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Clinical Trial
. 2014 Oct;55(10):2064-72.
doi: 10.1194/jlr.M049726. Epub 2014 Aug 13.

Lipoprotein-apheresis reduces circulating microparticles in individuals with familial hypercholesterolemia

Katherine D Connolly  1 , Gareth R Willis  1 , Dev B N Datta  2 , Elizabeth A Ellins  3 , Kristin Ladell  4 , David A Price  4 , Irina A Guschina  5 , D Aled Rees  1 , Philip E James  1
Affiliations
Clinical Trial

Lipoprotein-apheresis reduces circulating microparticles in individuals with familial hypercholesterolemia

Katherine D Connolly et al. J Lipid Res. 2014 Oct.

Abstract

Lipoprotein-apheresis (apheresis) removes LDL-cholesterol in patients with severe dyslipidemia. However, reduction is transient, indicating that the long-term cardiovascular benefits of apheresis may not solely be due to LDL removal. Microparticles (MPs) are submicron vesicles released from the plasma membrane of cells. MPs, particularly platelet-derived MPs, are increasingly being linked to the pathogenesis of many diseases. We aimed to characterize the effect of apheresis on MP size, concentration, cellular origin, and fatty acid concentration in individuals with familial hypercholesterolemia (FH). Plasma and MP samples were collected from 12 individuals with FH undergoing routine apheresis. Tunable resistive pulse sensing (np200) and nanoparticle tracking analysis measured a fall in MP concentration (33 and 15%, respectively; P < 0.05) pre- to post-apheresis. Flow cytometry showed MPs were predominantly annexin V positive and of platelet (CD41) origin both pre- (88.9%) and post-apheresis (88.4%). Fatty acid composition of MPs differed from that of plasma, though apheresis affected a similar profile of fatty acids in both compartments, as measured by GC-flame ionization detection. MP concentration was also shown to positively correlate with thrombin generation potential. In conclusion, we show apheresis nonselectively removes annexin V-positive platelet-derived MPs in individuals with FH. These MPs are potent inducers of coagulation and are elevated in CVD; this reduction in pathological MPs could relate to the long-term benefits of apheresis.

Keywords: exosomes; extracellular vesicles; fatty acids; flow cytometry; low density lipoprotein-apheresis; microvesicles; nanoparticle tracking analysis; phosphatidylserine; tunable resistive pulse sensing.

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Figures

Fig. 1.
Fig. 1.
MP concentration and size distributions pre- and post-apheresis. MP size and concentration were measured in pre- and post-apheresis samples using TRPS (np100 and np200) and NTA. Mean concentration of MPs pre- and post-apheresis is shown for TRPS np100 (A), TRPS np200 (C), and NTA (E). Size/concentration distribution of MPs pre- and post-apheresis is shown for TRPS np100 (B), TRPS np200 (D), and NTA (F). Concentrations are given in particles/ml of plasma. Data are presented as mean ± SEM (n = 12). *P < 0.05.
Fig. 2.
Fig. 2.
MP origin following apheresis. MPs from pre- and post-apheresis samples were analyzed by flow cytometry to determine cellular origin. FSC-A and SSC-A of platelets from fresh plasma were used to determine a submicron gate where only annexin V-positive MPs were analyzed. A: A representative dot blot of FSC-A versus SSC-A indicates the position of the MP gate (kept consistent for all samples). Samples were stained with annexin V, CD41, CD144, CD235a, and CD11b (B) to identify the proportion derived from platelets, endothelial cells, erythrocytes, and monocytes, respectively (C). Data are presented as mean ± SEM (n = 12).
Fig. 3.
Fig. 3.
GC-FID analysis of MPs following apheresis. Total fatty acid concentration of plasma and MPs (A and C, respectively) followed by fatty acid profiling to determine compositional changes pre- to post-apheresis (B and D, respectively). Data are presented as mean ± SEM (n = 12). *P < 0.05, **P < 0.01.
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