Anticoagulants

Overview

• Anticoagulants decrease the formation of fibrin clots
  • heparin
  • warfarin (coumadin)
• bivalirudin

Heparin

• Mechanism
  • catalyzes the binding of antithrombin III to multiple clotting factors  
  • inactivates several factors
    • IIa (thrombin)
    • Xa
    • IXa
    • XIa
    • XIIa
• Clinical use
  • immediate anticoagulation
    • pulmonary embolism
    • acute coronary syndrome
    • stroke
    • MI
    • DVT
    • DIC
    • cardiovascular surgery
  • during pregnancy
    • does not cross placenta
• Toxicity
  • bleeding
  • osteoporosis
  • heparin-induced thrombocytopenia (HIT)
    • heparin binds to platelet factor IV
    • antibodies bind to and activate platelets
    • leads to hypercoagulable state and thrombocytopenia
  • hypersensitivity
• Pharmacology
  • IV delivery only for therapeutic anticoagulation
  • short half-life (2h)
  • large, water-soluble polysaccharide
  • low-molecular-weight heparins (e.g. enoxaparin) have advantages of
    • longer half-lives (2-4x)
    • less thrombocytopenia
    • enhanced activity against factor Xa
    • administered subcutaneously without laboratory (PTT) monitoring
    • not easily reversible
• Monitoring
  • partial thromboplastin time (PTT)
• Antagonist
  • protamine sulfate 
• positively charged to bind negatively charged heparin

Warfarin (Coumadin)

• Mechanism
  • ↓ hepatic synthesis of vitamin K-dependent clotting factors
    • prevents the reduction of vitamin K, a necessary step in the synthesis of clotting factors
      • vitamin K epoxide reductase is inhibited 
      • γ-carboxylation of clotting factors cannot occur  
    • affected clotting factors include
      • II
      • VII
      • IX
      • X
      • protein C
      • protein S
  • no effect on clotting factors already present
  • affects the extrinsic pathway
• Clinical use
  • chronic anticoagulation
    • DVT prophylaxis
    • post-STEMI
    • heart valve damage
    • atrial arrhythmias
• Toxicity
  • transient hypercoagulability 
    • transient protein C deficiency when beginning warfarin treatment
      • due to short half life of protein C
    • coagulation factors have relatively long half lives 
    • can lead to skin necrosis and dermal vascular thrombosis
    • give heparin as you begin warfarin treatment
  • bleeding
  • teratogenic
    • bone dysmorphogenesis
    • not used in pregnancy
  • drug interactions
    • P450 metabolism 
      • inhibitors → ↑ PT
        • decrease in P450 degrades less warfarin and levels rise
        • mnemonics
          • SICKFACES.COM
            • Sodium valproate
            • Isoniazid
            • Cimetidine
            • Ketoconazole
            • Fluconazole
            • Alcohol (binge drinking)
            • Chloramphenicol
            • Erythromycin
            • Sulfonamides
            • Ciprofloxacin
            • Omeprazole
            • Metronidazole
      • inducers → ↓ PT
        • increase in P450 degrades more warfarin and levels fall
        • mnemonics
          • BS CRAP GPS “induces” rage
            • Barbiturates
            • St John’s Wort
            • Carbamazepine
            • Rifampin
            • Alcohol (chronic)
            • Phenytoin
            • Griseofulvin
            • Phenobarbital
            • Sulfonylureas
    • ASA, sulfonamides, and phenytoin
      • displace warfarin from plasma proteins, leading to increased free fraction → ↑ PT
    • cholestyramine
      • ↓ oral absorption
        • due to low pKa
• Pharmacology
  • oral
  • long half life (>30 hr)
  • small, lipid-soluble
• Monitoring
  • prothrombin time (PT)
  • INR
    • (tested PT / reference PT)^(calibration value)
• Antagonist 
  • vitamin K (slow onset)
  • fresh frozen plasma (fast onset) 
• prothrombin complex concentrates (fast onset, low volume)

Lepirudin and Bivalirudin

• Mechanism
  • direct inhibtors of thrombin (IIa)
• Clinical use
  • alternative to heparin during heparin-induced thrombocytopenia 
• unstable angina during percutaneous transluminal coronary angioplasty

Direct Factor Xa Inhibitors (Apixaban, Rivaroxaban, Edoxaban, and Betrixaban)

• Mechanism
  • noncompetitive inhibitors of factor Xa
• Clinical use
  • treatment and prophylaxis for deep venous thrombosis and pulmonary embolism
  • stroke prophylaxis for patients with atrial fibrillation
• Monitoring 
  • PT and PTT are not reliable
  • Chromogenic anti-Xa assay
• Antagonist
  • andexanet alfa