensive. ‘I’heir performance requires a laboratory technician from the central laboratory to come to the patient’s bedside. Experience has shown that test results are rarely obtained in less than 4 hours (primarily due to the lack of technicians to perform the study). In addition to the operating room (OR) delays fi)r scheduled cases, this time lag precludes the test’s performance fi)r emergency operations (P.R., axillary nerve blocks for digit reimplan‘I-he thromboelastograph (‘TEC;) is an tation). instrument available in many anesthesia laboratories and is used to evaluate bleeding and clotting functions. Spiess and Ivankovich’ state. “Template Bleeding Times are not practical for use in the operating room setting. Howe\,er, data on both platelet number and function can be obtained by TE(; analysis. l’erhaps anesthesiologists could safely proceed with regional anesthesia procedures when the TE(; is IKH-I~~~” (p. 179). Previous studies of the effect of’ aspirin on ‘I‘EG have produced conflicting results. De(;aetano and Vermjllen:! gave volunteers 1 g of aspirin. The ‘I’EG results were unchanged 2 hours after ingestion. Goldschmidt Pt al.“ gave children with cyanotic congenital heart disease 500 mg of aspirin orally for 3 days. On the third clay, there was no change in the TEG findings. Loew and Vinazzer’ studied patients suffering from thrombophlebitis or postthrombotic syndrome. They gave the patients 500 mg of aspirin three times daily for 6 days. For the first 3 days, the aspirin was combined with heparin (5,000 units twice daily), and for the last 3 days, it was given alone. The patients’ blood was studied at an unspecified time following the final aspirin ingestion. The authors reported no effect of the aspirin on ‘I‘EC;. Hawkins5 studied TEG in 17 healthy volunteers 2 hours after the ingestion of 600 mg of aspirin. Contrary to the previous findings, she noted a significant prolongation of- the reaction time, initial clotting speed, and was no alteration in total coagulation time. There either the maximum clot elasticity or the time taken to reach this value, nor was there any change in clot retraction. This study evaluates platelet function after ingestion of aspirin by both TBT and TEG. ‘I-he study was designed to repeat these tests at varying time intervals to determine whether changes could be found and, if so, to follow the pattern of change and determine when values returned to normal.
378
J. Clin. Anesth.,
vol. 3, SepternbetYOctober
1991
Materials and Methods
b;igtit health: adult volunteer males and females \I’C’ (’ I srudicd. Sublects were excluded from this study if the\ had ingesteil aspirin within the past 2 weeks OI- had an allergy or sensitivitv 10 aspirin, uremia, \~)II Willebrand’s disease, or rhrornbocytopenia. ‘I-he st u(l), \Y‘IS approved bv the UCLA School of Medicine Human Subject I’roiection (:omniittee. All voluiiteers signed a consent f’orm fbr participation in the sTrdy, b\.it hdrawal of’ blood, and perfi~rn~ance of’ the ‘I‘B’I‘ test. All volunteers were screened by I‘B’I‘, ~I‘EX;, mid values were platelet count. ‘l‘hose having abnormal excluded.
After being trained by clinical laboratory personnel, we performed all the ‘I‘B’I‘ tests. With the volunteers seated comfortably, the skin of the forearm was cleansed with an isopropyl alcohol swab and allowed to air dry. A sphygmomanometer cuff was applied to the upper arm and inflated to 40 mmHg for the duration of’ the test. Next, a template (Simplate II, Organo11 ‘I‘echnika. Durham, NC:) was applied to ;I previouslv cleansed hairless area of’ the forearm, and the mechanism was tripped, causing the blades to make two 5 mm long by 1 mm deep longitudinal skin incisions. (Jean filter paper was applied to the borders of‘ the clot every 30 seconds without disturbing the tissue edges until the filter paper came away without any blood. ‘I‘he mean time in minutes for the two incisions were recorded as the .rBT. The manufacturer listed the expected range (mean i two standard deviations) as approximately 2.3 to 9)..5 minutes. ‘I‘hese values for normal were verified and accepted as IIOI‘ma1 by our clinical laboratory.
