Factor IX p.A37V mutation causes severe bleeding in a patient with phenprocoumon therapy

Area of Science:

• Hematology
• Genetics
• Pharmacology

Background:

• Bleeding is a common complication of oral anticoagulant therapy.
• Inadequate dosing is often cited as the cause of anticoagulant-related bleeding.

Observation:

• A patient experienced severe bleeding while on phenprocoumon therapy, despite having an INR within the lower therapeutic range.
• Laboratory tests revealed a prolonged activated partial thromboplastin time (aPTT) and significantly reduced factor IX activity.
• Acquired hemophilia was ruled out due to the absence of detected inhibitors.

Findings:

• Genetic sequencing identified a hemizygous mutation in the factor IX gene (c.110C>T, p.Ala37Val) in the affected patient.
• This specific mutation affects the factor IX propeptide, substituting alanine at position 37 with valine.
• Missense mutations in the factor IX propeptide can lead to severe bleeding complications.

Implications:

• The Ala37Val and related Ala37Thr mutations in the factor IX gene confer hypersensitivity to vitamin K antagonists.
• These findings highlight the importance of considering genetic factors in patients experiencing unexpected bleeding during anticoagulant therapy.
• Understanding these genetic predispositions can inform personalized anticoagulation strategies and improve patient safety.