Lipoprotein-associated phospholipase A2: review and recommendation of a clinical cut point for adults.

Recently, several epidemiologic studies have demonstrated an association between plasma lipoprotein-associated phospholipase A2 (Lp-PLA2) concentration and risk of subsequent cardiovascular events. Several major commercial and reference laboratories across the United States are now offering Lp-PLA2 testing for clinical use to evaluate cardiovascular risk and as a guide to intensity of therapy in individuals at intermediate risk for developing coronary heart disease. Each laboratory has established its own cut points, or "decision values," for Lp-PLA2, which vary from the 50th to the 95th percentile values of individual populations tested at each site. Uniform reporting of cut points has not been achieved. The purpose of this manuscript is to recommend appropriate decision values for Lp-PLA2, endorsed by a consensus panel of laboratorians and clinicians from the major laboratories where the test is performed. These coauthors possess considerable experience with assessment of cardiovascular risk marker decision values in general and are familiar with the validation of the Lp-PLA2 immunoassay and the Lp-PLA2 clinical studies conducted thus far. An ideal risk marker, studied in an ideal population, might yield a consistent cut point associated with a sudden increase in cardiovascular risk. While acknowledging that additional studies will be required to test and refine the recommended decision value, this article reviews the most current information with which to provide guidance to practicing clinicians regarding Lp-PLA2 levels. Since several studies have demonstrated increased risk associated with the second and third tertiles vs. the first tertile for Lp-PLA2, the 50th percentile cut point (235 ng/mL) is recommended as a conservative cut point associated with increased risk for cardiovascular disease. This cut point is not proposed as a treatment target, but rather as a level above which clinicians should consider a patient to be at higher risk for cardiovascular events, independent of established risk factors, high- and low-density lipoprotein cholesterol, and high-sensitivity C-reactive protein.

Time-resolved fluoroimmunoassays of the complete set of secreted phospholipases A2 in human serum.

Time-resolved fluoroimmunoassays (TR-FIA) were developed for all human secreted phospholipases A(2) (PLA(2)), viz. group (G) IB, GIIA, GIID, GIIE, GIIF, GIII, GV, GX and GXIIA PLA(2) and the GXIIB PLA(2)-like protein. Antibodies were raised in rabbits against recombinant human PLA(2) proteins and used in sandwich-type TR-FIAs as both catching and detecting antibodies, the latter after labeling with Europium. The antibodies were non-cross-reactive. The analytical sensitivities were 1 microg/L for the TR-FIA for GIB PLA(2), 1 microg/L (GIIA), 35 microg/L (GIID), 3 microg/L (GIIE), 4 microg/L (GIIF), 14 microg/L (GIII), 11 microg/L (GV), 2 microg/L (GX), 92 microg/L (GXIIA) and 242 microg/L (GXIIB). All secreted PLA(2)s were assayed by these TR-FIAs in serum samples from 34 patients (23 men and 11 women, mean age 53.2 years) treated in an intensive care unit for septic infections, and in control samples from 28 volunteer blood donors (14 men and 14 women, mean age 57.0 years). Five serum samples (3 in the sepsis group and 2 in the blood donor group) gave high TR-FIA signals that were reduced to background (blank) levels by the addition of non-immune rabbit IgG to the sera. This reactivity was assumed to be due to the presence of heterophilic antibodies in these subjects. In all other subjects, including septic patients and healthy blood donors, the TR-FIA signals for GIID, GIIE, GIIF, GIII, GV, GX and GXIIA PLA(2) and the GXIIB PLA(2)-like protein were at background (blank) levels. Four patients in the sepsis group had pancreatic involvement and elevated concentration of GIB PLA(2) in serum (median 19.0 microg/L, range 13.1-33.7 microg/L, n = 4) as compared to the healthy blood donors (median 1.8 microg/L, range 0.8-3.4 microg/L, n = 28, P < 0.0001). The concentration of GIIA PLA(2) in the sera of septic patients (median 315.7 microg/L, range 15.9-979.6 microg/L, n = 34) was highly elevated as compared to that of the blood donors (median 1.8 microg/L, range 0.8-5.8 microg/L, n = 28, P < 0.0001). Our current results confirmed elevated concentrations of GIB and GIIA PLA(2) in the sera of patients suffering from acute pancreatitis or septic infections, respectively, as compared to healthy subjects. However, in the same serum samples, the concentrations of the other secreted PLA(2)s, viz. GIID, GIIE, GIIF, GIII, GV, GX and GXIIA PLA(2) and the GXIIB PLA(2)-like protein were below the respective analytical sensitivities of the TR-FIAs. It is concluded that generalized bacterial infections do not lead to elevated serum levels of GIIE, GIIF, GIII, GV and GX PLA(2)s above the detection limits of the current TR-FIAs.