Tlzromhoelustoffraph
Ana@is
The samples for native (whole blood) ‘I‘EG analysis were drawn before or after TBT on a random basis. After the skin of the forearm was cleansed, an unheparinized syringe was used to draw 2 to 3 ml of blood from an appropriate vein. A timer was started as soon as the sample was completely collected. After 4 minutes of gentle rolling of the sample syringe, a portion of the sample was injected into a plastic cup. A micropipet was used to measure 0.35 ml of blood, which was placed in a clean, stainless steel cuvette.
TEG, bleeding time, and aspirin: Trentulunge and Wults
The piston was lowered into the sample, and a small needle was used to eliminate any bubbles. Mineral oil (1 to 2 drops) was placed on the surface of the sample to eliminate the blood-air interface. When possible, two studies were performed on each sample, and the mean of the measured indices was recorded. All TEG measurements were made on a thromboelastograph D (Haemoscope Corporation, Glenview, IL) by laboratory technicians familiar with the machine’s operation. Each tracing was then coded so that indices could be coded in a blinded fashion at the completion of data gathering for that subject. Indices were then measured and verified directly from the tracing. The r value was defined as the time from the beginning of the tracing (4 to 5 minutes after blood drawing) to the point at which the tracing was 1 mm wide. The k value was defined as the time from the r value (1 mm) to the point at which the tracing was 20 mm wide. Both these indices were measured in millimeters from the tracing and converted to minutes (paper speed = 2 mm/min). The alpha” value was calculated from the k value (adjacent limb) and the width of the tracing (20 mm / 2 = 10 mm): alpha” = (180 / pi) . arctan (10/k). Finally, MA was defined as the maximum amplitude of the tracing in millimeters.
Platelet Count One to 3 ml of blood was sterilely withdrawn from the forearm of each subject using a preheparinized syringe and analyzed by trained laboratory technicians for hemoglobin, hematocrit, and platelet count using a Cell-Dyn 1600 analyzer (Sequoia-Turner, Mountain View, CA).
Design Following determination of initial values for platelet count and TBT and TEG measurements, each volunteer was given 650 mg of aspirin orally. Previously, Dybdahl et al.” calculated the maximum bleeding time to occur at 2.4 to 2.6 hours after aspirin ingestion. They and others7.* observed that bleeding times returned to normal within 5 to 6 days. Therefore, repeat studies were done at 4 hours, 24 hours, 72 hours, and 168 hours (1 week; arbitrarily selected to demonstrate the effect of aspirin on the measured values).
to ensure effective screening procedures, baseline values comparable to other studies, and relevance of these results. Next, data were examined for normality and outlying values. Assuming normally distributed data, repeated measures analysis of variance (ANOVA) was used to assess differences over time within the measured variables. Any significant differences were further characterized by performed paired t-tests among all possible combinations of pretreatment and posttreatment values for each index. It was expected that as TBT increased, r would increase and MA would decrease, reflecting both a delay in clot formation and an aspirin-induced decrease in platelet adhesiveness, respectively. Repeated ANOVAs and appropriate post hoc comparisons were expected to substantiate a parallel increase in TBT and r posttreatment, decreasing with time from aspirin ingestion. MA was expected to demonstrate the reverse-a sharp decrease after aspirin ingestion with a return to normal within 1 week.
Results Tublr 1 shows the ranges, means, and standard deviations for the age, hemoglobin concentration, and platelet count in this sample of six males and two females. No abnormalities were found. Tuble 2 presents the summary data for the baseline measurements of TBT and TEG. These values compare favorably with published normal values.” F+re~ 1, 2 and 3 illustrate the changes over time (mean and 95% confidence intervals) for TBT and the four measured TEG indices. The results of a repeated measures ANOVA, as well as appropriate post hoc paired comparison t-tests, are indicated in the graphs and legends. TBT was significantly increased 4, 24, and 72 hours after aspirin ingestion, returning to baseline at 1 week. TBT at 1 week differed significantly from TBT at 4 and 24 hours, but not from 0 and 72 hours. None of the TEG indices demonstrated significant changes over the same time course.
