Thrombolytic Thrombolytic AgentsAgents

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 TherapyThrombolysis

PLASMINOGEN ACTIVATOR

PLASMINOGEN PLASMIN

PLASMINOGEN ACTIVATOR INHIBITOR-1

(PAI-1)

alpha - ANTIPLASMIN2

FIBRIN FIBRIN DEGRADATION 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.

Thrombolytic Therapy

• The plasminogen molecule contains structures called LYSINE-BINDING 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 TherapyPLASMIN has the ability to “digest” FIBRIN to soluble

degradation products.

The blood contains two physiologically active plasmin-ogen 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

StreptokinaseStreptokinase 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

• 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.

Facts about t-PA

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 SK APSAC UK SCUPA rtPA

Half-Life (min) 23 90 16 7 5Fibrin-Selective + + ++ ++++ +++Duration of Infusion 60 min 2-5 m 5-15 m Hours HoursAntigenicity Yes Yes No No? No?Incidence of Reperfusion (%) 60-70 60-70 60-70 60-70 60-70Frequency of Reocclusion (%) 15 10 10 NA 20Fibrinogenolysis ++++ ++++ +++ ++ ++Platelet Activation +++ +++ 0 ? ++++

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.