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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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Questions (9)

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

QID:4789
1

Dextran

0%

(10/2384)

2

Rivaroxaban (Xarelto)

77%

(1834/2384)

3

Coumadin

4%

(93/2384)

4

Fondaparinux (Arixtra)

18%

(422/2384)

5

Aspirin

0%

(10/2384)

Select Answer to see Preferred Response

PREFERRED RESPONSE 2

Rivaroxaban (Xarelto), an oral anticoagulant, is a direct inhibitor of factor Xa.

Rivaroxaban (Xarelto) is a member of a new class of oral, direct (antithrombin-independent) factor Xa inhibitors, which restrict thrombin generation both in vitro and in vivo. Inhibition of Factor Xa interrupts the intrinsic and extrinsic pathway of the blood coagulation cascade, inhibiting both thrombin formation and development of thrombi.

Eriksson et al. compare rivaroxaban to enoxaparin for the prevention of symptomatic venous embolism following total hip arthroplasty. Major venous thromboembolism occurred in 4 of 1686 patients (0.2%) in the rivaroxaban group and in 33 of 1678 patients (2.0%) in the enoxaparin group. Additionally, major bleeding events were similar between the two groups.

Illustration A shows the mechanisms of action of various agents used for thromboprophylaxis.

Incorrect Answers:
Answer 1: The antithrombotic effect of dextran is mediated through its binding of erythrocytes, platelets, and vascular endothelium, increasing their electronegativity and thus reducing erythrocyte aggregation and platelet adhesiveness. Dextrans also reduce factor VIII-Ag Von Willebrand factor, thereby decreasing platelet function.
Answer 3: Coumadin inhibits vitamin K 2,3-epoxide reductase, thereby limiting the production of vitamin K-dependent clotting factors (II, VII, IX, X) as well as Protein C and Protein S.
Answer 4: Fondaparinux is an indirect inhibitor of factor Xa, not direct.
Answer 5: Aspirin inhibits the production of prostaglandins and thromboxanes.

ILLUSTRATIONS:

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Question COMMENTS (4)

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

QID:4843
1

Lovenox

6%

(172/3100)

2

Rivaroxaban

8%

(247/3100)

3

Tranexamic acid

75%

(2324/3100)

4

Fondaparinux

10%

(301/3100)

5

Coumadin

1%

(46/3100)

Select Answer to see Preferred Response

PREFERRED RESPONSE 3

Tranexamic acid (TXA) works through the competitive inhibition of plasminogen activation.

TXA (Lysteda) is an antifibrinolytic that promotes and stabilizes clot formation. It competitively inhibits the activation of plasminogen by binding to the lysine binding site. TXA is effective in reducing the need for blood transfusions while not increasing the risk of VTE and renal complications. However, it is still advised that patients with cardiac stents and previous thromboembolic events including ischemic stroke not be administered TXA.

Godier et al. provide a commentary on the mechanism of action of TXA. They discuss how studies have shown decreased rates of myocardial infarction following trauma in patients that received TXA. They believe this is due to anti-inflammatory effects caused by binding to plasminogen receptors and stunting the fibrinolytic pathway.

Morrison et al. retrospectively review 896 patients who suffered combat injury, with 293 receiving TXA. Despite being more severely injured, the TXA group had a lower rate of mortality than the control group (P=.03).

Illustration A shows the mechanism of action of TXA. In the absence of TXA, plasminogen, tissue plasminogen activator (t-PA) and fibrin form linkages that lead to fibrinolysis.

Incorrect Answers:
Answer 1: Lovenox is a factor IIa and Xa inhibitor.
Answer 2: Rivaroxaban is a direct factor Xa inhibitor.
Answer 4: Fondaparinux is an indirect factor Xa inhibitor.
Answer 5: Coumadin works by limiting the production of vitamin-K dependent clotting factors II, VII, IX, and X.

ILLUSTRATIONS:

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

QID:4372
1

Coumadin

8%

(313/3826)

2

Enoxaparin

11%

(424/3826)

3

Unfractionated heparin

76%

(2901/3826)

4

Dalteparin

3%

(105/3826)

5

Protamine sulfate

2%

(61/3826)

Select Answer to see Preferred Response

PREFERRED RESPONSE 3

Of the options listed unfractionated heparin is associated with the highest rate of bleeding and thrombocytopenia. This may occur as part of a syndrome called Heparin Induced Thrombocytopenia (HIT).

Unfractionated heparin works in the coagulation cascade by binding and enhancing the ability of antithrombin III to inhibit factors IIa, III, Xa. A known complication of unfractionated heparin use is Heparin Induced Thrombocytopenia (HIT). Heparin Induced Thrombocytopenia (HIT) is caused by the formation of abnormal antibodies that activate platelets leading to abnormal formation of blood clots inside a blood vessel, leading to bleeding and thrombocytopenia.

