Minimal Factor XIII activity level to prevent major spontaneous bleeds
Factor XIII deficiency is a rare but serious bleeding disorder. This study aimed to validate a bleeding severity classification, and to identify the minimal FXIII level at which patients remain asymptomatic, in order to guide factor prophylaxis.
This was an international multi-center cross-sectional study. 64 patients from 12 countries were identified as part of the European Prospective Rare Bleeding Disorders Database (PRO-RBDD). A previous retrospective study had suggested the following bleeding severity classification: severe (undetectable FXIII), moderate (0-29 U/dl), and mild (>30 U/dl). The patients were analyzed according to this classification in order to validate it. FXIII levels were tested using the ammonia release assay and centralized testing was attempted. Bleeding severity was classified as follows: Grade 1 (asymptomatic), Grade 2 (spontaneous minor - mucocutaneous), Grade 3 (spontaneous major - umbilical, GI, CNS, hemarthrosis, hematoma).
FXIII level correlated with bleeding severity, with 90% of patients with severe FXIII deficiency exhibiting Gr.3 bleeding, as compared to 46% of moderate, and 0% of mild patients. Conversely, 43% of mild patients were asymptomatic. Unsurprisingly, patients with severe FXIII deficiency presented at a younger age (median 0 years) and were most likely to be symptomatic. All patients suffering from Gr.3 bleeding had a FXIII level under 16 U/dl. Thus using a cut-off of 15 U/dl was predicted to have a sensitivity of 97% and specificity of 76% in discriminating between patients at risk of having Gr.3 bleeds.
Limitations include a study population that is skewed towards symptomatic patients as the majority of patients were identified by presenting to the hospital with bleeding. In addition, less than half of the samples were sent to the central laboratory to confirm FXIII level, though there was high concordance in the samples that were sent. Strengths include a relatively large sample size for a rare disorder, and a heterogeneous group of patients from multiple countries. Moreover, as the population will be studied prospectively there is an opportunity to test the validity of the cut-off of 15 U/dl as a trough level for prophylaxis.