Anticoagulation and fibrinolysis Flashcards Preview

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Flashcards in Anticoagulation and fibrinolysis Deck (14):
1

Mechanisms of anticoagulation

-Tissue factor pathway inhibitor (TFPI)
-Protein S and C system
-Antithrombin
-Heparin cofactor II
-Thrombomodulin
-Inhibition of plasmin: Plasminogen activating inhibitor (PAI), alpha-2 plasmin inhibitor (a2PI), thrombin activated fibrinolysis inhibitor (TAFI)

2

Mechanisms of fibrinolysis

-Plasmin (and plasminogen)
-tPa (fibrin/annexin activated) activation of plasminogen
-uPA (uPAR activated) activation of plasminogen

3

TFPI

-Prevents activation of X by TF/VII, forcing TF/VII activation of IX and coagulation to proceed through tenase complex
-TFPI is produced by endothelium and can be associated w/ heparin-like GAGs on endothelium surface
-TFPI can also be in solution, but this form of it requires protein S for stabilization (this form also allows TFPI to bind to platelets and inhibit their activation)
-Heparin also releases TFPI to inhibit thrombus formation

4

Protein C and S

-Proteolytically inactive both factors Va and VIIIa (the cofactors)
-Activated protein C (APC) is responsible for the proteolysis
-Protein C is bound to its endothelial protein C receptor (EPCR) until activated by a complex of thrombin/thrombomodulin
-Once activated, APC binds to platelets and endothelium in complex with protein S to destroy endothelial/platelet bound factor VIIIa and Va
-Inhibition sequence is opposite of activation sequence: inhibits Va first, then inhibits VIIIa
-APC can also inhibit PAI1, thereby increasing fibrinolysis
-Both protein C and S are vit K dependent proteins

5

Antithrombin 1

-Most important inhibitory protein, it is only biologically active when associated w/ heparin-like GAGs (GAGs are negatively charged and bind to lysine residues on antithrombin)
-Antithrombin/heparin complex exposes antithrombin's active site, allowing it irreversibly inhibit thrombin
-Heparin GAGs are on endothelium and sub endothelium, thus they are present at sites of thrombin generation

6

Antithrombin 2

-Antithrombin can also inactive factors IXa and Xa (indirectly inactivates Va, VIIIa, and XIa by inactivating thrombin)
-When bound to large MW heparin GAGs, antithrombin inhibits thrombin
-When bound to small MW heparin GAGs, antithrombin inactivates IXa and Xa (preferentially Xa)
-Small MW heparins are primarily used in Rx over large MW ones
-Heparin cofactor II can also inactivate thrombin
-Those w/ antithrombin deficiencies have a higher predisposition to thrombotic events

7

Fibrinolytic system

-Fibrin is degraded down into fibrin degradation products (fdp) by plasmin (if it wasn't cross-linked by XIII) or into D-dimers by plasmin (if it was cross-linked by XIII)
-Positive D-dimer test indicates that thrombin, XIII, and plasmin must all be active and generated (mostly a surrogate for thrombin)
-Plasmin can also degrade fibrinogen into fibrinogen degradation products (FDP)
-Plasmin formed from pronz plasminogen, which is activated with by tPA or uPA (both of which require receptors for activity)
-Plasmin is also central in tissue remodeling and angiogenesis (activates metalloproteinases, angiogenic GFs up regulate plasminogen expression on endothelium)

8

Plasmin

-Plasmin binds to fibrin (or fibrinogen) at lysine residues to limit plug formation by degradation
-Free plasmin in blood can degrade many proteins including VIII and V, fibrinogen, and GPIIb/IIIa (thus limiting platelet aggregation)
-Plasmin is inhibited by many proteins, but most notably by alpha-2 plasmin inhibitor (a2PI) which is produced in the liver
-In a mature clot a2PI is covalently linked to the fibrin by XIII, resulting in resistance to degradation by plasmin
-a2PI in circulaiton rapidly inactivates free plasmin

9

tPa

-Tissue plasminogen activator (tPA) is synthesized and secreted by endothelium activated by thrombin, cytokines, or increased venous pressure
-tPA requires cofactors fibrin or annexin (tPA/plasminogen receptor, on endothelium, expression induced by thrombin) to be activated and thus activate plasminogen to plasmin
-tPA bound to fibrin activates plasmin to degrade the fibrin, tPA bound to annexin activates plasmin to remain on endothelium (bound to annexin) and provide an anticoagulant barrier

10

uPA

-uPA is also synthesized and secreted by endothelium, stimulated by thrombin, and requires its receptor uPAR in order to activate plasminogen
-uPAR (found on endothelium and monocytes) is closely linked to annexin-bound plasminogen, so when uPA binds to uPAR the two receptors interact and uPA converts plasminogen to plasmin
-uPAR expression induced by thrombin

11

Plasminogen activator inhibitor 1 (PAI1)

-PAI1 is synthesized in the liver, by endothelium, and megakaryocytes
-It is only stable when bound to subendothelial matrix (to prevent fibrinolysis when there is endothelial damage)
-PAI1 inhibits both uPA and tPA to prevent palsmin activation
-PAI1 bound to subendothelial matrix protein vitronectin is active form
-Under circumstances when tPA is secreted by endothelium, active PAI1 is also secreted by endothelium or released by activated platelets
-PAI1 can be inhibited by APC, thus enhancing fibrinolysis

12

Thrombin activated fibrinolysis inhibitor (TAFI)

-TAFI is converted to its active form by thrombin bound to thrombomodulin
-Activated TAFI removes terminal arginine and lysine residues from fibrin
-These positively charges residues are required for plasminogen to bind to fibrin, and for plasmin to cleave fibrin
-Thus TAFI prevents fibrinolysis by reducing plasmin generation (reducing plasminogen binding), and by reducing plasmin activity (plasmin cannot cleave fibrin)

13

Thrombomodulin

-Thrombomodulin complexes w/ thrombin to achieve anticoagulation and procoagulation results
-The thrombomodulin/thrombin complex directly inhibits the bound thrombin
-The complex activates protein C to degrade Va and VIIIa, and to deactivate PAI1 (resulting in increased fibrinolysis)
-Thrombomodulin/thrombin complex also activates TAFI, preventing plasmin generation and activity (leading to inhibition of fibrinolysis)

14

Rx of fibrinolysis

-EACA (Amicar) prevents plasminogen activators (tPA and uPA) and plasminogen from binding to fibrin