Dorr et al. reviewed multimodal thromboprophylaxis for total hip and knee arthroplasty based on risk assessment in 1179 patients. They recommend careful use and monitoring of thromboprophylaxis after arthroplasty procedures to protect patients from thromboembolic events while also limiting adverse clinical outcomes secondary to thromboembolic, vascular, and bleeding complications.

Mont et al. performed a study on preventing venous thromboembolic disease in patients undergoing elective hip and knee arthroplasty. They recommended all patients do early mobilization and receive pharmacologic prophylaxis and mechanical compressive devices for the prevention of thromboembolic disease. The group did not recommend any specific pharmacologic agents and/or mechanical devices.

Illustration A shows a figure of the coagulation cascade and the target molecule of both unfractionated heparin and low molecular weight heparin.

Incorrect Answers:
Answer 1: Coumadin is not associated with HIT.
Answer 2, 4: Low-molecular-weight heparin LMWH (enoxaparin or dalteparin) is a blood thinner which inhibits the clotting coagulation cascade. The mechanism of action of LMWH works by the inhibition of factor Xa. Although Heparin Induced thrombocytopenia (HIT) is much more rare with LMWH compared to regular unfractionated heparin, it is still possible and has been known to sometimes cause bleeding and thrombocytopenia.
Answer 5: Protamine sulfate is an inhibitor of heparin, and used to reverse its effects.

ILLUSTRATIONS:

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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? Review Topic

QID:3591
1

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

9%

(150/1665)

2

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

74%

(1237/1665)

3

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

9%

(142/1665)

4

Routine post-operative duplex ultrasonography screening is not recommended

3%

(48/1665)

5

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

5%

(82/1665)

Select Answer to see Preferred Response

PREFERRED RESPONSE 2

AAOS Clinical Guideline on Preventing PE in Arthroplasty Patients includes aspirin as a thromboembolism prevention modality. Therefore the statement "aspirin is not approved as a preventative medication for VTED in low risk patients" is false.

Mont et al discuss the 10 recommendation in the AAOS clinical practice guideline, Preventing Venous Thromboembolic Disease in Patients Undergoing Elective Hip and Knee Arthroplasty. The orthobullets interpretation of their recommendation is:

1. Post-operative screening ultrasonography is not indicated. (ANSWER 4)
2. Previous venous thromboembolism is the only risk factor for thromboembolism clearly supported by evidence.
3. Known bleeding disorders and active liver disease are the only risk factor for bleeding clearly supported by evidence.
4. Patients should discontinue antiplatelet agents (e.g., aspirin, clopidogrel) preop. (ANSWER 1)
5. All patients should get pharmacologic agents and/or mechanical compressive devices for prophylaxis.
6. Patients with previous venous thromboembolism should receive pharmacologic prophylaxis AND mechanical compressive.
7. Patient with known bleeding disorder and/or active liver disease should use mechanical compressive prophylaxis. (ANSWER 5)
8. Patient should be mobilized early.
9. Intrathecal, epidural, and spinal anesthesia should be used. (ANSWER 3)
10. IVC filters are not clearly supported by the literature in patients who also have a contraindication to chemoprophylaxis and/or known residual venous thromboembolic disease

Eikelboom et al discussed the differences between the AAOS recommendations and those of the American College of Chest Physicians. They identify weakness in the methodology of the AAOS recomendations and "recommend the ACCP guidelines because the methodology is explicit and rigorous and the treatment recommendations reflect all of the evidence from the randomized trials."


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

QID:3099
1

Ginkgo

66%

(882/1339)

2

Vitamin D

1%

(8/1339)

3

Ephedra

2%

(24/1339)

4

St. John's Wort

28%

(372/1339)

5

Selenium

3%

(41/1339)

Select Answer to see Preferred Response

PREFERRED RESPONSE 1

Ginkgo and ginseng are two common supplements used in the general population that have inhibitory effects of platelet function. Adverse peri-operative complications consisting of increased bleeding and hematoma formation have been reported with the use of these two herbal supplements. The most commonly used supplements that could have an effect in the peri-operative period include echinacea, ephedra, garlic, ginkgo, ginseng, kava, St John's wort, and valerian. Bleeding has been shown to be effected by garlic, ginkgo, and ginseng; cardiovascular instability from ephedra; and hypoglycemia from ginseng. Kava and valerian have pharmacodynamic herb-drug interactions that can increase the sedative effect of anesthetics. St John's wort has been shown to alter the metabolism of certain drugs used in the perioperative period.

Ang-Lee et al review common supplements used today and their potential anesthesia/operative effects. The article places emphasis on proper history taking of not only medications but also supplements which is often times left out of documentation.


