Prothrombin Complex Concentrates for Perioperative Vitamin K Antagonist and Non–vitamin K Anticoagulant Reversal

Jerrold H. Levy, M.D., F.A.H.A., F.C.C.M.; James Douketis, M.D.; Thorsten Steiner, M.D.; Joshua N. Goldstein, M.D., Ph.D.; Truman J. Milling, M.D.


Anesthesiology. 2018;129(6):1171-1184. 

In This Article

Abstract and Introduction


Vitamin K antagonist therapy is associated with an increased bleeding risk, and clinicians often reverse anticoagulation in patients who require emergency surgical procedures. Current guidelines for rapid anticoagulation reversal for emergency surgery recommend four-factor prothrombin complex concentrate and vitamin K coadministration. The authors reviewed the current evidence on prothrombin complex concentrate treatment for vitamin K antagonist reversal in the perioperative setting, focusing on comparative studies and in the context of intracranial hemorrhage and cardiac surgery. The authors searched Cochrane Library and PubMed between January 2008 and December 2017 and retrieved 423 English-language papers, which they then screened for relevance to the perioperative setting; they identified 36 papers to include in this review. Prothrombin complex concentrate therapy was consistently shown to reduce international normalized ratio rapidly and control bleeding effectively. In comparative studies with plasma, prothrombin complex concentrate use was associated with a greater proportion of patients achieving target international normalized ratios rapidly, with improved hemostasis. No differences in thromboembolic event rates were seen between prothrombin complex concentrate and plasma, with prothrombin complex concentrate also demonstrating a lower risk of fluid overload events. Overall, the studies the authors reviewed support current recommendations favoring prothrombin complex concentrate therapy in patients requiring vitamin K antagonist reversal before emergency surgery.


DESPITE the increasing use of non–vitamin K antagonist oral anticoagulants, vitamin K antagonists, such as warfarin, are still widely used in patients with atrial fibrillation, venous thromboembolism, and mechanical heart valves. In 2015, approximately 3 million patients were prescribed warfarin in the United States alone.[1] As with all anticoagulants, the main risk associated with vitamin K antagonist therapy is an increased risk for bleeding. Thus, annual rates of major hemorrhagic events ranged from 1.0 to 7.4% in a systematic review of patients with atrial fibrillation receiving vitamin K antagonist therapy for stroke prevention, while rates of intracranial hemorrhage in the same population ranged from 0.1 to 2.5%.[2]

Patients receiving vitamin K antagonist therapy who require surgery or an invasive procedure present a specific challenge to clinicians, with an estimated 250,000 to 400,000 patients affected per year in North America alone.[3] Data from the Randomized Evaluation of Long-Term Anticoagulation Therapy trial demonstrated that major bleeding (defined as 2 g/dl or more reduction in hemoglobin, transfusion of two or more units of red blood cells, or a critical area or organ bleed) occurred in 3.3% of warfarin-treated patients undergoing elective surgery, increasing to 21.6% in patients who required emergency surgery.[4] Consequently, effective perioperative management is a key consideration in this population. In patients undergoing elective surgery, current guidelines recommend discontinuing vitamin K antagonist therapy 5 days before the procedure to restore patients' international normalized ratio to a normal range and to minimize the risk of perioperative bleeding.[3] However, in patients who require an emergency surgical procedure, rapid vitamin K antagonist reversal is recommended by replacing the vitamin K–dependent coagulation factors II, VII, IX, and X.[5]

Intravenous vitamin K monotherapy is recommended only for vitamin K antagonist reversal in patients in whom surgery can be delayed[6] because it can take more than 48 h to normalize functional factor levels and restore them to the normal range.[5] Therefore, in situations requiring rapid vitamin K antagonist reversal, treatment with prothrombin complex concentrates, concomitantly with vitamin K, is more commonly administered. Although fresh frozen plasma (plasma frozen within 8 h of collection) or plasma (frozen within 24 h of collection) was traditionally used for rapid reversal of anticoagulation with vitamin K antagonists, there are multiple limitations to its use, including the need for blood type matching before administration; time required to thaw the product; and risks of fluid overload, pathogen transmission, and transfusion-related acute lung injury.[5] Furthermore, only minimal benefits have been shown from plasma when reducing the international normalized ratio to less than 1.7 in adults, as well as minimal efficacy for anticoagulation reversal.[7,8]

Prothrombin complex concentrates, which are classed as either four-factor prothrombin complex concentrates (containing coagulation factors II, VII, IX, and X) or three-factor prothrombin complex concentrate (containing factors II, IX and X, but only minimal levels of factor VII; Table 1), are stored at room temperature, administered in a smaller volume and shorter infusion time than plasma, and are virally inactivated to minimize the risk of pathogen transmission. Current treatment guidelines recommend prothrombin complex concentrates, specifically four-factor prothrombin complex concentrates, with concomitant intravenous vitamin K, as the preferred therapy for urgent vitamin K antagonist reversal (Table 2).[5,6,9,10]

The perioperative management of hemostasis in patients receiving vitamin K antagonists was previously reviewed in this journal in 2008.[11] Since then, multiple new studies have investigated vitamin K antagonist reversal in perioperative and periprocedural settings, and prothrombin complex concentrates have become more widely available in the United States and are recommended in guidance documents. Despite the fact that prothrombin complex concentrate is recommended in all guidelines, plasma is still frequently administered for vitamin K antagonist reversal.[12] This article provides an update on the latest evidence for the use of prothrombin complex concentrates in patients requiring urgent vitamin K antagonist reversal for emergency surgery, but it also reviews current use for non–vitamin K antagonist oral anticoagulant reversal.