Fibrinolytics

Question 1

Clot dissolution

Answer 1

-fibronlytic pathways to dissolve clot after blood vessel is healed

Question 2

General mechanism of fibrinolytics (thrombolytics)

Answer 2

-inc conversion of plasminogen to plasmin
-plasmin degrades fibrin and dissolves clot
-slide 4

Question 3

Fibrinolytic pathway

Answer 3

-plasminogen in inactive form deposits on growing clot
-t-PA activates plasminogen to plasmin
-plasmin digests fibrin and fibrinogen

Question 4

Plasminogen

Answer 4

-anticoagulant

Question 5

tissue plasminogen activator (t-PA)

Answer 5

-serine protease*
-cleaves Arg-Val bond
-activate plasminogen to plasmin for fibrinolytic pathway
-Alteplase
-Reteplase
-Tenecteplase

Question 6

Plasmin

Answer 6

-inactivated by a2 antiplasmin
-proteolytic enzyme that digests fibrin and fibrinogen

Question 7

t-PA inhibited by

Answer 7

-PAI-1 and PAI-2

Question 8

Inidications for thrombolytic therapy

Answer 8

-acute MI initiate ASAP
-acute ischemic thrombotic stroke within 3h after onset and exclusion of intracranial hemorrhage
-PE

Question 9

Acute MI care

Answer 9

-stent placement
-bare-metal vs drug covered stents
-drugs prevent RESTENOSIS by inhibiting smooth muscle cell proliferation but inc risk of subsequent thrombosis

Question 10

Alteplase (ativase)

Answer 10

-rhuman t-Pa
-527 aa residues
-binds fibrin

Question 11

Reteplase (retevase)

Answer 11

-rhuman t-PA w deletion of aa (355/527)
-more potent/fast onset
-lacks fibrin binding domain (less specific)

Question 12

Tenecteplase (TNKase)

Answer 12

-rmutant t-PA
-longer t1/2
-single IV bolus
-more fibrin specific than t-PA

Question 13

tPA structure

Answer 13

-Alteplase
-slide 9
-finger and kringle make up fibrin binding
-tenectplase point mutations
-reteplase no finger?

Question 14

Mutations in Tenecteplase

Answer 14

-inc half life
-reduce inhibition by pAI
-enhance activity at thrombi

Question 15

Plasminogen bound to firbin selectively activated by tPA that is

Answer 15

-also bound to fibrin

Question 16

slide 10

Answer 16

slide 10

Question 17

therapeutic tPA

Answer 17

-IV only
-short duration
-t1/2: Altepase 5-10, Reteplase 13-16, Tenecteplase 90-130min)
-Cl by liver and kidney

Question 18

tPA side effects

Answer 18

-bleeding most common
-internal bleeding
-superficial or surface bleeding

Question 19

Anti-fibrinolytic agents

Answer 19

-stop bleeding caused by thrombolytic drugs
-aminocaproic acid (EACA) (2h IV and oral t1/2)
-tranexamic acid (more potent)(2h IV/11h PO)
-lysine

Question 20

Antifibrinolytic agents MOA

Answer 20

-plasmin binds fibrin via lysine binding site for activation
-drugs mimic lysine to bind to plasminogen and plasmin
=block plasmin binding to target fibrin

Question 21

Antifibrinolytics use

Answer 21

-stop bleeding caused by thromolytic drugs
-adj tx in hemophilia
-re-bleeding from intracrainal aneurysms

Question 22

Antifibrinolytic risks

Answer 22

-Thrombosis from fibrinolysis inhibition
-thrombi formed during therapy are not easily lysed

Question 23

slide 14

Answer 23

slide 14