Selective Apheresis of C-Reactive Protein for Treatment of Indications with Elevated CRP Concentrations

Abstract

Almost every kind of inflammation in the human body is accompanied by rising C-reactive protein (CRP) concentrations. This can include bacterial and viral infection, chronic inflammation and so-called sterile inflammation triggered by (internal) acute tissue injury. CRP is part of the ancient humoral immune response and secreted into the circulation by the liver upon respective stimuli. Its main immunological functions are the opsonization of biological particles (bacteria and dead or dying cells) for their clearance by macrophages and the activation of the classical complement pathway. This not only helps to eliminate pathogens and dead cells, which is very useful in any case, but unfortunately also to remove only slightly damaged or inactive human cells that may potentially regenerate with more CRP-free time. CRP action severely aggravates the extent of tissue damage during the acute phase response after an acute injury and therefore negatively affects clinical outcome. CRP is therefore a promising therapeutic target to rescue energy-deprived tissue either caused by ischemic injury (e.g., myocardial infarction and stroke) or by an overcompensating immune reaction occurring in acute inflammation (e.g., pancreatitis) or systemic inflammatory response syndrome (SIRS; e.g., after transplantation or surgery). Selective CRP apheresis can remove circulating CRP safely and efficiently. We explain the pathophysiological reasoning behind therapeutic CRP apheresis and summarize the broad span of indications in which its application could be beneficial with a focus on ischemic stroke as well as the results of this therapeutic approach after myocardial infarction.

Keywords: CRP; apheresis; inflammation; stroke.

Figure 1

Molecular pathomechanism of CRP-mediated tissue damage. Upon inflammation or acute oxygen-deprivation, cells display a dramatic shortage of adenosine triphosphate (ATP). ATP is essential to prevent apoptosis which manifests in the outer cell membrane: Phosphatidylcholine (PC) is converted into lyso-phosphatidylcholine (LPC) by phospholipase (sPLA2 IIa). Due to the lack of ATP, this alteration cannot be reversed. CRP subsequently binds to LPC on anaerobic cells and recruits complement factors (C1q-C4). These opsonized cells will be disposed by phagocytes, which in turn induce CRP synthesis. Without CRP or in situations with low CRP concentrations (e.g., after CRP apheresis), energy deprived-cells are spared and may switch back to aerobic metabolism, repair molecular changes and revitalize again, leading to an overall reduced tissue damage [41,43,44,45]. CRP C-reactive protein; C1q Complement component 1q; IL-6 Interleukin 6; LPC Lysophosphatidylcholine; PC Phosphatidylcholine; sPLA2 IIa secretory phospholipase A2 type IIa.

Figure 2

Schematic illustration of CRP apheresis. The procedure is described in detail by Ries et al. 2019 [45].

Figure 3

Porcine Heart Slices after AMI with and without CRP apheresis. Slices of the left ventricle 14 days after AMI. Slices were generated after an Evans Blue staining of the heart. Circles localize a characteristic transmural scar of a control animals (left) versus spotted scar morphology after CRP apheresis (right). Figure previously published and taken from [41].

Figure 4

Study flow of the CASTRO1 trial. MRI magnetic resonance imaging; NIHSS National Institute of Health Stroke Scale; mRs modified Rankin scale.