Anticoagulation

Author: David Abbasi

Topic updated on 03/23/13 11:44am

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	Xa	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

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
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

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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Qbank (7 Questions)

TAG

(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? Topic

Review Topic

1. Patients should discontinue antiplatelet agents before undergoing elective hip or knee arthroplasty
2. Aspirin is not approved as a preventative medication for VTED in low risk patients
3. Neuraxial (epidural, spinal, intrathecal) anesthesia is recommended when possible
4. Routine post-operative duplex ultrasonography screening is not recommended
5. Mechanical prophylaxis mechanisms are recommended in patients with a known bleeding disorder

PREFERRED RESPONSE ▶

DISCUSSION: 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."

REFERENCES:

1. Eikelboom JW, Karthikeyan G, Fagel N, Hirsh J. American Association of Orthopedic Surgeons and American College of Chest Physicians guidelines for venous thromboembolism prevention in hip and knee arthroplasty differ: what are the implications for clinicians and patients? Chest. 2009 Feb;135(2):513-20. PMID:19201714 (Link to Abstract)

2. Mont MA, Jacobs JJ, Boggio LN, Bozic KJ, Della Valle CJ, Goodman SB, Lewis CG, Yates AJ Jr, Watters WC 3rd, Turkelson CM, Wies JL, Donnelly P, Patel N, Sluka P; AAOS. Preventing venous thromboembolic disease in patients undergoing elective hip and knee arthroplasty. J Am Acad Orthop Surg. 2011 Dec;19(12):768-76. PubMed PMID: 22134209. PMID:22134209 (Link to Abstract)

Question Authors:

Patrick O'Donnell MD/PhD, John Badylak MD, Patrick McCulloch MD,

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TAG

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

Review Topic

1. Ginkgo
2. Vitamin D
3. Ephedra
4. St. John's Wort
5. Selenium

PREFERRED RESPONSE ▶

DISCUSSION: 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.

REFERENCES:

1. Ang-Lee MK, Moss J, Yuan CS. Herbal medicines and perioperative care. JAMA. 2001 Jul 11;286(2):208-16. PMID:11448284 (Link to Abstract)

2. Moore TJ. Perioperative medical management. In: Fischgrund JS, ed. Orthopaedic Knowledge Update 9. Rosemont, IL: American Academy of Orthopaedic Surgeons; 2008:105-113.

Question Authors:

Jan Szatkowski MD, Patrick McCulloch MD, Michael Hughes MD,

Please Rate Educational Value!

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TAG

(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? Topic

Review Topic

1. Pneumonia
2. Fatal pulmonary embolism
3. Inferior vena cava filter placement
4. Renal failure
5. Postoperative hematoma

PREFERRED RESPONSE ▶

DISCUSSION: 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.

REFERENCES:

1. Dorr LD, Gendelman V, Maheshwari AV, et al: Multimodal thromboprophylaxis for total hip and knee arthroplasty based on risk assessment. J Bone Joint Surg Am 2007;89:2648- 2657 PMID:18056497 (Link to Abstract)

2. Lee MC, Nickisch F, Limbird RS: Massive retroperitoneal hematoma during enoxaperan treatment of pulmonary embolism after primary total hip arthroplasty: Case-reports and review of the literature. J Arthoroplasty 2006;21:1209-1214 PMID:17162185 (Link to Abstract)

Question Authors:

Ben Taylor MD, Patrick McCulloch MD,

Please Rate Educational Value!

2.0

Average 2.0 of 8 Ratings

TAG

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

Review Topic

1. Binds to platelets and inhibits their aggregation
2. Inhibits vitamin K-dependent clotting factors
3. Blocks COX-2 function
4. Unselective COX inhibiter
5. Decreases Anti-thrombin III activity

PREFERRED RESPONSE ▶

DISCUSSION: 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.

REFERENCES:

1. Hyers TM: Management of venous thromboembolism: Past, present, and future. Arch Intern Med 2003;163:759-768. PMID:12695266 (Link to Abstract)

Question Authors:

Derek Moore, John Badylak MD, Patrick McCulloch MD,

Please Rate Educational Value!

3.0

Average 3.0 of 10 Ratings

TAG

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

Review Topic

1. Aspirin
2. Clopidogrel (e.g. plavix)
3. Low molecular weight heparin
4. Warfarin
5. Hirudin

PREFERRED RESPONSE ▶

DISCUSSION: 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.

REFERENCES:

1. Buckwalter J, OKeefe R, Einhorn T (EDS). Orthopaedic Basic Science, 3rd ed. American Academy of Orthopaedic Surgeons. Rosemont, IL. 2007

Question Authors:

Patrick O'Donnell MD/PhD, Patrick McCulloch MD, Ben Taylor MD,

Please Rate Educational Value!

3.0

Average 3.0 of 10 Ratings

TAG

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

Review Topic

1. Warfarin
2. Enoxaparin
3. Dalteparin
4. Heparin
5. Hirudin

PREFERRED RESPONSE ▶

DISCUSSION: 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.

