LAUSR

Dear Editors, Severe FXI deficiency (FXI:C<1%) is a rare disease, generally associated with bleeding symptoms, which is occasionally treated with plasma or FXI concentrate. FXI deficiency may be associated with the development of anti‐FXI antibodies, especially in patients carrying the mutation p.Glu117X where the proportion of patients with inhibitors may be as high as 30%.1 We report the case of a woman affected by severe FXI deficiency (<1%), characterized by minor bleeding (gum bleeding, heavy menses, bleeding after tooth avulsion on one occasion), diagnosed at the age of 35 years. The analysis of the FXI coding gene found the nonsense mutation p.Glu117X. Before diagnosis, the patient underwent appendicectomy without bleeding. After diagnosis, she had tooth avulsions and underwent other minor procedures (such as colonoscopy and finger cyst removal) while in prophylaxis with tranexamic acid without bleeding. Afterward, she received 13 infusions of fresh frozen plasma because of arthroscopic meniscectomy and a postdental procedure mandibular hematoma. At 70 years, while lamenting nausea, weight loss, abdominal discomfort, and fatigue, she underwent a surgical evaluation for epigastric hernia, which revealed a gastric polyp that was subsequently biopsied after plasma infusion for 2 days. One month later, the patient was tested for the first time for FXI inhibitor2 and found positive (59 BU). After 4 months, the inhibitor titer decreased to 27 BU. The biopsy was suggestive (but not conclusive) for gastro‐intestinal stromal tumor. For this reason, laparoscopic surgery (gastric wedge resection and correction of the epigastric hernia) was proposed. The use of recombinant activated factor VII (rFVIIa, Novoseven; Novo Nordisk) during surgery was planned based on the data from the literature. Since 2002, several patients with severe FXI deficiency (with or without inhibitors) were treated with rFVIIa without major bleeding.3 A standard dose (47‐90 μg/kg) was used in one of the reported patients, but, due to the occurrence of thrombotic events, a decreased dose was subsequently used.4-6 However, few reports are available on the efficacy of low‐dose rFVIIa in patients with inhibitors and they are not consistent across populations, inhibitor titers, and rFVIIa doses.4,5,7 Ex vivo thrombin generation (TG) assays were used in patients with FXI deficiency undergoing surgery upon rFVIIa infusion and showed that relatively low doses of rFVIIa can elicit TG similar to that achieved with higher doses.5 In preparation of the surgical procedure, we elected to evaluate the in vitro TG in platelet‐poor plasma for the patient and a healthy control according to Hemker et al8 with a homemade method as previously described9 and rotational thromboelastometry (ROTEM® Delta; Werfen).10,11 Whole blood samples were spiked with increasing doses of rFVIIa (0, 0.21, 0.43, 0.71, 1.0, and 1.29 μg/mL equivalent to 0, 15, 30, 50, 70, and 90 μg/kg in vivo, assuming a whole blood volume of 70 mL/kg). Aliquots of spiked whole blood were centrifuged 3000 g for 20 minutes (room temperature); plasmas were then collected for TG. TG was initiated by the addition of 1 PM tissue factor (Recombiplastin 2G; Werfen Orangeburg) and synthetic phospholipids (1 μmol/L) composed of DOPS, DOPE, and DOPC in the proportion of 20:20:60 (Avanti Polar Lipids) as triggers. TG was monitored by a specific fluorogenic substrate (417 μmol/L) (Bachem) and recorded and calculated with a fluorimeter