Hemostasis (Blood Clotting)

Question 1

What is the most common type of bleeding disorder?

Answer 1

Von Willebrand Disease from a lack of Von Willebrand factor that binds Factor 8a. Platelet-related bleeding.

Question 2

What are the soluble mediators of platelet function?

Answer 2

ADP and Thromboxane A2 (latter is a potent vasoconstrictor)

Question 3

What is the significance of GPIIb/Illa integrin in thrombosis?

Answer 3

Once platelets are activated it works with fibrinogen to recruit more platelets for plug to form

Question 4

Define the 3 steps that occur in primary hemostasis.

Answer 4

Adhesion, activation and aggregation

Question 5

When platelet count is very low, what happens to capillaries?

Answer 5

Loss of platelets lose trophic factors that maintain cell to cell contact in the endothelium. This thrombocytopenia results in petechiae (small bruises)

Question 6

What clotting factor activates fibrin for hemostasis?

Answer 6

Factor 2 or thrombin activates fibrinogen into fibrin in the clotting cascade

Question 7

What cell associated clotting factor initiates the extrinsic pathway of the clotting cascade?

Answer 7

Tissue factor or factor 7a

Question 8

What clotting factors require vitamin k to work properly?

Answer 8

Clotting factors 2, 7, 9 and 10 are vitamin-K dependent zymogens that require carboxylation of GLU residues into GLA.

Question 9

What drug targets vitamin K in the coagulation process?

Answer 9

Warfarin targets vitamin K to prevent vitamin K Reductases from carboxylation Glu residues (this works as an anticoagulant)

Question 10

What key step must happen for secondary hemostasis to take place?

Answer 10

Cross-linking of fibrin to form a strong sealant in the formation of the clotting plug.

Question 11

What are the 3 effects of thrombin in the clotting cascade?

Answer 11

1. Converts fibrinogen into fibrin
2. Stimulates factor 13 to form covalent bonds for strong clots
3. Recruits more platelets

Question 12

What do these 3 substances all have in common? (Heparin, thrombomodulin, Protein C) Describe how each works.

Answer 12

They are all anti-coagulants.

1. Heparin - GAG that stimulates the binding of antithrombin to inhibit thrombin.
2. Thrombomodulin - cofactor of protein C that inhibits thrombin
3. Protein C - vitamin-K dependent cofactor that inhibits factors 5 and 8.

Question 13

In what 2 ways can thrombin (factor 2) feedback on the clotting cascade? Describe the significance.

Answer 13

1. Can amplify Factor 8* and Factor 9. Factor 8 is an ACCELERANT to which Factor 9 can ramp up the production of Factor 10a.
2. Thrombin activates Factor 5 (non-enzymatic) binds factor 10a to make EVEN more thrombin to form FIBRIN!

Question 14

Deficient Factor 8 results in Hemophilia ___, whereas deficient Factor 9 causes ____.

Answer 14

8 = Hemophilia A;
9 = Hemophilia B;
These are both XLR diseases and involve deep-tissue bleeding (i.e. muscular hematomas) to which loss of Factor 8 is more common.

Question 15

Describe the pathogenesis of Von Willebrand’s Disease.

Answer 15

Loss of VWF = less stable Factor 8 (reduced half-life). This results in poor platelet function and clotting (bad primary and secondary hemostasis).

Question 16

Describe 3 important complexes that are ESSENTIAL to coagulation.

Answer 16

1. (Tissue Factor) Factor 7 and factor 9 make factor 10 [extrinsic pathway]
2. Factors 8 and 9 complex to make factor 10
3. Factors 5 and 10 make Factor 2 (prothrombin)

Question 17

What are the soluble, non-enzymatic cofactors in the clotting cascade?

Answer 17

VWF, Factors 5 and 8 are the soluble accelerants or cofactors that stimulate the cascade.

Question 18

What is the significance of GLA residues on vitamin-K dependent clotting factors? What is the clinical significance of this?

Answer 18

The negative charge of GLA enables the interaction of calcium and platelet membrane. This facilitates blood clotting. Calcium chelators (i.e. sodium citrate) on the blue top of blood sample tubes work by blocking calcium.

Question 19

Name at least 2 problems that can affect Vitamin K absorption.

Answer 19

1. Choleostasis
2. Ileal resection
3. Chron’s disease

Question 20

How is the intrinsic pathway activated?

Answer 20

When factor 12 contacts a negatively charged surface such as polyphosphate molecules, RNA or platelet membranes. This activation is Tissue factor-independent.

Question 21

Explain the significance of HMKG in the intrinsic pathway

Answer 21

HMKG binds Factor 11a that allows factor 12 to bind onto endothelium. This process is an additional way for Factor 9 to get activated which feeds into factor 10 (point of convergence).

Question 22

Presence of what peptides in the blood indicates the presence of clots in circulation?

Answer 22

Fibrinopeptides (A and B) can be measured to see if someone is forming a clot. May be an indicator for stroke or DVTs.

Question 23

Define Factor 13.

Answer 23

Factor 13 is activated by thrombin to create covalent bonds to bind fibrin molecules to each other.

Question 24

What is thrombomodulin? How does this relate to Protein C?

Answer 24

TM is a circulating anti-coagulant that binds thrombin to recruit Protein C. Protein C inhibits the accelerants (cofactors 5 and 8).

Question 25

Describe the cause and effects of Factor V Leiden Mutation.

Answer 25

Factor V Leiden mutation is the most common thrombophilic disorder in the US. Mutation of factor V interferes with protein C’s ability to cleave it. This results in a prolonged pro-coagulant effect.

Question 26

What is the function of anti-thrombin?

Answer 26

Anti-thrombin inhibits Thrombin AND Factor 10. This is the target for heparin to modulate anti-coagulation.

Question 27

Prolonged use of warfarin therapy, post-surgically can put a patient at risk of developing a skin necrosis, blisters and a red lesion because of a deficiency of what protein in the clotting cascade?

Answer 27

Loss of Protein C function can result in a procoagulant state that features skin necrosis and painful blisters.