(Circulation. 1997;96:569-574.)
© 1997 American Heart Association, Inc.
Articles |
Aprotinin Inhibits Plasmin-Induced Platelet Activation During Cardiopulmonary Bypass
From the Division of Cardiovascular Surgery (O.S., T.J., Y.T., N.A., Y.S., T.M.) and the Division of Hematology (H.K., T.N.), Institute of Clinical Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan.
Correspondence to Dr Osamu Shigeta, Institute of Clinical Medicine, University of Tsukuba, Tsukuba, Ibaraki 305, Japan.
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Abstract |
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Background In the past few years, aprotinin has been used in cardiac surgery with impressive results of reducing blood loss, but several adverse effects of aprotinin also have been reported. One of the most likely mechanisms is the inhibition of plasmin by aprotinin, although this indirect effect has not been reproduced in all experimental studies.
Methods and Results We evaluated the platelet function
and fibrinolytic activity during human cardiac surgery, with or without
aprotinin. During cardiopulmonary bypass (CPB) in humans
without aprotinin (n=16), decrease of platelet aggregation induced
by thrombin, increase of 
-granule secretion of platelet and
microparticle formation, and increase of
plasmin/2-antiplasmin complex (PIC) were observed. In
contrast, low-dose aprotinin (1.0x106 KIU), which was
administered only into the priming fluid of extracorporeal circuits
(n=10), maintained platelet aggregation induced by thrombin and
reduced -granule secretion and microparticle formation of
platelets during CPB. In vitro, plasmin (0.8 CU/mL) released
-granules of washed platelets, and this activation was
completely inhibited by aprotinin (10 KIU/mL).
Conclusions Aprotinin has indirect effects to inhibit platelet activation, and this may partly explain the reduction of blood loss during cardiac surgery. To prevent the adverse effects, a single and minimal use of aprotinin is important. The results of in vivo and in vitro studies suggest that platelet preservation was demonstrated by the lower concentration of aprotinin (1.0x106 KIU per patient or 10 KIU/mL) compared with the concentration that inhibits plasma fibrinolysis.
Key Words: platelets • cardiopulmonary bypass • surgery • fibrinolysis
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Bleeding is one of the major complications after CPB, and extensive homologous transfusion may transmit viral hepatitis and acquired immunodeficiency syndrome. To reduce blood loss after cardiac surgery, platelet-protective drugs were investigated in many clinical centers.1 2 3 4 5 In the past few years, aprotinin has been used in cardiac surgery and impressive result were obtained,6 7 8 9 10 but several adverse effects of aprotinin have been reported including disseminated intravascular coagulation, acute anaphylaxis, and acute renal failure.11
Aprotinin (Trasylol; Bayer AG) is a low-molecular-weight (6512 Dalton) peptide isolated from bovine lung containing 16 different amino acids in a chain of 58 members, forming a kringle domain shape with three disulfide bonds (cysteine-cysteine bridges), and inhibits enzymatic activity of trypsin, kallikrein, and plasmin.11 Approximately 50 KIU/mL of aprotinin is required to inhibit plasma plasmin and about 200 KIU/mL to inhibit plasma kallikrein.12 The plasma half-life of aprotinin is <1 hour.13 The drug was first used in cardiac surgery in the early 1960s when it was thought that excessive postoperative bleeding was due to increased fibrinolysis.11 Additionally, aprotinin in high doses completely inhibited kallikrein-induced activation of neutrophils.14
One of the most likely mechanisms of the reduction in blood loss in cardiac surgery is the inhibition of plasmin by aprotinin. However, this indirect effect has not been reproduced in all experimental studies and remains unconfirmed in the clinical state.
In this study we focused on platelet activation by plasmin and the inhibitory effect of aprotinin on platelet activation during clinical CPB and in in vitro experiments.
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Methods |
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From September 1995 to September 1996, platelet functions were measured in 26 adult patients who did not receive any antiplatelet drugs within 10 days before surgery and underwent CPB without blood transfusions at the University of Tsukuba Hospital. Ten patients (aprotinin group) underwent cardiac surgery with aprotinin administration only into the oxygenator priming fluid at the beginning of CPB. Sixteen patients (control group) had cardiac surgery without aprotinin. One patient in the aprotinin group needed the oxygenator exchange because of fluid leakage. Other patients underwent the operation uneventfully. The mean age and weight of the control and aprotinin groups were almost the same (Table
). The duration of CPB
ranged between 2 and 3 hours.
