Familial Multiple Coagulation Factor Deficiencies (FMCFDs) in a Large Cohort of Patients—A Single-Center Experience in Genetic Diagnosis

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.

Hemostatic protocol and risk-reduction surgery for treating coronary artery disease with aortic stenosis in a patient with combined coagulation factor VIII and XI deficiency: a case report

“…Combined FVIII and FXI deficiency is an extremely rare disorder and is called the first group of Familial Multiple Coagulation Factor Deficiencies, which was only reported in 10 male and one female patient and were not related to a surgery. 8 , 9 Although the bleeding tendency of FXI deficiency is generally mild, severe intractable bleeding may be provoked by the combined effect of FVIII deficiency perioperatively. The present coagulation management for off-pump CABG based on the protocol achieved perioperative target levels of the FVIII:C and FXI:C values.…”

Insights into the Molecular Genetic of Hemophilia A and Hemophilia B: The Relevance of Genetic Testing in Routine Clinical Practice

“…67 Other coagulation abnormalities, related to natural anticoagulants (deficiencies of antithrombin, protein C, protein S), platelet disorders, and fibrinolytic factors, have been assumed to modulate the bleeding phenotype. 68 69 70 71 With the application of NGS in routine diagnostic, identification of such coincidental inheritance is rather straightforward due to the use of multiple gene panels. Such findings need to be interpreted carefully and might provide more evidence to elucidate this phenomenon.…”

Experiences in Routine Genetic Analysis of Hereditary Hemorrhagic, Thrombotic, and Platelet Disorders

“…In our recent study, we describe a pedigree with type 3 VWD in which a member with an additional genetic variant in SERPINC1 gene bleeds much less compared with members without that variant. 40 However, extensive pedigrees or a very large number of unrelated patients are necessary to identify which affected alleles are inherited together and may serve as genetic modifiers. If the phenotype relies mainly on a laboratory phenotype, it is recommended to confirm this phenotype by a separate second analysis.…”