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Oral vitamin K antagonists ( VKAs ) have been used for over 50 years in the treatment and primary or secondary prevention of thromboembolic events associated with atrial fibrillation , stroke , myocardial infarction , cardiac valve surgery , deep vein thrombosis and pulmonary embolism . 1 , 2 Warfarin , one of the most well studied and used VKAs , was first discovered at the Wisconsin Alumni Research Foundation as a result of an unknown , fatal haemorrhagic disease that affected cattle in the 1920s . The agent is a type of coumarin that was present in spoiled sweet clover hay consumed by the sick animals , and it was initially marketed as a rodenticide . Its commercialisation as a therapeutic agent only occurred in 1954 , for the treatment of venous thromboembolism . 3
Bleeding risk Despite the widely demonstrated anticoagulant benefits of warfarin , its effects persist for days after discontinuation of treatment , and its administration requires frequent routine monitoring owing to the risk of major haemorrhagic complications , namely intracranial haemorrhage ( ICH ), the most devastating complication resulting from use of VKAs , and gastrointestinal bleeding , which can have a substantial clinical and economic impact . A metaanalysis of studies involving patients with venous thromboembolism showed a significant case – fatality rate of major bleeding and risk for ICH associated with
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oral anticoagulants . 4 Additionally , in a large cohort study of patients with atrial fibrillation who received warfarin , more than 75 % of patients who were hospitalised due to ICH suffered severe disability or died . 5
Therefore , patients presenting with acute bleeding while on VKAs require prompt reversal through normalisation of vitamin K-dependent coagulation factors ( VKDFs ). While it is possible to simply discontinue therapy with VKAs to prevent excessive bleeding in patients undergoing elective surgery or administer vitamin K for this purpose , these approaches are not fast enough in case of imminent surgical procedures or major bleeding episodes , and other bleeding reversal strategies are now available . Frozen fresh plasma ( FFP ) can effectively replenish VKDF levels , but there is currently not enough evidence supporting its suitability for urgent
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anticoagulation reversal . Moreover , FFP is associated with circulatory overload and transfusion-related acute lung injury , and also presents an increased risk of transmission of infectious agents . Other administration issues include the need for ABO blood typing , the time wasted preparing the product for infusion , and the high infusion time and volume necessary to fully restore VKDFs . By contrast , prothrombin complex concentrates ( PCCs ), which are lyophilised concentrates of plasma products containing VKDFs , require small infusion volumes and can be readily administered to patients . 6
PCCs : history PCCs were traditionally used for the treatment of haemophilia and other congenital bleeding disorders . They may consist of three ( factors II , IX and X ) or
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