Anticoagulants Flashcards
Which factors are glycoproteins
8, 5, 3, Protein S
Which factors are serine proteases
7, 9, 10, 11, 12
2
Protein C (Anticoagulant)
Links factors to anionic lipids
Ca++
Factor 5 Leiden is resistant to ______
Activated protein C
All factors except ___ are made in the ____
vWF, liver
vWF is produced where?
Endoth., subendoth., Megakaryocytes
Tissue factor pathway aka
extrinsic pathway
Collagen exposure initiates this pathway
Intrinsic
TF is expressed where?
Factor 7 resides where?
TF = On surface of cells outside of (but near) blood vessels
Factor 7 = In blood
7 activates…
10
Calcium’s role in 7/10 interaction with tissue factor
Ca++ located near the site of binding, helps interaction with phospholipid membranes
___, ___, and ___ bind to collagen on the wall of damaged blood vessels
What are the next 4 steps?
- Factor 7
- HMWK
- Prekallikrein
- Factor 7 cleaves: Prekallikrein –> kallikrein AND cleaves 11->11a
- Kallikrein activates more 7
- HMWK anchors kallikrein and 11a to damaged surface
- Factor 9 binds factor 8a on platelet surface —-> Activates factor 10
Thrombins two effects
- Converts fibrinogen –> fibrin (insoluble)
- Activates factor 13 (which in turn cross links fibrin)
Prothrombin time
recalcified blood and thromboplastin
- Clots in 12-14 seconds
- Monitor oral anticoag therapy
aPTT
Recalcified blood + phospholipid
- Clots in 24-36s
- Monitor heparin therapy
BT
2-9 minutes
Abnormal when defect is in platelet number or function
Prolonged PT
oral anticoag
defect in extrinsic or common
Prolonged aPTT
Intrinsic/common
(heparin)
INR =
(Patient PT / Control PT)C
C= international sensitivity index that corrects for different thromboplastin reagents
Therapeutic range should = 2-3
(except for recurrent PE or prosthetic valves, 3-4)
All coumarin derivatives are _____
water soluble lactones
Warfarin is most common (racemic mixture, S isomer is most potent)
inandione anticoagulant example and 2 properties
Anisindione
Orally active with significant AE’s
Warfarin MOA
Inhibiton of vitamin K epoxide reductase
Vitamin K actions
Vitamin K is essential for post trans modification of factors 2, 7, 9, 10 C, S
Vitamin K carboxylase catalyzes the gamma-carboxylation of Glu in prothrombin (Vit K is oxidized in this process, needs epox. red. to be renewed)
This must happen for onset of Warfarin action
depletion of the pool of factors in circulation
(maximal anticoagulation takes 3-5 days to achieve)
Dosage of warfarin
Loading dose = 5mg/day
Maintenance dose = 2.5-5 mg/day
Warfarin metabolism
CYP2C9
(half life = 36-48 hours)
**termination of action is NOT correlated with warfarin levels in circulation, but with the regeneration of normal clotting factors
Treatment for warfarin overdose
STOP WARFARIN
administer Vit K1 (high levels can activate the reductase)
**plasma if severe hemorrhage to replace clotting factors
Warfarin CI’d in…
pregnancy
(in those who are or may become)
passes through placenta – fetal hemorrhage and FWS (nasal hypoplasia
Drugs with Decreased PT
(DDI’s with warfarin)
- Barbiturates
- Cholestyramine
- Rifampin
- Diuretics
- Vit K
Heparin MOA
Binds to +charged region of AT3
(increases rate that it interacts with plasma protease factors)
* can dissociate and then interact with more AT3
Antithrombin inactivates which factors
Thrombin, 5a, 7a, 9a
Time to effect of heparin
immediate
anticoagulation effect disappears within hours of stopping therapy (cleared rapidly from blood, t1/2 is 30-180min)
Dosing of heparin
adjust according to coagulation studies
aPTT therapeutic range = 1.5-2x normal
Iatrogenic hemorrhage can be caused by
warfarin
heparin
Heparin induced hemorrage treatment
protamine sulfate
(binds to heparin to neutralize)
Heparin-induced thrombocytopenia is due chiefly to ____
direct action on platelets
Develops 7-12 days after starting therapy
**AB’s develop against platelet-heparin complex
Heparin risks in treatment
HIT
Osteoporosis (with extended therapy)
Heparin - Straight chain sulfated mucopolysaccharides produced by ____
mast cells and basophils
_______ are required for heparin binding to AT3
Sulfate groups
(N or O sulfation)
- LMWH obtianed from?
- Vs. standard heparin?
- MOA?
- depolymerization of unfractionated porcine heparin
-
(Vs Regular heparin)
- Equal efficacy,
- increased BA from subQ site of administration,
- NO MONITORING needed
- More predictable PK profile
- Lower risk for HIT and osteoporosis
- Longer Half life
- Preferentially binds to factor 10a, only SLIGHTLY affects thrombin activity
Fondaparinux Sodium MOA
Synthetic sulfated pentasaccharide that inhibits Factor 10a
Indirectly inhibits 10a by binding to AT
no monitoring required
Use for Fondaparinux
advantage?
disadvantage?
VTE and Hip/knee surgical prophylaxis
Advantage = Low thrombocytopenia risk
**Activation NOT reversed by protamine sulfate!
Drugs for prevention of thrombosis in NV Afib
Rivaroxaban, Apixaban
Both = dose reduction in patients with IMPAIRED renal function
Increased risk of stroke after stopping
Edoxaban function, use, and risks
orally available 10a inhibitor
Tx of VTE and PE after 5-10 days of IV anticoagulant, prevent thrombosis in NV Afib
Risk = ischemic events after stopping, and spinal hematoma in LP or epidural
**Dont use in patients with GOOD renal function (CrCL >95)
Non-heparinoid parenteral agents dont act through
example?
AT3
(inhibit FREE thrombin and fibrin-bound thrombin)
Desirudin
- Desirudin MOA
- no effect on…
- Excretion?
- May cause?
- specific IRREVERSIBLE inhibitor of thrombin (bivalent binding at active site and exosite I)
- **no effect on AT, aPTT increases dose-dependent
- Excreted renally
- May cause HS rxns
Bivalirudin MPA
Binds to catalytic site and exosite I of thrombin
Binding is REVERSIBLE (rapid onset and short duration)
Given IV during PCI procedure
does NOT induce antibody formation
Bivalirudin vs desirudin
B = reversible, no AB’s
D = irrev. HS rxn
Argatroban MOA?
- Inhibits which thrombins?
- Monitoring needed?
- Metabolism?
binds reversibly to active site of thrombin (doesnt interact with AT)
- Can inhibit free and clot-associated thrombin
- aPTT monitoring
- 3A4 and 3A5 metabolism
Argatroban is derived from ____ and approved for…
Dabigatran etexilate (prodrug) is an oral direct thrombin inhibitor that is indicated for…
Argatroban = L-arg, Prophylaxis and Tx for patients with HIT
Dabigatran = indicated for Prevention of stroke/systemic embolus with NV afib
