Management of the Anticoagulated Patient

Educational Objectives

The goal of this program is to improve the perioperative treatment of patients who take drugs for anticoagulation. After hearing and assimilating this program, the clinician will be better able to:

1. Elaborate on the mechanisms of action of various types of anticoagulation drugs.

2. Minimize perioperative risk in patients who take anticoagulation drugs.

3. Evaluate patients who take anticoagulation drugs for risk of perioperative bleeding.

Summary

Surgery in a patient who takes anticoagulation drugs: before stopping anticoagulation medication, consult with the prescribing physician about benefits compared with risks

Coagulation cascade: extrinsic pathway — tissue factor is a lipoprotein on the surface of subendothelial smooth muscle cells and fibroblasts; initiates coagulation after injury to blood vessels; increases the activity of factor VIIa; factor VIIa activates factor X to factor Xa; factor Xa converts prothrombin to thrombin; intrinsic pathway — factor XII is activated by contact with glass, mechanical heart valves, and extracorporeal circuits; also activated by in vivo contact with DNA released from activated neutrophils or polyphosphates (released from platelets); factor XIIa activates factor XI to factor Xia; then factor Xia activates factor IX to factor IXa; factor IXa activates factor X to factor Xa and converts prothrombin to thrombin

Heparin and heparin derivatives: heparin — a polymer of alternatively arranged glucuronic acid and acetylglucosamine molecules; found in mast cells; commercially prepared from pig intestine mast cells; mechanism of action — heparin binds to antithrombin III to form a complex that inhibits factor Xa and thrombin; chronic hepatic failure or malnutrition may impart resistance to the effects of heparin because of deficiency of antithrombin III; infusion of antithrombin III concentrate restores the response to heparin; monitoring activity of heparin — the level of anti–factor Xa accurately reflects activity of heparin; however, rapid results of tests typically are not available; results of tests of partial thromboplastin time (PTT) or activated clotting time (ACT) are available more quickly, but these tests are less accurate; protamine (heparin antagonist drug) — binds and inactivates heparin; the half-life of heparin is ≈1 hr; this value can be used to estimate dosing of protamine; the drug rapidly normalizes PTT and ACT; however, rapid infusion may be associated with anaphylactoid or anaphylactic reactions; therefore, the drug should be administered slowly

Low-molecular-weight heparins: enoxaparin (Lovenox) — inhibits factor Xa and thrombin; contraindicated in individuals with creatinine clearance <30 mL/min and those with a history of heparin-induced thrombocytopenia; the half-life is 5 to 7 hr; the anti–factor Xa effect is 12 to 24 hr/dose; monitoring PTT is not necessary; protamine will partially reverse the effect of enoxaparin if given within 8 hr of the last dose; fondaparinux (Arixtra) — inhibits factor Xa, but not thrombin; the duration of effect is longer than to that of heparin or enoxaparin (half-life is 17 hr); contraindicated in individuals with creatinine clearance <30 mL/min; an antidote to reverse the effects is lacking; however, clearance can be increased by dialysis; theoretically, andexanet α can reverse the effects

Warfarin: the most commonly used oral anticoagulant agent; the therapeutic index is very low; a vitamin K antagonist that inhibits synthesis of factors VII, IX, and X, prothrombin, protein C, and protein S

Monitoring: measurement of prothrombin time (PT) and international normalized ratio (INR) is necessary to ensure adequate pharmacologic dosing and avoid excessive anticoagulation

Pharmacokinetics: warfarin is metabolized primarily by cytochrome P450 2C9; variability in metabolism and responsiveness among individuals is wide; many drugs can affect the metabolism of warfarin and its binding to plasma proteins

