Intraoperative coronary thrombosis: Can aprotinin and protamine be incriminated?

CASE REPORTS

Intraoperative

Coronary Thrombosis: Can Aprotinin Incriminated?

Vincent

T

HE USE OF aprotinin, advocated

recently

Umbrain,

a proteinase for coronary

MD, Frank Christiaens,

inhibitor. artery

to prevent postoperativc

surgery (CABG) aprotinin

on hemostasis are related receptors

GpI,,

and

Gp

Thc effccts of

to the prcscrvation II,-JII;,.

which

of

MD, and Frederic

gen-plasmin

Camu,

intcraction,

Be

MD

which rapidly disaggrcgatcs platc-

Iets.”

blood loss and

decrease homologous bloed requirements.1-4 platelet

has been

bypass graft

and Protamine

Three patients who received aprotinin

during CABG

and

whom following the administration of protaminc massive graft occlusion occurred are reported. in

assure

cells or thc adhesion to damaged cndothelial subendothelial layer. and to an inhibition of the serum proteases kallikrein and plasmin. Aprotinin also inhibits thc coagulation factors XIIa, Xla, IXa, and VIIla, resulting in artifactual prolongation of indices of anticoagulation that measure the intrinsic coagulation cascade. Howcvcr, this agent has no effect on thc cxtrinsic coagulation cascade because it does not influcnce activation of factor Vl1 or subsequent fibrin generation.’ Trcatment with inhibitors of fibrinolysis may theoretically be associated with an incrcascd risk of a thrombotic tendency. In two recent European multicenter studies. no adverse cardiovascular events were reported following aprotinin thcrapy. J.5 Howevcr, Böhrer et al” noticed increascd thrombus formation in aprotinin-treated paticnts. Unexplained thrombosis has also been observed following thc usc of aprotinin in CABG.’ Aside from defective tibrinolyplatelct

sis othcr factors may also contribute

to intravascular

High-dose

steroids

A 70-year-old

have

Relevant

cardiomyopathy

since

arterial

hypcrtcnsion.

ization

showed

tinin be incriminated?

by two editorials.

J Cardiothorac

sis: Can protamine Anesth 8:142-143.

be incriminated?

Vast

Please sec:

segment analysis of inferior pressure monitoring.

.md sufentanil

(SpO:),

and

and

an ejection

apical fraction

orally and includ-

with continuous

ST

leads, and radial artery and 2.5 kg!kg

artety

was maintained

of sufenta-

catheterization

was per-

with 50% Or/NzO

(total dose: 17 ugikg)

Coagulation

activated clotting time (ACT.

mg.

was induced with 0.025 mg/kg of

pulmonary

increments

I

0.

catheter-

was instituted.

ECG

and anterior

Anesthesia

isoHurane up to 0.4%.

and, if necessary.

was monitored

Hemochron,

(pre-CPB)

with the celite

Inc. Technidyne

Corp,

Edison, NJ). AII of the venous grafts were Hushed with 10 U/mL heparin physiologic solution. Before cardiopulmonary 30 mg!kg of methylprednisolone

CPB

Vast

of aprotinin

pressure

(MAP)

2.500

of

bypass (CPB)

and l2..5OCl kallikrein

inactivator

were given. Until that moment, mean

never decrcased an ACT

U of heparin

procedure.

mmHg j

below X0 mmHg.

Five

valuc above 700 seconds an

were given and CPB started.

Fiemish Free University of

Brussels Medical School, Brussels, Belgium. Address reprints requesu to Vincent Umhrain, MD. Deparrment of Anesthesiology, Flemish Free Universiry of Brussels Medical School. Laarbeeklaan 101, B- 1090 Brussels, Belgium. Copyright ~31994 hy W.B. Saunders Company 10.~3.0770194/0802-OOlS$O3.oOiO Kcv words: aprurinin. prolamine, corona- rhromhosis

During

CPB

MAP

and again l?,S(X) KIU!kg

The

varicd

between

of aprotinin

60 and lob

were given. Beforc

weaning from CPB all grafts were checked for patency, kinking. or bleeding.

