Clot Formation

Question 1

What are the two main parts of hemostasis?

Answer 1

coagulation cascade and platelet activation/aggregation

Question 2

Damage to endothelium exposes the ECM which causes what to occur?

Answer 2

vMF is exposed and undergoes conformational change fro binding to platelets in circulation

Question 3

How does vMF bind platelets?

Answer 3

via GP1b

Question 4

A defect in vMF results in what disease?

Answer 4

Von Willebrand Syndrome

Question 5

A defect in GP1b results what disease?

Answer 5

Bernard Soulier Disease

Question 6

What happens when platelets bind to vMF on exposed endothelium?

Answer 6

they are activated, releasing the contents of their alpha and dense granules

and they undergo conformational change that allows them to bind fibrinogen to begin to aggregate and from a primary (weak) clot

Question 7

What do platelet alpha granules contain?

Answer 7

TxA2, P-selectin, Fibrinogen, Factors V and VIII (main ones)

Question 8

What do platelet dense granules contain?

Answer 8

ADP, Ca2+, histamine, serotonin, epinephrine

Question 9

What is the significance of Ca2+ being released from dense granules?

Answer 9

activation of coagulation factors requires Ca2+

Question 10

How does endothelial damage stimulate the extrinsic pathway?

Answer 10

It exposes TF

Question 11

How else is TF up-regulated on damage endothelial surfaces?

Answer 11

cytokines TNF, IL-1 and bacterial endotoxins up-regulate TF expression

Question 12

What does the exposed TF do?

Answer 12

binds factor VII, making the TF/VIIa complex

Question 13

What inhibits the TF/VIIa complex formation?

Answer 13

tissue-factor pathway inhibitor

Question 14

What else does TFPI do?

Answer 14

inactivates factor Xa

Question 15

Where is TFPI expressed?

Answer 15

healthy endothelial cells only

Question 16

What does TF/VIIa complex do?

Answer 16

activates Xa

Question 17

How is the intrinsic coagulation pathway activated?

Answer 17

Kallikrein and ANY negatively charged surface can activated XIIa

Question 18

What does XIIa do?

Answer 18

activate XIa, which activates IXa

Question 19

What does activation of every coagulation require?

Answer 19

1) phospholipid surface

2) calcium

Question 20

The enzymatic reaction that allows Ca2+ to bind to coagulation factors for activation requires what cofactor?

Answer 20

K+ (Coumadin is a drug that inhibits this)

Question 21

What does IXa do?

Answer 21

binds with VIIIa to activate more Xa

Question 22

What is VIII activated by once released from platelet alpha granules?

Answer 22

thrombin (also activates Va)

Question 23

At this point, the extrinsic and intrinsic pathways combine as Xa. What happens next?

Answer 23

Xa and Va convert prothrombin (II) to thrombin (IIa)

Question 24

What inhibits activation/function of VIIIa and Va?

Answer 24

Protein C

Question 25

How is Protein C activated?

Answer 25

expressed on healthy endothelial cells and is activated via thrombomodulin

Question 26

How does thrombomodulin activate protein C?

Answer 26

It changes the function of thrombin to activate Protein C instead of cleaving fibrinogen to fibrin

Question 27

What cofactor does Protein C need to act?

Answer 27

Protein S (K+ dependent)

Question 28

What does thrombin do (3 things)?

Answer 28

1) activates PAR on the surface of platelets, which with ADP and TxA2 enhance platelet aggregation 2) Converts fibrinogen in the primary clot to fibrin and 3) activates XIIIa to crosslink strands of platelet-fibrin-platelet chains to form the strong secondary clot

Question 29

In the primary clot, how is fibrinogen connected to platelets?

Answer 29

via GPIIb/IIIa molecules

Question 30

Defect in GPIIb/IIIa results in what disease?

Answer 30

Glanzmann thrombasthenia

Question 31

How is fibrin inactivated to prevent overclotting?

Answer 31

plasmin cleaves it

Question 32

How is plasmin activated? (4 things)

Answer 32

activated by: 1) factor XIIa 2) tissue plasminogen activator (tPA) 3) Urokinase-like plasminogen activator (uPA) in plasma 4) Streptokinase (bacterial product)

Question 33

Where is tPA produced?

Answer 33

healthy endothelial cells

Question 34

When is tPA most active? Why?

Answer 34

when attached to fibrin, which ensures that its mostly confined to sites of recent thrombosis

Question 35

How is plasmin inactivated?

Answer 35

1) free plasmin rapidly complexes with a2-antiplasmin | 2) plasminogen activator inhibitors (PAIs)

Question 36

What are PAIs stabilized by?

Answer 36

vitronectin

Question 37

What causes PAIs activation?

Answer 37

increased by inflammatory cytokines, especially IFN-y

Question 38

What disease greatly reduces plasma a2-antiplasmin?

Answer 38

cirrhosis

Question 39

How would you treat cirrhosis to prevent hemorrhaging?

Answer 39

caproic acid