Table
1.
Control Values
Variable
Age (yr)
Hemoglobin
Statistical Analysis Age, sex, and platelet count distributions, as well as pretreatment platelet function studies, were reported
k %)
Platelet count (X 1OOK)
Minimum 26 12.8
191
Maximum 60 16.1
280
Mean 34.5 14.4
229
J. Clin. Anesth., vol. 3, September/October 1991
SD 10.8 1.2
27.4
379
95% Error
Ears
lor Bleedlno
*1 I
IO.
8.
Time
tllCl”teS 4.
95X
Error
Bars
lor
TEG Indlces.
r and k
16. I4.
??
6.
’
‘8.
‘2. r IO. f nmutes a. 4 6.
I Ii x
i
4.
2.
2, O-
. 0
t
0
4
72
24
Hours after
Asprln
168
0
Hours after
lngest,on
Figure
1. Bleeding time over time after- aspirin ingestion. All values are means -t 1.96 SEM. p < 0.0.5 (:” = mean values significantly different from control mean).
72
24
4
Aspr~n
168
lngestw
2. ‘l‘h~~ornl~oelasto~~~~~~t~~ indices over time al’ter ;I+ pirin ingestion. All values are tneaus + 1.96 SEM (J = time tlom beginning of trace to 1 mm deflection; k = rime Irom 1 mm deflection (0 20 mm deflection). Figure
Discussion Second, These
data raise several
nificant
difference
of aspirin
points.
was shown
was ingested,
mean
First,
although
in TBT
after
TBT
a sig-
proached
mg
opposite
times were within
aspirin).
650
the changes significance from
that
in mean (p = 0.07),
expected
MA
over
time
ap-
but in a direction
(increasing
MA
after
Third, during this study it became apparent results of both tests vary widely, which means
the that
the normal range at all times. It may be that two or more doses of aspirin are effective in increasing bleeding time to abnormal values (X.5 minutes). As a follow-up, we tested two additional subjects after giving
they should be interpreted cautiously, individuals without comparison values.
them 650 mg of aspirin on 3 consecutive days. On the third day, TBT and TEG analyses were performed. TBT times exceeded the upper limit of normal (9.5
Fourth, we found an aspirin effect on bleeding time later than that reported by Dybdahl et al.” Figure 1 demonstrates that the maximum bleeding time oc-
minutes)
curred at 24 hours, which concurs with the finding of Amezcua et al8 Since estimates for maximum bleed-
differ 380
for both
from
baseline
subjects.
TEG
parameters
did not
measurements.
J. Clin. Anesth., vol. 3, September/October
1991
especially
in
TEG,
951
30. Degrees,
a
]
Error
Bars
for TEG Indlces:
1
II
i:
4 HOWS after
24 Asplrln
72
168
lngestlon
Figure 3. Thromboelastography indices over time after aspirin ingestion (u’ = [180 / n] . [arctan (IO/k)]; MA = maximum amplitude of tracing in mm).
ing time
appear
to involve
interpolation,
and Wults
Acknowledgments
IO. , 0
Trentulunge
tion. Rodgers and Levin ‘0 reviewed the value of TBT in clinical medicine. They found no evidence that bleeding time is a predictor of risk of hemorrhage or that bleeding time from a standard cut in the skin reflects the risk of bleeding elsewhere in the body.
a and MA
20.
