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Prothrombin Complex Concentrates to Reverse Warfarin

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Christopher Arendt, PharmD, RPh
Mayo Clinic College of Medicine
Rochester, MN, USA

If you prick us, do we not bleed? - William Shakespeare, The Merchant of Venice, Act III, Scene 1

For decades we have used oral anticoagulants to reduce thrombotic risk. All too familiar with the effects of the vitamin K antagonist (VKA) warfarin in the pre-, peri- and post operative arenas are the surgeon, anesthesiologist, perfusionist, and allied staff. Center specific protocols and professional guidelines have been developed to contend with the balance between bleeding and clotting risks and anticoagulation management at various times in a patients surgical care [1,2,3]. Warfarin reversal has traditionally been done with intravenous (IV) or oral phytonadione (Vit K) and Fresh Frozen Plasma (FFP) to replete vitamin K dependent clotting factors (II, VII, XI, X). But as Bob Dylan so thoughtfully stated in 1964, "...times, they are a changin".

With short ischemic times heart and lung transplantation are ascribed to urgent anticoagulant reversal. Delays due to long anticoagulant duration of warfarin (7 days) and slow international normalized ratio (INR) reversal effects of phytonadione (12-24 hours) alone do not lend themselves to the rapid sequence of events [4]. The use of FFP in the reversal strategy is also less than optimal, as multiple plasma units (15 to 20 mL/kg) infused over hours are necessary to correct the INR. FFP has been associated with fluid volume overload, increased risk of transfusion-related acute lung injury (TRALI), necessity of thawing, ABO matching, and infectious risk [5]. Transfusions are associated with high rates of morbidity and mortality in critically ill, and worsening outcomes, respiratory, renal, cardiac, and neurologic complications in cardiac surgical patients [6].

Cardiac Surgery has traditionally used high rates of allogeneic blood transfusion [5]. Reducing exposure to transfusions reduces HLA sensitization in transplant [12]. Centers are adopting Blood Management strategies to lessen expense and exposure, creating patient-centered approaches to transfusion [10]. One approach at reducing blood exposure is the use of Prothrombin Complex Concentrates (PCCs) to reverse the effects of warfarin. PCCs come from pooled donors and measures 25 times the vitamin K dependent clotting factor concentrations of FFP. They have the advantage of small administration volumes, improved viral inactivation, room-temperature stability, and lack of ABO incompatibility [7]. Until recently, off-label use of 3-factor PCC, Profilnine SD (Grifols, Barcelona, Spain), and Bebulin VH (Baxter) (containing factor II, IX, X and very little if any factor VII), and Factor Eight Inhibitor Bypassing Activity (FEBIA), an activated 4-Factor PCC (containing II, IX, X and activated Factor VIIa), were the only options available. These agents are approved for prevention and control of bleeding in patients with hemophilia B. In 2013 the FDA approved a non-activated 4-Factor PCC [Kcentra], CSL Behring, Marburg, Germany) composed of Factors II, IX, X, VII and Protein S and C, and trace amounts of Heparin. While licensed for urgent reversal of warfarin abroad for several years as Beriplex (CSL Behring, King of Prussia, PA, USA) and Octaplex (Octapharma, Lachen, Switzerland), it was only recently FDA approved for warfarin reversal during acute major bleeding (April 2013) or urgent invasive procedure (December 2013).

4-Factor PCC has not been studied extensively in heart and lung transplant, only in small studies of cardiac surgery patients and massive bleed populations. When compared to FFP in the context of excessive bleed after cardiac surgery, it is superior at correcting the INR and significantly reducing the need for RBC transfusion [8,9,11,12]. 4-Factor PCCs rapidly reverse vitamin K dependent factors within 30 minutes of administration (INR < 1.3) when initial INR > 2 compared to the FFP (12-96 hours) [8,10,12].

There are practical considerations to the 4-Factor PCCs. PCCs and FEBIA are considered fractionated components of blood,accepted by Jehovah's Witness patients along with rFVIIa [14]. PCCs are administered along with IV Vitamin K to prevent rebound increase in PT/INR [12]. Dosings of 4-Factor PCC are based on current INR and actual body weight. [See Figure 1][4]. Each dose is calculated based on Factor IX activity. There have been reported dosing errors with Kcentra [15]. Special attention by the clinician should be placed on adding the units listed on the vial and not the product packaging. Doses are administered within 4 hours of reconstitution. Administration is at room temperature through a separate peripheral infusion line. The infusion rate is listed as 0.12 mL/kg/min up to a max of 8.4 mL/min (210 units/min). Monitoring should consist of baseline INR and repeated INR 30 minutes after administration. INR should be reassessed in 3-6 hours (due to the shorter t 1/2 of Factor VII and the onset of action of Vit K). Re-dosing 4-Factor PCC is not advised. Additional coagulation factors may be administered if hemostatic goals are not achieved. links imageObservation for hypersensitivity reactions is vital, especially if antithrombin III or human albumin intolerances are known. Because of the small amount of heparin in each dose, caution should be exercised if the patient has known heparin-induced thrombocytopenia [16]. Thrombotic complications are possible with the use of 4-Factor PCC, but they are equivalent to FFP (4% vs 3%), and lower than activated Factor VII (5-20%) [8].

Significant bleeding is associated with cardiac surgery. Minimizing contributors to bleeding risk is important, especially in transplant patients. Transfusion sparing strategies, utilizing factor concentrates, present an opportunity to reduce patient sensitization, volume overload, infectious risk, and to minimize infusion reactions. While little data is currently available surrounding the use of 4-Factor PCCs with heart/lung transplants, extrapolation of cardiac surgical bleed information provides us with a working template from which we can start to create warfarin reversal strategies. ■

Disclosure Statement: The author has no conflicts of interest to disclose.

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