Congenital Factor XIII Deficiency With the Presence of Inhibitor: A Case Study Serap Karaman,* Emre Akkaya, MD,† Sema Genc,† Fuat Bilgili,‡ Alper S. Kendirci, MD,‡ Deniz Tugcu,* Aysegul Unuvar,* Zeynep Karakas,* Demet Demirkol,§ Zuhal Bayramoglu, MD,∥ and Beyhan Omer† Summary: Coagulation factor XIII (FXIII) is a fibrin-stabilizing factor with additional roles in wound healing and interactions between the decidua and fetus. Congenital FXIII deficiency is rare bleeding disorder. Inhibitor development against FXIII in inherited FXIII deficency is also uncommon, but may cause severe, life- threatening bleeding. FXIII is the last step in the coagulation cas- cade with normal coagulation paramaters (PT, aPTT), the detection of inhibitor to FXIII is quite difficult. The treatment of inhibitor- positive congenital FXIII deficiency is challenging due to the lack of a role of by-pass agents such as FVII. The best known ways of treatment in these cases are the use of high-dose FXIII concentrates and immunosuppression. Herein, we report the management of postoperative bleeding diathesis in a patient with FXIII deficiency who developed inhibitors, and to follow the clinical course of the disease with FXIII concentrate and immunosuppression. Key Words: congenital FXIII deficiency, laboratory diagnosis, inhibitor treatment (J Pediatr Hematol Oncol 2019;00:000–000) F actor XIII (FXIII) is crucial in the formation of cross- linked fibrin clots and is the last enzyme in the clotting cascade. It is a protransglutaminase that consists of 2 A sub- units and 2 B subunits. 1 The A subunit includes a catalytic site, and the B subunit functions as a carrier protein, which facili- tates the cross-linking of fibrin monomers by leading to the formation of the complex between the proenzyme form of FXIII, fibrinogen, and activator thrombin. 2 FXIII-A is also produced by monocytes, macrophages, megakaryocyte/plate- lets, chondrocytes, and osteoblast/osteocyte lineages. 3,4 FXIII deficiency causes a rare type of bleeding dis- order, and can be congenital or acquired. Congenital FXIII deficiency is mostly due to a mutation of genes encoding A and B subunits. 5 Patients with FXIII-A deficiency have life-long bleeding diathesis, and the severity and the frequency of bleeds are directly related with residual FXIII activity. 6,7 However, severe FXIII-B deficiency is a less common form, and FXIII-A antigen concentrations are also low in these patients and the bleeding type complies with mild-to-moderate FXIII deficiency. 2,8 The classification of the severity of bleeding is as follows: grade 1 bleeding occurs after trauma or antiplatelet or anticoagulant therapy, grade 2 represents minor bleeds, and grade 3 occurs with sponta- neous major bleeds with undetectable plasma FXIII level. 9 Nevertheless, the acquired form of FXIII deficiency occurs due to inhibition of FXIII activation/activity or acceleration of the elimination of FXIII from the circulation because of the autoimmune or neoplastic diseases such as leukemias, severe liver disease, inflammatory bowel disease, and sys- temic lupus erythematosus. 10–12 FXIII also has some other roles in wound healing, bone extracellular matrix stabiliza- tion, and the interaction between the embryo and decidua of the uterus. 13,14 In this study, we aimed to present the management of postoperative bleeding diathesis in a patient with FXIII deficiency who developed inhibitors, and to follow the clinical course of the disease with FXIII concentrate and immunosuppressive therapy. CASE PRESENTATION An 8-year-old boy with FXIII deficiency was admitted to the orthopedics clinic with severe pain and progressive decrease in the range of motions of bilateral hip joints due to bilateral dysplasia. Bilateral osteotomy was planned. During follow-up for cerebral palsy, epilepsy, and hydrocephaly with VP-shunt, he was first referred to the hema- tology clinic at the age of 3 years for the investigation of coagulopathy due to a history of subdural and intracranial bleeding on the fifth postnatal day. The patient was diagnosed as having congenital FXIII deficency. The FXIII level was measured using an FXIII chromogenic assay from Siemens and was reported as 9%. During the patient’s follow-up, he underwent some minor interventions and procedures such as circumcision, orcihopexy, and small interventions for muscle spasity. FXIII concentrate plasma-derived was administered before each oper- ation and only tranexamic acid and local fibrin-sealant were used for these interventions with no significant bleeding. However, the frequency of gingival bleeding, epistaxis, and infections had increased in last 6 months. The day before surgery, a FXIII concentrate 500 U (20 U/kg) with tranexamic acid (10 mg/kg, dose x3/d) was administered. On the day of surgery, a 500 U FXIII infusion was administered again, and the surgery was completed without any complications. Before surgery, the patient’s hemoglobin (Hb) concentration (13.4 g/dL), hematocrit (Htc) (40.2%), white blood cells (WBC) (7.7×103), prothrombin time (PT) (11.37 s), and activated partial thromboplastin time (aPTT) (21.9 s) were in normal ranges. FXIII activity was 15.5% (70 to 140), the inhibitor level against FXIII was negative, and C-reactive protein concentration was 1.76 mg/L (0 to 5). After surgery, the Hb and Htc values decreased rapidly to 7.7 g/dL and 22.4%, respectively, and the platelet count was 134,000/ μL. Bleeding from operation lodge and incision sites was detected (Fig. 1). There were no major vascular leakages observed in imaging. The bleeding was persistent, so FXIII concentrate was administered at 1250 U for the first day, and 500 U in the following 5 days, and for vascular stabilization, corticosteroid therapy (2 mg/kg/d) was started. After the infusion of the concentrate, the factor level was found as 10%, the PT and aPTT concentrations were still within reference Received for publication June 13, 2019; accepted October 22, 2019. From the Departments of *Pediatric Hematology-Oncology; †Biochemistry; ‡Orthopedics and Traumatology; §Child Intensive Care Unit; and ∥Pediatric Radiology, Faculty of Medicine, Istanbul University, Istanbul, Turkey. The authors declare no conflict of interest. Reprints: Sema Genc, Department of Biochemistry, Istanbul Faculty of Medicine, Capa, Istanbul 34390, Turkey (e-mail: nsgenc@hotmail. com). Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved. CLINICAL AND LABORATORY OBSERVATIONS J Pediatr Hematol Oncol  Volume 00, Number 00, ’’ 2019 www.jpho-online.com | 1 Copyright r 2019 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.