Abstract
Factor XIII (FXIII) deficiency is an extremely rare autosomal recessive bleeding disorder with a reported prevalence of 1 in 5 million people worldwide. The adult hemophilia clinic in St. John’s, NL, Canada manages 5 patients with severe FXIII deficiency and 1 heterozygote. 3 of the 5 severe FXIII patients are siblings. Another sister died of intracranial hemorrhage after trauma. These 3 FXIII patients were also found to have a FXII deficiency, and were described in 1970 in Pediatrics by Mary Hanna shortly after their diagnosis. All 5 of the patients in our cohort report a very strongly positive bleeding history prior to beginning prophylaxis with Fibrogammin P at a dose of 10 U/kg every 3-4 weeks. One heterozygote patient has so far had minimal bleeding. Here we report the bleeding scores of the 5 severely deficient patients prior to and after beginning prophylaxis with Fibrogammin P in 1996. A recombinant FXIII A-subunit concentrate was licensed in Canada in 2012. Therefore treating clinicians now have a choice of therapy for their patients. This product recommends prophylaxis at a dose of 35 U/kg. This product is considerably more expensive than the plasma-derived product currently used. Fibrogammin P is not currently licensed in Canada.
Bleeding scores are an important tool to quantify the bleeding history of a patient. The bleeding score that was used to score this FXIII cohort is the MCMDM–1VWD. A study by Bowman et al. calculated the bleeding scores of 100 healthy subjects (35 males, 65 females. These subjects were found to have a mean bleeding score of 0.16 with a standard deviation of 1.7. A bleeding score of equal to or greater than 4 is considered abnormal.
The bleeding scores of our cohort ranged from 19 to 29 with a mean score of 23.7 prior to starting prophylaxis with Fibrogammin P. Four out of five patients reported significant umbilical cord bleeding, 1 or more episode of intracranial hemorrhage, hemarthrosis, or at least 1 major bleed post surgery prior to starting prophylaxis on Fibrogammi P. After starting Fibrogammin P, patients report very little bleeding, and score in the normal range for the period they have been on prophylaxis. These patients were exposed to hepatitis B and C, but not HIV through prior exposure to blood products. There were no further seroconversions since starting therapy with Fibrogammin P. Three of these patients underwent 7 surgeries, receiving either 10-20 U/kg of Fibrogammin either 1 or 2 days prior to surgery and 10 U/kg for 5 days post-surgery. Patients and physicians reported very satisfactory outcomes. Only one patient had a breakthrough bleed on prophylaxis. He required a transfusion of packed cells and an extra treatment of Fibrogammin P for significant rectal bleeding due to internal hemorrhoids. In this very small group of patients no clinically significant inhibitor to FXIII has been documented.
Some studies reported in the literature suggest that it is important to keep FXIII levels above 10% to prevent spontaneous hemorrhage. Although our patients are doing well, we know their trough FXIII levels run from 0.2 to 0.5%. Choosing the optimal dose and optimal therapy for these patients is now more nuanced. As patients have had good outcomes to date on low dose Fibrogammin prophylaxis, switching to either high dose prophylaxis with Fibrogammin or recombinant FXIII to keep trough FXIII levels above 10% will result in approximately a 4 or 38.5-fold increase in cost respectively for prophylaxis alone. These estimations do not include any extra therapy required. On the other hand it is essential to make every effort to prevent intracranial hemorrhage.
No relevant conflicts of interest to declare.
Author notes
Asterisk with author names denotes non-ASH members.
