Sekhri Arunabh, Lisinschi Adriana, Furqan Muhammad, Palaniswamy Chandrasekar, Mukhi Nikhil, Gupta Ridhi, Nelson John C
Department of Medicine, Westchester Medical Center, New York Medical College, Valhalla, NY.
Am J Ther. 2016 May-Jun;23(3):e911-5. doi: 10.1097/MJT.0000000000000077.
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.
维生素K依赖性凝血因子（II、VII、IX和X）谷氨酸残基的羧化作用对其生物学功能至关重要。这些因子与γ-谷氨酰羧化酶结合进行羧化反应是由野生型前肽介导的，前肽是实际多肽之前的一小段氨基酸序列。某些残基处的错义突变会严重降低突变前肽与酶的亲和力。据报道，这种突变发生在因子IX前肽的第10密码子处，在正常情况下这是一种临床无症状的代谢事件。然而，在华法林存在的情况下，此类突变以及由此导致的因子IX前肽与酶的亲和力下降会导致因子IX活性严重选择性降低。这可能会引发危及生命的出血并发症，并且是华法林超敏反应的原因之一。必须尽早识别此类病例，以避免额外的华法林治疗。反复出血发作、国际标准化比值处于亚治疗至治疗范围且部分凝血活酶时间相对延长，应引起对潜在因子IX前肽突变的怀疑。
