Acquired Factor XIII Deficiency Is Associated with High Morbidity and Mortality in Critically Ill Patients

Introduction: Factor XIII (FXIII) plays a major role in clot stabilization and FXIII deficiency results in inadequate cross-linking of soluble fibrin into a stable clot. Thus, acquired FXIII deficiency could be the underlying cause of hemorrhage in a critical care clinical setting. In a previous study, we identified a cutoff of FXIII activity of 36,5% to distinguish patients with high risk of major bleeding.

Objective: To assess clinical data and transfusion requirements in a mixed medical and surgical population with acquired FXIII deficiency and confirm if 36,5% activity is the best cut-off point for FXIII activity to distinguish between low and high risk of major bleeding.

Methods: In this retrospective, non-interventional study, we screened all patients with acquired FXIII deficiency admitted to Gregorio Marañon Hospital in Madrid, Spain, between January 2020 and March 2022. FXIII activity at our hospital is routinely measured in patients who experience bleeding despite a normal conventional coagulation test. A level of <70% is considered to indicate FXIII deficiency. All patients with FXIII levels lower than 70% were included in the study. Clinical, analytical and transfusion data were retrospectively collected.

FXIII activity was measured in human citrated plasma by quantitative functional detection using an automated latex enhanced immunoassay, HemosIL Factor XIII Antigen (Instrumental laboratory, Bedford, MA, USA) on the ACL Top 500 analyzer. The study protocol was designed and applied in accordance with the principles of the Declaration of Helsinki and informed consent was obtained from participants. Statistical analysis was performed using IBM SPSS Statistics v28.0.

Results: Seventy-one patients were diagnosed with acquired FXIII deficiency, of which 5 outpatient diagnosis were excluded from the analysis. Characteristics at baseline and at the time of FXIII deficiency diagnosis are shown in Table 1. Of note, this group of patients had a remarkable comorbidity burden (80.3%) and a high admission rate to Intensive Care Unit (ICU) (86.3%).

The mean time from admission to FXIII deficiency diagnosis was 21 days, with a median time of 13 days (8-25). Mean FXIII functional activity was 44.4 % (median 43.3%), with 21 patients showing an activity lower than 36.5%. We found no significant difference in FXIII activity between medical and surgical patients. At the time of diagnosis, mean hemoglobin level had fallen from 11 g/dL at admission to 8.7 g/dL at diagnosis, and no change in coagulation tests was acknowledged. Functional activity determination of factors II, V, VII, VIII, IX, X, XI and XII did not show other related factor deficiencies. Change in clinical severity, as measured by SOFA scale, was neither found. However, a significantly lower level of FXIII activity was found in patients with vasopressor requirements at the time of diagnosis (46% vs 38%, p<0.05) and those who presented multiorgan disfunction syndrome (MODS) at any time during hospitalization (51% vs 42%, p<0.05).

No statistically significant difference was found in transfusion requirements when a cut-off of 36.5% in FXIII activity was used, except for fresh frozen plasma requirements (85% vs 58%, p<0.05). Nevertheless, a tendency towards significance was noticed in need for bleeding control, development of MODS and global mortality. Indeed, patients with FXIII activity less than 36.5% experienced less survival time during the first 2 years after hospital admission (p=0.004) (Fig.1).

Conclusions: Factor XIII deficiency should be investigated in patients with hemorrhage despite normal hemostasis tests. Actually, as we demonstrated, it appears in complex clinical settings, being associated with comorbidities and high rates of ICU admission, and has relevant clinical implications, as patients with lower FXIII functional activity show shorter survival. Consequently, more research is needed to assess the best approach and management of this patients.

No relevant conflicts of interest to declare.