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Conventional methods of anesthetic treatment and CPB were used in both groups. The anesthesia was induced with fentanyl citrate (10 µg/kg). Heparin (Novo Nordisk A/S) was administered at an initial dose of 3 mg/kg through venous catheters. Activated clotting time was maintained for >400 seconds throughout CPB. A membrane oxygenator (HPO-25RHF, MERA) and a roller pump were used in the extracorporeal circuit. Blood flow was maintained at 2.5 L/m2 per minute. Multidose cold crystalloid cardioplegic solution was used for myocardial preservation. Systemic hypothermia (30°C to 32°C) was maintained during aortic cross-clamping.
Sample Preparation
Five milliliters of blood was collected from patients at six
separate times: at the start of the surgery; 5 minutes after heparin
administration; 5 minutes, 1 hour, 2 hours, and 3 hours after the start
of CPB; or at the end of CPB through an arterial blood
pressure monitor catheter. Four milliliters of whole blood was mixed
with 0.5 mL of ACD solution (citric acid 6.8 mmol/L,
trisodium citrate 11.2 mmol/L, glucose 24
mmol/L) at room temperature. The rest of the whole blood (1 mL)
was placed in a tube containing ethylenediaminetetraacetic acid (EDTA)
for blood cell count. In some patients (control group, n=5; aprotinin
group, n=2), 100 µL of plasma was stored at -20°C for
analysis of PIC.
Platelet-Rich Plasma
The blood, mixed with ACD, was centrifuged at
180g for 10 minutes at room temperature, and PRP was
obtained. A 100-µL sample of PRP was fixed with 1%
paraformaldehyde (E Merck) for flow cytometric
analysis.
Washed Platelets
To wash the platelets or dilute the antibodies, PIPES buffer
(PIPES 5 mmol/L, Dojindo; NaCl 145 mmol/L, KCl
4 mmol/L, Na2HPO4 0.5
mmol/L, MgCl2 1 mmol/L, glucose 5.5
nmol/L, and bovine albumin 3.5 mg/mL, pH 7.4) was
prepared. The rest of the PRP was mixed with an equal volume of washing
buffer (1:8, ACD solution:PIPES buffer) and then centrifuged at
400g for 15 minutes at room temperature. The platelet
pellet was resuspended gently and washed again with the same solution.
The pellet was finally suspended in PIPES buffer at the concentration
of 2.0x108/mL for the assay of thrombin-induced
platelet aggregation.
For in vitro studies, venous blood from healthy volunteers who had no
medication for at least 10 days before donation was collected into
plastic tubes containing ACD buffer. The washed platelet
preparation was carried out by the same methods described in in vivo
studies. The washed platelets were incubated with aprotinin or
tranexamic acid (Transamin-S, Daiich Pharmacy Co) or
plasminogen (Chromogenix AB) for 15 minutes at 37°C
followed by incubation with human -thrombin (Green Cross) for 5
minutes or plasmin (Chromogenix AB) for 15 minutes and then fixed with
1% paraformaldehyde.
Platelet Aggregation
The platelet aggregation study was performed with the use of
Hema Tracer (SSR Engineering Co Ltd). The threshold concentration of
thrombin (that is, the lowest concentration of the agonist capable of
producing irreversible aggregation of at least 60% to 70% light
transmission of buffer in 5 minutes) was determined with the sample of
the start of operation. The same concentration of thrombin was used to
determine the percent aggregation of washed platelets in all
subsequent samples.
Expression of CD-62, CD42b, and CD41b by Flow Cytometric
Analysis
Platelet surface antigen was stained with FITC-labeled or
phycoerythrin-labeled mAb and analyzed by flow cytometry
(FACSort; Becton Dickinson). The mAbs used in this study are as
follows: CD62-PE (Becton Dickinson), a mAb that recognizes -granule
membrane protein (GMP-140) expressed on the platelet surface after
platelet secretion (and we consider that this is a kind of
platelet activation); CD42b (DACO A/S), a mAb against GPIb; and
CD41b (TP80, Nichirei), a specific anti-GPIIb/IIIa antibody.
A 20-µL aliquot of each fixed platelet (PRP) sample was incubated with 5 µL of 1:5 diluted mAb (saturating concentration of the antibodies of DC62 or CD42b or CD41b) in the dark for 30 minutes at room temperature to allow antibody binding. The samples mixed with CD42b or CD41b were incubated again with the second antibody (FITC-conjugated goat anti-mouse IgG, DACO A/S) in the dark for 30 minutes at room temperature, and then 400 µL of ISOTON II (Coulter, Inc) solution was added to dilute the samples.
Platelet -granule secretion was monitored by detection of
GMP-140 (CD62) expression on the platelet surface. The threshold
level for GMP-140–negative cells was set to include 98% of nonstained
platelets. Microparticles were identified by gating on GPIIb/IIIa
(CD42b)-positive events and distinguished from normal-sized
platelets by forward scatter size analysis (the forward
scatter cutoff was set to the immediate left of the signal intact
platelet population of a resting PRP sample).15 Ten
thousand positive platelet events were analyzed, and
microparticles were reported as a percentage of total platelet
events.
