Molecular Aspects of Rare Coagulation Factor Deficiencies

Rare coagulation factor deficiencies are inherited disorders affecting factors I, II, V, VII, X, XI, XIII, and combined forms. They mainly present with bleeding symptoms of variable severity. These deficiencies show significant clinical heterogeneity, with no consistent correlation between factor levels and bleeding intensity. Prevalence is higher in populations with high consanguinity rates. Understanding relies on the study of genetic and molecular mechanisms. Diagnosis is based on hemostasis testing, including prothrombin time (PT), activated partial thromboplastin time (aPTT), and factor activity assays. In case of abnormalities, Molecular analysis is undertaken using genomic DNA extracted from peripheral blood samples. Depending on the clinical context and the level of detail required, sequencing is performed using either Sanger sequencing or next-generation sequencing (NGS) platforms, enabling the identification of pathogenic variants responsible for the coagulation disorder. Variant interpretation follows American College of Medical Genetics and Genomics (ACMG)/Association for Molecular Pathology (AMP) guidelines. Large deletions or duplications are assessed via Multiplex Ligation-dependent Probe Amplification (MLPA) or Copy number variations (CNV) analysis. Molecular analysis revealed a wide range of mutations depending on the deficient factor. Missense mutations are the most common, followed by nonsense, splicing, and insertion/deletion mutations. Some mutations prevent factor production, while others alter its structure or secretion. Each mutation type has a distinct impact on the bleeding phenotype. Genetic characterization improves diagnostic accuracy and guides clinical management. Modern molecular tools have enhanced the understanding of these disorders' pathophysiology. A multidisciplinary approach is essential for optimal patient care. Ongoing research is key to developing targeted therapies.