Anticoagulant Drugs Flashcards
Explain the difference between the intrinsic and extrinsic clotting pathways
extrinsic pathway: requires a factor (tissue factor - forms as a nucleus for initiation of coagulation) extrinsic to the blood; important when vessel is damaged and blood leaks out
intrinsic pathway: triggered when collagen is exposed on the wall of the blood vessel
Intrinsic pathway
all components in blood
initiated by contact with negatively charged collagen of diseased or injured vessel
activation of factor IX is the important step
Extrinsic pathway
relies on factors outside bloodstream for activation
release of tissue thromboplastin initiates pathway
rapid
recognizes factor VII, activated by binding to tissue factor, activate factor X
activation: tissue factor expressed on surface of cells outside blood vessels –> factor VII normally resides in blood –> tissue factor binding to factor VII activates it –> factor VIIa binds and cleaves factor X
List the steps in the common clotting pathway
Proteolytic cleavage by factor X leads to activation –> factor X cleaves prothrombin to thrombin; pathways converge at factor X
prothrombin activator converts prothrombin to thrombin –> thrombin cleaves fibrinogen to form fibrin –> form fibrin clot; thrombin also activated factor Xll which then cross-links fibrin to form a stable clot incorporated into platelet plug
Feedback mechanisms which increase coagulation
thrombin: activates factor V and Vlll; enhances platelet activation
platelet activation: increases activation of factor Vll, factor X, and cleavage of prothrombin
Feedback mechanisms which decrease coagulation
antithrombin: neutralizes procoagulant serine proteases (thrombin, Xa, IXa); reaction accelerated by heparin
protein C system: activated by thrombin binding to thrombomodulin; activated protein C complex forms a complex with protein S to inactivate factors Va and Vllla
factor Xa: activates tissue factor pathway inhibitor to block initial activation of factor Vll
Clot formation in hemostasis
vasospasm of injured blood vessel constricts passage –> platelets release chemical making nearby platelets sticky; platelet plug forms –> a strong clot forms by a cascade mechanism that culminates in activation of thrombin; thromboplastin to thrombin, fibrin thrombus forms –> plasminogen to plasmin –> fibrin digested, blood flow restored
Thrombin is the key…
protease to cleave fibrinogen to fibrin to form the clot
Clotting factors
serine proteases
glycoproteins
Ca2+
transglutaminase
fibrinogen/fibrin
Serine proteases
cleave down-stream factors to activate them:
factors XII, XI, X, IX, VII, II (pro-coagulants) - stimulate pathway to result in coagulation
cleave factors Va and VIIIa:
protein C (anti-coagulant) - destroying the factors involved in coagulation
Glycoproteins
co-factors for activation of proteases:
factors VIII, V, lll (tissue factor), protein S
bind to and inhibit thrombin:
anti-thrombin lll
Tranglutaminase
cross-links fibrin fibers
Understand the role of Ca2+ in coagulation, and the rationale for use of Ca2+ chelators in collection of clinical blood samples
links certain factors to phospholipid membanes
chelate the Ca2+ (with citric acid), inhibit coagulation in the tube
Fibrinogen/fibrin
the substrate protein for factor lla (thrombin) that polymerizes to form a clot
Hemophilia A
deficiency in factor Vlll
Hemophilia B
deficiency in factor IX
Factor V leiden
resistance to activated protein C, resistant to anti-coagulant factor
Where are clotting factors produced?
all made in the liver except for von Willebrand factor (endothelium, subendothelium, megakaryocytes; factor Vlll also endothelium)
therefore liver disease can have unpredictable effects on coagulation
Define the conditions for each of the following lab tests for coagulation and give normal time ranges: prothrombin time, bleeding time, activated partial thromboplastin time
common tests of hemostatic function
used for diagnostic purposes or to monitor anticoagulant therapy
Prothrombin time
used to measure the efficacy of warfarin
plasma + thromboplastin + Ca - clots in 12-14 sec
Bleeding time
Activated partial thromboplastin time
plasma + phospholipid (no TF) + activating agent - clots in 26-33 sec
used to monitor heparin therapy
Define the international normalized ratio (INR) and understand it’s clinical relevance
a way to normalize prothrombin time test; measures time it takes for blood to form a blood clot
a normal PT time (PTnorm) is 11-14 seconds based on the method used by the lab; due to differences in batches of tissue factor, tissue factor producers must assign an international sensitivity index to their product
normal INR 0.8-1.2, therapeutic INR ~2-3, >3 risk of hemorrhage
Explain the mechanism of action for the following anti-coagulant drugs: indirect thrombin inhibitors (heparin, LMW heparins), direct thrombin inhibitors (hirudin, bivalirudin, argatroban, dabigatran), Xa inhibitors (fondaparinux, rivaroxaban, apixaban, edoxaban, betrixaban), and warfarin/coumadin
use anticoagulants to prevent excessive clotting that can lead to occlusion of blood vessels - stroke, post MI, unstable angina, DVT, PE, artificial surfaces
Vitamin K antagonists
Warfarin
Warfarin MOA
vitamin K is essential for post-translation modification of clotting factors Vll, lX, X, prothrombin (ll) and anticoagulation proteins C & S
vitamin K carboxylase catalyzes the gamma-carboxylation of Glu in prothrombin, gamma-glutamyl carboxylase puts extra carboxyl group at the end of glutamic acid of protein –> vitamin K is oxidized in the process –> warfarin inhibits vit K-epoxide reductace (VKORC1) preventing vit K epoxide to be reduced back to its active form
