SM_260b: Anticoagulant Therapy for VTE Flashcards
Describe indirect anticoagulants
Indirect anticoagulants
- Antagonize Vitamin K: warfarin
- Require antithrombin: heparin, LMWH (dalteparin, enoxaparin), fondaparinux
- Direct: factor Xa inhibitors (rivaroxaban, apixaban, edoxaban), thrombin inhibitors (dabigatran, argatroban)
Describe synthesis of Vitamin K dependent clotting factors
Synthesis of Vitamin K dependent clotting factors
Describe clotting cascade
Clotting cascade
____ is the main regulator of the carboxylation reaction
Vitamin K epoxide reductase is the main regulator of the carboxylation reaction
- Carboxylated proteins: II, VII, IX, X, C, S, Z are Vitamin K dependent clotting factors
Warfarin causes ____ deficiency in all Vitamin K dependent clotting factors
Warfarin causes acquired deficiency in all Vitamin K dependent clotting factors
- Vitamin K epoxide reductase is main modulator of warfarin response
- Vitamin K epoxide reductase mutations either increase sensitivity to warfarin or cause hereditary warfarin resistance
- Homozygosity for missense mutation results in inherited combined deficiency of II, VII, IX, and X
____ increases resistance to warfarin
VKORC1 increases resistance to warfarin
____ increases sensitivity to warfarin by decreasing warfarin clearance
CYP2C9 increases sensitivity to warfarin by decreasing warfarin clearance
- Genetic polymorphisms
- Drug inhibitors / enhancers
Describe drugs that increase sensitivity to warfarin
Increase sensitivity to warfarin
- Antibiotics: erythromycin, fluconazole, INH
- Cardiac: amiodarone, propranolol
- Anti-inflammatories: piroxicam
- GI: cimetidine, omeprazole
Describe drugs that increase resistance to warfarin
Increase resistance to warfarin
- Antibiotics: nafcillin, rifampin
- Anticonvulsants: most
- Other: sucralfate, cholestyramine
Ginkgo and garlic interactions with warfarin can cause ___
Ginkgo and garlic interactions with warfarin can cause bleeding
St. John’s wort interaction with warfarin can cause ____
St. John’s wort interaction with warfarin can cause thrombosis
Warfarin is ___-acting and requires ___ to achieve therapeutic levels
Warfarin is slow-acting and requires 5 days of dosing to achieve therapeutic levels
- Full anticoagulation effect occurs when prothrombin levels are reduced to 20%
Warfarin is monitored using ___ and ___
Warfarin is monitored using PT and iNR
- INR standardizes PT results
- INR = (patient PT / control PT) ISI
Goal INR is ___
Goal INR is 2-3
____, ____, and ____ are adverse effects of warfarin
Bleeding, teratogenic, and warfarin necrosis are adverse effects of warfarin
____ reverses effects of warfarin
Vitamin K reverses effects of warfarin
Describe how to manage elevated INR but no bleeding
Elevated INR but no bleeding
- INR > 3-10: hold warfarin
- INR > 10: hold warfarin, give oral Vitamin K if possible or IV Vitamin K if not
Describe how to manage bleeding while on warfarin
Bleeding while on warfarin
- Hold warfarin, give Vitamin K IV
- Give 4 factor prothrombin complex concentrate or FFP if unavailable
Describe heparin
Heparin
- Polymeric, highly sulfated glycosaminoglycan
- 30-50 saccharide units
- Pentasaccharide sequence binds antithrombin
- Longer chains also bind thrombin
- Inhibits factor Xa and thrombin
Describe unfractionated heparin
Unfractionated heparin
- Inactivated in gut and given IV or SQ
- Metabolized in liver and kidney
Describe mechanism of unfractionated heparin
Unfractionated heparin
- Binds antithrombin to activate it and enhance its effects
- Heparin-antithrombin complex inhibits thrombin
- Thrombin bound to fibrin is protected from heparin - prevents further clot formation but doesn’t dissolve clot
- Inhibits smooth muscle proliferation and angiogenesis
- Bound form usually inactive
Unfractionated heparin acts ___
Unfractionated heparin acts immediately
- aPTT and/or UFH anti-Xa levels are used to monitor dose
____, ____, and ____ are adverse reactions of unfractionated heparin
Bleeding, heparin-induced thrombocytopenia, and osteoporosis are adverse reactions of unfractionated heparin
- Mild inhibition of aldosterone may increase potassium
Heparin-induced thrombocytopenia occurs when ___
Heparin-induced thrombocytopenia occurs when antibodes bind heparin-platelet factor 4 complex and agglutinate platelets, leading to paradoxical thrombosis despite low platelets
- Discontinue heparin immediately and start alternative anticoagulants (direc thrombin inhibitors)
Describe advantages and disadvantages of unfractioned heparin
Unfractioned heparin
- Advantages: effect immediate, 5000 U sc q8-12h is safe and effective thromboprophylaxis for low risk patient, reversed by protamine
- Disadvantages: protein binding so effect must be monitored, heparin-induced thrombocytopenia
LMWH works primarily through ___
