Anticoagulation Medications - Basic Science

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聽(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 蔚-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)

Action	Numeric Key	Letter Key	Function Key
Show Bullets		S	Enter (frontside only)
20%	1	N
40%	2	H
60%	3	F	Enter (backside only)
80%	4	E
100%	5	M
Previous Card			Left Arrow
Next Card		N	Right Arrow
Toss	0	T

Action	Numeric Key	Letter Key	Function Key
Choose 1	1
Choose 2	2
Choose 3	3
Choose 4	4
Choose 5	5
Submit Response			Enter
Previous Question			Left Arrow
Next Question		N	Right Arrow
Open/Close Bookmode		C
Open Image			Spacebar