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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? Review Topic

QID:2929
1

Pneumonia

1%

(5/488)

2

Fatal pulmonary embolism

3%

(14/488)

3

Inferior vena cava filter placement

1%

(3/488)

4

Renal failure

19%

(92/488)

5

Postoperative hematoma

76%

(370/488)

Select Answer to see Preferred Response

PREFERRED RESPONSE 5

Usage of low-molecular-weight heparins (LMWH) have been shown to have an increased rate of postoperative hematomas and wound complications in several large studies.

The referenced study by Dorr et al noted that wound complications and hematomas only existed in warfarin or low-molecular weight heparin patients, and not in patients treated with ASA, clopidogrel, or compression devices.

The referenced study by Lee et al reviews the complication of retroperitoneal hematoma during LWWH usage.


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

QID:648
1

Binds to platelets and inhibits their aggregation

0%

(3/712)

2

Inhibits vitamin K-dependent clotting factors

99%

(705/712)

3

Blocks COX-2 function

0%

(1/712)

4

Unselective COX inhibiter

0%

(0/712)

5

Decreases Anti-thrombin III activity

0%

(3/712)

Select Answer to see Preferred Response

PREFERRED RESPONSE 2

Warfarin (coumadin) is an anti-coagulant that works by inhibiting vitamin K dependent clotting factors II, VII, IX, X, and protein C and S.

The reference by Hyers is a review article discussing the antithrombotic agents that have been used in the last 50 years and also discusses some of the newer ones that have since been developed.

Wrong Answers:
Answer 1: Plavix and aspirin are two examples of anticoagulants which work by platelet inhibition. Aspirin irreversibly inhibits the formation of thromboxane A2, which is the molecule responsible for normal platelet aggregation. Plavix inhibits platelet aggregation by blocking activation of the glycoprotein IIb/IIIa pathway. Activation of this glycoprotein is the "final common pathway" for platelet aggregation and is important in the cross-linking of platelets by fibrin.

Answer 3: Selective COX inhibitors (ie. Celebrex) target COX-2 alone and do not affect COX-1 function. Selective inhibition of COX-2 results in anti-inflammatory action without disrupting the beneficial effects of COX-1( maintaining gastric mucosa, regulating renal blood flow, influencing platelet aggregation).

Answer 4: Unselective COX inhibitors (ie. ibuprofen) target both COX-1 and COX-2.

Answer 5: Antithrombin III (ATIII) is a potent inhibitor of the coagulation cascade. It is a nonvitamin K-dependent protease that inhibits coagulation by lysing thrombin and factor Xa. Antithrombin III activity is markedly potentiated by heparin, resulting in anticoagulation.


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Question COMMENTS (8)

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

QID:873
1

Aspirin

2%

(8/423)

2

Clopidogrel (e.g. plavix)

3%

(12/423)

3

Low molecular weight heparin

88%

(373/423)

4

Warfarin

3%

(12/423)

5

Hirudin

4%

(15/423)

Select Answer to see Preferred Response

PREFERRED RESPONSE 3

Protamine functions to partially reverse the pharmacologic effects of low molecular weight heparin (LMWH). Protamine may help to stop bleeding related to LWMH, although anti-factor Xa activity is not fully normalized by protamine. Vitamin K reverses the pharmacologic effect of warfarin. As aspirin and clopidogrel function directly at the level of the platelet, there is no medical method to "reverse" these effects. Hirudin is a naturally occuring enzyme with anti-coagulant property in the salivary glands of leeches.


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Question COMMENTS (3)

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

QID:1323
1

Warfarin

87%

(1166/1339)

2

Enoxaparin

3%

(41/1339)

3

Dalteparin

2%

(27/1339)

4

Heparin

4%

(50/1339)

5

Hirudin

4%

(50/1339)

Select Answer to see Preferred Response

PREFERRED RESPONSE 1

Warfarin (Coumadin) exerts its anticoagulation effect by inhibiting the carboxylation of normal clotting factors. Warfarin is a vitamin K antagonist that prevents the reductive metabolism of vitamin K epoxide back to its active form, hydroquinone, by inhibiting the enzymes responsible for the reaction. The vitamin K-dependent factors are II, VII, IX, X, proteins C, and S.

The reference by Hyers is a review article discussing the antithrombotic agents that have been used in the last 50 years and also discusses some of the newer ones that have since been developed.

Berry in his review discusses the risk factors, efficacy, and safety of agents used in 2003 after total hip arthroplasty.

Answer 2: Enoxaparin binds to and increases the activity of antithrombin III. By activating antithrombin III, enoxaparin potentiates the inhibition of coagulation factors Xa and IIa.

Answer 3: Dalteparin is a low molecular weight heparin

Answer 4: Heparin binds to the enzyme inhibitor antithrombin III. The activated AT then inactivates thrombin and other proteases involved in blood clotting, most notably factor Xa.

Answer 5: Hirudin (the active component released by leeches), is often considered the most potent inhibitor of thrombin.


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