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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
Overview of Anticoagulants (details below)
 
Method
Mechanism
Advantage
Disadvantage
Compression stocking Mechanical no bleeding risk compliance
ASA Inhibits the production of prostaglandins and thromboxanes convenience limited efficacy
IV heparin Enhances ability of Antithrombin III to inhibit factors IIa, III, Xa reversible IV administration
Unfractionated heparin (subcutaneous) Enhances ability of ATIII to inhibit factors IIa, III, Xa reversible bleeding
LMWH (Lovenox) Enhancing ability of ATIII to inhibit factors IIa (thrombin) and Xa

fixed dose, no lab monitoring required

bleeding
Fondaparinux Indirect Xa inhibitor (works through ATIII)
no lab monitoring required   
Coumadin  Affects Vit K metabolism in the liver, limiting production of clotting factors  II, VII, IX, X most effective difficult to reverse
Dextran Dilutional efficacy

fluid overload

Rivaroxaban (Xarelto), Apixaban (Eliquis), Edoxaban (Savaysa) Direct Xa inhibitor    
Dabigatran (Pradaxa),  Direct thrombin inhibitor    

 

 
Compression Stocking
  • Mechanism 
    • increases fibrinolytic system
    • decreases venous stasis
  • Evidence
    • literature supports efficacy in TKA
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
      • 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
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
  • 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, ginsing, 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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