Wcaning

ngikg:min,

198

Monitoring

0.1 mg/kg of pancuronium, induction,

hypokinesia

revealed

consisted of 2.5 mg of lorazepam

oxygen saturation

formed. Anesthesia

mg/dL),

following ACT values were all abovc 700 seconds during the whole

lYY4.

prorn lhe Department of Anesrheslology,

anterolateral

angiography

the usual dosage of metoprolol.

additional

thrombo-

J Cardiothorac

a severe

of 0.33. Premedication

nil. After

(324

consisted of aspirin 160 mg, metoprolol

of 60.5 seconds. To obtain

Anesth H: 137-

corona-

and hypothyroidism risk factors included

minutes later, heparin 300 Uikg were given and resulted in an ACT

coronary thrombosis: Can apro-

141. lYY4, and Horrow J: Intraoperative

angina) Coronary

S mg three times a day. Cardiac

Radionuclide

ing artcrial

for triple-

an ischemic

25 mg three times a day. levothyroxin

and isosorbide dinitrate akinesia.

included

hypercholesterolemia

smoking. Daily treatment 2lWl mg, alprazolam

histoty

1980 (stable

and at present euthyroid).

arterial This article is accompanied

medical

(treated

units (KIU)/kg

Royston D: Intraoperative

REPORT

woman weighing 82 kg was scheduled

vcssel CABG.

midazolam,

clot-

been associatcd with thc development of an inhibitor of tissue plasminogen activator ([-PA)” and their use during cardiac surgery preventcd thc generation of tibrin split products.’ Protaminc has been incriminated, because the heparin-protamine complex may initiatc thromboxanc AZ synthesis,“’ possibly offsetting thc C! and C3 complement activation induccd hy the plasminoting.

CASE Case 1

from CPB was supported

and dobutamine.

5 pg!kg/min.

with dopamine.

7.5

The total duration

of

CPB was 90 minutes, and the total amount of 150 mg of protamine sulphate

(Rochc,

Brussels.

period of 20 minutcs. aprotinin

Belgium)

Meanwhile

was given. Thc

ACT

was administered

an additional value

after

over

12,500 KIU/kg protamine

a of

was 346

seconds at 35 minutes aftcr the end of bypass. Then the pulmonary artety pressure (PAP)

rose (mean 32 mmHg),

mixed venous oxygen saturation rrspectively.

JournalofCard/ofborac/cand

arterial pressure and

dropped to gO/SO mmHg and 62s..

Once again the (posterior)

grafts were checked.

An

VascularAnesthesia, Vol 8. NO 2 (April), 1994: pp 198-201

APROTININ,

arterial

PROTAMINE.

bloed gas (ABG)

7.43. PaC 20.7

meq:L.

basc

support

pg!kg!min

moment

pressure tuted.

collapse

without

was quickly

placed

the patient

of 75/50

diffuse

thrombi

could

occurred

in the original

only

MAP

contractility

of

be partially

Further

A

efforts

balloon

RCA.

Until

was insti-

artery

tirst septal

branch,

with

unstable

were

a 7-year-old

was

terolemia

Thc

ago).

had also

was given and. myocardial

to save the patient.

and

grafts:

man weighing

RCA.

LAD

anterolateral naty

and

risk factors

terolemia

mg/dL)

Ml.

ease (complete

and smoking

diography

Cardiac

demonstrated

was transferred 25.000

U IV.

to the CCU. furosemide.

and isosorbide received

dinitrate.

30 mg orally.

hours

before

Before

induction).

extracorporeal

93 mmHg

of aprotinin.

577

seconds.

aprotinin added.

MAP

never

below

pressure

varied

between

140:80

mmHg.

KIU!kg

of aprotinin

period

of 15 minutes

minutes

post-CPB.

this period. decreased rapidly, tion

epinephrine. IABP

was placed

three

venous

Exploration tomy

output with

was

from

was

(MAP

CPB was normal

mixed

venous

oxygen

saturation

white

and thrombec-

a complete

His hemodynamic PCWP

saturation

He was discharged from dopamine.

status

16 mmHg, 67%

the

and not pulsatilc.

heparinization

developed

and

and an

On inspection

thrombosis

Full

medica-

U. was given

artery.

looking

MAP

CaCI,.

to

784.

to the intensive 3 pg!kg!min.

was

re-

AV-black remained MPAP

Y0 mmllg.

