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Chakri Gavva MD Manasa Reddy MD Ravi Sarode MD Department of Pathology , Division of Transfusion Medicine and Hemostasis , University of Texas Southwestern Medical Center , Dallas , TX , USA

Despite the emergence of direct oral anticoagulants , vitamin K antagonists ( VKAs ) continue to be prescribed for the prophylaxis and treatment of venous and arterial thromboembolic events ( TEEs ) in certain clinical conditions such as mechanical heart valves , left ventricular assist devices ( LVAD ), and antiphospholipid syndrome . VKAs , including warfarin , phenprocoumon , fluindione and acenocoumarol , primarily inhibit vitamin K epoxide reductase ( VKOR ), an enzyme necessary for the conversion of vitamin K epoxide to vitamin K1 . ¹ Vitamin K1 is then converted to a reduced form – vitamin KH2 – a cofactor required for the carboxylation of the vitamin K-dependent factors ( VKDFs ) factor II , factor VII , factor IX , factor X , and anticoagulant proteins C ( PC ) and S ( PS ). By inhibiting VKOR , VKAs reduce the carboxylation of these factors , rendering them functionally inactive and placing the patient in an overall anticoagulated state . ¹ The therapeutic effect of VKAs is measured by the international normalised ratio ( INR ), which is a value calculated from the prothrombin time . The target INR range for most indications of VKAs is 2.0 – 3.0 ( 2.5 – 3.5 for patients with a mechanical cardiac valve ), corresponding to factor II and factor X activities of 30 – 15 %. ²

Patients receiving VKA therapy have

an increased risk of bleeding during surgical procedures ³ with one study demonstrating a major bleeding frequency of 3.3 % for elective surgeries , 7.8 % for major surgeries , and 21.6 % for urgent surgeries . ⁴ Therefore , it is imperative to achieve a normal or near-normal INR ( ≤1.5 ) at the time of non-minor surgeries to minimise periprocedural bleeding . ³ The method by which to reverse the anticoagulant effects of the VKA is contingent on the thromboembolic risk of VKA cessation , bleeding risk of the surgery and timing of the surgery ( Table 1 ).

Assessing thromboembolic risk of VKA cessation The main indications for VKA therapy include patients with atrial fibrillation , a mechanical cardiac valve , or history of venous thromboembolism ( VTE ). These patients can be further categorised as low risk (< 5 % annual risk for a TEE ), medium risk ( 5 – 10 % annual risk for a TEE ), or high risk (> 10 % annual risk for a TEE ). The American College of Chest Physicians ( ACCP ) has previously published an algorithm to risk-stratify these patients on the basis of indication for VKA , additional patient comorbidities and clinical history . ³ The CHA2DS2- VASc ( congestive heart failure , hypertension , age ≥75 years , diabetes mellitus , previous stroke / transient ischemic attack , vascular disease , age 65 – 74 years , and sex category ) score may be used in place of the older CHADS2 ( congestive heart failure , hypertension , age ≥ 75 years , diabetes mellitus , and previous stroke / transient ischaemic attack ) score to assist with riskstratifying patients with non-valvular atrial fibrillation . ⁵

Pre-operative VKA reversal with vitamin K Patients with a therapeutic INR who are undergoing minor dental procedures , minor dermatological procedures , or cataract surgery may continue receiving VKAs with emphasis on local haemostasis during the procedure . ³ For patients who are at lower risk of TEEs and undergoing an elective surgery , cessation of VKA therapy five days before surgery should be sufficient to achieve a normal INR in the majority of patients . ⁶ Various management strategies exist to reverse the effects of VKAs in those who are at medium – high risk for TEEs and undergoing an elective surgery . For this patient population , the 2012 ACCP guidelines on perioperative antithrombotic therapy recommend cessation of VKAs and bridging anticoagulation with either low-molecular weight heparin or unfractionated heparin until the day of surgery . ³ However , bridging may be associated with increased health care costs , unnecessary exposure to heparin , and an increased risk of bleeding . ⁷ An alternative approach is to supplement the patient with 3mg intravenous ( IV ) vitamin K , 12 – 18 hours prior to the surgery and hold the dose of VKA one day prior to the procedure . ² A study of 178 patients ( with 44 % being categorised as moderate – high risk for TEEs ) demonstrated the safety and effectiveness of this method . A total of 94 % of patients achieved an INR ≤1.5 with restoration of VKDFs to haemostatic levels (> 30 %), and for those patients with follow-up data , none suffered a TEE in the six weeks following the surgery . No patient experienced an adverse reaction to IV vitamin K . ² This approach may also be considered for patients undergoing an

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