Thrombolytic

Agents
Benedict R. Lucchesi, M.D., Ph.D.
Department of Pharmacology
University of Michigan Medical School

ThrombolyticTherapy
Streptokinase
TissuePlasminogenActivator(rtPA)
Urokinase
Retavase
Tenecteplase,TNKtPA(TNKase)

AnticoagulantTherapy
Thrombolysis
PLASMINOGENACTIVATOR

PLASMINOGENACTIVATOR
INHIBITOR1
(PAI1)

PLASMINOGEN

PLASMIN
alphaANTIPLASMIN
2

FIBRIN

FIBRINDEGRADATION
PRODUCTS

The primary action of all thrombolytic agents is to convert plasminogen to

plasmin. Plasmin possess enzymatic activity that brings about the degradation of
fibrin (fibrinolysis) that results in clot lysis.

ThrombolyticTherapy

TheplasminogenmoleculecontainsstructurescalledLYSINE
BINDINGSITES(kringles).
Thelysinebindingsitesbindplasminogentofibrin.
Theinactiveproenzyme,plasminogen,isassociatedwiththefibrin
inthethrombusorbloodclot.
Thelysinebindingsitesplayanimportantroleinregulating
FIBRINOLYSIS.

ThrombolyticTherapy
PLASMINhastheabilitytodigestFIBRINtosoluble
degradationproducts.
Thebloodcontainstwophysiologicallyactiveplasmin
ogenactivators:
1. Tissuetypeplasminogenactivator
2. Singlechainurokinasetypeplasminogen

activator
Inadditiontherearetwoinhibitorsofthefibrinolytic
systempresentinblood:
1. Plasminogenactivatorinhibitor1
2. alpha2antiplasmin

Streptokinase

Nonenzymeproteinproducedby
severalstrainsofhemolytic
streptococci.

Streptokinase
INDIRECTLYactivatesplasminogen(Plg)to
plasminPl)in3steps.

Step1Streptokinaseformsanequimolarcomplex
withplasminogen(PlgSKcomplex).The
conformationalchangetakesplaceinplasminogen
andexposesanactivesite
Step2Activesitecatalyzestheactivationof
plasminogen(Plg)toplasmin(Pl)
Step3PlgSKisconvertedtoPlSK

Streptokinase
Plasmahalflifeof20min
Neutralizedbyantistreptokinaseantibodiesdue

topreviousinfectionswithhemolytic
streptococci
Antistreptokinasetiterincreases50100times
withinafewdaysafteradministration,remains
highfor46months
Repeatedtherapywithinthistimeisimpractical

TissuePlasminogenActivator
FactsabouttPA

itshowsaspecificityforfibrin
activationofplasminogenis2to3ordersofmagnitude

greaterwhenplasminogenisboundtofibrin.
plasminisformedonthefibrinsurfacewithintheclot.
plasminboundtofibrinisprotectedfromtherapid
inactivationofitsenzymaticactivity.
freeplasminintheplasmahasat1/2of0.1secondsas
comparedtoplasminthatisboundtofibrin(10to100
secs).
rtPA(Alteplase;Activase)approvedforusein:
myocardialinfarctionandstroke.

GuidelinesforuseofrtPAin
stroke2

Thrombolysisisnotrecommendedunlesstheproper

diagnosis(withCTofthebrain)madebyphysicians
expertindiagnosingstrokeandreadingCT.
Avoidthrombolysiswherethereisevidenceofrecent
majorinfarction,masseffect,edemaorpossible
hemorrhage,onheparininthelast48hrsorwarfarin
orwithaplateletcount<100,000.
PatientstreatedwithrtPAforstroke,shouldnotbe
givenaspirin,ticlopidine,clopidogrel,heparin,or
warfarin.

ComparativePharmacologic
Features
Feature
Half-Life (min)
Fibrin-Selective
Duration of
Infusion
Antigenicity
Incidence of
Reperfusion (%)
Frequency of
Reocclusion (%)
Fibrinogenolysis
Platelet Activation

SK
23
+
60 min
Yes

APSAC
90
+
2-5 m
Yes

UK

SCUPA

rtPA

16
++

7
++++

5
+++

5-15 m
No

Hours
No?

Hours
No?

60-70

60-70

60-70

60-70

60-70

15
++++
+++

10
++++
+++

10
+++
0

NA
++
?

20
++
++++

TenecteplaseTNKtPA
(TNKase)
ActsmorerapidlythantPA,hasmore

rapidplasmaclearance,shorterhalflive
(1119min).
Moreconvenientadministration10U
over<2minfollowedin30minbyasecond
ivbolus.

TenecteplaseTNKtPA
(TNKase)

Description:

tenecteplaseisabioengineeredplasminogenactivator,
tenecteplaseisalsoknownasTNKtPA."TNK"referstothe
sitesofthetPAmoleculethathavebeenmodified(T103N,
N117Q,KHRR296299AAAA).

Actions:

tenecteplaseisavariantoftPA.
tenecteplasereducesfibrinogenby510%andplasminogen
by1015%,comparedtodecreasesof40%and50%,
respectively,foralteplase;becauseofthis,TNKtPAmaybe
morefibrinspecificthanalteplase.

TenecteplaseTNKtPA
(TNKase)
Uses:

forthetreatmentofacuteMI.
DistinguishingFeatures:
comparedtoalteplase,tenecteplasehasaprolongedhalf

life(alphahalflife1120min;betahalflife41138
min),increasedspecificityforfibrin,andincreased
resistancetoplasminogenactivatorinhibitor1(PAI1)
itsmainadvantagemightbethatitcanbeadministeredas
asingleIVbolusinjection.