Previous

100 mmllg. weaning

of protaminc

pressure

the administration unstable

mine.

0.1 mg) failed thrombosis

stahilization open-heart

a nifedipine.

10 minutes

7ll:JS Inotropic

was placed. venous

(episode

thc

four with

+g, kg:min. kgf min).

veins

norepinephrine, the patient

73 mmHg).

became

hemo-

ventricular (dopa3 x

was reopened noticed.

After

tibrillation

and

of 2 x 50 mg of lidocaine.

After

inotropic in stable

100 mEq. and

and a thrombectomy

an extremely

support

4 pgfmin.

regained

was

2 x 0.1 mg, NaHCOI.

was performed.

supramaximal

IY min

support

The thorax grafts

in an

(ie.

epinephrine

of ventricular

administration

200 mg. propanolol.

CPB

mmHg.

IS bgíkg:min.

10

and 140 mg

and resulted

after

the patient

pressure

four

during

300 U :kg). a second CPB was started

weaning

(MAP

the

massage.

bretylium, hcparin.

of

between

391 scconds.

of aprotinin

fibrillation).

of the patient

varied

below

of

CPB a

35.X”C) was normal

of protamine).

and the IABP

U

During

mmHg

minuten

dobutamine.

2 g 01

2.500

temperature

Twentytive (arterial

MAP

ACT

was never

received and

was nevcr

and

fentanyl The

MAP

patient

6.000 KIU:kp

ventricular

5 &kg;min,

CPB.

was added.

were givcn slowly over

after

of sufentanil.

the

of

3.5 mg

that

of 5X8 seconds.

of l20/75

Another

of 146 scconds.

of

in an ACT

and the ACT

ACT

consisted Monitoring

h.O(Nl KIU:kg.

from CPB (rcctal

an artrrial

and

to CPB

of

2 X 10 mg orally

to case I except Before

and

consisted

10 mg. lorazepam

instead

aprotinin.

(7S?

LAD)

medication

Premedication

similar

7 years

disease

0.2 mg intramuscularly.

wcrc

resulted

stopped

stenosis

nifedipine

orally.

dose of 7.500 L’ of heparin

Again with

mg

was 121 seconds.

which

70 dnd

Daily

diabetes

dificult

(dobutamine.

and epinephrine. hemodynamic

15

6 to 10 condition

hut died 10 hours later. DISCUSSION

20

declined

Inotropic I g of

5,000

femoral

were

76 to 85 mmHg,

support

of 140 seconds

appeared.

Heparin.

oxygen

7.000

stable at 85 to 97 mmHgduring

5 kg:kg:min,

paced.

Another

bypass the PAP increased.

alterations

the patient

(blood

were given over a

in an ACT

unsuccessful.

venous

4.2 L!min).

14.000

2.5 kgikgimin).

of the grafts showed diffuse

mixed

inotropic

and the ACT

via the right

and was consequently mmHg.

55 and 85 mmHg

(dopamine.

Meanwhile,

satisfactory

was

after

bypass grafts

(Fogarty)

started.

U of heparin

remained

1 kgikgimin).

by

dose of 5,000

and resulted

and ST segment

was started

followed

of

dopamine.

to 58 mmHg,

70 and

KIUikg

Weaning

minutes

between

values of 330, 450.

CPB

and 200 mg of protamine MAP

Thirty

in ACT

During

and a total

450 seconds.

tcchniques

U of heparin

resulted

respectively.

was given

2

was Ij.5 seconds.

oscillated

50

onset

were hypercholes-

75?

10 mg. nifedipine

dosc 60 pg/kg)

below

cxtrasystoles.

10 mg of nifcwas stopped

anesthesia

(total

induction

dynamically

2 grams of methylprednisolone.

and 22,500

which

heparin.

next day. the patient

induction

MAP

received

and

30 mg orally.

(heparin

and

before

circulation.

two 5.000 U increments. and

ACT

and the patient

7.000 KIU/kg

orally

Monitoring

1.The

to case

The

u\cd

pg, min. infusion.

akinesia.

angina

included

of 2.5 mg of lorazepam,

and 20 mg of furosemide

were similar

unstable

nifedipine,

dis-

Echocar-

and apical

x

technique

betere

total

of an

akinesia.

and glycopyrrolate

heparin.

ECG

two-vessel LAD).

medication

20 mg orally,

premedication

dipine.

showed

developed

Daily

The

2

mcthylprcdnisolonc.

hypcrcholes-

black. and sequelae

hypokinesia

the patient

an

Coro-

11 (non-insulin-

and 80% stenosis

lateral

hospitalization

suffered

(20 packíyear).

catheterization RCA

type

na\

(3 venous

earlier.

hypertension.

left bundle-branch

occlusion

had

3 months

mellitus

arterial

CABG

He

(Ml)

diabetes

nephropathy.

(348

anterolateral

diagonal).

infarction

included

with

showed a sinus rythm.

During

tirst

myocardial

dependent)

69 kg underwent

circumflex.

presented antecedents

triple-vessrl

3 x 10 mg orally.

dinitrate

anesthcsia

A 71.ycar-old

stenosis

dinitrate

atenolol

orally.

.?

50i’r

patient

(23 pack-year.

showed

(one

veins to the

Cardiac

risk factors

and smoking

and postcrolatcral

iso\orbide

The

and maturib

Coronary

arteriography

RCA.

inferior

MI

for CABG

and four

and circumflex).

posterolateral

(232 mg;dL)

stenosis

to the LAD

for the last 2 months.

angina

Corona-

X4 kg was scheduled

graft

(non-insulin-dependent).

isosorbide

c‘uw

man weighing

mammaty

performcd.

50 mmHg.

failcd

hY-year-old

bypass grafts

hrparin

died the ncxt day due to heart failure

3

internal

Thrombosis

below

Cl1.W

to correct

and an arterial

was

Additional

descended

decreased.

venous

20

followed

ratio.

the IABP

grafts

removed.

arteries.

never

rhythm

after

two

a l:l

The patient

Cardiac

success. An intra-aortic

of the three

thrombectomy

YY.l%.

rinc. 20 kg/kg/h. and arrhythmias.

of dopamine.

0.75 pg/kglmin.

a sinus

~11

hicarbonate

of epincphrine.

Immediately

thrombosis

and

SaO,

and used with

showed

mmHg.

noticed

although

meq:L.

of milrinone.

results:

standard

to 30 kg;kg:min

0.2 p,g/kg/min

infusion

(IABP)

162 mmHg.

-3.3

delicit

of dobutaminc.

the hemodynamic that

Pa02

was increased

by a continuous pump

at that time gave the following

30.9 mmHg,

inotropic

199

AND CORONARY THROMBOSIS

20

cardiac care unit

and epincph-

These three paticnts had a low cardiac output syndrome with diffuse intracoronary thrombosis following protamine reversal of hcparin anticoagulation after prcvious aprotinin administration. The incidence of such complications is very low. but nonetheless warrants this report and further invcstigation on the intcractions among heparin, protaminc. stcroids, and aprotinin. In all patients, macroscopic clots wcrc found and extracted in several venous bypass grafts during surgical cxploration. Two factors have to be considercd in the ctiology of thc problems encountered in these paticnts: secondary heart failure and coagulation disorders. Becausc weaning from cardiopulmonary bypass was achicved with minimal inotropic support and signs of cardiac failure only appeared 20 to 30 minutes after

200

UMBRAIN, CHRISTIAENS, CAMU

aprotinin

and protamine

administration.

to a primary

cardiac

origin.