REFERENCES:

1. Buckwalter, Einhorn, Simon (ed): Orthopaedic Basic Science: Biology and Biomechanics of the Musculoskeletal System, ed 2, AAOS 2000, pp 217-237

2. Hyers TM: Management of venous thromboembolism: Past, present, and future. Arch Intern Med 2003;163:759-768. PMID:12695266 (Link to Abstract)

3. Berry DJ: Venous thromboembolism after a total hip arthroplasty: Prevention and treatment. Instr Course Lect 2003;52:275-280. PMID:12690855 (Link to Abstract)

Question Authors:

Jan Szatkowski MD, Patrick McCulloch MD, Michael Hughes MD,

Please Rate Educational Value!

3.0

Average 3.0 of 9 Ratings

Evidence & References Show References

Level of Evidence 5 and Other Journal Articles (includes Case Reports, Expert Opinions, Personal Observations, and Biomechanic Studies)

Mont MA, Jacobs JJ, Boggio LN, Bozic KJ, Della Valle CJ, Goodman SB, Lewis CG, Yates AJ Jr, Watters WC 3rd, Turkelson CM, Wies JL, Donnelly P, Patel N, Sluka P; AAOS. Preventing venous thromboembolic disease in patients undergoing elective hip and knee arthroplasty. J Am Acad Orthop Surg. 2011 Dec;19(12):768-76. PubMed PMID: 22134209. PMID:22134209 (Link to Abstract)
Eikelboom JW, Karthikeyan G, Fagel N, Hirsh J. American Association of Orthopedic Surgeons and American College of Chest Physicians guidelines for venous thromboembolism prevention in hip and knee arthroplasty differ: what are the implications for clinicians and patients? Chest. 2009 Feb;135(2):513-20. PMID:19201714 (Link to Abstract)
Mont MA, Jacobs JJ, Boggio LN, Bozic KJ, Della Valle CJ, Goodman SB, Lewis CG, Yates AJ Jr, Watters WC 3rd, Turkelson CM, Wies JL, Donnelly P, Patel N, Sluka P; AAOS. Preventing venous thromboembolic disease in patients undergoing elective hip and knee arthroplasty. J Am Acad Orthop Surg. 2011 Dec;19(12):768-76. PubMed PMID: 22134209. PMID:22134209 (Link to Abstract)
Ang-Lee MK, Moss J, Yuan CS. Herbal medicines and perioperative care. JAMA. 2001 Jul 11;286(2):208-16. PMID:11448284 (Link to Abstract)

Textbooks

Review of Orthopaedics, 6th Edition, Mark D. Miller MD, Stephen R. Thompson MBBS MEd FRCSC, Jennifer Hart MPAS PA-C ATC, an imprint of Elsevier, Philadelphia, Copyright 2012
AAOS Comprehensive Orthopaedic Review, Jay R. Leiberman. Published by American Academy of Orthopaedic Surgeons, Rosemont IL. Copyright 2009
Orthopaedic Knowledge Update 10, John M Flyn. Published by American Academy of Orthopaedic Surgeons, Rosemont IL. Copyright 2011
Hoppenfeld SP. Surgical Exposures in Orthopaedics: The Anatomic Approach. Lipponcott, Williams, and Wilkins, Philadelphia, PA, Copyright 2009
Orthopaedic In-training Examination (OITE) Questions 2004-2012, American Academy of Orthopaedic Surgeons, Rosemont IL. Copyright 2004-2012
Self-Assessment Examination (SAE) Questions 2004-2012, American Academy of Orthopaedic Surgeons, Rosemont IL. Copyright 2004-2012
Moore TJ. Perioperative medical management. In: Fischgrund JS, ed. Orthopaedic Knowledge Update 9. Rosemont, IL: American Academy of Orthopaedic Surgeons; 2008:105-113.
Buckwalter J, OKeefe R, Einhorn T (EDS). Orthopaedic Basic Science, 3rd ed. American Academy of Orthopaedic Surgeons. Rosemont, IL. 2007

Undefined

Dorr LD, Gendelman V, Maheshwari AV, Boutary M, Wan Z, Long WT. Multimodal thromboprophylaxis for total hip and knee arthroplasty based on risk assessment. J Bone Joint Surg Am. 2007 Dec;89(12):2648-57. PubMed PMID: 18056497. PMID:18056497 (Link to Abstract)
Dorr LD, Gendelman V, Maheshwari AV, et al: Multimodal thromboprophylaxis for total hip and knee arthroplasty based on risk assessment. J Bone Joint Surg Am 2007;89:2648- 2657 PMID:18056497 (Link to Abstract)
Lee MC, Nickisch F, Limbird RS: Massive retroperitoneal hematoma during enoxaperan treatment of pulmonary embolism after primary total hip arthroplasty: Case-reports and review of the literature. J Arthoroplasty 2006;21:1209-1214 PMID:17162185 (Link to Abstract)
Hyers TM: Management of venous thromboembolism: Past, present, and future. Arch Intern Med 2003;163:759-768. PMID:12695266 (Link to Abstract)
Buckwalter, Einhorn, Simon (ed): Orthopaedic Basic Science: Biology and Biomechanics of the Musculoskeletal System, ed 2, AAOS 2000, pp 217-237
Hyers TM: Management of venous thromboembolism: Past, present, and future. Arch Intern Med 2003;163:759-768. PMID:12695266 (Link to Abstract)
Berry DJ: Venous thromboembolism after a total hip arthroplasty: Prevention and treatment. Instr Course Lect 2003;52:275-280. PMID:12690855 (Link to Abstract)

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Anticoagulation

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