Prothrombin complex concentrate for factor VII replacement in a patient undergoing left ventricular assist device implantation with factor VII deficiency
Authors: Katelyn W. Sylvester, Gregory Couper, Jean M. Connors
Journal: American Journal of Hematology (2015)

Factor VII (FVII) deficiency is the most common among the autosomally recessive inherited coagulation disorders and may result in prolonged, excessive bleeding after injury or surgery 1. FVII, a vitamin K-dependent glycoprotein, is an integral part of the extrinsic phase of the clotting cascade. After damage to the endothelium, tissue factor is exposed to plasma components and binds to circulating FVII forming the tissue factor:factor VIIa complex 2, 3. This complex activates factors IX and X leading to activation of thrombin resulting in a thrombin burst to initiate clotting. FVII plasma levels are affected by environmental factors such as vitamin K deficiency in liver disease and during anticoagulation with vitamin K antagonists. FVII deficiency is suspected when a prolonged prothrombin time cannot be attributed to acquired factors. The activated partial thromboplastin time, thrombin time and fibrinogen concentrations remain normal. There is poor correlation with FVII levels and bleeding risk. Typically bleeding is not seen with FVII levels greater than 5% 4. Bleeding patterns are variable, but are typically mucus membrane-derived in adults 1. Patients with congenital FVII deficiency requiring major surgery may have a greater risk of bleeding than the general population. Perioperative bleeding management for these patients is determined on a case-by-case basis, considering baseline factor levels, bleeding history, and type of surgery. Unlike other coagulation factor deficiencies, hemostasis can be maintained throughout surgery with FVII levels as low as 5–15% 1, 4. We present the perioperative cardiac surgery management of a patient with newly diagnosed FVII deficiency. A 58 year-old male with end-stage biventricular systolic dysfunction secondary to nonischemic cardiomyopathy with an estimated left ventricular ejection fraction of 27%, atrial fibrillation, and hypertension was transferred from outside of the United States to our institution for a heart transplant evaluation. Prior to transfer, the patient had been successfully maintained on warfarin long-term for atrial fibrillation without bleeding. During his transplant evaluation, he had persistently elevated INR values for 3 weeks after warfarin withdrawal despite vitamin K repletion of 25 mg over five days. A hematologic evaluation revealed normal aPTT and fibrinogen, but FVII level of 21%. A decision was made to implant a Thoratec biventricular extracorporeal ventricular assist device (VAD) despite his mild FVII deficiency. Given this patient's lack of bleeding history while being anticoagulated with warfarin, hematology recommended using four-factor prothrombin complex concentrate (4PCC) in the event of intraoperative bleeding in lieu of surgical prophylaxis. Preprocedure INR was 1.5, he was not pretreated with blood products or factor concentrates. The patient underwent cardiopulmonary bypass (CPB) for 248 min. After CPB ended and unfractionated heparin was reversed, the patient experienced moderate bleeding with a FVII level of 27. Intraoperatively, 4PCC 25 units/kg was administered as a source of FVII with two units of platelets. One hour after administration, FVII increased from 27 to 58 with a single dose of 25 units/kg of 4PCC. Recombinant factor VIIa (rFVIIa) was not used. Postoperatively an additional 4PCC 25unit/kg and one unit of FFP were used, but no bleeding or thrombotic complications occurred during the remainder of his hospital stay. For patients with FVII deficiency thought to be at high risk for bleeding perioperatively, a baseline FVII level should be drawn immediately prior to surgery and every 4–6 hours for the duration of the surgery 5. If FVII levels are unacceptable prior to surgery, surgical prophylaxis regimens include administration of exogenous FVII to maintain levels approximately 25%, despite limited data to support this practice. Since hemostasis can generally be maintained throughout surgery despite low FVII levels (as low as 5%), surgical prophylaxis for patients without a clinical history of bleeding may be unnecessary 1, 4, 6. In these cases, patients can be monitored perioperatively for bleeding complications and be supported with FVII if needed. This minimizes the potential risk of thrombosis. As part of a surgical prophylaxis regimen or as treatment for acute bleeding, options for exogenous FVII include recombinant FVIIa or activated PCC which provide FVII in the activated form, or alternatively, inactivated FVII can be administered as either FFP or nonactivated 4PCC. Recombinant FVIIa has been used to manage patients with FVII deficiency undergoing surgical procedures 1. Despite its efficacy, use is cautioned as it carries a black box warning for serious arterial and venous thrombotic events 5. Our patient was at a high risk of thrombosis due to the VAD and history of atrial fibrillation, elevating the concern for thrombosis with the use of rFVIIa or activated PCC. Although FPP has been used successfully to restore FVII levels, the concentration of FVII in FFP is low and the half-life is short, so large volumes are required to provide sufficient quantities of FVII. It is difficult to reach and maintain desired FVII levels without fluid overload 1. We used 4PCC as a source of FVII in this patient. 4PCC contains all vitamin K-dependent clotting factors, as well as heparin, antithrombin III, human albumin and the natural anticoagulants proteins C and S. Administering nonactivated FVII in 4PCC as compared with rFVIIa and activated PCC, theoretically decreases the thrombotic risk to the patient. Katelyn W. Sylvester1 Gregory Couper2 Jean M. Connors3* 1Department of Pharmacy Services, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 2Division of Cardiac Surgery, Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 3Hematology Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts