Anticoagulants for Venouse Thromboembolism (VTE) Flashcards
Contrast the prognosis of DVT versus PE
DVT/deep vein thrombosis is rarely fatal
PE/pulmonary embolism can result in death within minutes of symptom onset – occurs when an embolus breaks off a thrombus in a vein and occludes blood vessels of the pulmonary artery tree; acute PE can cause arrhythmia and massive right ventricular failure
what are the phases of treatment for venous thromboembolism/VTE and how do they differ?
- acute phase (first 7 days): use of fast acting parenteral or a direct oral anticoagulant (DOAC)
- early maintenance phase (8 days - 3 months)
- extended phase (>3 months)
intermediate/extended phases typically accomplished using DOAC or warfarin
which coagulation factors are involved in the intrinsic versus extrinsic versus common pathway of coagulation?
intrinsic: XII (12) —> XI (11) —> IX (9) —> VIII (8)
extrinsic: tissue factor (TF) —> VII (7)
common: X (10) —> II (prothrombin) —> I (fibrinogen)
Which assays are used to measure the factors in the intrinsic versus extrinsic coagulation pathways, respectively?
activated partial thromboplastin time (aPTT): measures intrinsic + common pathways [XII (12) —> XI (11) —> IX (9) —> VIII (8)]
prothrombin time (PT): measures extrinsic + common pathways [tissue factor (TF) —> VII (7)]
[common: X (10) —> II (prothrombin) —> I (fibrinogen)]
Name the two classes of parenteral anticoagulants, and the three classes of oral anticoagulants, respectively?
parenteral:
1. antithrombin potentiators (Heparins)
2. Direct thrombin inhibitors (DTIs)
oral:
1. direct Factor Xa inhibitors
2. Direct Thrombin Inhibitors (DTIs)
3. vitamin K reductase (VKOR) inhibitors
What is the effect of heparin on coagulation?
heparin – heterogeneous mixture of sulfated mucopolysaccharides
binds antithrombin (AT) and dramatically accelerates the rate at which AT inhibits activated coagulation factors, particularly thrombin (IIa) and factor Xa
What are the three forms in which heparin is available as a parenteral anticoagulant?
- unfractionated heparin (UFH, largest): large enough to inhibit both thrombin/IIa and factor xa
- low-molecular weight heparins (LMWHs, mid-size): Enoxaparin, Dalteparin, inhibits factor Xa
- synthetic pentasaccharide (smallest): Fondaparinux, inhibits factor Xa
which of these forms of heparin is able to inhibit both thrombin/IIa and factor Xa?
a. Enoxaparin
b. Dalteparin
c. UFH
d. Fondaparinux
c. unfractionated heparin: large enough to inhibit both thrombin/IIa and factor Xa
a. Enoxaparin and b. Dalteparin are low molecular weight heparins (LMWHs); d. Fondaparinux is a synthetic pentasaccharide —> these can only inhibit factor Xa
Enoxaparin
Low molecular weight heparin – parenteral anticoagulant used to treat the VTE
heparin binds antithrombin, accelerating the rate at which it inhibits factor Xa
Fondaparinux
synthetic pentasaccharide derivative of heparin – parenteral anticoagulant used to treat VTE
heparin binds antithrombin, accelerating the rate at which it inhibits factor Xa
how do UFHs, LMWHs (Enoxaparin), and Fondaparinux (synthetic pentasaccharide) affect the following assays:
a. prothrombin time (PT)
b. activated partial thromboplastin time (aPTT)
c. thrombin time (TT)
d. anti-factor Xa
a. prothrombin time (PT, extrinsic): increased by UFH (largest form of heparin)
b. activated partial thromboplastin time (aPTT, intrinsic): increased by UFH
c. thrombin time (TT): increased by UFH
d. anti-factor Xa: increased by UFH, Enoxaparin, and Fondaparinux
*LMWHs and Fondaparinux are too small, can only bind/inhibit Factor Xa (common pathway) - this is why anti-factor Xa is best assay for their activity
when is use of unfractionated heparin vs LMWHs and Fondaparinux implicated, respectively?
UFH: IV infusion during acute phase of VTE treatment, requires close monitoring (interpatient variability)
LMWHs (Enoxaparin) and Fondaparinux: subcutaneous (SC) injection during acute phase of VTE, improved pharmacokinetics (longer t1/2, better renal clearance) - does not require routine monitoring/dose adjusting
what are two major adverse reactions associated with heparin use?
- bleeding (UFH, LMWHs, Fondaparinux) - often associated with underlying cause
- Heparin-induced thrombocytopenia (HIT) - mostly associated with UFH, must monitor platelet count, necrotizing skin lesion can occur at injection sites
how can protamine and ciraparantag be used in the management of adverse reactions related to heparin use?
major adverse effect of heparin use is bleeding
protamine: binds/neutralizes heparin, used in life-threatening hemorrhage (rapidly reverses anticoagulant effects of UFH)
Ciraparantag: new drug, may safely reverse anticoagulant effects of UFH/LMWHs/fondaparinux
what kind of drugs are Bivalirudin, Argatroban, and Desirudin, what is the mechanism of action?