Bccausc

thrombosis dut

all thrcc

patients

showcd goed cardiac

contractility

bypass and their MAP

never was below 60 mmHg, hypopcr-

fusion-rclated cannot

coronary

be excludcd

up to 23 minutes

thrombosis

during

aftcr

seems improbablc.

the subscqucnt

hut

low cardiac

output syndrome of unknown origin. In all thrcc cases. left ventricular

dysfunction

was not prcscnt

minutes after CPB (Tablc The protaminc spectrum pcriphcral

hemodynamic

whose

tion. including

compatible

pulmonary

cvolved

into

aminc

rcduction

a

rcac-

in two of thcm. it

reversal of heparin anticoagu-

such a rapid

administration.

and

diffuse

protaminc

in rcaction and coagulation

coronary

in the pathogcnfollowing

thromboelastography

potential.14

80

64

71

28

38

30

Platelets (mm?)

322

252

254

Baseline ACT (sec)

196

155

122

605-835

408.508

391-588

346

140

138

ACT range during CPB (sec) ACT after protamine (sec)

a

times consistent with

Heparin-protaminc

although

Wang

that aprotinin

may falsely incrcasc

ments. Several

hundrcd

alrcady

com-

10” KIU

or more)

C4a and C5a complement

concentrations,

black the kallikrein-kinin

to incrcased

interactions. platelct

When activated. this will

disaggregation.

paticnts, increased concentrations been mcasured.l” let function rcports

in somc

of thromboxane

A: have

Thc ctfects of thromhoxanc

could rcsult in intravascular

indicated

that

release is minimal Harke

But

the

incrcasc

following aprotinin

ct al’” and Royston?.”

clotting.

pathway activation Following could

Previous

in thromboxanc

Al

treatment.” ACT

coagulation

dut to surgical manipulations.

In these

valucs were lower during CPB (Table

Royston’s argumcnts.

bc possiblc

with

intravascular

formation

2).

coagulation

of microscopic

fìhrin

deposits in thc grafts. 11 is not belicvcd. howcvcr. that ACT

Patwlt

3

PCWP (mmtig) SVR (dyne

s.

PVR (dyne

s cm 5)

cm-?

SVR (dyne PVR (dyne

s s.

Cl (L/min/mI) Abbreviation: capillary wedge

of platclcts

inhibiting

treatment

be rnorc

with aprotinin.

ablc to rcspond to thc

produced whcn protaminc

is adminis-

tcred. It has indeed been shown that factor-VIII-mediatcd platelct

adhesion

has a kcy function

in thc hcmostatic

factor

VIII.‘“.“’

aprotinin

Evidencc

in thc litcraturc

indicatcs

that

prescrvcs the GPIh rcccptors of platclets, which is

important

for the normal platelet

function in microvascular

rcactions. and inhibits the adhesion of platclets to thrombinstimulated

human

coagulation

cndothclium

age. tissue-factor-dcpcndent via factor

and result

as thc

aprotinin

as wcll

as the

intrinsic

proccss. In thc prcscncc of cndothelial VIIa.

which

in microscopic

fibrinolytic

system

and steroids. Indecd. of t-PA

dam-

processes may initiate thromis not inhibitcd fibrin

dcposition

is restraincd

thrombin

in the endothelial

normally

by in

by both induccs

cell. which initiates

9

5

thc convcrsion of plasminogen

4

process of fìbrinolysis. Steroids signiticantly impair thc [-PA

1.074

1,543

1,416

85

95

NA

2.4

synthcsis whilc

2.4

12

14

12

7

790

1,486

1,298

cm ?

130

136

NA

2.4

3.2

CVP, central venous

pressure;

inhibits

thc activity of plasmin. steps of the fibrinolytic

process and their combined eífect may have been to reduce anticoagulation,

protamine

after a short period

2.7

PVR,

pulmonary vascular resistance; Cl, cardiac index; NA, not available.

is added

to reversc

hcparin

thc clots will furthcr grow in the grafts and

with subsequcnt

PCWP, pulmonary

pressure; SVR, systemic vascular resistance;

aprotinin

to plasmin and activatcs thc

Thcsc two agcnts act on diffcrcnt clot lysis. Oncc

3

5)

cm

to

system. Bccause plasmin cxcrts a

11

14

PCWP (mmlig)

inhibit

not high enough

1

Postbypass CVP (mmHg)

IO these patients (2 to effectively

16

2.0

Cl (Llminim’)

be a

thrombosis.

administcrcd

hut most probably

presence of thrombin

production

Prebypass CVP (mmlig)

could

and stcroids

these platelcts will, following the

grafts

PatferM 2

protamine

major effect on the CÌPI,, reccptors

aprotinin.