0’
bleeding time, and aspirin:
this
finding
deserves further investigation for a more definitive answer. There are several reasons why the in vivo (TBT) test may detect differences in platelet function before the in vitro (TEG) test. The intravenous (IV) bleeding time, using an incision in the forearm, releases tissue thromboplastin, collagen, ADY, and other plateletstimulating substances in the microenvironment of the incision. The TBT test measures only the time to initial platelet plug formation and capillary retraction. The TEG test examines clot strength over time and is largely dependent on platelet retraction and platelet fibrin interaction. The TEG test uses blood obtained from within a blood vessel and, therefore, is isolated from these stimuli. Aspirin has been shown to inhibit the secondary wave of platelet aggregation. It would be expected that a test wherein platelets were stimulated would be more sensitive to low doses of inhibiting agents.* Finally, with the tests giving variable results, it is not possible to know which of the two would be more predictive of epidural bleeding in the clinical situation. TBT is currently the standard from which judgments regarding patient bleeding potential are made. Whether anesthesiologists are correct in using TBT as a predictor for potential morbidity remains a ques-
We would like to thank the staff of the Anesthesia Blood Gas Laboratory for their patience and assistance in performing this study.
References I. Spiess BD, Ivankovich AD: Thromboelastography: a coagulation-monitoring technique applied to cardiopulmonary bypass. In: Ellison N, Jobes DR, eds. I$‘jectiue Hemo.stusi,c in Cardiac Surgery. Philadelphia: WB Saunders, 1987:163-81. 2. DeGaetano G, Vermylen J: Effect of aspirin on the thromboelastogram of human blood. Thrombos Diuthes Hrvnorrh
1973;30:494-8.
3. Goldschmidt B, Stirland SJ, Fjarnstead PG: The effect of acetylsalicylic acid on platelet function in cyanotic congenital heart disease. Acta Paudiutr Stand 1974;63:869-74. 4. Loew D, Vinazzer H: Influence of simultaneous administration of low dose heparin and acetylsalicylic acid on blood coagulation and platelet functions. Ha~mostasis 1974;3:319-28. RI: Thromboelastography of human blood 5. Hawkins after aspirin. Clin Pharmucol Ther 1974; 13:274-s. 6. Dybdahl JH, Daae LNW, Eika C, Godal HC, Larsen S: Acetylsalicylic acid-induced prolongation of bleeding time in healthy men. Scund J Haemetol 1981;26:50-6. 7. Weiss HJ, Aledort LM, Kochwa S: The effect of salicylates on the hemostatic properties of platelets in man. 1 Cliu Inves/ 1968;47:2 169-N. 8. Amezcua JL, O’Grady J, Salmoy JA, Moncada S: Prolonged paradoxical effect of aspum on platelet behaviour and bleeding time in man. Thromb Res 1979; 16:6979. L, Cohen E, Vagher JP, Caprini JA: Com9. Zuckerman parison of thromboelastography with common coagulation tests. Thromb Haemost 1981;46:752-6. 10. Rodgers RPC, Levin J: A critical reappraisal of the bleeding time. Semin Thromb Hemostas 1990; 16: l-20.
*Bruce Spiess, MD, Chief, Division of’Cardiothoracic Anesthesia, University of Washington School of Medicine, Seattle, WA.
J. Clin. Anesth., vol. 3, September/October
1991
381
Study
of Anesthesiology,
Oljective:
togruphy (TEG)
UCLA
School
of Medicine,
Los Angeles,
To compare templute bleeding time (TBT)
CA.
with thromboelus-
in human subjects qfter uspirin ingestion.
Health! volunteers whre gizlen a single 650 mg dose qf aspirin or u dose
Design:
qf 650 mg of uspzrin on three successive days. TBT and TEG studies were PeTformed prior to uspirin ingestion and 4, 24, 72, and 168 hours after iqestion.
Setting: Inpatient operating room support urea at the UCLA Center,for Health Sciences. Volunteers:
Residents and nurses who were in good generul heulth, had not taken
aspirin fvr 2 weeks, had normul platelet counts, and hud no exjidence of bleeding or cougulution disorders. Intervention: TBT and TEG studies were performed
prior to and qfter the
ingestion of uspirin. J. Clin. Anesth.
3:377-381,
1991
Measurements and Main Results: TBT studies were significantly prolonged ut 4,24, and 72 hours compared with controls. Muximum bleeding time prolongution occurred 24 hours ufter aspirin iqestion.