Preparation for surgery: stop warfarin 5 to 7 days before elective surgery, and substitute a shorter-acting parenteral anticoagulant agent until 1 or several days before surgery; emergent reversal may be accomplished by administering vitamin K and fresh frozen plasma (FFP) that contains clotting factors; however, vitamin K is stored in the liver and may interfere with the effects of warfarin for weeks; infusion of an adequate volume of FFP requires significant time and large volume; risk for transfusion reaction is high; alternatively, prothrombin complex concentrate (PCC) may be infused; dosing is dependent on the patient’s weight and preoperative INR; INR 2 to 4 requires a PCC dose 25 U/kg; INR 4 to 6, 35 U/kg; and INR >6, 50 U/kg; the concentration of factor IX varies from batch to batch and must be determined; in heavy patients, the concentration should be ≤5000 U; the recommended maximum rate of infusion is ≈200 U/min; in the majority of patients, the necessary dose is administered in 10 to 20 min

Dabigatran (Pradaxa): an oral anticoagulant agent that inhibits thrombin; monitoring of coagulation is not required

Preparation for elective surgery: according to the American Society of Regional Anesthesia and Pain Medicine (ASRA), dabigatran should be stopped 4 days preoperatively (5 or 6 days preoperatively in patients with renal dysfunction); before urgent surgery, the coagulation status may be estimated using the PTT; normal PTT signifies no anticoagulation; however, the degree of elevation of PTT correlates poorly with pharmacologic effect; ecarin clotting time (ECT) accurately assesses the pharmacologic effect, but the test is not widely available; antagonist — a 5-g intravenous (IV) bolus of idarucizumab (eg, Praxbind) normalizes the ECT almost immediately; however, the drug is expensive

Factor Xa inhibitors: oral anticoagulant agents; include rivaroxaban (Xarelto), apixaban (Eliquis), edoxaban (Savaysa), and betrixaban (Bevyxxa); routine monitoring is not required; anti–factor Xa activity correlates poorly with PT and PTT; direct measurement is required, but not widely available; preparation for elective surgery — ASRA recommends stopping the drug 3 days preoperatively; andexanet α (Andexxa) is approved by the US Food and Drug Adminsitration (FDA) to reverse the anticoagulant effects of rivaroxaban and apixaban; animal studies found that andexanet α reverses the effects of edoxaban and betrixaban, but FDA approval is lacking; if the dose or timing of administration is not known, an IV bolus dose of 800 mg followed by infusion at a rate of 8 mg/min for 2 hr is recommended; whether continuing the infusion beyond 2 hr is necessary in patients undergoing longer surgical procedures and whether additional doses are necessary to prevent postoperative bleeding have not been determined; andexanet α is expensive ($50,000 per patient); comparative studies found that the benefits of andexanet α are superior to those of PCC

Medications affecting the function of platelets

Nonsteroidal anti-inflammatory drugs (NSAIDs): decrease the function of platelets by inhibiting cyclooxygenase (COX; catalyzes the formation of thromboxane); aspirin — the most commonly used antiplatelet drug; irreversibly inhibits COX; the pharmacologic effect lasts days, because new platelets must be synthesized; stop aspirin 7 to 10 days preoperatively; urgent surgery requires transfusion of platelets; however, in patients with high cardiovascular risk and low risk of perioperative bleeding, aspirin may be continued (consult the prescribing physician); other COX inhibitors — reversibly inhibit COX; before elective surgery, stop diclofenac and ibuprofen 1 day preoperatively, etodolac and indomethacin 2 days preoperatively, naproxen and meloxicam 4 days preoperatively, and piroxicam 10 days preoperatively; stopping these drugs before urgent surgery may be followed by prolonged bleeding that is unresponsive to transfusion of platelets; the risks associated with transfusion of platelets include development of antiplatelet antibodies that reduce efficacy of future platelet transfusions

