Biochemistry of Coagulation

Question 1

What does aspirin do to platelets?

Answer 1

It irreversibly inhibits their cyclooxygenase - so it irreversibly inhibits them

Question 2

What are the 4 phasea of hemostasis?

Answer 2

1. vascular constriction limits flow of blood to injury
2. platelets activate and aggregate to form temporary loose platelet plug
3. a fibrin mesh (clot) forms and entraps the plus
4. clot is dissolved in order for normal blood flow to resume after tissue repair

Question 3

What molecules i primarily responsible for stimulatin gplatelet clumping?

Answer 3

fibrinogen

Question 4

What do platelets release when they are activated?

Answer 4

ADP and TXA2 - they both activate additional platelets

and other proteins important for the coagulation cascade

Question 5

Although normal platelet count is 150,000 to 450,000, how many do we actually need before we have trouble clotting?

Answer 5

50,000 (below that and we’ll have issues with stopping bleeding, below 10,000 and we’ll have issues with spontaneous bleeding)

Question 6

What do platelets adhere to in the area of injury?

Answer 6

exposed collagen on the subednothelial layer

Question 7

What factor mediates the adhesion of platelets to collagen?

Answer 7

vonWillebrand factor

and GpIX-GpV and GpVI

Question 8

Specifically, how does vWF work?

Answer 8

It acts as a bridge between the collagen fibrils on the subendothelial layer and the glycoprotein IB (GpIX-GpV) on the surface of the platelet

Question 9

What enzyme is usually lacking in thrombotic thromobocytopenic purpura? What does it usually do?

Answer 9

ADAMTS13 - which usually cleaves vWF aggregates

If they’re not broken down, they block up the vessels and cause a microangiopathic hemolytic anemia

Question 10

What’s the pentad of symptoms in TTP? Do they need all of them for a diagnosis?

Answer 10

microangiopathic hemolytic anemia, thrombocytopenia, fevers, renal failure, and neurologic deficits

They don’t need all of them - only RBC fragmentation and thrombocytopenia

Question 11

What’s the treatment for TTP?

Answer 11

early plasmapheresis

and Rituxan

Question 12

When ADP binds to new platelets, what does it do?

Answer 12

It leads to further unmasking of GpIIb-IIIa binding sites for additional platelet aggregation

Also indices swelling of activated platelets, promoting platelet/platelet contact and adherence

Question 13

How does platelet adherence lead to production of the vasoconstrictor TXA2?

Answer 13

It leads to activatin of pohospholipase A2 which hydrolyzes membrane phospholipids to liverate arachidonic acid, which is then broken down to TXA2 by cyclooxygenase

Question 14

GpIIb-GpIIIa acts as a receptor fo vWF and what else?

Answer 14

fibrinogen

Question 15

What cleaves fibinrogen to produce fibrin monmers that polymerize with platelets to form the soft clot

Answer 15

thrombin

Question 16

Where are clotting factors synthesized?

Answer 16

liver

Question 17

There are two pathways in clotting cascades: intrinsic and extrinsic. Where do they converg?

Answer 17

they both converge on factor 10 to ocnvert to 10a

Question 18

What does factor Xa do>

Answer 18

converts prothrombin (factor 2) to thrombin (factor 2a),

Question 19

Again, what does thrombin do?

Answer 19

It cleaves fibrinogen into fibrin monomers that cross link to form clot

Question 20

What factor is needed for cross-linking of fibrin polymers?

Answer 20

activated factor XIII

Question 21

What’s the most important thrombin inhibitor?

Answer 21

antithrombin III

Question 22

What drug potentiates the activity of antithrombin III?

Answer 22

heparin - it alters it’s structure slightly so it can bind thrombin more readily

Question 23

Activated protein C with it’s necessary cofactor protein S do what to put the breaks on coagulation?

Answer 23

They degrade factors Va and VIIIa via proteolysis so you decrease thrombin production

Question 24

What serine protease is largely responsible to degrading fibrin?

Answer 24

plasmin (formed from plasminogen)

Question 25

What are two endogenous plasminogen activators?

Answer 25

tPA (from vascular endothelial cells)

single-chain urokinase

Question 26

What vitamin is vital for the coagulation cascade?

Answer 26

vitamin K - used as a cofactor

Question 27

What drugs works as a vitamin K antagonist to reduce activation of factors 2, 7, 9, and 10?

Answer 27

warfarin (coumadin)

Question 28

What does warfarin block specifically

Answer 28

the vitamin K reductase enzymes used to regenerate active vitamin K

Question 29

What are the factors not able to do if not gamma-carboxylated?

Answer 29

they can’t bind the necessary calcium nor form complexes

Question 30

What other proteins are blocked by warfarin, which is why you need to “bridge with heparin”. What does this mean for clotting?

Answer 30

protein S and C

this means that warfarin will actually make you clot initially

Question 31

What drug can cause thrombocytopenia by triggering an autoimmune prothrombotic disorder?

Answer 31

heparin - you get IgG antibodies that cause platelet activation