warfarin inhibits synthesis of clotting factors ll, Vll, lX, and X
Know the routes of administration and potential side-effects of each of the anticoagulant drugs
Warfarin route of administration and side effects
oral
metabolized in liver by CYP2C9 (most variable CYP) reason for lots of interactions
termination of action is not correlated with plasma warfarin levels, but reestablishment of normal clotting factors
adverse effects: hemorrhage
contraindications: never use in pregnancy
Warfarin overdose
latrogenic hemorrhage
discontinue warfarin therapy –> administer vit K, high levels of vit K can activate warfarin inhibited reductase
in serious hemorrhage, plasma replaces clotting factors faster than vit K therapy
Warfarin necrosis
deficiency of protein C; protein C requires vit K-dependent carboxylation for its activity as an anticoagulant
warfarin initially decreases protein C levels faster than the coagulation factors, it can paradoxically increase the blood’s tendency to coagulate when treatment is first begun
pts given heparin to combat this
Vitamin K
fat-soluble vitamin
involved in post-translation modification of prothrombin, factors Vll, lX, and X
uses: individuals with abnormalities in fat absorption; reverse anticoagulant effect of excess warfarin
Indirect factor lla/Xa (thrombin) inhibitors
heparin
low molecular weight heparins (enoxaparin, daltaparin)
non-heparinoids (fondaparinux)
MOA of heparin
heparin acts by accelerating AT reactions to inactivate thrombin and factor Xa
free AT can inactivate factors Xa, IXa, XIa, XIIa, IIa, and VIIa
heparin binding to AT changes the conformation of the protein and allows the formation of a ternary complex (heparin-AT-target factor); heparin binding to AT and the subsequent conformational change increases the interaction of AT with the target factors
long chain heparins have extra interaction with thrombin in complez that makes them bind thrombin more selectively than factor Xa
LMWH are too small to bind AT and thrombin, thus have greater specificity for inhibition of factor Xa
Heparin route of administration and side effects
effective immediately
intermittent IV injection, continuous IV infusion, SC injection
adverse effects: latrogenic hemorrhage, treat - protamine sulfate, binds tightly to heparin through electrostatic interactions to neutralize the anticoagulant action; thrombocytopenia and osteoporosis
Heparin-induced thrombocytopenia
unfractionated heparin can cause thrombocytopenia and thrombosis in patients producing an antibody to a complex of heparin, platelet factor 4
HIT risk: unfractionated heparin > LMWH > fondaparinux
Heparin chemistry
the pentasaccharide is the functinoal unit that is the active binder of antithrombin
sulfate groups (negative charge) required for binding to antithrombin
Low molecular weight heparins
dalteparin and enoxaparin
obtained from depolymerization of unfractionated porcine heparin
compared to standard heparin: equal efficacy, increased bioavailability from SQ site of adm, less frequent dosing
advantages: more predicatble PK profile, lower incidence of thrombocytopenia and osteoporosis
Indirect factor Xa inhibitor
fondaparinux sodium - synthetic sulfated pentasaccharide
MOA: indirectly inhibits factor Xa by selectively binding AT; binds through negatively charged phosphated carbohydrate moieties
use: venous thromboembolism, prophylaxis in pts undergoing hip fracture, surgery, hip replacement, knee replacement, or abdominal surgery
Fondaparinux route of administration and side effects
given SQ
low potential for thrombocytopenia - action no reversed by protamine sulfate
Direct factor Xa inhibitors
rivaroxaban, apixaban, edoxaban
all bind to factor X (bind in active site of factor X serine protease)
Rivaroxaban and apixaban route of administration and side effects
oral
risk of hematoma/paralysis in pts undergoing spinal puncture/epidural anesthesia
increased risk of thrombosis upon discontinuation
Edoxaban route of administration and side effects
oral
renal excretion - not used in pts with CrCl > 95 ml/min
increased risk of ischemic events upon discontinuation
risk of hematoma/paralysis in pts undergoing spinal puncture/epidural anesthesia
Antidote for factor Xa inhibitors
andexanet - reversal agent for Xa inhibitors apixaban and rivaroxaban; recombinat protein that mimics factor Xa; can bind drug, but lacks enzymatic activity
given IV
black box warning: increased risk for thromboembolic events
Direct thrombin inhibitors
dabigatran
bivalirudin
argatroban
Dabigatran MOA
bind to the active site of thrombin, to exosites of thrombin, or both
DTIs can inhibit both soluble and fibrin-bind thrombin
DTIs can also reduce platelet aggregation
comes as a prodrug; ester groups have to be cleaved to form active molecule
anticoagulant activity reversed by praxbind IV - humanized IgG1 FAB fragment against dabigatran
Dabigatran route of administration
oral
Non-heparinoid parenteral agents
do not act through AT-III
inhibit free thrombin and fibrin-bound thrombin
hirudin
lepirudin: given IV; highly specific direct inhibitor of thrombin (bivalent binding at active site and exosite I); inhibition of thrombin is irreversible; treatment of HIT
Bivalirudin
binds catalytic site and exosite I of thrombin
cleaved by thrombin at Arg-Pro, then dissociates, becomes inactive; binding is reversible
Bivalirudin route of administration and side effects
given IV during percutaneous coronary angioplasty
low risk of bleeding
Argatroban MOA
binds reversibly to active site of thrombin
does not require AT for activity
can inhibit free & clot-associated thrombin
given IV