Bleeding time returned to control values
“Resident
by the end of‘ 168 hours (1 week). No TEG pammeter
tProfessor
by aspirin ingestion. &clusion: TEG results muy not ider$ty patients who huve an increased bleeding
Address reprint requests to Dr. Waits at the Department ot‘ Anesthesiology, UCLA School of Medicine, Los Angeles, CA 900241778, USA. Received f’or publication April 24, 1990; revised manuscript accepted for publication January 3 I, I99 I.
0 I991 Butterworth-Heinemann
was sign$icuntly
changed
time us u result qf uspirin ingestion.
Keywords: Thromboelastography; tests; aspirin.
bleeding time; platelet function
Introduction Aspirin prolongs bleeding time. For this reason, anesthesiologists itant
to perform
regional
nerve
blocks
J. Clin. Anesth.,
in patients
who
have
vol. 3, September/October
are hes-
recently
1991
in-
377
gested aspirin. It is a poliq at L:(LA 10 test these patients for prolonged bleeding using the template bleeding time (-I‘B’I‘). If the bleeding time falls withregional anesthesia may be in the normal range, elected. TBT tests are labor-intensive. ‘I’heir performance requires a laboratory technician from the central laboratory to come to the patient’s bedside. Experience has shown that test results are rarely obtained in less than 4 hours (primarily due to the lack of technicians to perform the study). In addition to the operating room (OR) delays fi)r scheduled cases, this time lag precludes the test’s performance fi)r emergency operations (P.R., axillary nerve blocks for digit reimplan‘I-he thromboelastograph (‘TEC;) is an tation). instrument available in many anesthesia laboratories and is used to evaluate bleeding and clotting functions. Spiess and Ivankovich’ state. “Template Bleeding Times are not practical for use in the operating room setting. Howe\,er, data on both platelet number and function can be obtained by TE(; analysis. l’erhaps anesthesiologists could safely proceed with regional anesthesia procedures when the TE(; is IKH-I~~~” (p. 179). Previous studies of the effect of’ aspirin on ‘I‘EG have produced conflicting results. De(;aetano and Vermjllen:! gave volunteers 1 g of aspirin. The ‘I’EG results were unchanged 2 hours after ingestion. Goldschmidt Pt al.“ gave children with cyanotic congenital heart disease 500 mg of aspirin orally for 3 days. On the third clay, there was no change in the TEG findings. Loew and Vinazzer’ studied patients suffering from thrombophlebitis or postthrombotic syndrome. They gave the patients 500 mg of aspirin three times daily for 6 days. For the first 3 days, the aspirin was combined with heparin (5,000 units twice daily), and for the last 3 days, it was given alone. The patients’ blood was studied at an unspecified time following the final aspirin ingestion. The authors reported no effect of the aspirin on ‘I‘EC;. Hawkins5 studied TEG in 17 healthy volunteers 2 hours after the ingestion of 600 mg of aspirin. Contrary to the previous findings, she noted a significant prolongation of- the reaction time, initial clotting speed, and was no alteration in total coagulation time. There either the maximum clot elasticity or the time taken to reach this value, nor was there any change in clot retraction. This study evaluates platelet function after ingestion of aspirin by both TBT and TEG. ‘I-he study was designed to repeat these tests at varying time intervals to determine whether changes could be found and, if so, to follow the pattern of change and determine when values returned to normal.
378
J. Clin. Anesth.,
vol. 3, SepternbetYOctober
1991
Materials and Methods
b;igtit health: adult volunteer males and females \I’C’ (’ I srudicd. Sublects were excluded from this study if the\ had ingesteil aspirin within the past 2 weeks OI- had an allergy or sensitivitv 10 aspirin, uremia, \~)II Willebrand’s disease, or rhrornbocytopenia. ‘I-he st u(l), \Y‘IS approved bv the UCLA School of Medicine Human Subject I’roiection (:omniittee. All voluiiteers signed a consent f’orm fbr participation in the sTrdy, b\.it hdrawal of’ blood, and perfi~rn~ance of’ the ‘I‘B’I‘ test. All volunteers were screened by I‘B’I‘, ~I‘EX;, mid values were platelet count. ‘l‘hose having abnormal excluded.