Adenosine diphosphate (ADP) inhibitors: bind to and block the P2Y12 receptor (important in aggregation of platelets); clopidogrel (Plavix) and prasugrel (Effient) irreversibly block the receptor; ticagrelor (Relenza) acts reversibly; clopidogrel — a prodrug whose active metabolite is the moiety that irreversibly blocks the P2Y12 receptor; at steady state, the majority of the metabolite is bound in the peripheral tissue and remains for days after the last dose; new or transfused platelets are inhibited for ≥1 wk; ASRA recommends stopping clopidogrel 7 days preoperatively; emergent reversal is not possible; prasugrel — ASRA recommends stopping the drug 10 days preoperatively; emergent reversal is not possible; ticagrelor — found superior to clopidegrel in preventing myocardial infarction and occlusion of coronary stents; also indicated for prevention of stroke; ASRA recommends stopping it 5 days before elective surgery; transfusion of platelets is unlikely to be effective

Glycoprotein IIb/IIIa receptor inhibitors: block the IIb/IIIa receptor on the surface of platelets that binds fibrinogen and von Willebrand factor to inhibit aggregation of platelets; abciximab (ReoPro) is a monoclonal antibody with a duration of action >1 day; the duration of action of eptifibatide (Integrilin) and tirofiban (Aggrastat) is a few hours; these drugs are given by IV infusion and are commonly used in the cardiac catheterization laboratory and for treatment of acute coronary syndrome in the cardiac intensive care unit; the effects of abciximab are reversed by platelet transfusion; the short duration of action of eptifibatide and tirofiban precludes the need for reversal

Readings

Badr DA et al. Uterine body placenta accreta spectrum: A detailed literature review. Placenta. 2020;95:44-52; doi: 10.1016/j.placenta.2020.04.005; Gonen N et al. Placental histopathology and pregnancy outcomes in “early” vs “late” placental abruption. Reprod Sci. 2021; 28:351-360; doi: 10.1007/s43032-020-00287-3; Koscielny J et al. How do I reverse oral and parenteral anticoagulants? Hämostaseologie. 2020;40:201-213; doi:10.1055/a-1113-0557; Lambrecht S, Van De Velde M. Interventional radiology for the obstetric patient. Curr Opin Anesthesiol. 2020;33:566-570; doi: 10.1097/ACO.0000000000000884; Lefkowitz JB. Kottke-Marchant K. (Ed.), An algorithmic approach to hemostasis testing, College of American Pathologists, Northfield, Ill (2008), pp. 3-12; Mok M et al. Interventional radiology in women with suspected placenta accreta undergoing caesarean section. Int J Obstet Anesth. 2008;17:255-261; doi: 10.1016/j.ijoa.2007.11.010; Spandorfer J. The management of anticoagulation before and after procedures. Med Clin North Am. 2001;85:1109-1116; doi: 10.1016/s0025-7125(05)70366-7.

Disclosures

For this program, members of the faculty and planning committee reported nothing to disclose.

Acknowledgements

Dr. Dershwitz was recorded exclusively for Audio Digest using virtual teleconference software in compliance with current social-distancing guidelines during the COVID-19 pandemic. Audio Digest thanks the speakers and the Cleveland Clinic Foundation for their cooperation in the production of this program.

CME/CE INFO

Accreditation:

The Audio- Digest Foundation is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

The Audio- Digest Foundation designates this enduring material for a maximum of 0 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Audio Digest Foundation is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's (ANCC's) Commission on Accreditation. Audio Digest Foundation designates this activity for 0 CE contact hours.

Lecture ID:

AN631201

Expiration:

This CME course qualifies for AMA PRA Category 1 Credits™ for 3 years from the date of publication.

Instructions:

To earn CME/CE credit for this course, you must complete all the following components in the order recommended: (1) Review introductory course content, including Educational Objectives and Faculty/Planner Disclosures; (2) Listen to the audio program and review accompanying learning materials; (3) Complete posttest (only after completing Step 2) and earn a passing score of at least 80%. Taking the course Pretest and completing the Evaluation Survey are strongly recommended (but not mandatory) components of completing this CME/CE course.

Estimated time to complete this CME/CE course:

Approximately 2x the length of the recorded lecture to account for time spent studying accompanying learning materials and completing tests.