Hemostasis Flashcards
yMechanism of action of clopidogrel
Irreversible binding to P2Y12 receptor ->inhibition of ADP-induced integrin activation and granule secretion n-> inhibition of platelet aggregation
What mutation could be responsible for clopidogrel resistance in cats
Mutation of gene for P2Y1 receptor (possibly due to gain of function of P2Y1 receptor which is not targeted by clopidogrel)
(+ possible mutations of cytochrome P450 enzymes affecting metabolism)
Mechanism of action of aspirin (= acetylsalicylic acid). Why is its efficacy questionable?
Irreversible inhibition of COX-1 in platelets -> inhibition of thromboxane-A2 production (for the whole life of the platelet) -> decreased platelet aggregation
Platelet aggregation depends on several other factors so the effect of aspirin on platelet aggregation might not be as pronounced, especially in cats (might require high doses, less efficient than clopidogrel)
What are the 3 classes of anti-platelet drugs, drugs examples, and their overall mechanism of action
- Adenosine diphosphate (ADP) receptor antagonist (thienopyridines and nucleoside analogs) -> P2Y12 inhibition (inhibits ADP-induced aggregation)
Clopidogrel, cangrelor / ticagrelor - Cyclooxygenase inhibitors -> COX-1 inhibition (inhibits thromboxane-A2 production)
Aspirin (acetylsalicylic acid) - Fibrinogen receptor antagonists -> GPIIb/IIIa (alpha-IIb-beta-3) inhibition (inhibits binding of fibrinogen to platelets and therefore clot formation)
Abciximab, eptifibatide, tirofiban
What is the difference between nucleoside analogs and thienopyridines
Nucleoside analogs do not require hepatic metabolism for activation and cause a non-competitive reversible inhibition of P2Y12 (vs. need for transformation by cytochromes P450 and irreversible inhibition for thienopyridines)
-> more rapid and reversible platelet inhibition by nucleoside analogs
Mechanism of action of warfarin
Inhibition of vitamin K epoxide reductase in the liver -> inactive vitamin K (epoxide) cannot be transformed back to active form (hydroquinone) -> inhibition of gamma-carboxylation of factors II, VII, IX, X and proteins C and S -> inability to interact with Ca2+ to contribute to clot formation
- inhibition of proteins C and S leads to initial transient hypercoagulability
What are the available tests for therapeutic monitoring of warfarin, clopidogrel, unfractionated heparin, low molecular weight heparin, and direct oral anticoagulants? Which ones are recommended by the CURATIVE guidelines?
- Warfarin: PT
*Warfarin use not recommended by CURATIVE, but if being used recommend PT - use INR in humans - Clopidogrel: PFA-100 (using ADP-collagen or PGE-1 activator), platelet aggregometry, TEG-platelet mapping (using ADP)
*Monitoring not recommended in CURATIVE - UFH: drug specific anti-Xa activity, ACT, aPTT (target 1.5-2.0 times baseline), TF and kaolin activated TEG
*Anti-Xa activity recommended in CURATIVE (0.35-0.7 U/mL) - LMWH: drug specific anti-Xa activity
*No recommendation in CURATIVE (but if using anti-Xa should target 0.5-1.0 U/mL 2-4h post-dose) - Direct oral anticoagulants: drug specific anti-Xa activity, PT, R value on TEG (target 1.5-1.9-fold prolongation)
*No recommendation in CURATIVE
Mechanism of action of heparin - what is the difference between UFH and LMWH
- Binds to antithrombin -> inhibitor of factors IIa, IXa, Xa, XIa, XIIa (mostly IIa and Xa)
- Causes release of TFPI from endothelium
Low molecular weight heparins cannot bind both AT and FIIa (only AT and FXa) -> LMWH inhibits FXa 4 times more than FIIa (vs. UFH inhibits both in a 1:1 ratio)
–> Fewer major bleeding events
–> not fully reversible by protamine
LMWH is not highly protein bound, and does not bind readily to the endothelial cells –> bioavailability more predictable
What could contribute to the variability of anticoagulant effects of UFH
- Activity dependent on antithrombin ->decreased effect in case of antithrombin deficiency (liver disease, PLN, sepsis)
- UFH is highly bound to proteins, endothelial cells and macrophages -> altered / unpredictable bioavailability (not the case for LMWH)
What is the molecular weight of UFH vs. LMWH
UFH: 5000 - 30000 Da
LMWH: 5000 Da
Dose of UFH in cats and dogs
Dogs: 150-300 U/kg SC q8h or 30-50 U/kg/h IV CRI
Cats: 50-300 U/kg SC q6-8h
(From CURATIVE:
Dogs:
- IV: 100 units/kg bolus followed by CRI 20-37.5 units/kg/h
- SQ: 150-300 units/kg q6
Cats:
- 250 units/kg q6 SQ)
What are the different classes of anticoagulants, their overall mechanism of action, and some examples
- Vitamin K antagonists -> inhibit vitamin K epoxide reductase
Warfarin - Heparins -> bind anti-thrombin and inhibit FXa (LMWH and UFH) and FIIa +/- FIXa, FXIa, FXIIa (UFH)
- UFH: heparin
- LMWH: dalteparin, enoxaparin - Direct thrombin inhibitors -> inhibit fibrin-bound thrombin and circulating thrombin (do not require AT)
Dabigatran - Factor Xa inhibitors -> inhibit FXa (do not require AT)
Rivaroxaban, apixaban
What are the different generations of thrombolytics with examples
- First generation: streptokinase, urokinase
-> activate plasminogen to plasmin with no fibrin specificity (can activate circulating plasminogen) - Second generation: alteplase (recombinant tPA)
-> fibrin specific - Third generation: reteplase, lanoteplase, tenecteplase, staphylokinase
-> more fibrin specific + some resistance to PAI-1 - Fourth generation: desmoteplase
-> more fibrin specific + resistance to PAI-1
Mechanism of action of desmopressin for hemostasis
Triggers the endothelial release of vWF and factor VIII - mostly efficient for patients with type I vWD, and potentially coagulopathy secondary to uremia. Could be indicated for hemophilia A but does not significantly increased factor VIII activity in these dogs.
What is the dose of DDAVP for stimulation of hemostasis
1-5 mcg/kg SQ using the intranasal product or 0.3-1 mcg/kg IV or SQ using the injectable product
Can be repeated q6h but efficiency will decrease with subsequent doses (none after 3-4)
