Hemostasis Part 2 (complete) Flashcards Preview

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Flashcards in Hemostasis Part 2 (complete) Deck (14):

How does antithrombin function as a regulator of coagulation?

- It's a serine protease inhibitor (SERPIN)

- 2, 7, 9-12
- Kallikrein


Explain how heparin affects antithrombin's function

- Accelerates the rate of antithrombin function by 100s/1000s fold

Two mechanisms:
1) Specific pentasaccharide sequence in heparin induces allosteric conf change in antithrombin => efficient binding to/inhibition of target
2) Heparin acts as a cofactor for antithrombin --- a longer form of heparin binds antithrombin and target and brings them together => both inactivated, 1:1


Explain how protein C is activated

- Thrombin generated from prothrombin
- Thrombin binds to thrombomodulin
- When bound, thrombin activity is neutralized (no more coagulation from this one)
- The T-T complex binds to and ACTIVATES protein C


Explain how the protein C-protein S system regulates coagulation

- Cleaves and inactivates 5a and 8a => decreased generation of thrombin (2a)
- Protein S helps move APC closer to activated platelet surface


What is factor V Leiden?

- A mutation of Factor V
- Makes it resistant to protein C
- Sometimes called APC resistance
- Common risk factor for venous thromboembolism
- Pop'n have difficulties "unclotting"


Describe how tissue factor pathway inhibitor (TFPI) functions in regulating coagulation

- TFPI is a proteinase inhibitor
- Expressed in endo cells
- Inhibits extrinsic tenase by bindng and inactivating the complex


Explain the role of plasmin in fibrinolysis

- Plasmin is an active serine protease
- Can cleave fibrinogen and fibrin
- Can break down ECM proteins => helps in remodeling process of damage blood vessel

Plasminogen is synthesized in the liver and circulates in plasma, also in extravascular tissues/body fluids


Explain how plasminogen is activated to plasmin

- Activated by tissue plasminogen activator (t-PA) --- produced mainly in endo cells
- Also urokinase *u-PA)

regulated/secreted by endos => short t1/2 --- must be in presence of fibrin to be a good activator => as clot forms, plasminogen binds to fibrin generated => t-PA activates plasminogen to plasmin

porurokine bound to clot and then cleaved by plasmin => active form


Describe how plasminogen activation inhibitor 1 (PAI-1) regulates fibrinolysis

- Targets t-PA and u-PA
- PAI-1 produced in many cells types, short t1/2
- PAI-1 mainly found in blood => circulates/inactivates t-PA


Describe how alpha2-antiplasmin regulates fibrinolysis

- A primary plasmin inhibitor in blood
- Also a SERPIN
- Binds to/inactivates plasmin, 1:1 ratio
- Rapidly inhibits free plasmin in circulation => prevents systemic fibrinogen degradation
- Fibrin-bound plasmin is kinda protected from alpha2-antiplasmin


Describe how thrombin-activatable fibrinolysis inhibitor (TAFI) regulates fibrinolysis

- A zymogen --- synthesized in liver
- Circulates in blood as complex w/ plasminogen
- Activated when cleaved after binding to the TT complex => becomes an exopeptidase
- Chews ends off fibrin molecules => reduces # of plasminoen binding sites and decreases its availability to t-PA or u-PA => downregulates plasmin generation, slows clot lysis


What are the mechanisms the endothelial cell lining uses to prevent clot formation in the resting state?

- Produces heparin sulfate
- Expresses thrombomodulin => protein C activation
- Expresses TFPI
- Synthesizes t-PA and u-PA
- Synthesizes PGI2 and nitric oxide => vasodilation
- Metabolizes ADP (a platelet agonist) to AMP + adenosine (platelet inhibitor)


What is primary hemostasis?

- platelet adhesion
- aggregation
- activation


What is secondary hemostasis?

- activation of coag cascade
- formation of fibrin clot