Use of recombinant factor VIIa for hip replacement surgery in a patient with severe factor XI deficiency and drug‐induced platelet defect

Patients with factor XI (FXI) deficiency rarely develop spontaneous bleeding, As shown in several case reports by Rosenthal et al. [1,2], bleeding usually occurs following trauma or surgery. Similar observations were made by Ragni et al. [3] in 25 FXI-deficient kindreds. No patient experienced deep muscle haematoma, haemarthroses, or bleeding into central nervous system (CNS), gastrointestinal tract, or retroperitoneal space. Bleeding is especially severe at sites with high fibrinolytic activity [4]. If specific FXI concentrates are not available, recombinant factor VIIa [FVIIa; eptacog alfa (activated)] is a treatment option, especially, in cases where fluid overload induced by fresh frozen plasma (FFP) should be avoided. We report the case of an 85-year-old female with hip fracture who underwent hip replacement surgery and was treated perioperatively with eptacog alfa (activated) in combination with tranexamic acid. The patient was admitted for surgery of an acute traumatic hip fracture. Several years before, FXI deficiency had been diagnosed after severe postoperative bleeding that followed cholecystectomy, requiring massive transfusion. The patient reported frequent haematomas and increased bleeding after minor injury since childhood, and occasional nosebleeds. Coagulation and clinical chemistry analyses were done using reagents and instrumentation from DadeBehring, Marburg, Germany. Laboratory diagnostics showed a FXI level below the detection limit of 3%, with otherwise normal coagulation factors (Table 1). The activated partial thromboplastin time (aPTT) using Actin FS reagent was prolonged; prothrombin time was normal. Platelet aggregation tests showed moderately impaired epinephrin-induced aggregation, presumably owing to treatment with ibuprofen. Expression of GP IIb/IIIa and GP Ib/IX were normal in flow-cytometric analysis (FACS) using reagents and instrumentation from Becton Dickinson, Heidelberg, Germany. The patient received 1 g of tranexamic acid and 4.8 mg (80 μg kg−1 body weight) of eptacog alfa (activated) before surgery, 2.4 mg (40 μg kg−1 body weight) of eptacog alfa (activated) 4 h after the initial bolus, and 1.2 mg (20 μg kg−1 body weight) after 8, 16, and 24 h, resulting in a total dose of 10.8 mg or 180 μg kg−1 body weight. Additional doses of 1 g or tranexamic acid were administered after 8, 16, and 24 h. Total hip replacement surgery was performed without complications. Total intra- and postoperative blood loss was 600 mL, which is within the expected range for patients without coagulation disorders. The patient received a total of one unit of erythrocyte concentrate, and 100 mL of re-transfused cell saver blood. Initial haemoglobin level was 10.7 g dL−1, haematocrit was 31%. The lowest haemoglobin level was 7.3 g dL−1, lowest haematocrit was 21%, measured 4 h after the start of surgery. After transfusion, haemoglobin level was 10.2 g dL−1, haematocrit was 29%, and remained stable. A drop in platelet count and fibrinogen level is related to intraoperative blood loss. d-dimer levels were elevated before surgery as a consequence of trauma and haematoma, with a further increase during surgery, and declining levels after surgery. About 4 h after surgery, the patient complained of chest pain. An electrocardiogram (ECG) revealed no signs of cardiac ischemia. Troponine I and creatine kinase levels were not elevated. No other side-effects were reported. Three months later, the patient fractured her contralateral hip and hip replacement surgery was performed using the same treatment scheme. Again, no relevant bleeding complications and no thromboembolic complications occurred. FXI is activated by thrombin on the surface of activated platelets [5]. The resulting FXIa is a central component of the positive feedback loop [6], leading to the efficient production of large quantities of thrombin necessary for effective activation of thrombin-activatable fibrinolysis inhibitor (TAFI), which impairs the conversion of plasminogen to plasmin, as well as plasmin cleavage of fibrin [7]. FXI deficiency leads to impaired procoagulant and antifibrinolytic function, resulting in a bleeding tendency. FXI concentrates are not generally available. Recombinant FVIIa has been suggested as a ‘universal haemostatic agent’, leading to the production of large quantities of thrombin even in patients with non-functional coagulation feedback loop or severely impaired platelet procoagulant function. In the present case, the patient had been treated with ibuprofen, which leads to impaired platelet function and an increased bleeding risk in addition to that resulting from FXI deficiency. We therefore decided to treat the patient with eptacog alfa (activated) in combination with tranexamic acid. This combination had been suggested by O’Connell in a review published in 2004 [8]. Treatment was successful, with no increased bleeding or other complications. FXI remained unchanged. Interestingly, platelet function measured with the PFA assay (using the PFA-100 instrument from DadeBehring Diagnostics, Marburg, Germany) was worse during treatment than before treatment, indicating that eptacog alfa (activated) did not lead to platelet ‘hyperactivity’. It is possible that in patients with FXI deficiency alone and without additional platelet defect, lower doses than those administered in the present case are effective [9]. Schulman et al. [10] reported the case of a 63-year-old female undergoing spinal surgery, who received a bolus dose of 29 μg kg−1 body weight, followed by a continuous infusion of 3.6 μg kg−1 body weight per hour for several days. A slightly lower dose was administered for a second operation six years later. Four case reports deal with the treatment of patients with FXI deficiency and an acquired inhibitor with eptacog alfa (activated). Hedner [11] reported a patient who underwent orchidectomy because of bleeding from his testis. This patient was treated with 60 μg kg−1 body weight every three hours for three days. Bern et al. [12] used a dose of 90 μg kg−1 body weight preoperatively, repeated every two hours for a total of 8 h, followed by the same dose every three hours for two doses, and every four hours for four doses. In addition, epsilon-aminocaproic acid (EACA), an antifibrinolytic agent, was given for six days. A 62-year-old female with FXI deficiency and a FXI inhibitor underwent a colposuspension procedure, using FXI concentrate. Following this procedure, the patient developed an inhibitor. For cataract surgery, the patient was treated with eptacog alfa (activated), using a bolus of 90 μg kg−1 body weight preoperatively, and a continuous infusion of 20 μg kg−1 body weight per hour for 24 h. No bleeding complications were observed [13]. Billon et al. [14] treated a 75-year-old patient with leukemia and an acquired FXI deficiency with 30 μg kg−1 body weight of eptacog alfa before and four hours after pleural puncture. FXI deficiency is not a licensed indication for eptacog alfa (activated), but as in other conditions with severe bleeding tendency, the drug is active in the prevention of bleeding complications. C.-E. Dempfle has acted as a paid speaker. The other authors stated that they had no interests which might be perceived as posing a conflict or bias.