Fibrinolytic Drugs

Question 1

Explain the role of plasminogen/plasmin in the process of blood clotting

Answer 1

plasminogen participates in fibrinolysis by binding to the fibrin clot along with tPA (primary enzyme involved in dissolving blood clots). It becomes activated to form plasmin, which will then degrade the clot, resulting in the formation of fibrin degradation products.

Question 2

Explain the mechanism for the conversion of plasminogen to active plasmin

Answer 2

all thrombolytics work to increase the conversion of plasminogen to plasmin
plasminogen is the inactive enzyme activated by t-PA (serine protease) to form plasmin; t-PA cleaves arg-val bond to activate plasmin (t-PA inhibited by PAI-1 and PAI-2)

Question 3

Give the names and specific mechanisms of action of the drugs used to dissolve blood clots

Answer 3

when the blood vessel defect has healed, the fibrinolytic pathway is activated to dissolve the clot

Question 4

indications for thrombolytic therapy

Answer 4

acute MI - initiate ASAP
acute ischemic thrombotic stroke - initiate only within 3 hours after onset
PE

Question 5

Explain the differences between atleplase, reteplase, and tenecteplase in terms of structure and selectivity

Answer 5

alteplase: binds fibrin; fibrin binding domain
tenectaplase: more fibrin specific than t-PA; has point mutations which increase half life, reduce inhibition by PAI, and enhance activity at thrombi
reteplase: lacks fibrin binding domain - less fibrin specific, amino terminus is removed, mainly protease domain

Question 6

Alteplase

Answer 6

recombinant human t-PA
binds fibrin

Question 7

Reteplase

Answer 7

recombinant human t-PA
amino terminus is removed, mainly has protease domain
more potent, faster onset
lacks fibrin binding domain - less fibrin specific

Question 8

Tenecteplase

Answer 8

recombinant, mutant form of t-PA
longer half-life, given by single IV bolus
more fibrin specific than t-PA

Question 9

Tissue plasminogen activator

Answer 9

IV adm only
adverse effects: bleeding, internal or superficial

Question 10

Explain the structural similarities of transexamic acid, aminocaproic acid, and lysine in terms of their mechanism of action in stabilizing blood clots

Answer 10

anti-fibrinolytic agents - used to stop bleeding caused by thrombolytic drugs
plasmin binds to fibrin through a lysine binding site to activate fibrinolysis (all have); drugs act as a lysine analog to bind the receptor on plaminogen and plasmin; result is blockage of plasmin binding to target fibrin