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Updated: Feb 27 2022

Anticoagulation Medications

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  • Introduction
    • The coagulation cascade comprises a series of reactions that lead to formation of fibrin, which leads to platelet activiation and clot formation
      • an imbalance of the coagulation cascade can cause thromboembolism and DVT
    • Virchow's triad describes risk factors for thromboembolism and DVT and includes
      • venous stasis
      • endothelial damage
      • hypercoagulable state
    • Orthopaedic surgery predisposes high risk of thromboembolism and certain procedures may require anticoagulation
      • there are many choices of anticoagulants, each has advantages and disadvantages
      • chemical DVT prophylaxis may not be indicated in isolated lower extremity fractures below the knee
  • Overview of Anticoagulants (details below)
      • Overview of Anticoagulants
      • Mechanism
      • Advantage
      • Disadvantage
      • Compression stocking
      • Mechanical
      • No bleeding
      • Compliance
      • Inhibits the production of prostaglandins and thromboxanes
      • convenience
      • IV heparin
      • Enhances ability of Antithrombin III to inhibit factors IIa, IIIXa
      • Reversible
      • IV administration
      • Unfractionated heparin (subcutaneous)
      • Enhances ability of ATIII to inhibit factors IIaIIIXa
      • Reversible
      • Bleeding
      • LMWH (Lovenox)
      • Enhancing ability of ATIII to inhibit factors IIa (thrombin), III, Xa
      • Fixed dose, no lab monitoring required
      • Bleeding
      • Indirect Xa inhibitor (works through ATIII)
      • No lab monitoring required
      • Coumadin
      • Affects Vit K metabolism in the liver, limiting production of clotting factors IIVIIIXX
      • Most effective
      • Difficult to reverse
      • Dextran
      • Dilutional
      • Efficacy
      • Fluid overload
      • Rivaroxaban (Xarelto), Apixaban (Eliquis), Edoxaban (Savaysa) 
      • Direct Xa inhibitor
      • Oral
      • Bleeding
      • Dabigatran (Pradaxa)
      • Direct thromBin inhibitor
  • ASA (acetylsalicylic acid)
    • Introduction
      • thromboxane function
        • under normal conditions thromboxane is responsible for the aggregation of platelets that form blood clots
      • prostaglandins function
        • prostaglandins are local hormones produced in the body and have diverse effects including
          • the transmission of pain information to the brain
          • modulation of the hypothalamic thermostat
          • inflammation
    • Mechanism of ASA
      • inhibits the production of prostaglandins and thromboxanes through irreversible inactivation of the cyclooxygenase enzyme within platelets
        • acts as an acetylating agent where an acetyl group is covalently and irreversibly attached to a serine residue in the active site of the cyclooxygenase enzyme.
        • this differentiates aspirin different from other NSAIDs which are reversible inhibitors
    • Metabolism
      • renal
  • Unfractionated Heparin (SQ)
    • Mechanism
      • binds and enhances ability of antithrombin III to inhibit factors IIa, III, Xa
    • Reversal
      • protamine sulfate
    • Metabolism
      • hepatic
    • Risk
      • bleeding
      • HIT (heparin induced thrombocytopenia)
  • Low Molecular Weight Heparin
    • Overview
      • molecular name: enoxaparin
      • trade name: Lovenox, Clexane
      • has advantage of not requiring lab value monitoring
    • Mechanism
      • LMWH acts in several sites of the coagulation cascade, with its principal action being inhibition of factor Xa
      • reversed by protamine
    • Metabolism
      • renal
    • Risk
      • bleeding
  • Fondaparinux
    • Overview
      • trade name: Arixtra
      • has advantage of not requiring lab value monitoring
    • Mechanism
      • indirect factor Xa inhibitor (acts through antithrombin III)
    • Metabolism
      • renal
    • Evidence
      • studies show decreased incidence of DVT when compared to enoxaparin in hip fx and TKA patients
    • Risk
      • highest bleeding complications
        • not to be used in conjunction with epidurals
  • Warfarin
    • Mechanism of anticoagulation
      • inhibits vitamin K 2,3-epoxide reductase
        • prevents reduction of vitamin K epoxide back to active vitamin K
      • vitamin K is needed for gamma-carboxylation of glutamic acid for factors
        • II (prothrombin), VII (first affected), IX, X
        • protein C, protein S
    • Monitoring
      • target level of INR (international normalized ratio) is 2-3 for orthopaedic patients
      • not achieved for 3 days after initiation
    • Reversal
      • vitamin K (takes up to 3 days)
      • fresh frozen plasma (acts immediately)
    • Risk
      • difficult to dose requires the frequent need for INR lab monitoring
      • can have adverse reaction with other drugs including
        • rifampin
        • phenobarbital
        • diuretics
        • cholestyramine
  • Rivaroxaban (Xarelto)
    • Overview
      • others in the same class include apixaban (Eliquis) and edoxaban (Savaysa or Lixiana)
      • mechanism of action of these drugs can be deduced from the name.
        • Rivaro(Identifier)-xa(FactorXa)-ban(inhibitor)
    • Mechanism
      • direct Xa inhibitor
    • Metabolism
      • liver
    • Antidote
      • no current antidote
      • andexanet alpha being investigated
    • Risk
      • bleeding
    • Half-life
      • 8-hours (12-hours for apixaban)
      • urgent surgical procedures delayed until half-life spanned from last dose
  • Dabigatran (Pradaxa)
    • Mechanism
      • reversible direct thrombin (factor IIa) inhibitor
    • Metabolism
      • renal
    • Antidote
      • idarucizumab (FDA approved Oct 2015)
    • Risk
      • GI upset
      • bleeding
  • Tranexamic acid (TXA)
    • Overview
      • an antifibrinolytic that promotes and stabilizes clot formation
      • studies have shown that TXA reduce perioperative blood loss and transfusion in THA and TKA
    • Mechanism
      • synthetic derivative of the amino acid lysine
      • competitively inhibits the activation of plasminogen by binding to the lysine binding site
      • at high concentrations, is a non-competitive inhibitor of plasmin
      • has roughly 8-10 times the antifibrinolytic activity of ε-aminocaproic acid
    • Dosing
      • intravenous
        • 10-20 mg/kg initial bolus dose followed by repeated doses of the initial TXA dose every 3 hours for 1-4 doses
        • 10-20mg initial bolus followed either by an infusion of 1-10 mg/kg/hr for 4-30 hours
      • topical application is as effective as IV
        • sprayed onto open wound at completion of procedure
        • no detectable TXA in the bloodstream after topical application
      • oral adminsitration is as effective as IV
        • 1.95g given 2 hours preoperatively
    • Metabolism
      • <5% of the drug is metabolized
      • biological half-life in joint fluid is 3h, present in tissues for up to 17h
    • Risks
      • systematic review shows no increase in thromboembolic events
      • relatively few adverse reactions have been reported in the arthroplasty literature
  • Herbal Supplements
    • Increased bleeding
      • gingko, ginseng, and garlic have been found to increase the rate of bleeding
      • related to effect on platelets
      • proper history taking can avoid complications
    • Increased warfarin effect (increase INR)
      • omega-3 fish oil
        • affects platelet aggregation and vitamin K dependent coagulation factors
    • Reduced warfarin effect (reduces INR)
      • coenzyme Q10
      • green tea
        • direct warfarin antagonist (reduces INR)
      • St John's wort
        • increases catabolism of warfarin (reduces INR)
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