L8

Inherited Coagulation Disorders and Pharmacogenetics

• Phenotypic tests can measure F8 activity, PTT, and PT/INR, and approximately 30% of "carrier" females may exhibit disordered coagulation tests or mild clinical bleeding due to skewed X inactivation.
• Females may rarely have severe hemophilia due to skewed X-chromosome inactivation or a disorder of X-chromosome inactivation, with one functional F8 allele in most women resulting in 50% activity.
• Factor IX Leyden is a rare subtype of Hemophilia B, and androgen therapy or puberty can increase F IX activity.
• A case presentation of a 23-year-old suffering from a labrum tear revealed Von Willebrand disease, characterized by VWF and FVIII circulating as a noncovalent complex that regulates platelet aggregation and clot formation.
• Von Willebrand Disease (VWD) is the most frequent congenital clotting disorder with a 1% prevalence, characterized by a broad clinical phenotype spectrum and treatment options such as Desmopressin or "factor."
• Thromboembolism involves the formation of thrombus in deep veins, and Factor V Leiden, with a 1601G>A transition in exon 10 of the F5 gene, is associated with a 6-7 fold increase in relative risk of venous thromboembolism in heterozygotes.
• Warfarin is a vitamin K antagonist used to manage patients at risk of thromboembolic disease, and its dose should be adjusted to maintain within the therapeutic window, monitored by coagulation tests (PT/INR).
• The PT/INR measures the time taken for blood to clot, with a lower than normal PT/INR indicating too much clotting factor, necessitating warfarin administration.
• A patient with a CYP2C9*2 allele inhibiting warfarin metabolism is likely to need more warfarin than usual due to the drug accumulating in the blood, leading to a higher anticoagulation effect and risk of bleeding.
• Factor V Leiden is a common inherited tendency to develop venous thrombosis, while VWD is a prevalent, usually mild, heritable bleeding disorder associated with heterogeneous defects of VWF and inheritance patterns.
• Pharmacogenetics aims to target drug therapy based on individual genetic profiles to maximize benefits and limit adverse effects.
• The optimal dose of warfarin is related to genotype, specifically CYP2C9 alleles, emphasizing the importance of pharmacogenetics in drug therapy.