NYMC Faculty Publications

The Conundrum of "Warfarin Hypersensitivity": Prolonged Partial Thromboplastin Time From Factor IX Propeptide Mutation

Author Type(s)

Faculty

DOI

10.1097/MJT.0000000000000077

Journal Title

American Journal of Therapeutics

First Page

911

Last Page

915

Document Type

Article

Publication Date

1-1-2016

Department

Medicine

Keywords

Anticoagulants, Drug Hypersensitivity, Factor IX, Hemorrhage, Humans, International Normalized Ratio, Male, Middle Aged, Mutation, Missense, Partial Thromboplastin Time, Polymorphism, Single Nucleotide, Protein Precursors, Warfarin

Disciplines

Medicine and Health Sciences

Abstract

Carboxylation of glutamic acid residues of vitamin K dependent clotting factors (II, VII, IX, and X) is essential to their biological functioning. Binding of these factors to γ-glutamyl carboxylase enzyme for carboxylation reaction is mediated by wild-type propeptide, a small sequence of amino acids that precede the actual polypeptide. Missense mutations at certain residue severely decrease the affinity of mutated propeptide for the enzyme. Such mutations are reported to occur at codon-10 of factor IX propeptide, a clinically silent metabolic event in normal conditions. However in the presence of warfarin, such mutations and resultant decrease affinity of factor IX propeptide for the enzyme that causes severe selective decrease in factor IX activity. This can potentially leads to life-threatening bleeding complications and known as one of the causes of warfarin hypersensitivity. It is imperative to recognize such cases early on to avoid additional warfarin therapy. Recurrent bleeding episodes, subtherapeutic to therapeutic range international normalized ratio values with relatively prolong partial thromboplastin time should raise the suspicion of underlying factor IX propeptide mutations.

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