After being trained by clinical laboratory personnel, we performed all the ‘I‘B’I‘ tests. With the volunteers seated comfortably, the skin of the forearm was cleansed with an isopropyl alcohol swab and allowed to air dry. A sphygmomanometer cuff was applied to the upper arm and inflated to 40 mmHg for the duration of’ the test. Next, a template (Simplate II, Organo11 ‘I‘echnika. Durham, NC:) was applied to ;I previouslv cleansed hairless area of’ the forearm, and the mechanism was tripped, causing the blades to make two 5 mm long by 1 mm deep longitudinal skin incisions. (Jean filter paper was applied to the borders of‘ the clot every 30 seconds without disturbing the tissue edges until the filter paper came away without any blood. ‘I‘he mean time in minutes for the two incisions were recorded as the .rBT. The manufacturer listed the expected range (mean i two standard deviations) as approximately 2.3 to 9)..5 minutes. ‘I‘hese values for normal were verified and accepted as IIOI‘ma1 by our clinical laboratory.
Tlzromhoelustoffraph
Ana@is
The samples for native (whole blood) ‘I‘EG analysis were drawn before or after TBT on a random basis. After the skin of the forearm was cleansed, an unheparinized syringe was used to draw 2 to 3 ml of blood from an appropriate vein. A timer was started as soon as the sample was completely collected. After 4 minutes of gentle rolling of the sample syringe, a portion of the sample was injected into a plastic cup. A micropipet was used to measure 0.35 ml of blood, which was placed in a clean, stainless steel cuvette.
TEG, bleeding time, and aspirin: Trentulunge and Wults
The piston was lowered into the sample, and a small needle was used to eliminate any bubbles. Mineral oil (1 to 2 drops) was placed on the surface of the sample to eliminate the blood-air interface. When possible, two studies were performed on each sample, and the mean of the measured indices was recorded. All TEG measurements were made on a thromboelastograph D (Haemoscope Corporation, Glenview, IL) by laboratory technicians familiar with the machine’s operation. Each tracing was then coded so that indices could be coded in a blinded fashion at the completion of data gathering for that subject. Indices were then measured and verified directly from the tracing. The r value was defined as the time from the beginning of the tracing (4 to 5 minutes after blood drawing) to the point at which the tracing was 1 mm wide. The k value was defined as the time from the r value (1 mm) to the point at which the tracing was 20 mm wide. Both these indices were measured in millimeters from the tracing and converted to minutes (paper speed = 2 mm/min). The alpha” value was calculated from the k value (adjacent limb) and the width of the tracing (20 mm / 2 = 10 mm): alpha” = (180 / pi) . arctan (10/k). Finally, MA was defined as the maximum amplitude of the tracing in millimeters.
Platelet Count One to 3 ml of blood was sterilely withdrawn from the forearm of each subject using a preheparinized syringe and analyzed by trained laboratory technicians for hemoglobin, hematocrit, and platelet count using a Cell-Dyn 1600 analyzer (Sequoia-Turner, Mountain View, CA).
Design Following determination of initial values for platelet count and TBT and TEG measurements, each volunteer was given 650 mg of aspirin orally. Previously, Dybdahl et al.” calculated the maximum bleeding time to occur at 2.4 to 2.6 hours after aspirin ingestion. They and others7.* observed that bleeding times returned to normal within 5 to 6 days. Therefore, repeat studies were done at 4 hours, 24 hours, 72 hours, and 168 hours (1 week; arbitrarily selected to demonstrate the effect of aspirin on the measured values).
to ensure effective screening procedures, baseline values comparable to other studies, and relevance of these results. Next, data were examined for normality and outlying values. Assuming normally distributed data, repeated measures analysis of variance (ANOVA) was used to assess differences over time within the measured variables. Any significant differences were further characterized by performed paired t-tests among all possible combinations of pretreatment and posttreatment values for each index. It was expected that as TBT increased, r would increase and MA would decrease, reflecting both a delay in clot formation and an aspirin-induced decrease in platelet adhesiveness, respectively. Repeated ANOVAs and appropriate post hoc comparisons were expected to substantiate a parallel increase in TBT and r posttreatment, decreasing with time from aspirin ingestion. MA was expected to demonstrate the reverse-a sharp decrease after aspirin ingestion with a return to normal within 1 week.
