Antithrombotics

A) Vitamin K Antagonists¶

• Warfarin (Coumadin)
• MOA: Vitamin K epoxide reductase inhibitor
  • Inhibits Prothrombin (II), VII, IX, X, C, S
• Needs to be bridged for 5 days if HR (most surgeries)
  • Bridge when HR or valves: Use LMWH when INR \<2
• Monitored via INR ≥ PT, 97% bound to albumin
• Can be used in breastfeeding
• Reversal: INR ≥ 10 = oral vit k
  • Increased bleeding = 4F-PCC (works in minutes), IV vitamin K (12-24hrs, risk of anaphylaxis) ≥ FFP
  • Four-Factor Prothrombin Complex (4F-PCC)
    • Contains Factors II, VII, IX, and X as a lyophilized powder
  • Indicated in brain hemorrhage
  • No bleeding, INR 4.5-10: withhold
  • No bleeding, INR 3-4.5: watch and wait
• CI: Pregnancy (crosses placenta)
  • Vit k, nasal hypoplasia, stippled epiphyses in first trimester
• Warfarin-Induced Skin Necrosis
  • 2-5 days after initiation
  • Well demarcated, center lesion necrotic, thrombi in microvasculature
  • Protein c or s def, initiation
  • Treatment
  • Vitamin K, heparin, discontinue warfatin
  • ± Protein C (concentrated or in FFP)
• Warfarin Metabolism
  • CYP450 Inhibitors (Increased Warfarin effect)
  • Risk of Hemorrhage
  • Acetaminophen, NSAIDs, Metronidazole, Amiodarone, Cimetidine, Cranberry Juice, Ginkgo biloba, VitE, omeprazole, Thyroid hormone, SSRIs
  • CYP450 Inducers (Decreased Warfarin effect)
  • Risk of Thrombosis
  • Carbamazepine, Phenytoin, Ginseng, St. John Wort, OCPs, Phenobarbital, Rifampin, Spinach/Sprouts (Vitamin K)
• INR Management
  • INR \<5 + none or minimal bleeding:
  • Hold warfarin for 1-2 days or decrease dose
  • INR 5-9 + none or minimal bleeding:
  • Hold warfarin and resume when INR is therapeutic, give 1-2.5mg oral VitK if increased risk of bleeding
  • INR ≥9 + none or minimal bleeding
  • Hold warfarin and give 2.5-5mg oral VitK
  • Any serious or life-threatening bleeding:
  • Hold warfarin, five 10mg IV Vitk, FFP, recombinant factor VIIa, or PCC

B) Factor Xa Inhibitors¶

I) Heparins/Glycosaminoglycans/Binds Antithrombin¶

A) Unfractionated Heparin (UFH) (Parenteral)¶

• Must monitor using aPTT
• Dose dependent, saturable, weaker binding to endothelial, macrophage, hbpps
• Activates Antithrombin (III) ≥ binds fibrin
• Accelerates Antithrombin clot inhibition
  • Inhibiting Thrombin and Factor Xa
• Forms thrombin-antithrombin complex
• Can cause platelet activation?
• Causes TFPI release
• Neutralized by PF4 (platelet rich thrombi)
• Heparin Inducted Thrombocytopenia (HIT)
• Protamine sulfate (1mg to 100U) to reverse
• SE: Osteoporosis, increase bilirubin

B) Low-Molecular-Weight Heparin (LMWH) (Parenteral)¶

• Enoxaparin (Lovenox)
• Made from Unfractionated Heparin
• Greater capacity to potentiate factor Xa inhibition than thrombin due to being a short chain (2:1 – 4:1 Xa to iia)
• VTE + Cancer
• Dose independent, renal clearance, rare resistance, no monitoring
• Little aPTT affect, measure anti-Xa to monitor (Heparin-Xa)
• Every 4 hours
• Obesity, renal insufficiency, pregnant, valves

C) Antithrombin III Inhibitors (Indirect Factor Xa inhibitors) (Parenteral)¶

• Fondaparinux (Arixtra)
• (smallest heparin chains) AT3
• Can be used in surgical, ortho, VTE patients, only binds AT3, no thrombin rate inhibition, Xa only, renal cleared, can use in HIT, no antidote, no need to monitor

II) Direct Factor Xa Inhibitors¶

• Factor Xa for monitoring
• Stroke prevent, long term anticoagulation in nonvalvular afib
• VTE treatment w/o cancer
• Apixaban (Eliquis)
• 10mg BID for ??
• 5-5mg PO BID
• Rivaroxaban (Xarelto)
• 15mg BID for 21 days for VTE
• 20mg PO daily with dinner
• Renal Excretion
• Edoxaban (Lixiana, Savaysa)
• 60mg PO daily

C) Direct Thrombin Inhibitors (DTIs) (Parenteral)¶

- Inhibit Thrombin (IIa)
- Bivalent
  - Lepirudin/Desirudin (Revasc): Renal clearance, no metab
  - Bivalirudin (Angiomax)
    - Not renal, no metab
    - Activated clotting time, aptt
    - PCI instead of heparin
- Univalent
  - Argatroban (acova)
    - Liver metabolism, not renal
    - HIT treatment
    - aPTT, prolongs INR
      - measure Factor X instead to monitor warfarin
  - Dabigatran (Pradaxa, Oral)
    - 150mg PO BID or 75mg PO BID if Crcl = 15-30
    - Direct Thrombin Inhibitor, Renally excreted, aPTT to monitor
      - PPIs decrease absorption

• D) Other
  • Antithrombin III, Protein C