Familial Multiple Coagulation Factor Deficiencies: Follow-up Analyses

Background The familial multiple coagulation factor deficiencies (FMCFDs) is a group of rare disorders with reduced plasma activity of more than one coagulation factor. It may arise from coincidental inheritance of separate coagulation factor deficiencies or from a single defect affecting one gene or part of chromosome. The bleeding symptoms are with different severity, which creates difficulties in diagnosis and treatment. Genetic analyses of such patients improved the diagnostic accuracy and led to better decision making in treatment.

Materials and Methods A total of 86 index patients (Ps), with known deficiencies of more than one coagulation factor have been genetically investigated by direct sequencing and of affecting genes.

Results According to the underlying genetic mechanism, the patients were divided into three groups: Group I combined defects in two individual genes: 51 Ps were identified and combination either of 2 procoagulation factors (41 Ps) or 2 anticoagulation factors (2 Ps) or pro- and anticoagulation factors (8 Ps) were defined. Group II summarized only patients (16) with genetic variants in F7 and F10. Majority of Ps present with large deletion affecting the end of the chromosome 13. In the remaining 5 Ps, different genetic defects were characterized. Group III represents Ps with combined FVIII and FV deficiency (19 Ps). Mutations were identified in both LMAN1 and MCFD2 genes. Analyses of our data show that all coagulation factors occur in different combinations, where F7 and F8 were with the highest frequency. The most common combinations in Group I were F8–FG (4 Ps), F5–F7 (5 Ps), F7–F8 (3 Ps), and F8–VWF (3 Ps). The largest group of Ps was the one with combined F8 and F5 deficiency. In all Ps, genetic alterations were identified. Genetic variants with the highest prevalence were the missense mutations. With a second high prevalence were large deletions (16%). This finding was surprising having in mind that the normal prevalence of this genetic defect is 5%, but can be good which is explained with high number of Ps in Group II. All other genetic variants showed frequencies, comparable to that of the single-gene deficiencies.

Conclusion The FMCFDs are uncommon compared with the monogenic coagulation factor deficiency disorders. We presented the largest cohort of patients with FMCFDs. Identification and genetically diagnosing of such Ps will provide improved managements of the bleeding phenotype and better understanding of genotype–phenotype correlation.

Publication History

Article published online:
13 November 2020