260. Anticoagulant Therapy for VTE

Question 1

WARFARIN

• What factors does warfarin inhibit?
• what pharmacogenetics impact warfarin sensitivity?
• how long until effect of dose achieved?
• monitoring?
• 3 adverse effects with tx

Answer 1

Inhibits II, VII, IX, X, C, S
Affected by VKORC1, CYP2C9 polymorphisms (and drug and herbal interactions)
- slow acting, 5 days to therapeutic levels
- monitor with INR (standardized PT): goal is INR 2-3 (trial and error - start low and increase to effect)

adverse effects

1. Bleeding - tx with vit K/hold warfarin, PCC/FFP if need more urgent reversal
2. Teratogenic
3. Warfarin Skin Necrosis (due to P C reduced first) - prevent with overlap with heparin

Question 2

Heparin

• mechanism
• routes
• monitoring?
• metabolism
• time to effect?
• 4 adverse effects
• reversal?

Answer 2

• MoA: binds ATIII = inhibits F Xa and thrombin
• Route: IV or SC (inactivated by gut)
• TDM: aPTT +/- UFH antiXa levels (goal PTT: 1.5-3x normal)
• metabolism: liver and kidney
  Rxns:
  1. Bleeding (esp elderly)
  2. Heparin-Induced Thrombocytopenia (HIT) - binds PF4 and activates platelets - need to discontinue heparin ASAP and start direct thrombin inhibitor instead
  3. Osteoporosis (enhances resorption, inhibits formation)
  4. Some hyperkalemia via hypoaldosteronemia

Reversed by PROTAMINE

Question 3

LMWH

• 2 types used in us
• route
• advantages (2), disadvantages (3)

Answer 3

Dalteparin, Enoxaparin
route: SC injection
+: no TDM, less HIT/osteoporosis SE
-: renally cleared, expensive, sc injection

Question 4

Fondaparinux

• route
• advantages (3)
• disadvantages (3)

Answer 4

Route: SC injection
+: no TDM, less SE/platelet interaction, 1x/day injection
-: renally cleared (avoid in renal insufficiency), no reversal, more expensive than heparin

Question 5

Direct Thrombin Inhibitors

• types (3)
• use
• monitoring?
• problematic

Answer 5

1. Bivalirudin: IV only
2. Dabigatran: oral only
3. Argatroban: IV invusion, use for HIT tx
   - reversibly binds thrombin (short half life = IV)
   - tx HIT
   - Needs TDM: monitor with aPTT
   - problematic to convert to warfarin because argatroban prolongs PT/INR - unclear to decipher warfarin effect

Question 6

DOACs

• types (2: 5)
• route
• monitoring?
• use
• which is excreted most by kidney? least?
• which needs previous IV/SC use prior to initiation (2)?
• reversal?
• SE (2)

Answer 6

Anti-Xa agents: Rivaroxaban, Apixaban, Edoxaban, Betrixaban
Direct Thrombin Inhibitor: Dabigatran
All ORAL = no TDM
Use: prevention of thrombosis in AFIB, Tx/prevention of DVT/PE

highest renal clearance: Dabigatran
least renal clearance: Apixaban

Needs previous IV use: Dabigatran, Edoxaban

Reversal:
Idarucizumab: reverses Dabigatran
Andexanet Alpha: reverses rivaroxaban, apixaban

SE: Intracranial bleeding (less than warfarin tho), TERATOGENIC + Do NOT use in breastfeeding (can use warfarin in breast feeding)

Question 7

Tissue Plasminogen Activator (tPA)

• mechanism
• indication (3)

Answer 7

Activated plasminogen to plasmin = accelerate thrombus breakdown
Indication: Acute coronary thrombosis, massive PE, thrombotic stroke

Question 8

What are 2 signs of bleeding with anticoagulation?

Answer 8

Cullen’s Sign: periumbilical bleeding

Turner’s Sign: flank bleeding (retroperitoneal)