Anticoagulant Drugs (Hock) Flashcards
What is the key enzyme in the coagulation pathway?
Thrombin
How do PRO-COAGULANT SERINE PROTEASES work and what factors are these?
-Cleave down-stream factors to activate them
Factors:
XII (12)
XI (11)
X (10)
IX (9)
VII (7)
II (2)
How do ANTI-COAGULANT SERINE PROTEASES work and what factors are these?
-Cleave factors Va (5) and VIIIa (8)
Factor:
Protein C
What glycoprotein factors activate proteases?
Factors:
VIII (8)
V (5)
III (3)(tissue factor)
Protein S
What glycoprotein factors bind and inhibit thrombin?
Factor:
Anti-thrombin III
What is factor IV (4) and what does it do?
Calcium
-Links certain factors to phospholipid membranes
what factor is transglutaminase and how does it contribute to clotting?
factor: XIII (13)
Cross-links fibrin fibers
What factor is prothrombin/thrombin?
II and IIa
What causes Hemophilia A?
Deficiency in Factor VIII (8)
What causes Hemphilia B?
Deficiency in factor IX (9)
What does the mutation Factor V Leiden cause?
Resistance to activated protein C
*increases chance of developing a clot
Where are clotting factors produced?
Liver
(except von Willebrand Factor)
Where is von Willebrand factor produced?
In the endothelium, subendothelium, and megakaryocytes
Besides von Willebrand Factor, what other factor is produced in the endothelium?
Factor VIII (8)
What affect can liver disease have on coagulation?
Since clotting factors are produced in the liver, liver disease has an unpredictable effect on coagulation
When is the extrinsic pathway for coagulation triggered?
A factor extrinsic to the blood (tissue factor) encounters blood and initiates coagulation
*important when vessel is damaged and blood leaks out
When is the intrinsic pathway for coagulation triggered?
Inside of blood vessel is damaged and collagen is exposed on the wall of the blood vessel
*factors then bind to collagen
Activation of which factor is the important step for the intrinsic pathway?
Factor 9
*this factor is activated by both the extrinsic and intrinsic pathways to activate factor X
What is the first factor recognized by the extrinsic pathway?
Factor 7
What pathway allows blood to clot in a test tube?
Intrinsic pathway
(glass acts like collagen)
What makes up the intrinsic pathway?
All components in blood
What initiates the intrinsic pathway?
Contact with negatively charged collagen of a diseased of injured vessel
What does the extrinsic pathway rely on for activation?
Factors outside the bloodstream
What activates the extrinsic pathway?
The release of tissue thromboplastin
How long does it take the extrinsic pathway to start clot formation?
About 15 seconds (rapid)
Where is tissue factor expressed?
On the surface of cells outside but near blood vessels
Where does Factor VII (the initiating factor of the extrinsic pathway) reside?
In the blood
How are Factor VII and Factor X initiated in the extrinsic pathway?
Tissue Factor (TF) binds Factor VII in the blood and activates it
Factor VIIa binds and cleaves Factor X which activates it
What affect does ketylating calcium have on coagulation?
Ketylating calcium inhibits coagulation
Once Factor X is activated, what does it do?
Factor Xa is the initiator of the “common pathway” (where the intrinsic and extrinsic pathways meet)
Factor X is responsible for cleaving prothrombin to thrombin
What does Thrombin do?
-Converts fibrinogen to fibrin
-Activates Factor XIII which cross-links fibrin to form a stable clot incorporated into a platelet plug
What 2 feedback mechanisms increase coagulation?
Thrombin
-Activates Factor V and VIII
-Enhances platelet activation
Platelet Activation
-Increases activation of factor VII, Factor X, and cleavage of prothrombin
What 3 feedback mechanisms decrease coagulation?
Antithrombin
-Neutralizes procoagulant serine proteases (thrombin, Xa, IXa) *accelerated by heparin
Protein C System
-Activated by thrombin binding to thrombomodulin
-Activated protein C complex (APC) forms complex with protein S to inactivate factors Va and VIIIA
Factor Xa
-Activates tissue factor pathway inhibitor to block initial activation of factor VII
What clotting factors are inhibited by warfarin?
II, VII, IX, X
What is the mechanism of action of warfarin?
Inhibits Vitamin K-epoxide reductase (VKORC1) which blocks the reduction of vitamin K
What is the role of gamma-carboxylation for clotting factors?
Factors need to bind to the phospholipid membrane in order to find each other
-They do this by binding to Ca+ which can then bind to the negatively charged phospholipid membrane
-The calcium binds to the two negatively charged oxygens located on the factors
-This process is done by the y-glutamyl carboxylase
What CYP metabolizes warfarin?
CYP2C9
**this is one of the most variable CYPs
How is warfarin inactovated?
Warfarin is inactivated when it is metabolized by CYP2C9
The termination of action of warfarin is based on what?
Termination of action of warfarin is not related to plasma warfarin levels, but instead the reestablishment of clotting factors in the blood