Results Tublr 1 shows the ranges, means, and standard deviations for the age, hemoglobin concentration, and platelet count in this sample of six males and two females. No abnormalities were found. Tuble 2 presents the summary data for the baseline measurements of TBT and TEG. These values compare favorably with published normal values.” F+re~ 1, 2 and 3 illustrate the changes over time (mean and 95% confidence intervals) for TBT and the four measured TEG indices. The results of a repeated measures ANOVA, as well as appropriate post hoc paired comparison t-tests, are indicated in the graphs and legends. TBT was significantly increased 4, 24, and 72 hours after aspirin ingestion, returning to baseline at 1 week. TBT at 1 week differed significantly from TBT at 4 and 24 hours, but not from 0 and 72 hours. None of the TEG indices demonstrated significant changes over the same time course.
Table
1.
Control Values
Variable
Age (yr)
Hemoglobin
Statistical Analysis Age, sex, and platelet count distributions, as well as pretreatment platelet function studies, were reported
k %)
Platelet count (X 1OOK)
Minimum 26 12.8
191
Maximum 60 16.1
280
Mean 34.5 14.4
229
J. Clin. Anesth., vol. 3, September/October 1991
SD 10.8 1.2
27.4
379
95% Error
Ears
lor Bleedlno
*1 I
IO.
8.
Time
tllCl”teS 4.
95X
Error
Bars
lor
TEG Indlces.
r and k
16. I4.
??
6.
’
‘8.
‘2. r IO. f nmutes a. 4 6.
I Ii x
i
4.
2.
2, O-
. 0
t
0
4
72
24
Hours after
Asprln
168
0
Hours after
lngest,on
Figure
1. Bleeding time over time after- aspirin ingestion. All values are means -t 1.96 SEM. p < 0.0.5 (:” = mean values significantly different from control mean).
72
24
4
Aspr~n
168
lngestw
2. ‘l‘h~~ornl~oelasto~~~~~~t~~ indices over time al’ter ;I+ pirin ingestion. All values are tneaus + 1.96 SEM (J = time tlom beginning of trace to 1 mm deflection; k = rime Irom 1 mm deflection (0 20 mm deflection). Figure
Discussion Second, These
data raise several
nificant
difference
of aspirin
points.
was shown
was ingested,
mean
First,
although
in TBT
after
TBT
a sig-
proached
mg
opposite
times were within
aspirin).
650
the changes significance from
that
in mean (p = 0.07),
expected
MA
over
time
ap-
but in a direction
(increasing
MA
after
Third, during this study it became apparent results of both tests vary widely, which means
the that
the normal range at all times. It may be that two or more doses of aspirin are effective in increasing bleeding time to abnormal values (X.5 minutes). As a follow-up, we tested two additional subjects after giving
they should be interpreted cautiously, individuals without comparison values.
them 650 mg of aspirin on 3 consecutive days. On the third day, TBT and TEG analyses were performed. TBT times exceeded the upper limit of normal (9.5
Fourth, we found an aspirin effect on bleeding time later than that reported by Dybdahl et al.” Figure 1 demonstrates that the maximum bleeding time oc-
minutes)
curred at 24 hours, which concurs with the finding of Amezcua et al8 Since estimates for maximum bleed-
differ 380
for both
from
baseline
subjects.
TEG
parameters
did not
measurements.
