Role of Platelets and Vascular Injury in Liver Disease Pathogenesis

In patients with chronic hepatitis C virus (HCV) with early fibrosis and cirrhosis, the decline in platelet count and growth factors (GFs) suggests that platelets are a key source of GFs and influence GF decline, according to study results published in Digestive Diseases and Sciences. The results also indicated that patients with early fibrosis had enhanced vascular injury markers (VIMs), suggesting an earlier onset of endothelial dysfunction before cirrhosis.

The study included patients with HCV with early fibrosis and cirrhosis (n=26). A liver pathologist used the most recent patient liver biopsy specimens to obtain Ishak fibrosis (IshF) and hepatic activity index (HAI) scores for fibrosis and inflammation. Patients were divided into 2 subgroups based on IshF: early fibrosis (IshF 0, 1, or 2) and cirrhosis (IshF 5 or 6). The researchers performed a retrospective evaluation of serum GFs and VIMs. They correlated analytes from an earlier time point with a model for end-stage liver disease (MELD) at a later time point.

The study also included data from anonymized healthy controls with serum samples obtained from the National Institutes of Health (NIH) Clinical Center Blood Bank.

Compared with healthy controls, the results indicated that patients with early fibrosis and cirrhosis had lower platelet counts. Of patients with HCV, patients with cirrhosis had lower platelet counts compared with patients with early fibrosis.

Patients with cirrhosis had lower platelet-derived growth factor A (PDGF-AA), platelet-derived growth factor B (PDGF-BB), transforming growth factor beta isoform 1 (TGFB1), and epidermal growth factor (EGF) compared with controls. However, patients with early fibrosis showed no difference in GFs compared with controls. All measured GFs with the exception of vascular epithelial growth factor (VEGF), which was lower in patients with advanced cirrhosis compared with patients with early fibrosis. There was no difference in VEGF between patients with cirrhosis, patients with early fibrosis, and healthy controls.

The researchers found a positive correlation between platelets and PDGF-AA, PDGF-BB, TGFB1, EGF, and P-selection, pointing to a progressive decline in both platelet numbers and GFs with HCV-associated disease progression.

The researchers observed a negative correlation between platelets and intercellular adhesion molecule 3 (ICAM-3) and vascular cell adhesion molecule 1 (VCAM-1), suggesting an increase in endothelial damage with HCV disease progression.

While p-selectin had no correlation with VIMs, it had a positive correlation with PDGF-AA, PDGF-BB, TGFB1, and EGF. This suggests that P-selectin is a marker of platelet activation in HCV-associated liver disease rather than a marker of endothelial injury.

In order to determine prognostic value, the researchers analyzed longitudinal associations of GFs and VIMs with Model for End-Stage Liver Disease (MELD) score from a later time point. The results indicated that soluble VCAM-1 and ICAM-3 were associated with increasing fibrosis, liver enzymes, and synthetic dysfunction. Higher VCAM-1 and ICAM-3 at an earlier time point were associated with higher MELD scores at a later time point.

The study had several limitations, including its small sample size and correlative nature.

“These findings emphasize the importance of collectively evaluating pathways involved in vascular homeostasis and platelet function to provide mechanistic insight into liver disease pathogenesis,” the researchers wrote.

Reference

Ali RA, Moon MS, Townsend EC, et al. Exploring the link between platelet numbers and vascular homeostasis across early and late stages of fibrosis in hepatitis C [published online August 12, 2019]. Digest Dis Sci. doi:10.1007/s10620-019-05760-x