Hemostasis Part 2 (complete)

Question 1

How does antithrombin function as a regulator of coagulation?

Answer 1

• It’s a serine protease inhibitor (SERPIN)

Inactivates:

• 2, 7, 9-12
• Kallikrein

Question 2

Explain how heparin affects antithrombin’s function

Answer 2

• 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

Question 3

Explain how protein C is activated

Answer 3

• 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

Question 4

Explain how the protein C-protein S system regulates coagulation

Answer 4

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

Question 5

What is factor V Leiden?

Answer 5

• 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”

Question 6

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

Answer 6

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

Question 7

Explain the role of plasmin in fibrinolysis

Answer 7

• 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

Question 8

Explain how plasminogen is activated to plasmin

Answer 8

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

t-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

u-PA:
porurokine bound to clot and then cleaved by plasmin => active form

Question 9

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

Answer 9

• 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

Question 10

Describe how alpha2-antiplasmin regulates fibrinolysis

Answer 10

• 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

Question 11

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

Answer 11

• 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

Question 12

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

Answer 12

• 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)

Question 13

What is primary hemostasis?

Answer 13

Involves:

• platelet adhesion
• aggregation
• activation

Question 14

What is secondary hemostasis?

Answer 14

Involves:

• activation of coag cascade
• formation of fibrin clot