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 ASA Inhibits the production of prostaglandins and thromboxanes convenience 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), III, 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 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)