The Development of a Novel Molecular Assay Examining the Role of Aminopeptidase P Polymorphisms in Acute Hypotensive Transfusion Reactions

Abstract

N Context.-Acute hypotensive transfusion reactions are potentially harmful adverse effects of transfusion attributable to bradykinin generation. They are most often seen in patients taking angiotensin-converting enzyme (ACE) inhibitors (ACE-Is) because of the role ACE plays in metabolizing bradykinin. However, a number of acute hypotensive transfusion reactions occur in patients not taking ACE-Is. Aminopeptidase P (APP), another important enzyme responsible for bradykinin degradation, is encoded by the polymorphic XPNPEP2 gene. Some polymorphisms in XPNPEP2 have been associated with decreased APP activity. However, the role that APP polymorphisms play in acute hypotensive transfusion reactions has never been investigated.Objective.-To develop a molecular assay to examine for the C-2399A single-nucleotide polymorphism (SNP) in the APP gene, XPNPEP2, in patients experiencing acute hypotensive transfusion reactions unassociated with ACEIs.Design.-We developed an assay using polymerase chain reaction and DNA sequencing with primers targeted at XPNPEP2 (59-GAGTATTATGTGGGGACCATCC-39 and 59-ATGCCTCGCAGAGACAAGAG-39). Polymorphism zygosity was determined by comparing the sense/antisense sequencing results. This assay was then applied to patients with acute hypotensive transfusion reactions not taking ACE-Is (n = 4).Results.-A C-2399A SNP assay was successfully developed and applied to patients with acute hypotensive transfusion reactions. In a pilot study, 2 patients (50%) were found to possess C-2399A polymorphisms. One was found to be homozygous, and the other was heterozygous.Conclusions.-Our C-2399A SNP assay can be used to study acute hypotensive transfusion reactions in patients not taking ACE-Is. Initial data indicate that the C-2399A polymorphism may be a contributing factor in such reactions. However, further studies are necessary to better define the role of APP polymorphisms in relation to acute hypotensive transfusion reactions unassociated with ACEIs.(Arch Pathol Lab Med. 2013;137:96-99; doi: 10.5858/ arpa.2011-0466-OA) A cute hypotensive transfusion reactions are relatively rare, but potentially serious adverse events in which a transfusion recipient manifests a marked decrease in blood pressure with a virtual absence of other signs and symptoms.1,2 Much of the pathophysiology of acute hypotensive transfusion reactions has been linked to bradykinins and their metabolites, mediators that can induce substantial vasodilation and smooth muscle relaxation in vivo, with a resultant decrease in blood pressure.3 Some studies have also shown that bradykinin accumulation and hypotensive episodes may be exacerbated in transfused patients taking angiotensin-converting enzyme (ACE) inhibitors (ACE-Is), because ACE is a key enzyme in the degradation of bradykinin.3-11 However, based on reports of acute hypotensive transfusion reactions occurring in the absence of ACE-I use, 5,12 it is possible that other pathways may contribute to the accumulation of bradykinin and/or their metabolites and result in hypotension in the se...

Hypotensive transfusion reactions in the era of prestorage leukoreduction

“…This increase in BK levels was thought to be most likely caused by reduced BK elimination due to exclusion of the lungs as the main site of BK metabolism and less likely related to increased production through contact system activation . Supporting the concept of abnormal BK metabolism as the cause of HyTRs during CABG, a recent study demonstrated that two of three patients not receiving ACEi who had undergone CABG and developed HyTRs were found to have a single‐nucleotide polymorphism of the APP gene, the C‐2399A, which results in decreased APP activity . Taken together with this study, these findings suggest that situations resulting in increased BK levels, such as altered metabolism for bypassing the lungs or the presence of a polymorphism that results in decreased enzyme activity, can predispose patients to develop an acute episode of hypotension after transfusion of a blood component.…”

“…8 Supporting the concept of abnormal BK metabolism as the cause of HyTRs during CABG, a recent study demonstrated that two of three patients not receiving ACEi who had undergone CABG and developed HyTRs were found to have a single-nucleotide polymorphism of the APP gene, the C-2399A, which results in decreased APP activity. 9 Taken together with this study, these findings suggest that situations resulting in increased BK levels, such as altered metabolism for bypassing the lungs or the presence of a polymorphism that results in decreased enzyme activity, can predispose patients to develop an acute episode of hypotension after transfusion of a blood component. However, the ultimate mechanism that precipitates a hypotensive episode upon transfusion of blood components is still unclear.…”

XPNPEP2 is overexpressed in cervical cancer and promotes cervical cancer metastasis

“…1,10,11 Most studies of XPNPEP2 focused on its effects in the cardiovascular system; for example, XPNPEP2 inactivates bradykinin, and a variant in XPNPEP2 was associated with ACE inhibitor-induced angioedema. 12 However, no studies have explored the relationship between XPNPEP2 and the occurrence and progression of cancer. Our data demonstrated for the first time that XPNPEP2 expression was significantly higher in CC tissue samples than in normal and CIN tissue samples.…”

Cardiovascular Instability Preceded by Orolingual Angioedema after Alteplase Treatment

“…It has recently been shown that the polymorphism of the APP gene is related to the occurrence of ACE inhibitor-associated angioedema (7,8). It should be noted that the same polymorphism has been also demonstrated to correlate with the occurrence of acute hypotensive transfusion reaction (9).…”