Lecture 18: Blood Coagulation

Question 1

What is importance of antiproteases?

Answer 1

Regulates (inactivates) enzymes activated by proteolysis–shit can get wonky fast if you don’t keep and eye on these bad boys

Question 2

What is the inactive form of thrombin (2a)?

Answer 2

Prothrombin (2)

Question 3

What is the final role of thrombin (2)?

Answer 3

Cleaves fibrinogen (1) to fibrin (1a)

Question 4

Where are digestive enzymes made?

Answer 4

Salivary glands, stomach, pancreas, small intestine

Question 5

What is the activator for pepsinogen?

How is it activated?

Answer 5

Low pH (2) of stomach acid

Spontaneously–autocatalytic

Acidic amino acids are pronated, salt bridges become broken–conformational change

Question 6

Where are majority of zymogens produced?

Answer 6

Pancreas

Question 7

What activates trypsinogen?

What changes in the molecule?

Answer 7

Enteropeptidase or trypsin

Active site completed following conformational change

Question 8

What is trypsin able to activate following its activation?

Answer 8

Other trypsinogen molecules + chymotrypsin, procarboxypeptidase, proelastase

Question 9

What is an enzyme cascade?

Answer 9

When a small amount of enzyme can cycle back and further activate its own molecules

Question 10

How is the digestive enzyme cascade regulated?

Answer 10

Self-Regulating, enzymes destroyed by other enzymes in the pathway

Question 11

What does floppy mean in the silly world of enzymes?

Answer 11

Unordered

Question 12

How is chymotrypsinogen activated?

Answer 12

Trypsin cleaves a peptide bond, yielding pi-chymotrypsin, which further autocleaves itself to eventually form alpha-chymotrypsin which is held together by 2 di-sulfide bonds

Question 13

What is formed in the final step to yield alpha-chymotrypsin?

Answer 13

New N-Terminal Amino Acid, which H-bonds of the Charge Relay System–yielding the oxyanion pocket

Question 14

When does activation of chymotrypsin occur?

Answer 14

When cleavage allows alignment of the catalytic site

Question 15

What inhibitor protects pancreas enzymes from self destruction? What does it act like?

Answer 15

Pancreatic Trypsin Inhibitor (PTI)

Competitive Inhibitor (gets stuck)

Question 16

What is the cause of emphysema?

Who is at greatest risk?

Answer 16

Genetic change in alpha1AP protein, which reduces secretion. Elastase destroys tissues.

Homozygotes, or heterozygotes who smoke them marlboro reds all day, every day

Question 17

What is the contact system?

Answer 17

Intrinsic Pathway (circulating in blood)

Question 18

What is the damaged tissue system?

Answer 18

Extrinsic Pathway (Fast!)

Question 19

What is the order of the Intrinsic Pathway

Answer 19

HMWK+Kallikrein+F12
F11
F9
F8
Converge at F10

Question 20

What is the order of the Extrinsic Pathway

Answer 20

TF3
F7
Converge at F10

Question 21

What is the order of the Common Pathway

Answer 21

F10
F5
F2 (Thrombin)
F1 (Fibrin)
F13 (Fibrin-Meshwork)

Question 22

What can increase F7?

Answer 22

F7a, F9, F10a

Question 23

What does activated kallikrein activate?

Answer 23

F12

Question 24

What does Thrombin activate?

Answer 24

F8, F5

F1i to F1a

F13 (Fibrin Cross Links)

Protein C

Question 25

What does Protein C inactivate?

Answer 25

F5 | F8

Question 26

What does Fibrinogen contain many of? What is the result?

Answer 26

Negatively charged AA Increased repulsion and solubility

Question 27

What does Thrombin activation of Fibrinogen accomplish?

Answer 27

Peptide removal, lowering negative charge driving aggregation

Question 28

What AA does F13a act on?

Answer 28

K/Q

Question 29

What do the granules of platelets contain?

Answer 29

Clotting factors, adenine, serotonin, growth factors

Question 30

What does phos-serine on exterior surface provide?

Answer 30

Binding site for clotting factors

Question 31

What is role of vWF? What if it is absent?

Answer 31

Links b/t platelet surface glycoprotein and ECM Carrier for F8 Cross-links can't form

Question 32

What limits clotting activity?

Answer 32

Dilution, liver removes factors from circulation, proteases degrade factors, plasma inhibitors block protease activity

Question 33

What is role of Antithrombin3 (AT3)?

Answer 33

Serpin inhibits thrombin by forming complex with it

Question 34

What is role of Heparin?

Answer 34

Inhibition of thrombin by increase of AT3 formation

Question 35

What is the Clot Buster? What activates it?

Answer 35

Plasminogen TPA (activates to Plasmin)

Question 36

What are the three critical site residues for all SERPINs?

Answer 36

His Asp Ser All serpins HAspS same 3 sites

Question 37

What proteases require Calcium (Vitamin K)? What is unique about them? What does the Calcium serve as?

Answer 37

F2 F9 F10 F7 "1972" Gla Domain of Glu residues modified to contains a second carboxyl group in their side chain -- gamma-carboxyglutamate Bridge for phospholipid binding

Question 38

What is unique about F2 in its Gla domain?

Answer 38

It is removed during activation

Question 39

What does mod of Glu to Gla require? Is this required for activity?

Answer 39

Vitamin K No, required to localize enzymes/substrates

Question 40

What medication is a Vitamin K antagonist?

Answer 40

Warfarin

Question 41

What is hemophilia (A/B) a disease in?

Answer 41

``` A = F8 (Ay-te) B = F9 ```

Question 42

Aspirin

Answer 42

Inhibits Platelet Activation (irreversible)

Question 43

Clopidrogel

Answer 43

Inhibits platelet Activation (irreversible)

Question 44

Coumadin

Answer 44

Inhibits Vit K dep factors/enzymes Warfarin discovered in 1972

Question 45

Dabigatran

Answer 45

Inhibits Thrombin Reversible

Question 46

Heparin Sodium

Answer 46

Activates AT3 (inactivates 10/2)

Question 47

Rivaroxaban

Answer 47

Inhibits 10 "X" in middle