Blood Coagulation

Question 1

What are some possible causes of slow clotting?

Answer 1

hemophilia, liver disease, rat poison

Question 2

How does liver disease cause slow clotting?

Answer 2

the liver synthesizes many of the clotting proteins including prothrombin, fibrinogen, etc.

Question 3

How does rat poison cause slow clotting?

Answer 3

they have antagonists of clotting. Causes massive internal bleeding

Specifically, warfarin blocks the conversion of glutamic acid to y-carboxy glutamic acid by acting as an inhibitor to the action of vitamin K (needed for the rxn), so coagulation factors synthesis is inhbitors

Question 4

What conditions might cause OVERclotting?

Answer 4

thromoemboli, stroke

Question 5

What are the three stages of clot formation?

Answer 5

1) Initiation
2) Amplification
3) Propagation and stabilization

Question 6

What is the first step in clot formation?

Answer 6

A cut exposes blood to nonvascular cells on the outside of the endothelial lining of vasculature. These nonvascular cells express the integral membrane protein, tissue factor (TF).

Question 7

What does tissue factor do?

Answer 7

Activates factor VII to VIIa and forms a complex with it- the TF-VIIa complex

Question 8

What does the TF-VIIa complex do?

Answer 8

activates factor X to Xa

Question 9

What does factor Xa do?

Answer 9

activates a small amount thrombin from prothrombin. Not enough to make a clot though!

This is the last step of initiation

Question 10

What does the activated thrombin then do?

Answer 10

activate platelets, which begin to express receptors on their cell surface

activates a protease, XI

and activates two accelerates, V and VIII

Question 11

What happens next?

Answer 11

XI gets activated to XIa by X, and XIa activates IX to IXa

Question 12

What does activated IXa do?

Answer 12

combines with an activated accelerator, VIIIa (don’t know what activates it) and together they bind to platelet receptors and activate more X to Xa

Question 13

What happens to the increased amounts of Xa that are made?

Answer 13

Xa will combine with activated Va (don’t know what activates it) on platelets via receptors to accelerate (by 1000x) the formation of more thrombin from prothrombin

Question 14

What do the increased levels of thrombin do?

Answer 14

activates platelets to express surface receptors that facilitate aggregation

activate fibrinogen to fibrin (forms a protein matrix around the platelets plugging the wound)

activated XIIIa from XIII

Question 15

What does activated XIIIa do?

Answer 15

facilities the cross-linking of fibrin molecules to form a strong clot

Question 16

What kinds of surface receptors do platelets begin to express when activated by thrombin?

Answer 16

VIIIa, IXa, fibrinogen/FIBRIN binding, collagen binding, fibronectin binding, and a receptor for Va (an accelerator)

Question 17

How can the initiation step (to produce/activate a small amount of thrombin for amplification) be inhibited?

How does this work?

Answer 17

LACI (lipoprotein associated coagulation inhibitor). LACI inhibits the activation of Xa from the TF-VIIa complex to inhibit thrombin activation

Question 18

How can the amplifications step of coagulation be inhibited?

Answer 18

anti-thrombin III+ herapin sulfate PG (found on downstream endothelial cells) complex

Question 19

How does the anti-thrombin III- heparin complex work?

Answer 19

heparin sulfate PG/herapin is a proteoglycan that activates a protein called anti-thrombin III that together form a molecule to limit amplification by inactivating thrombin, factor Xa, and factor IXa if they flow away from the wound site

Question 20

How can the propagation/stabilization step of coagulation be inhibited?

Answer 20

activated protein C-S complex destroys Va and VIIIa

Question 21

What does plasmin do?

Answer 21

it is a protease that dissolves clots by digesting fibrin

Question 22

What is thrombomodulin and what does it do?

Answer 22

It is a transmembrane protein expressed on endothelial cells that bind to activated thrombin and protein C. Protein C is then activated to a C-S complex (protein S is already on the cell surface) that inhibits accelerators Va and VIIIa. The Protein C-S complex is retained on the endothelial cell where it is activated to localize the anti-coagulative nature of it

Question 23

What is plasmin activated by?

Answer 23

activated protein C and plasminogen activator

Question 24

Deficiency of protein S, C, or antithrombin III causes what?

Answer 24

thromboembolytic disease

Question 25

What is hemophilia?

Answer 25

genetic disorder causing mutations in the synthesis of coagulation factors

Question 26

What drugs can inhibit platelet function?

Answer 26

aspirin