LMWH works primarily through potentiation of antithrombin effect on factor Xa
(lacks tail to bind thrombin)
____, ____, and ____ are examples of LMWH
Dalteparin, enoxaparin, and tizaparin are examples of LMWH
LMWH has ___ subcutaneous absorption than heparin
LMWH has better subcutaneous absorption than heparin
Describe advantages and disadvantages of LMWH
LMWH
- Advantages: better subcutaneous absorption than heparin, less binding to plasma proteins, more predictable effect so monitoring not routinely needed; outpatient use feasible; infrequently causes heparin-induced thrombocytopenia or osteoporosis
- Disadvantages: renally cleared, expensive, subcutaneous injection
Fondaparinux is a ____ that only has ____ activity
Fondaparinux is a synthetic 5 saccharide binding site of antithrombin that only has anti-Xa activity activity
- Given subcutaneously and has high bioavailability
- Minimal protein binding and no monitoring needed
- Once daily subcutaneous injection because half-life of 17 hours
- Minimal interaction with platelets
Describe advantages and disadvantages of fondaparinux
Fondaparinux
- Advantages: once daily dosing, no monitoring required, equivalent in efficacy
- Disadvantages: not used in renal failure and low body weight due to risk of bleeding, no reversal agent, expensive
Direct thrombin inhibitors ___ and ___
Direct thrombin inhibitors inactive clot-bound and soluble thrombin and do not require antithrombin as a co-factor
- Derived from medicinal leech
- Not inactivated by platelet factor 4 or heparinase
____, ____, and ____ are direct thrombin inhibitors
Bivalirudin, argatroban, and dabigatran are direct thrombin inhibitors
Bivalirudin is used for ___ and has a ___ half-life
Bivalirudin is used for thrombus prevention in coronary interventions and has a very short half-life (25 minutes)
Argatrobin reversibly binds to ___ and is used primarily in ___
Argatrobin reversibly binds to catalytic site of thrombin and is used primarily in treatment of heparin-induced thrombocytopenia
- IV infusion
- Monitor with aPTT
- Conversion to warfarin problematic because argatroban prolongs PT
Direct acting oral anticoagulants are ___ and have ___
Direct acting oral anticoagulants are oral and have more predictable pharmacokinetics that obviate the need for routine monitoring
- All approved for prevention of thrombosis in atrial fibrillation, treatment, and prevention of DVT and PE
Direct acting oral anticoagulants are ____, ____, ____, ____, and ____
Direct acting oral anticoagulants are rivaroxaban, apixaban, edoxaban, betrixaban, and dabigatran etexilate
Anti-Xa DOACs are ____, ____, ____, and ____
Anti-Xa DOACs are rivaroxaban, apixaban, edoxaban, and betrixaban
Direct thrombin inhibitor DOAC is ___
Direct thrombin inhibitor DOAC is dabigatran etexilate
Compare DOACs
DOACs
Compare DOACs and warfarin
DOACs and warfarin
____ is used for reversal of dabigatran
Idarucizumab is used for reversal of dabigatran
- Humanized monoclonal antibody fragment (Fab) that binds specifically to dabigatran
- Much higher affinity for dabigatran than thrombin
___ is used for reversal of rivaroxaban and apixaban
Andexanet alpha is used for reversal of rivaroxaban and apixaban
- Acts as a factor Xa decoy and retains high affinity for all direct FXa inhibitors
- Change of serin to alanine to eliminate catalytic activity and prevent prothrombin cleavage
Thrombolytics ___
Thrombolytics activate plasminogen to form plasmin in order to accelerate thrombus breakdown
- Indications: acute coronary thrombosis, massive PE, thrombotic stroke
tPA is a ___
tPA is a thrombolytic
Cullen’s sign is ___
Cullen’s sign is periumbilical bleeding with anticoagulation
Turner’s sign is ___
Turner’s sign is flank bleeding with anticoagulation
If bleeding occurs with anticoagulation, ___ and ___
If bleeding occurs with anticoagulation, stop anticoagulant and other offending agents contributing to bleeding (aspirin, NSAIDs) and use a reversal agent
Protamine is a reversal agent for ___
Protamine is a reversal agent for UFH
- Partly reverses LMWH
Vitamin K and 4-factor prothrombin complex concentrate are reversal agents for ___
Vitamin K and 4-factor prothrombin complex concentrate are reversal agents for warfarin
Idarucuzimab is a reversal agent for ___
Idarucuzimab is a reversal agent for dabigatran
Andexanet alpha is a reversal agent for ____
Andexanet alpha is a reversal agent for anti-Xa inhibitors
Acute management of thrombosis involves ___
Acute management of thrombosis involves beginning anticoagulant when thrombosis is suspected or diagnosed
Describe long-term management of VTE
Long-term management of VTE
- Everyone with acute VTE needs 3 months of anticoagulation
- After 3 months
- If provoked VTE: stop
- If unprovoked: indefinitely as long as risk of recurrent clot outweighs risk of bleeding
Summarize the anticoagulants
Anticoagulants
