Updated: 6/18/2021

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
      Fondaparinux
      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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(OBQ13.154) Which of the following medications used for thromboprophylaxis following orthoapedic surgery is a direct inhibitor of factor Xa?

QID: 4789
1

Dextran

1%

(19/3685)

2

Rivaroxaban (Xarelto)

79%

(2924/3685)

3

Coumadin

4%

(134/3685)

4

Fondaparinux (Arixtra)

15%

(570/3685)

5

Aspirin

0%

(16/3685)

L 2 B

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(OBQ13.208) Which of the following medications works through the competitive inhibition of plasminogen activation?

QID: 4843
1

Lovenox

5%

(246/4882)

2

Rivaroxaban

7%

(362/4882)

3

Tranexamic acid

77%

(3776/4882)

4

Fondaparinux

8%

(402/4882)

5

Coumadin

2%

(74/4882)

L 2 B

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(OBQ12.12) Which of the following pharmacologic agents is associated with the highest risk of bleeding and thrombocytopenia?

QID: 4372
1

Coumadin

9%

(439/4796)

2

Enoxaparin

11%

(512/4796)

3

Unfractionated heparin

75%

(3607/4796)

4

Dalteparin

3%

(134/4796)

5

Protamine sulfate

2%

(73/4796)

L 2 B

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(OBQ11.168) All of the following are AAOS recommendations regarding prevention of venous thromboembolic disease (VTED) in patients undergoing elective hip and knee arthroplasty EXCEPT?

QID: 3591
1

Patients should discontinue antiplatelet agents before undergoing elective hip or knee arthroplasty

9%

(209/2284)

2

Aspirin is not approved as a preventative medication for VTED in low risk patients

73%

(1665/2284)

3

Neuraxial (epidural, spinal, intrathecal) anesthesia is recommended when possible

8%

(192/2284)

4

Routine post-operative duplex ultrasonography screening is not recommended

3%

(76/2284)

5

Mechanical prophylaxis mechanisms are recommended in patients with a known bleeding disorder

6%

(131/2284)

L 2 C

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(OBQ10.11) Which of the following supplements affects blood clotting through its effect on platelets?

QID: 3099
1

Ginkgo

63%

(1242/1987)

2

Vitamin D

1%

(18/1987)

3

Ephedra

2%

(46/1987)

4

St. John's Wort

30%

(596/1987)

5

Selenium

3%

(67/1987)

L 3 C

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(OBQ09.120) Which drug works by preventing gamma carboxylation in factor X, factor IX, and prothrombin?

QID: 2933
1

Warfarin

69%

(1905/2779)

2

Heparin

10%

(284/2779)

3

Aspirin

1%

(24/2779)

4

Clopidogrel

6%

(176/2779)

5

Enoxaparin

14%

(380/2779)

L 3 C

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(OBQ09.116) Low-molecular-weight heparin has been shown to have an increased rate of which of the following when compared to aspirin, clopidogrel, and compression devices?

QID: 2929
1

Pneumonia

1%

(6/1064)

2

Fatal pulmonary embolism

3%

(37/1064)

3

Inferior vena cava filter placement

1%

(9/1064)

4

Renal failure

19%

(205/1064)

5

Postoperative hematoma

75%

(801/1064)

L 2 C

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(OBQ08.262) What is the mechanism of action of warfarin?

QID: 648
1

Binds to platelets and inhibits their aggregation

0%

(7/1526)

2

Inhibits vitamin K-dependent clotting factors

99%

(1505/1526)

3

Blocks COX-2 function

0%

(4/1526)

4

Unselective COX inhibiter

0%

(0/1526)

5

Decreases Anti-thrombin III activity

1%

(9/1526)

L 1 B

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(SAE07HK.56) Figure 33 shows the venogram of a patient who has a long history of alcohol abuse. Warfarin should be used cautiously because of the interaction with which of the following factors?

QID: 6016
FIGURES:
1

IV

1%

(6/523)

2

V

7%

(34/523)

3

VI

1%

(6/523)

4

VII

83%

(433/523)

5

VIII

7%

(37/523)

L 2 E

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(OBQ07.212) Protamine functions to reverse the pharmacologic effects of which of the following anti-coagulants?

QID: 873
1

Aspirin

1%

(12/1087)

2

Clopidogrel (e.g. plavix)

3%

(32/1087)

3

Low molecular weight heparin

89%

(970/1087)

4

Warfarin

4%

(44/1087)

5

Hirudin

2%

(26/1087)

L 2 D

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(OBQ04.218) Which of the following medications exerts its influence on the clotting cascade by inhibiting the carboxylation of normal clotting factors?

QID: 1323
1

Warfarin

86%

(1519/1762)

2

Enoxaparin

3%

(61/1762)

3

Dalteparin

2%

(38/1762)

4

Heparin

4%

(71/1762)

5

Hirudin

4%

(67/1762)

L 1 B

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