Thrombolytic
Agents
Benedict R. Lucchesi, M.D., Ph.D.
Department of Pharmacology
University of Michigan Medical School
Thrombolytic Therapy
• Streptokinase
• Tissue Plasminogen Activator (rt-PA)
• Urokinase
• Retavase
• Tenecteplase, TNK-tPA ( TNKase™)
Anticoagulant Therapy
Thrombolysis
PLAS MINOGEN ACTIVATO R
PLAS MINOGEN ACTIVATO R
INHIBITOR-1
(PAI-1)
PLAS MINOGEN
PLAS MIN
alpha - ANTIPLAS MIN
2
FIBRIN
FIBRIN DEGRADATION
PRO DUCTS
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.
Thrombolytic Therapy
•
•
•
•
The plasminogen molecule contains structures called LYSINEBINDING SITES (kringles).
The lysine-binding sites bind plasminogen to fibrin.
The inactive pro-enzyme, plasminogen, is associated with the fibrin
in the thrombus or blood clot.
The lysine-binding sites play an important role in regulating
FIBRINOLYSIS.
Thrombolytic Therapy
PLASMIN has the ability to “digest” FIBRIN to soluble
degradation products.
The blood contains two physiologically active plasminogen activators:
1. Tissue type plasminogen activator
2. Single-chain urokinase-type plasminogen
activator
In addition there are two inhibitors of the fibrinolytic
system present in blood:
1. Plasminogen activator inhibitor - 1
2. alpha-2 - antiplasmin
Streptokinase
Nonenzyme protein produced by
several strains of hemolytic
streptococci.
Streptokinase
• INDIRECTLY activates plasminogen (Plg) to
plasmin Pl) in 3 steps.
–Step 1
Streptokinase forms an equimolar complex
with plasminogen (Plg-SK complex). The
conformational change takes place in plasminogen
and exposes an “active site”
–Step 2 Active site catalyzes the activation of
plasminogen (Plg) to plasmin (Pl)
–Step 3 Plg-SK is converted to Pl-SK
Streptokinase
• Plasma half-life of 20 min
• Neutralized by anti-streptokinase antibodies due
to previous infections with ß-hemolytic
streptococci
• Anti-streptokinase titer increases 50 - 100 times
within a few days after administration,
remains high for 4 - 6 months
• Repeated therapy within this time is impractical
Tissue Plasminogen Activator
Facts about t-PA
• it shows a specificity for fibrin
• activation of plasminogen is 2 to 3 orders of magnitude
•
•
•
•
greater when plasminogen is bound to fibrin.
plasmin is formed on the fibrin surface within the clot.
plasmin bound to fibrin is protected from the rapid
inactivation of its enzymatic activity.
free plasmin in the plasma has a t 1/2 of 0.1 seconds as
compared to plasmin that is bound to fibrin (10 to 100
secs).
rt-PA (Alteplase; Activase™) approved for use in:
myocardial infarction and stroke.
Guidelines for use of rt-PA in
stroke - 2
• Thrombolysis is not recommended unless the proper
diagnosis (with CT of the brain) made by physicians
expert in diagnosing stroke and reading CT.
• Avoid thrombolysis where there is evidence of recent
major infarction, mass effect, edema or possible
hemorrhage, on heparin in the last 48 hrs or warfarin
or with a platelet count <100,000.
• Patients treated with rt-PA for stroke, should not be
given aspirin, ticlopidine, clopidogrel, heparin, or
warfarin.
Comparative Pharmacologic
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
16
++
7
++++
rtPA
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
++
++++
Tenecteplase TNK-tPA
(TNKase™)
• Acts more rapidly than t-PA, has more
rapid plasma clearance, shorter half-live
(11-19 min).
• More convenient administration - 10 U
over <2 min followed in 30 min by a second
iv bolus.
Tenecteplase TNK-tPA
(TNKase™)
• Description:
–tenecteplase is a bio-engineered plasminogen activator,
–tenecteplase is also known as TNK-tPA. "TNK" refers to the
sites of the tPA molecule that have been modified (T103N,
N117Q, KHRR 296—299 AAAA).
• Actions:
–tenecteplase is a variant of tPA.
–tenecteplase reduces fibrinogen by 5—10% and plasminogen
by 10—15%, compared to decreases of 40% and 50%,
respectively, for alteplase; because of this, TNK-tPA may be
more fibrin specific than alteplase.
Tenecteplase TNK-tPA
(TNKase™)
• Uses:
–for the treatment of acute MI.
• Distinguishing Features:
–compared to alteplase, tenecteplase has a prolonged half-
life (alpha half-life 11—20 min; beta half-life 41—138
min), increased specificity for fibrin, and increased
resistance to plasminogen activator inhibitor-1 (PAI-1)
–its main advantage might be that it can be administered as
a single IV bolus injection.