Lecture 28: Clotting Cascade (Staudinger) Flashcards
What is the extrinsic pathway of platelet activation?
What is the intrinsic pathway of platelet activation?
Activated by external trauma, quicker, involves factor VII
Activated by internal trauma, slower, involves factors XII, XI, IX, VIII
What is the common pathway of platelet activation?
E and I pathways converge to finish clotting, involves factors I, II, V and X
Overview of the clotting cascade
Endothelial damage > blood exposed to subendothelial substances (collagen, vWF, TF) > platelet adheres to the vascular wall > platelets on the wall express
GIIa/Iia which binds fibrinogen on the platelets and causes them to aggregate on the vascular wall
Tissue Factor effects:
On the surface of subendothelial cells, not normally on cells
Binds factor 7 in the blood > activates via proteolysis which produces factor VIIa > factor VIIa converts Factors 9 and 10 to 9a and 10a > these two will cleave PTF II to PTF IIa
Thrombin effects:
- Cleaves fibrinogen to fibrin > non covalent bonding of fibrin monomers
- Helps activate prothrombin on platelets by converting 5 and 8 to 5a and 8a > these two will enhance the effects of 10a and 9a, respectively
How does thrombin also enhance the effect of factor 10?
8a/9a complex provides another pathway for further activation of factor 10
What eventually stabilizes the clotting aggregates?
Factor 13a
What does heparin do?
Enhances the ability of antithrombin III (ATIII) to inactivate thrombin, factor 9a and 10a. ATIII binds heparin, making it a better substrate for proteases thrombin, factor 9a and 10a > binding of ATIII to the proteases blocks protease activity (suicide inhibition)
What is the difference between primary hemostasis and secondary hemostasis?
Primary: platelet aggregation/plug at injury site (weaker plug)
Secondary: fibrin enhances the plug (stronger plug)
What is the mechanism of action of anticoagulants?
Inhibits vitamin K action to block clotting
What are the two types of oral anticoagulants?
Hydroxycoumarins (Warfarin group) and Indanediones
How is Vitamin K activated?
Vitamin K is turned into quinone by Vit. K 2,3 epoxide reductase using NADH
Quinone turned into quinol (active form) by Vit. K Quinon reductase
Why is vitamin K important in clotting?
Clotting depends on Vit. K dependent reactions as it is required to synthesize factors 2,7,9,10, Protein S and C
What process activates the clotting factors?
Gamma - glutamyl carboxylation
Which form of warfarin is more potent in producing an anticoagulant response?
S-warfarin > R warfarin.
Only free warfarin is active pharmacologically
How does Protein C and S regulation coagulation?
What happens when you have deficiency in Protein C and S?
- they inactivate Factors 5a and 8a
- increased risk of DVTs
What causes Hemophilia A?
Defective Factor 8a > cannot clot properly
What does an INR tell you?
Measures the deviation from standard normal clotting time (too high = blood clots way slower than normal and vice versa)
What is the difference between PT (prothrombin time) and PTT (partial prothrombin time)?
PT measures extrinsic coagulation pathway (factors 1,2,5,7,9,10)
PTT measures intrinsic coagulation pathway (factors 12, 11, 9, 8, 10, 5, 2, 1, PK and HK
What are the normal values for PT and PTT?
PT: 12-13 s
PTT: 25-35 s
If you have prolonged PT and normal PTT, what does this signify?
Liver disease, decreased Vit. K, factor 8, DIC or patient is on anticoagulation therapy (warfarin)
