This Is a Title : Long Term succsesfull Prophylaxis in 190 Patients with Severe Congenital Factor XIII Deficiency, a Four Years Experience. Here Is the Sub-Title: Succsefull Prophylaxis in Factor XIII Deficiency
Authors: Naderi Majid , Dorgalaleh Akbar , Tabibian Shadi , Alizadeh Shaban , Sadat Hosseini Maryam , Karimi Mehran , Hosseini Soudabeh 
Published: November 2019

Abstract

Background:
factor XIII deficiency (FXIIID) is an extremely rare bleeding disorder with an estimated incidence of 1 per 1 to 3 million that transmitted in an autosomal recessive manner. The disorder is characterized by severe bleeding diathesis, impaired wound healing and recurrent spontaneous miscarriage. Sistan and Baluchistan Province in south east of Iran with high rate of consanguineous marriages has the highest incidence of FXIIID around the world. The aim of this study was to evaluate clinical manifestations and prophylaxis therapy in FXIII deficient patients with life threatening complications and to assess the risk of FXIII inhibitor development in patients with long term prophylaxis. We also investigated prophylaxis treatment in neonates with FXIIID.
Methods:
This study was conducted on 190 patients with FXIIID from southeast of Iran. Diagnosis of FXIIID was based on factor activity and molecular investigation of Trp187Arg which is the only reported mutation of FXIII in this region. We also selected some cases for sequencing to confirm the molecular results.Patients underwent regular prophylaxis and the efficacy of prophylaxis was assessed by prospective follow-up in duration of 4 years. The frequency of bleeding episodes as described by Tosetto et al. was recorded before and after prophylaxis each month. Patients with Intracranial hemorrhage (ICH) received Fibrogammin P® in a dose of 30 IU/Kg every 4 day as prophylaxis and in a dose of 10-26 IU/kg when ICH occurred. Patients with miscarriage underwent regular prophylaxis with FXIII concentrate with a dose of 10 IU/Kg every 2 weeks during pregnancy and also received the same dose as prophylaxis before gestation in 4 week intervals.In cases that had a history of prophylaxis for more than 4 years or had more than 50 injections, development of FXIII inhibitor was investigated by Bethesda assay. We evaluated plasma FXIII activity and FXIII inhibitor in day 28 after the last prophylaxis administration by Cobas Mira device. This assay was performed on a large amount of population for the first time. If the result of inhibitor was negative the test was replicated with 3 dilutions.We also enrolled 34 neonates with FXIIID to the study and divided them into two groups. Group 1 (17 neonates) received a standard dose of Fibrogammin (10-26 IU/Kg) while group 2 (17 neonates) received a dose of 60-80 IU/Kg. We followed both groups for 36 months and the frequency of bleeding episodes was recorded for each group and compared using independent t-test. Neonates in group 2 were assessed for thrombotic events promptly after administration of Fibrogammin P®, the following day and one week later.
Results:
Plasma FXIII activity in all patients was undetectable which is suggestive of severe deficiency. Genetic analysis revealed a homozygous Trp187Arg mutation in all patients and it was in agreement with the sequencing results of selected cases. Clinical manifestation of patients and the bleeding score of different diathesis before and after prophylaxis are indicated in table 1. Forty nine patients had the defined criteria for investigation of FXIII inhibitor development. Among them 14 had experienced ICH. Despite long term prophylaxis in these patients none of them was detected to develop FXIII inhibitors.
No patient with ICH experienced this phenomenon after prophylaxis treatment.
The majority of patients with miscarriage only experienced this diathesis once (62.5%). The prophylaxis program was successful in management of pregnancy in all 8 patients.
Comparison of two neonate groups revealed that bleeding episodes in group 2 were significantly lower than group 1 (p<0.05). We did not observe any thrombotic event in group 2, which is an important finding in safety of Fibrogammin P® also in prevention of potential loss of drug.
Conclusion:
Fibrogammin P® is effective in the management of FXIIID and surprisingly long term prophylaxis in the patients did not lead to development of FXIII inhibitor. Furthermore higher dose of Fibrogammin P® is safe and effective in neonates.
Table 1. Clinical manifestations and Tosetto bleeding scores of different bleeding diathesis before and after prophylaxis. Number of affected patients (%) Score before prophylaxis Score after prophylaxis Umbilical bleeding 157(82.5) 12 3 Hematoma 101 (53) 12 2 ICH 32(17%) 14 3 Epistaxis 26(14%) 11 2 Ecchymosis 25 (12.5%) 12 2 Hemarthrosis 7 (4%) 13 2 Miscarriage 8 (5%) - -

Disclosures
No relevant conflicts of interest to declare.