Red blood cell rigidification during cyclosporin therapy: a possible early warning signal for adverse reactions

Abstract

In a previous retrospective study with kidney-transplant patients, immunosuppressive treatment with Cyclosporin A (CsA) was found to be associated with impaired red blood cell (RBC) deformability. The aim of the present study was to evaluate and substantiate a possible causal relationship between the use of CsA and its effect on RBC deformability in a prospective study on non-transplant patients. Blood samples of 12 patients with psoriasis were taken before and after 2, 4, 8, 12 and 16 weeks of treatment with CsA (3-5 mg/day). Red cell deformability, expressed as Elongation Index (EI), was measured with the Laser-assisted Optical Rotational Cell Analyzer (LORCA), a new ektacytometric instrument. Mean values +/- SD for EI found after 16 weeks of treatment with cyclosporin (0.570 +/- 0.008) were significantly (p < 0.001) lower than the value before treatment (0.589 +/- 0.011). A dose-response relation could not be established within the small range of CsA doses used in this study. Irrespective of the dose, however, a significant correlation (r = -0.55; p = 0.0001) between duration of treatment and decrease in EI was demonstrated. In vitro incubation of blood with cyclosporin was not able to reproduce this effect, suggesting that a direct effect of the drug on RBCs is unlikely. Despite its use in relatively low doses, CsA causes a reduction in RBC deformability, an effect that increases during the course of treatment. It is suggested that this slow, but continuously increasing, RBC rigidification plays a role in the early pathogenesis of the adverse nephrotoxic complications frequently associated with this immunosuppressive regimen.

Exported Proteins Required for Virulence and Rigidity of Plasmodium falciparum-Infected Human Erythrocytes

“…To determine if proteins encoded by the targeted genes have any influence on erythrocyte membrane rigidity, we assessed the deformability of infected red blood cells with a laser-assisted optical rotational cell analyzer (LORCA) (Hardeman et al., 1998) (Figures 6A and 6B). The deformability ratio of erythrocytes infected with wild-type parasite to erythrocytes infected with mutant parasites for the four highest shear stresses was calculated and plotted to compare the influence of the deleted protein on the rigidity of the infected erythrocyte (Figure 6A).…”

“…Using micro-pipetting techniques it has been shown KAHRP and PfEMP3 contribute to altered membrane rigidity of P. falciparum -infected erythrocytes (Cooke et al., 2006). In this study, it was not possible to use micropipetting methods on such a large number of mutant cell lines and we therefore used LORCA, which has allowed a higher throughput analysis (Hardeman et al., 1998). However, the LORCA has disadvantages in that the sensitivity is not the same as micro-pipetting and as a result we may have missed identifying some mutant lines with rigidity phenotypes.…”

Cyclic undecapeptide Cyclosporin A mediated inhibition of amyloid synthesis: Implications in alleviation of amyloid induced neurotoxicity

“…It is also used as immunosuppressive agents during organ transplantation 17 .Upon administration, 90% of CsA remains bound to lipoproteins 20 . It can also bind to albumin, globulins and various other protein of the blood 21 . While in the systemic circulation, CsA can extensively associate with erythrocytes 21 .…”

“…It can also bind to albumin, globulins and various other protein of the blood 21 . While in the systemic circulation, CsA can extensively associate with erythrocytes 21 . The binding with erythrocytes can affect its bioavailability.…”

The pliant and ag(g)reeable erythrocyte

“…Could the technique only be of value in laboratory experiments? Fortunately, we were able to demonstrate in 2 clinical studies of patients, respectively with a recently transplanted kidney or with severe psoriasis where, in spite of the presence of a normal functioning spleen, significant differences in red cell deformability could be demonstrated during and after treatment with Ciclosporin [11,14]. Furthermore, the superior sensitivity The pattern on the right is the result of a mixture of 25% rigid cells and 75% normal cells; the ellipse-fit program calculates a mean EI of 0.4. of the laboratory method, relative to that of the spleen, could be demonstrated by the different deformation curves that can be assigned to different (age)fractions obtained by density-gradient centrifugation of a normal blood sample (Fig.…”