Factor XIII Deficiency in Patients with Acute Leukemia: One out of Three Is Presenting with Deficiency

Introduction: Factor XIII (FXIII) is a coagulation factor, playing an important role in the coagulation process by keeping the hemostatic clot and allowing tissue repair. The incidence of FXIII deficiency in acute leukemia is not well characterized. FXIII deficiency is known to have a high bleeding risk and cannot be detected by lab evaluation of aPTT and/or INR levels. In combination with thrombocytopenia in patients (pts) presenting with acute leukemia, FXIII deficiency increases bleeding risk (for example in invasive procedures or for intracranial hemorrhage). In 2013 a study was conducted in 9 pediatric pts (6 acute leukemias, 1 burkitt, and 2 solid tumors) in whom FXIII deficiency was found. These pts had bleeding complications that were resolved by FXIII concentrate substitution (Wiegering. V. et al. Haematologica, June, 10, 2013).Patients affected from AML and ALL could easily be screened at diagnosis regarding FXIII level. In the setting of newly diagnosed acute leukemia pts in whom thrombocytopenia is frequently occurring, a preemptive substitution of FXIII could be considered in order to reduce the risk of bleeding complications.

Methods: In this retrospective analysis (Jan. 2009 to June 2014) we identified a total of 103 ptspresentingwithnewly diagnosed acute leukemia in whom we assessed FXIII level. In 95 pts FXIII level was available at initial diagnosis of acute leukemia and during treatment. Substitution of FXIII concentrate have been used in case of factor’s deficiency below 70% (normal range 70%-130%).

Results: Patients presented withAML (64 primary AML and 20 secondary AML), or ALL (10), or 1 AUL. Median age was 67 years (range: 25-95). Thirty-four pts (35.8%) were younger than 60 years, 61 pts (64.2 %) were older than 60 years.

FXIII deficiency was found in 35/95 pts (36.8%) with a median level of 49% (range: 21%-68%). Of those 35 pts with FXIII deficiency 33 had AML (1 AML M0, 9 AML M1, 2 AML M1/2, 5 AML M2, 6 AML M4, 5 AML M5). All pts (5/95) with AML M3 showed a deficiency with a median level of 28%. A level below 70% could be found in 7 out of 13 FLT3-ITD positive pts (53.8%) and in 7 out of 24 NPM1 positive pts (29.2 %). Median FXIII level was 34% for FLT3-ITD positive pts, respectively 30% for NPM1. FXIII substitution in deficient pts was well tolerated and effective. No patient showed intracranial hemorrhage. In addition, invasive procedures like bone marrow biopsy and central line insertion were possible without clinically relevant bleeding complications. In responding pts achieving remission following chemotherapy, a trend towards higher concentration of factor XIII during treatment was observed.

Conclusions: Patients affected by AML or ALL are presenting usually with thrombocytopenia and have a high bleeding risk. In case of FXIII deficiency, risk of bleeding is increased potentially leading to a higher leukemia-related morbidity and mortality. Detection of FXIII deficiency is an established method and routinely available. Substitution of FXIII decreases the risk of bleeding and can reduce leukemia associated morbidity and mortality. In our study FXIII deficiency occurred in more than a third of our pts, including all AML M3 patients. We found a trend for more FXIII deficiency in FLT3-ITD high risk group patients. We suggest screening at diagnosis and during treatment of all acute leukemia pts and FXIII substitution in case of deficiency. To evaluate further the role of FXIII assessment and substitution in case of FXIII deficiency in acute leukemia, a prospective trial should be considered.