Table 1. Hemodynamic Data 1

it is believed the normaliza-

thcir adhcsion propcrties.

bin formation

Patient

thcir (from

proccss and that thc GPI,, rcccptor is the primary targct for

advised maintaining

valucs above 750 seconds to avoid cxtrinsic three cases. ACT

A- on platc-

activity.

nceds

developed

of protamine

was sufficient

plasmin

which incrcasc

factor prcsumably

following

intracoronary

Thc dose of aprotinin

have

valucs kcpt

factor in the presencc of aprotinin

for developing

measure-

aprotinin

with ACT

after administration

tion of thc coagulation

dcmonstratcd

celite-ACT

Bccausc all thrcc patients

clinical syndrome

arc a sutlicient

receiving

abovc 450 scconds.’ An additional

to bc associated with incrcascd

lead

patients

had succcssful operations

triggcring

CPB

et al’” recently

IS min aftcr its administration)

prot-

indicatcs

argument,

plexes have been reported plasminogen-plasmin

3 _

PT (% )

to bc present.

increased platelet adhesiveness and aggregation and depression of fibrinolytic

Pntw1t

aPTT (sec)

values less than 750 seconds during

mild

dcvelopcd

with a protaminc

occlusions 7 Immediately

grdft

from

cardiovascular

initially

hypertension

thrombosis. Does this implicatc esis of these

ranges

to catastrophic

was surprising that protaminc lation

severity

all 3 paticnts

pattcrn

PuIlent 2 _~__

1).

vasodilatation

collapse.‘z.13 Though

1

Pat4enl

for thc tirst 3.5

revcrsal syndrome can result in a variahlc

of rcactions

Table 2. Coagulation Data of the Three Patients

cardiac failure w;ih

excludcd as a reason for thc intracoronary

(15 to 30 min) finally occlude the grafts

left ventricular

dysfunction

and hemody-

namic impairmcnt. Incrcascd

risk for dcveloping

was used was demonstrated the cndothelium

was irritatcd

thrombosis

whcn aprotinin

by Böhrer et al6 at sites whcre along the course of catheters.

201

APROTININ, PROTAMINE, AND CORONARY THROMBOSIS

Such sites could also be the saphenous vein graft preparations, the proximal and distal coronary artery anastomosis sites, and the insertion sitcs of catheters. Endothelial interruption or irritation is known to result in decreased endothclial-derived relaxing factor production and subsequent increased vascular contraction.2’ This may be further enhanced by initiation of the extrinsic coagulation cascade with activation of factor VIIa by tissue thromboplastin. Enhanccd thrombocyte adhcsion and aggregation to the vascular intima would result, due to decreased fibrinolysis

and preserved platelet receptor functions in the prescnce of aprotinin. To summarize, three cases of diffuse intracoronary thrombosis in patients treated with aprotinin are described. All patients developed their syndrome after protamine reversal of heparin-induced anticoagulation. Thc scquence of these complications suggests that aprotinin, corticosteroids, local disruptions of the endothelium, and possibly other unknown factors can act syncrgistically to result in a picture of diffuse graft occlusion.

REFERENCES 1. Royston D: The serum antiprotease novel approach Fibrinol

to reducing

1556Y,

aprotinin

postoperative

(Trasylol).

bleeding.

A

Blood Coag

on the need for bloed transfusion after repeat open heart

surgery. Lancet 2:1289-1291, 3. Royston

D: tligh

years experience.

lYX7

5:63-72.

J Cardiothorac

A review of the fìrst tive

Vast Anes 6:76- 100. 1992

having aortocoronary

W. Barankay

in cardiac

and

bypass grafts. Perfusion

thrombi on pulmonary

Three

C, Richter years

F. I.ang J, Vahl

arte-

catheters

aprotinin.

