L8

Study Notes

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.