Section 7: Normal Hemostasis - Regulation & Fibrinolysis Megan F7

Describe the activation of Protein C

-Vitamin K dependent

- activated by Thrombin (Thrombomodulin Complex)

- once thrombin is bound, it can no longer convert fibrinogen to fibrin but can still activate this

Function of Protein C

- inactivates Va and VIIIa

- liberates Tissue Plasminogen Activator (tPA) from endothelial cells, which converts plasminogen to plasmin

Function of Protein S

Serves as cofactor to Protein C

Function of Protein Z

- cofactor to Protein Z-Related Protease Inhibitor (ZPI)

- major role is to degrade Factor Xa

Function of Protein Z-Related Protease Inhibitor (ZPI)

- cofactor to Protein Z

- major role is to degrade Factor Xa

- degrades Factor XIa

Function of Antithrombin (AT)

- forms irreversible complex with Factors IIa, IXa, Xa, XIa, and Plasmin to slowly neutralize them

- main targets are IIa & Xa

Mechanism of Action of Heparin

Causes a conformational change in the AT molecule & increases its inhibitory effect

Role of Heparin Cofactor II

- specificity is narrowly restricted to Thrombin (IIa) neutralization

- present in platelets too and may play role in regulation of Thrombin generated on platelet surface

Role of Tissue Factor Pathway Inhibitor (TFPI)

- low concentration inhibitor to extrinsic pathway

- secreted into plasma by endothelial cells

- inhibits TFIII / Factor VIIa Extrinsic Tenase Complex

Fibrinolysis

Breakdown of fibrin clot

Fibrinogenolysis (Primary Fibrinolysis)

Breakdown of fibrinogen

Endogenous Activators of Plasminogen

- Activated Protein C (APC) —> tPA released from endothelial cells

- Urokinase

- XIIa & Kallikrein

- XIa (maybe in a minor way)

Exogenous Activators of Plasminogen

- tPA

- Streptokinase

- Urokinase

- Recombinant tPA

Action of Plasmin

- lyses of fibrin and fibrinogen

- activity occurs within clot, thus fibrin becomes major substrate for activity

FDPs

Fragments X, Y, D, and E

Fibrinogen & Fibrin Degradation Products from Fibrinogenlysis or Fibrinolysis

D-Dimer

- result of plasmin acting to break down the fibrin clot (results in generation of this)

- 2 D fragments held together by covalent bonds formed as a result of Factor XIIIa

- present only in Fibrinolysis, NOT Fibrinogenolysis

How FDPs act as inhibitor to coagulation

FDPs attach to fibrin monomers & prevent polymerization and clot formation

Function of Alpha-2-Antiplasmin

- binds & inactivates free circulating plasmin

- rapid inhibitor

- prevents lysis of fibrinogen & degradation of Factors V and VIII

Function of Alpha-2-Macroglobulin

- plasmin inhibitor

- only necessary when Alpha-2-Antiplasmin binding sites are saturated

- slower inhibitor

- prevents lysis of fibrinogen and degradation of Factors V and VIII

Function of Plasminogen Activator Inhibitor 1 (PAI-1)

- most important inhibitor to plasminogen activator system

- released from injured endothelial cells and activated platelets

- neutralizes tPA and urokinase

Function of Thrombin Activatable Fibrinolytic Inhibitor (TAFI)

- alters fibrin clot so it is less recognizable as a substrate for plasmin (thus, inhibits fibrinolysis)

- activated by Thrombin / Thrombomodulin Complex

- production enhanced by Factor XIa