Bivalirudin, Argatroban: direct thrombin inhibitors (DTI) – parenteral anticoagulants, unlike heparins, do not require antithrombin as a cofactor
Bivalirudin and Argatroban are both reversible inhibitors
Bivalirudin: binds active site + fibrin-binding site
Argatroban: binds only active site
how do direct thrombin inhibitors (DTIs) such as Bivalirudin and Argatroban impact the following coagulation assays:
a. prothrombin time (PT)
b. activated partial thromboplastin time (aPTT)
c. thrombin time (TT)
d. anti-factor Xa
a. prothrombin time (PT): increased
b. activated partial thromboplastin time (aPTT): increased
c. thrombin time (TT): increased
d. anti-factor Xa: no change
[recall factor X is activated before thrombin in common pathway: X (10) —> II (prothrombin) —> I (fibrinogen)]
When is use of Bivalirudin or Argatroban implicated?
Bivalirudin, Argatroban: direct thrombin inhibitors (DTI) - parenteral anticoagulants
DOC for the treatment of VTE in patients with a diagnosis/history of the HIT (heparin-induced thrombocytopenia)
administered via IV
what adverse affects are associated with Bivalirudin and Argatroban?
Bivalirudin, Argatroban: parenteral direct thrombin inhibitors (DTI)
bleeding is most common adverse effect
Bivalirudin - renal excretion, use with caution in patients with renal insufficiency
what kind of drugs are Apixaban, Rivaroxaban, Edoxaban, and Betrixaban, and what is their mechanism of action?
ApiXAban, RivaroXAban: direct factor Xa inhibitors – direct oral anticoagulants (DOAC) used to treat VTE
recall Factor Xa is in common coagulation pathway: X (10) —> II (prothrombin) —> I (fibrinogen)
reduce thrombin generation – suppression of platelet aggregation, fibrin formation
Bivalirudin
direct thrombin inhibitor (DTI) - parenteral anticoagulant, used in treatment of VTE
reversible inhibitor, binds active site + fibrin-binding site
Argatroban
direct thrombin inhibitor (DTI) - parenteral anticoagulant, used in treatment of VTE
reversible inhibitor, binds active site
Apixaban
direct factor Xa inhibitor: oral anticoagulant used to treat VTE
Rivaroxaban
direct factor Xa inhibitor: oral anticoagulant used to treat VTE
how will Apixaban and Rivaroxaban affect the following coagulation assays:
a. prothrombin time (PT)
b. activated partial thromboplastin time (aPTT)
c. thrombin time (TT)
d. anti-factor Xa
Apixaban and Rivaroxaban: direct factor Xa inhibitors (oral anticoagulants, treat VTE)
a. prothrombin time (PT): increased
b. activated partial thromboplastin time (aPTT): increased
c. thrombin time (TT): no change
d. anti-factor Xa: increased
When is use of Apixaban and Rivaroxaban indicated?
Apixaban and Rivaroxaban: direct factor Xa inhibitors (oral anticoagulants, treat VTE)
approved for all treatment phases of VTE - wider therapeutic index than warfarin
what important adverse reactions and drug–drug interactions are associated with Apixaban and Rivaroxaban?
Apixaban and Rivaroxaban: direct factor Xa inhibitors (oral anticoagulants, treat VTE)
adverse reactions: bleeding (less risk than warfarin), can be reversed with recombinant factor Xa (Andexxa)
Apixaban metabolized by CYP3A4
what kind of drug is Dabigatran and what is its mechanism of action?
Dabigatran: oral anticoagulant – direct thrombin inhibitor (DTI) used to treat VTE
competitively/reversibly blocks active site of thrombin (factor IIa) —> blocks thrombin-mediated conversion of fibrinogen to fibrin and platelet activation
*converted to active drug by plasma esterases
when is use of Dabigatran indicated?
Dabigatran: oral anticoagulant – direct thrombin inhibitor (DTI)
approved for all phases of VTE treatment (acute, early maintenance, extended)
only started after 5+ days of treatment with UFH or LMWH or fondaparinux (heparin/derivatives)
how can idarucizumab (Praxbind) be used to reverse the adverse effects of Dabigatran?
Dabigatran: oral anticoagulant – direct thrombin inhibitor (DTI) used to treat VTE
bleeding is major side effect - can be reversed with idarucizumab (Praxbind), mAb of dabigatran
what is the mechanism of action of warfarin?
Warfarin: oral anticoagulant, Vitamin K reductase (VKOR) inhibitor
recall clotting factors II (2), VII (7), IX (9), and X (10) are synthesized in liver as prozymogens and require Vit. K for conversion to zymogens
*therefore, warfarin has no effect on zymogens already in circulation
which clotting factors are reduced by warfarin?
Warfarin: oral anticoagulant, Vitamin K reductase (VKOR) inhibitor
recall clotting factors II (2), VII (7), IX (9), and X (10) are synthesized in liver as prozymogens and require Vit. K for conversion to zymogens
*therefore, warfarin has no effect on zymogens already in circulation
Which clotting factors are synthesized in the liver and require vitamin K to become zymogens?
clotting factors II (2), VII (7), IX (9), and X (10)
[Warfarin: oral anticoagulant, Vitamin K reductase (VKOR) inhibitor ]
when is warfarin use implicated?
Warfarin: oral anticoagulant, Vitamin K reductase (VKOR) inhibitor
approved for prevention/treatment of VTE - narrow therapeutic index, requires monitoring
what are the important adverse effects (2) and drug-drug interactions of warfarin?
Warfarin: oral anticoagulant, Vitamin K reductase (VKOR) inhibitor
adverse:
1. bleeding - can be reversed with human prothrombin complex (Kcentra) or fresh frozen plasma to replace Vit. K dep. clotting factors (2, 7, 9, 10)
2. skin necrosis: 3-10 days post treatment, typically on extremities
drug-drug: drugs/food that affect CYP3A4, CYP2C9, CYP1A2, or fluctuating intake of dietary Vit. K (green leafy vegetables, beef liver)
