Monomeric C-Reactive Protein and Cerebral Hemorrhage: From Bench to Bedside

Abstract

C-reactive protein (CRP) is an important mediator and a hallmark of the acute-phase response to inflammation. High-sensitivity assays that accurately measure levels of CRP have been recommended for use in risk assessment in ischemic stroke patients. Elevation of CRP during the acute-phase response in intracerebral hemorrhage (ICH) is also associated with the outcomes such as death and vascular complications. However, no association has been found with the increased risk of ICH. The aim of this review is to synthesize the published literature on the associations of CRP with acute ICH both as a risk biomarker and predictor of short- and long-term outcomes as well as its role as a pathogenic determinant. We believe before any clinical utility, a critical appraisal of the strengths and deficiencies of the accumulated evidence is required both to evaluate the current state of knowledge and to improve the design of future clinical studies.

Keywords: CRP; SAP; biomarkers; inflammation; intracerebral hemorrhage; outcomes; risk assessment; stroke.

Figure 1

C-reactive protein staining in human brain after hemorrhagic and ischemic stroke and in normal aged control subjects. In the perihematoma areas, a diffuse neuropil staining was present, together with almost all cells' silhouettes taking up the stain (A). Further away from the hemorrhagic core, the diffuse staining pattern diminished, but with some neurons clearly retaining an affinity for the antibody. Although distant from the hemorrhage, white matter fiber tracts showed relatively intense staining for CRP, especially those surrounding intracallosal vessels (B). Focal intravascular staining sometimes was observed (C), and only on occasion were microglia-like cells immunoreactive for CRP (D). By immunofluorescence, CRP could be clearly localized inside blood vessels (K), and in the cytoplasm of activated astrocytes (L) and neurons (M). On the contrary, in the region immediately surrounding an ischemic area, a high number of gemistocytic astrocytes was noted (E), while further away from the lesion core numerous neuronal silhouettes were observed (F–H). On occasion, diffuse staining could be noted along the white matter tracts and blood vessels. In the control brain, and in the hemispheres contralateral to the lesion, only occasional neuronal silhouettes were stained, with their respective densities being clearly lower compared to the lesioned (ipsilateral) hemispheres (I,J). Scale bars, 20 μm. Reproduced with permission from (27).

Figure 2

mCRP increases vascular permeability and aberrant angiogenesis. Top shows hemorrhagic blood vessels produced within a matrigel murine skin implant-compared with normal vessels after VEGF incorporation. Dorsal matrigel implants containing mCRP (10 μg/ml; 72 h) produced strong and visible hemorrhagic angiogenesis (B; arrows) compared with a typical, normal looking vascular response seen in the presence of VEGF (A; 25 ng/ml). In (C) the graph shows a significant increase in monolayer permeability in the presence of mCRP (10 μg/ml; 8 h) using a Millipore-based filter assay, similar to that produced by 10% DMSO (p < 0.01 increase in FITC dextran penetrating the monolayer in the presence of either mCRP or the positive control DMSO), and lighter regions in the images shown indicate areas of increased permeability. Lower images show intact control monolayer (left); mCRP-treated monolayer and (right) DMSO-treated monolayer showing enhanced permeability and surface damage. Lighter regions in the images shown indicate areas of increased permeability. (D) Expression of adhesion molecules was examined in BAEC treated with mCRP (10 μg/ml; 24 h). NCAM expression was increased by approximately 2.8-fold whilst VCAM, ICAM and integrins were not affected (data not shown). β-tubulin was used as the house keeping control (gel and bar chart shown). Reproduced with permission from (34).