Barbara Preisler1, Behnaz Pezeshkpoor1, Atanas Banchev2, Ronald Fischer3, Barbara Zieger4, Ute Scholz5, Heiko Rühl1, Bettina Kemkes-Matthes6, Ursula Schmitt7, Antje Redlich8, Sule Unal9, Hans-Jürgen Laws10, Martin Olivieri11, Johannes Oldenburg1, Anna Pavlova1. 1. Institute of Experimental Hematology and Transfusion Medicine, University Clinic Bonn, 53127 Bonn, Germany. 2. Department of Paediatric Haematology and Oncology, University Hospital "Tzaritza Giovanna-ISUL", 1527 Sofia, Bulgaria. 3. Hemophilia Care Center, SRH Kurpfalzkrankenhaus Heidelberg, 69123 Heidelberg, Germany. 4. Department of Pediatrics and Adolescent Medicine, University Medical Center-University of Freiburg, 79106 Freiburg, Germany. 5. Center of Hemostasis, MVZ Labor Leipzig, 04289 Leipzig, Germany. 6. Hemostasis Center, Justus Liebig University Giessen, 35392 Giessen, Germany. 7. Center of Hemostasis Berlin, 10789 Berlin-Schöneberg, Germany. 8. Pediatric Oncology Department, Otto von Guericke University Children's Hospital Magdeburg, 39120 Magdeburg, Germany. 9. Division of Pediatric Hematology Ankara, Hacettepe University, 06100 Ankara, Turkey. 10. Department of Pediatric Oncology, Hematology and Clinical Immunology, University of Duesseldorf, 40225 Duesseldorf, Germany. 11. Pediatric Hemostasis and Thrombosis Unit, Department of Pediatrics, Pediatric Hemophilia Centre, Dr. von Hauner Children's Hospital, University Hospital, LMU Munich, 80337 Munich, Germany.
Abstract
BACKGROUND: Familial multiple coagulation factor deficiencies (FMCFDs) are a group of inherited hemostatic disorders with the simultaneous reduction of plasma activity of at least two coagulation factors. As consequence, the type and severity of symptoms and the management of bleeding/thrombotic episodes vary among patients. The aim of this study was to identify the underlying genetic defect in patients with FMCFDs. METHODS: Activity levels were collected from the largest cohort of laboratory-diagnosed FMCFD patients described so far. Genetic analysis was performed using next-generation sequencing. RESULTS: In total, 52 FMCFDs resulted from coincidental co-inheritance of single-factor deficiencies. All coagulation factors (except factor XII (FXII)) were involved in different combinations. Factor VII (FVII) deficiency showed the highest prevalence. The second group summarized 21 patients with FMCFDs due to a single-gene defect resulting in combined FV/FVIII deficiency or vitamin K-dependent coagulation factor deficiency. In the third group, nine patients with a combined deficiency of FVII and FX caused by the partial deletion of chromosome 13 were identified. The majority of patients exhibited bleeding symptoms while thrombotic events were uncommon. CONCLUSIONS: FMCFDs are heritable abnormalities of hemostasis with a very low population frequency rendering them orphan diseases. A combination of comprehensive screening of residual activities and molecular genetic analysis could avoid under- and misdiagnosis.
BACKGROUND:Familial multiple coagulation factor deficiencies (FMCFDs) are a group ofinherited hemostatic disorders with the simultaneous reduction of plasma activity of at least two coagulation factors. As consequence, the type and severity of symptoms and the management ofbleeding/thrombotic episodes vary among patients. The aim of this study was to identify the underlying genetic defect in patients with FMCFDs. METHODS: Activity levels were collected from the largest cohort of laboratory-diagnosed FMCFD patients described so far. Genetic analysis was performed using next-generation sequencing. RESULTS: In total, 52 FMCFDs resulted from coincidental co-inheritance of single-factor deficiencies. All coagulation factors (except factor XII (FXII)) were involved in different combinations. Factor VII (FVII) deficiency showed the highest prevalence. The second group summarized 21 patients with FMCFDs due to a single-gene defect resulting in combined FV/FVIII deficiency or vitamin K-dependent coagulation factor deficiency. In the third group, nine patients with a combined deficiency of FVII and FX caused by the partial deletion of chromosome 13 were identified. The majority ofpatients exhibited bleeding symptoms while thrombotic events were uncommon. CONCLUSIONS: FMCFDs are heritable abnormalities of hemostasis with a very low population frequency rendering them orphan diseases. A combination of comprehensive screening of residual activities and molecular genetic analysis could avoid under- and misdiagnosis.
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