PIC Analysis
To evaluate the fibrinolytic activity during CPB, PIC was
measured with the frozen plasma with the use of the PIC test kit
(Teijin Diagnostics).
Statistical Analysis
The results are expressed as mean±SE. The effects of aprotinin
on platelet aggregation, GMP-140 expression, and microparticle
formation at various times during CPB were compared by Student's
unpaired t test. A value of P<.05 was considered
significant.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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In Vivo Studies
In the control group, platelet counts corrected by hematocrit and the expression of mean platelet surface antigen (GPIb or GPIIb/IIIa) did not show significant differences during 2 to 3 hours of CPB (Fig 1
, A through C).
However, the thrombin-induced platelet aggregation in the control
group showed significant decrease during 2 hours of CPB. In addition,
the percentage of GMP-140–positive platelets increased 5 minutes
after the start of CPB, and microparticles also increased throughout
CPB (Fig 1, D through F).
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—
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Aprotinin (1.0x106 KIU) administered at the start of CPB
did not affect the platelet count corrected by hematocrit or the
expression of mean platelet surface antigen GPIb or GPIIb/IIIa for
2 to 3 hours of CPB. However, the thrombin-induced platelet
aggregation was maintained at a high level during CPB and showed
significant differences between the aprotinin group versus the control
group 5 minutes after the start of CPB (65±4% versus 43±6%,
P=.010), 1 hour after the start of CPB (63±7% versus
44±6%, P=.042), and after CPB (63±5% versus 43±8%,
P=.046) (Fig 1D
). Aprotinin also attenuated -granule
secretion of platelets and showed significant differences between
the two groups at 5 minutes after the start of CPB (20.2±2.6% versus
29.5±2.8%, P=.049) (Fig 1E) and reduced microparticle
formation of platelets at 1 hour after the start of CPB (5.6±0.6%
versus 12.8±2.2%, P=.013) (Fig 1F).
Fig 2 shows PIC concentration during CPB. The decrease
of PIC concentration at the start of CPB may be due to hemodilution.
Since the activated plasmin concentration relates to the rate
of change of PIC, the increase of PIC during CPB in the control group
indicates that the activation of plasminogen occurred
constantly after the start of CPB. In contrast, the concentration of
PIC in the aprotinin group was kept at a lower value during the first
hour of CPB.
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In Vitro Studies
In the study of washed platelets incubated with thrombin, the
percentage of GMP-140–positive platelets increased in a
concentration-dependent manner. A full activation (
80% to 90% of
platelets express GMP-140 antigen on the surfaces) was obtained by
thrombin at the concentration of 0.1 unit/mL. With the same
platelets, aprotinin (200 units/mL or 400 units/mL), incubated for
15 minutes in 37°C before thrombin stimulation, did not show any
effects on thrombin-induced GMP-140 expression on the surfaces of
platelets (Fig 3).
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——
The washed platelets, incubated with plasmin for 15 minutes at
37°C, also showed the increase of percentage of GMP-140–positive
platelets (Fig 4). The
full secretion of -granules of the platelets was obtained by
incubation with plasmin at the concentration of >1.0 CU/mL. In the
lower concentration of plasmin incubation (0.8 CU/mL), there were
several minutes of nonresponse periods at the beginning of the
incubation, and the maximum secretion was obtained after 15 minutes of
incubation at 37°C (Fig 5).
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Fig 6 shows that aprotinin inhibited the -granule secretion induced
by plasmin. In this
experiment, washed platelets were incubated with aprotinin for 15
minutes at 37°C followed by incubation with plasmin (0.8 CU/mL) for
15 minutes at 37°C. The complete inhibition of the -granule
secretion was obtained by 10 KIU/mL of aprotinin. Tranexamic acid and
plasminogen also reduced the GMP-140 expression on the
surfaces of washed platelets induced by plasmin in a
concentration-dependent manner (Fig 7).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Platelet analysis by flow cytometry and thrombin-induced platelet aggregation (platelet count adjusted) have an advantage that the data have no need to be corrected by hemodilution. The value of the percentage of GMP-140–positive platelets and microparticles in the samples at the start of surgery was relatively higher than those in healthy donors (GMP-140, 4.5±2.5%; microparticles, 3.6±1.4%; n=10). This may be due to the time loss between the collection of samples and the platelet fixation by 1% paraformaldehyde.
