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
What happens when a patient overdoses on warfarin?
-Can lead to lactogenic hemorrhage
If a patient overdoses on warfarin what should you do?
-Discontinue warfarin therapy
-Administer Vitamin K1 (activates resistance)
*In serious hemorrhage: Giving plasma replaces clotting factors faster than Vit K
What is Protein C?
An innate coagulant that requires vitamin K-dependent carboxylation for its activity
What causes warfarin necrosis?
-Some patients have protein C deficiency
-Warfarin initially decreases protein C levels faster than coagulation factors do which can paradoxically increase coagulation when treatment is first begun
***Deficiency in protein S would lead to the same necrosis
What is used to prevent warfarin necrosis?
Patients are started on heparin at the same time as warfarin to combat this
Can you take warfarin during pregnancy?
NO
-crosses placenta, teratogen
What drugs reduce the anticoagulation effect of warfarin?
Vitamin K:
(bypasses warfarin-induced epoxidise reductase inhibition)
Broad-Spectrum Antibiotics:
(reduce availability of vitamin K in the GI tract)
What is Vitamin K and what does it do?
Fat-soluble vitamin
-Involved in post-translational modification of prothrombin, factors VII, IX, and X
What does a vitamin K deficiency cause?
Abnormalities in fat absorption
What is the single vitamin K antagonist?
Warfarin
What are the indirect factor IIA/Xa Inhibitor medications?
-Unfractionated heparin
-Enoxaparin
-Daltaparin
-Fondaparinux (non-heparinoids)
What is the mechanism of action of heparin?
-Free antithrombin inactivates clotting factors (Activity is 3:1 thrombin:factor Xa)
-Heparin binds AT and changes its conformation to form a ternary complex
LMWH:
-LMWH are too small to bind antithrombin and thrombin so they have greater specificity for inhibition of Factor Xa
***Heparin accelerates AT reactions to inactivate thrombin and factor Xa
How long does it take heparin to become effective?
Heparin is effective immediately
How is heparin administred?
-Intermittent IV injection
-Continuous IV infusion (*easiest to control)
-SubQ injection
What are the adverse effects of heparin?
Latrogenic Hemorrhage
(hemorrhage can occur at any site)
Thrombocytopenia (HIT)
Osteoporosis
What is the treatment for latrogenic hemorrhage resulting from heparin?
-Stop heparin
-Life threatening bleeding:
(administer antagonist protamine sulfate which binds tightly to heparin to neutralize the anticoagulation action)
What is protamine sulfate?
Heparin inhibitor
-low molecular weight polycationic protein that forms a stable complex with heparin through electrostatic interactions
How is protamine sulfate administered?
IV
**not as effective as LMWH
**does not reverse the effects of fondaparinux
How does heparin bind to antithrombin?
Through negatively charged sulfate groups (SO3-)
What are the low molecular weight heparins?
-Dalteparin
-Enoxaparin
How do LMWH’s compare to heparin?
-Equal efficacy
-Increased SubQ bioavailability (only route)
-Less frequent dosing
-Longer half-life
No monitoring needed!
What are the advantages of LMWH over Heparin?
-More predictable
-Lower incidence of thrombocytopenia and osteoporosis (more specificity)
Can UFH and LMWH be given in patients with renal failure?
UFH: YES
LMWH: NO
How are LWMH administered?
SubQ only
What is the only Factor Xa inhibitor?
Fondaparinux Sodium
What is the structure of Fondaparinux Sodium?
synthetic sulfated pentasaccharide
(active part of heparins)
What is the mechanism of action of fondaparinux sodium?
Indirectly inhibits factor Xa by selectively binding antithrombin (AT)
How is fondaparinux sodium administered?
SubQ, can be given at home
How often is fondaparinux sodium administered?
Once daily
(half life around 1 day)
What monitoring is used for fondaparinux sodium?
NONE
-has a predictable dose response
What is fondaparinux used for?
-VTE
-Prophylaxis in patients undergoing knee OR hip surgery OR abdominal surgery
Can fondaparinux sodium be reversed by protamine sulfate?
No, only heparin and LMWH
What medication is a non-heparinoid?
Fondaparinux sodium
What is an advantage of fondaparinux sodium relating to possible side effects?
Low potential for thrombocytopenia
What are the Direct Factor Xa Inhibitors?
Rivaroxaban
Apixaban
Edoxaban
How is dosing of Direct Factor Xa Inhibitors changed with impaired renal function?
-Need a dose reduction
What procedure poses an added risk with Direct Factor Xa Inhibitors?
Spinal punctures or epidural anesthesia procedures increase the risk for hematoma and paralysis
True or False: Factor Xa Inhibitors have an increased risk of thrombosis upon discontinuation
True
What are Factor Xa Inhibitors used to treat?
-VTE and PE
-Prevent thrombosis in afib
At what CrCl should Edoxaban (Savaysa) not be used?
CrCl > 95 ml/min
Upon premature discontinuation of Edoxaban, the risk for what increases?
Ischemic events
What is the antidote for Factor Xa inhibitors?
Andexanet
(only inhibits apixaban and rivaroxaban)
What Factor Xa Inhibitors does andexanet inhibit?
Apixaban and Rivaroxaban
What is the black box warning for andexanet?
Increased thromboembolic events
What is the mechanism of action of direct thrombin inhibitors?
-Bind active site of thrombin, to exosites of thrombin or both (bivalent)
-Inhibit BOTH soluble and fibrin-bound thrombin
-Also reduce platelet activation
What type of fibrin can direct thrombin inhibitors inhibit?
BOTH soluble and fibrin-bound
What is the mechanism of action of non-heparinoid parenteral agents?
Do not act through AT-III
*inhibit both free and fibrin-bound thrombin
What is hirudin?
-Peptide from saliva gland of medicinal leaches
-Non-heparinoid parenteral agent
-Prevents thrombin from cleaving fibrinogen and coagulation
What is Lepirudin (Refludan)?
Direct Thrombin Inhibitor
-Recombinant hirudin grown in yeast
*Given IV
*Inhibition of thrombin is reversible
-Increase aPTT dose-dependently
What is lepiruden used to treat/
HIT
What is the mechanism of action of Bivalirudin?
*Direct thrombin inhibitor
-Binds catalytic site and exosite I of thrombin
Is the binding of bivaliruden to thrombin reversible or irreversible?
Reversible
What part of bivaliruden is cleaved by thrombin?
Between the Arg - Pro
*this part binds the catalytic site of thrombin
-dissociates after being cleaved
When is bivaliruden given?
Given IV during percutaneous coronary angioplasty (PCI) placement
What is the mechanism of action of argatroban?
*Direct Thrombin inhibitor
-Binds reversibly to active site of thrombin
***Inhibits both free and clot-associated thrombin
What is argatroban used to treat?
HIT or Coronary artery thrombosis in patients with HIT
*Also prophylaxis in PCI procedures
What is argatroban derived from?
L-arginine
Can dabigatran be used in severe renal impairment?
NO
What is the antagonist of dabigatran?
Praxbind
(humanized IgG1 FAB fragment)
What is Idarucizumab (Praxbind) use to reverse?
Dabigatran
**does not bind other thrombin inhibitors