JA: High dose

experience

Vast Anes 6:324-32X,

H. Fleischer

high-dose

A. Hannel

surgery:

patients. J Cardiothorac

receiving

in

1,7X4

lYY2

C: Early formation

of

in cardiac surgical patients

J Cardiothorac

Vast

Anes 4:222-

22s. 1990 7. Yared JP. Estafanous

FG: Bloed conservation

during cardiac

surgery. Curr Opin Anaesth S:X2-XX, 1992 X. Cwikel BJ. Barouski-Miller Dexamethasone in HTC

PA, Coleman

cells. J Biol Chem 259:6847-685

Y. Jansen NJG. Van Oeveren cardiopulmonary DR.

Zapol

WM,

during protamine

66597~604,

1087

ll.

Kaplan

dependent

A.

Meier

coagulation

kinin generation. 12. Lowenstein

rever-

Vast Anes 3:99-108,

R.

Ilessel

11 EA:

J Cardiothorac

Thomas

H.

SJ. et al: CSa and thromvaso- and broncho-

rcversal of heparin. Mandle

R:

The

F: I.essons

from

Anesthesiology ttageman

pathways of coagulation.

Semin Thrombosis

in

1991

factor

tibrinolysis and

Hemostasis 3: 1-26. lY76 studying

infrequent

events:

by heparin 1990

following open-hcart

hypercoagu-

surgcry. Perfusion

lYY2

15. Van Oeveren

W. Jansen NJG.

on hemostatic

16. Harke telle

reactions

P, Gupta NK, et al: Transient

lability in adult patients

aprotinin

Protaminc

Vast Anes 4:604-608.

H. Gennrich

Untersuchungen

plasmatische

Bidstrup BP. et al: Etfects of

mechanisms

during cardiopulmonary

M: Aprotinin-ACD

Blut. 1. Experimen-

tiber den Einfluss von Aprotinin

und thromhozytarc

by-

19X7

Gerinnung.

auf die

Anaesthcsist

29:266-

276. 1980 17. Royston duccd

hlood

associatcd

D. Bidstrup loss after

with

Cardiothorac IX. Wang

an

BP, Taylor

open

increase

heart in the

KM.

Sapsford

surgery

with

activated

RM:

Re-

aprotinin

clotting

is

time.

J

Vast Anes 3:XOA. IYXY JS, Lin CY.

Hung

heparin induced anticoagulation

WT.

Karp

RB:

Monitoring

of

with kaolin activated clotting time

in cardiac surgical patients treated with aprotinin.

mediators

Surg S:?ll-217.

associated with pulmonary

constriction

activator

1. 1984

on the inflammatory

bypass. Eur J Cardiothor

boxane generation

TD:

W, Van Vliet M, et al: The role of

types of corticosteroids

10. Morel

PL. Gelrhrter

induction of an inhibitor of plasminogen

hepatoma

different

J Cardiothorac

pass. Ann Thorac Surg 44:640-645.

5. Dietrich

6. Bdhrer

13. Lock

administration.

7:119-123.

in open heart surgery: Background

1990

aprotinin

response associated with protamine

13. Horkay F, Martin

dose aprotinin:

4. Royston D: Aprotinin results in patients

hemodynamic

sal of heparin anticoagulation. I Y8Y

IYYO

2. Royston D. Bidstrup BP. Taylor KM, Sapsford RN: Effect of aprotinin

Adverse

Anesthesiology

77: IOXO-1084, l9Y2 IY. Meycr D, Baumgartner in platelet

HR: Role of Von Willehrand

adhcsion to the subendothelium.

Br J Haematol

factor 54:l-9.

1YX 21). Sakariassen

KS, Nievelstein

role of platelet membrane adherencr

to

human

63:6X1-691.

19X6

21. Johns AR:

artery

Endothelium

vicw and clinical implications. IYOI

PF. Coller

glycoproteins

BS. Sixma JJ: The

lb and Ilb-lila

subendothelium. derived

Br

relaxing

J Cardiothornc

in platelet J Haematol

factor: Basic re-

Vast

Anes 5:69-X0,