Van Oeveren and associates16 demonstrated the decrease of GPIb (receptor to von Willebrand factor) by 50% in the untreated patients during CPB, whereas GPIb did not decrease in the aprotinin-treated patients (6.0x106 KIU or 2.0x106 KIU per patient).17 To the contrary, Winters and associates18 reported that during pharmacological fibrinolysis, the inhibition of platelet function in plasma was not due to degradation of platelet adhesive receptors. In our study, GPIb and GPIIb/IIIa receptors on the surface of platelets were not changed significantly before and during bypass. The increase of microparticle formation may explain the decrease of GPIb or GPIIb/IIIa receptors per platelet during CPB, even though the concentration of the receptors on the platelet surface was not changed.
Wachtfogel et al14 suggested that the protective effect of aprotinin on platelets is probably indirect and is due to inhibition of various platelet agonists that are produced during CPB, but they did not show the effect of plasmin to platelets because endothelial cells are not present and plasmin is not generated in their simulated extracorporeal circulation model.
During CPB, many factors including thrombin, ADP, collagen,
epinephrine, temperature, share stress, and contact with a
synthetic surface may activate the platelets. To evaluate
the -granule secretion by thrombin in vitro, platelets were
washed to prevent coagulation and incubated with thrombin. The
percentage of GMP-140–positive platelets was increased by
thrombin, although aprotinin had no effect on the activation of
platelets by thrombin (Fig 3). ADP also increased GMP-140
expression on the surfaces of platelets in PRP, and aprotinin did
not show any effect (data not shown).
At this point, we tested the effect of plasmin on platelets because
aprotinin is one of the plasmin inhibitors. As shown in
Figs 4 and 5, plasmin enhanced the -granule secretion of washed
platelets but required longer times to get the maximum secretion of
platelets than did thrombin or ADP.19 Mean
fluorescence intensity of GPIb-FITC and GPIIb/IIIa-FITC on the
surface of washed platelets incubated with plasmin did not show
significant differences in in vitro study. The enhancement of
-granule secretion induced by plasmin was not detected in PRP, which
contains a large amount of 2-plasmin
inhibitors. Washed platelet aggregation induced by
plasmin (0.8 CU/mL) was observed at 15 to 20 minutes of incubation at
37°C, and Ca2+ (3 mmol/L) attenuated this
aggregation (data not shown). Winters et al18 and others
also reported that platelet adhesive receptors (GPIIb/IIIa, GPIb,
GPIa) were degraded by plasmin at 37°C in the absence of exogenous
Ca2+. The mechanism of these results was not clear, but
platelet activation by plasmin has a time lag in response and
depends on Ca2+ and temperature.20 21
Aprotinin inhibits the catalytic activity of plasmin at the dose of 50
KIU/mL, and this was one of the reasons that a high dose
(6x106 KIU per patient) of aprotinin was administered in
patients undergoing cardiac surgery.11 We used
1.0x106 KIU of aprotinin in patients, and the
platelets were preserved during 2 to 3 hours of CPB. Platelet
functions were not measured after 3 hours of CPB because blood
transfusion was done in most cases. The additional aprotinin might be
required to protect platelets after 2 hours of CPB. In the in vitro
study, 10 KIU/mL of aprotinin completely inhibited the enhancement of
the washed platelet -granule secretion induced by plasmin (Fig 6). Tranexamic acid binds to lysin binding sites and inhibits the
binding of plasmin to fibrin.22 23 The activation of
washed platelets by plasmin was completely inhibited by tranexamic
acid at a concentration of 2.5 mg/mL (Fig 7).
Plasminogen also inhibited platelet activation by
plasmin, but the complete inhibition was not achieved even with
plasminogen, with a concentration 4 times higher than
plasmin (Fig 7). These indicate that both the catalytic center and the
lysin binding sites of plasmin are required to release -granules of
washed platelets, and plasminogen showed competitive
binding to the surface of platelets with plasmin. If plasmin binds
to the surface of platelets, and the triplets of plasmin,
plasminogen activator, and platelets (or
platelet fibrin) are formed,24 plasmin on the surface
of platelets may be resistant to the inactivation by
2-antiplasmin in plasma, and lower concentrations of
plasmin may activate the platelet.
Platelet activation by plasmin is one of the serious problems in the treatment of patients who have received thrombolysis therapy because tissue plasminogen activator might cause another thromboembolism after the recanalization of blood vessels.25 26 27 Identification of plasmin receptors on the surface of platelets and control of platelet activation by plasmin are important subjects.
Conclusions
The conversion of plasminogen to plasmin was caused
during CPB, and aprotinin protected platelets during CPB in vivo
and inhibited the washed platelet -granule secretion induced by
plasmin in in vitro studies. This suggests that aprotinin inhibits
plasmin-induced platelet activation, and this may partly explain
the reduction of blood loss during cardiac surgery.
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Selected Abbreviations and Acronyms |
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Received October 31, 1996; revision received December 17, 1996; accepted January 2, 1997.
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References |
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