J. Clin. Anesth., vol. 3, September/October
1991
especially
in
TEG,
951
30. Degrees,
a
]
Error
Bars
for TEG Indlces:
1
II
i:
4 HOWS after
24 Asplrln
72
168
lngestlon
Figure 3. Thromboelastography indices over time after aspirin ingestion (u’ = [180 / n] . [arctan (IO/k)]; MA = maximum amplitude of tracing in mm).
ing time
appear
to involve
interpolation,
and Wults
Acknowledgments
IO. , 0
Trentulunge
tion. Rodgers and Levin ‘0 reviewed the value of TBT in clinical medicine. They found no evidence that bleeding time is a predictor of risk of hemorrhage or that bleeding time from a standard cut in the skin reflects the risk of bleeding elsewhere in the body.
a and MA
20.
0’
bleeding time, and aspirin:
this
finding
deserves further investigation for a more definitive answer. There are several reasons why the in vivo (TBT) test may detect differences in platelet function before the in vitro (TEG) test. The intravenous (IV) bleeding time, using an incision in the forearm, releases tissue thromboplastin, collagen, ADY, and other plateletstimulating substances in the microenvironment of the incision. The TBT test measures only the time to initial platelet plug formation and capillary retraction. The TEG test examines clot strength over time and is largely dependent on platelet retraction and platelet fibrin interaction. The TEG test uses blood obtained from within a blood vessel and, therefore, is isolated from these stimuli. Aspirin has been shown to inhibit the secondary wave of platelet aggregation. It would be expected that a test wherein platelets were stimulated would be more sensitive to low doses of inhibiting agents.* Finally, with the tests giving variable results, it is not possible to know which of the two would be more predictive of epidural bleeding in the clinical situation. TBT is currently the standard from which judgments regarding patient bleeding potential are made. Whether anesthesiologists are correct in using TBT as a predictor for potential morbidity remains a ques-
We would like to thank the staff of the Anesthesia Blood Gas Laboratory for their patience and assistance in performing this study.
References I. Spiess BD, Ivankovich AD: Thromboelastography: a coagulation-monitoring technique applied to cardiopulmonary bypass. In: Ellison N, Jobes DR, eds. I$‘jectiue Hemo.stusi,c in Cardiac Surgery. Philadelphia: WB Saunders, 1987:163-81. 2. DeGaetano G, Vermylen J: Effect of aspirin on the thromboelastogram of human blood. Thrombos Diuthes Hrvnorrh
1973;30:494-8.
3. Goldschmidt B, Stirland SJ, Fjarnstead PG: The effect of acetylsalicylic acid on platelet function in cyanotic congenital heart disease. Acta Paudiutr Stand 1974;63:869-74. 4. Loew D, Vinazzer H: Influence of simultaneous administration of low dose heparin and acetylsalicylic acid on blood coagulation and platelet functions. Ha~mostasis 1974;3:319-28. RI: Thromboelastography of human blood 5. Hawkins after aspirin. Clin Pharmucol Ther 1974; 13:274-s. 6. Dybdahl JH, Daae LNW, Eika C, Godal HC, Larsen S: Acetylsalicylic acid-induced prolongation of bleeding time in healthy men. Scund J Haemetol 1981;26:50-6. 7. Weiss HJ, Aledort LM, Kochwa S: The effect of salicylates on the hemostatic properties of platelets in man. 1 Cliu Inves/ 1968;47:2 169-N. 8. Amezcua JL, O’Grady J, Salmoy JA, Moncada S: Prolonged paradoxical effect of aspum on platelet behaviour and bleeding time in man. Thromb Res 1979; 16:6979. L, Cohen E, Vagher JP, Caprini JA: Com9. Zuckerman parison of thromboelastography with common coagulation tests. Thromb Haemost 1981;46:752-6. 10. Rodgers RPC, Levin J: A critical reappraisal of the bleeding time. Semin Thromb Hemostas 1990; 16: l-20.
*Bruce Spiess, MD, Chief, Division of’Cardiothoracic Anesthesia, University of Washington School of Medicine, Seattle, WA.
J. Clin. Anesth., vol. 3, September/October
1991
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