Exploring the Link Between Platelet Numbers and Vascular Homeostasis Across Early and Late Stages of Fibrosis in Hepatitis C

Abstract

Background: Thrombocytopenia is a hallmark of advanced liver disease. Platelets, growth factors (GFs), and vascular integrity are closely linked factors in disease pathogenesis, and their relationship, particularly in early disease stages, is not entirely understood. The aim was to compare circulating platelets, growth factors, and vascular injury markers (VIMs) in hepatitis C-infected (HCV) patients with early fibrosis and cirrhosis.

Methods: Retrospective evaluation of serum GFs and VIMs by ELISA were evaluated from twenty-six HCV patients. Analytes from an earlier time-point were correlated with MELD at a later time-point.

Results: Platelets and GFs decreased, and VIMs increased with fibrosis. Platelets correlated positively with PDGF-AA, PDGF-BB, TGFB1, EGF, and P-selectin, and negatively with ICAM-3 and VCAM-1. P-selectin showed no correlations with VIMs but positively correlated with PDGF-AA, PDGF-BB, TGFB1, and EGF. Soluble VCAM-1 and ICAM-3 were linked to increasing fibrosis, liver enzymes, and synthetic dysfunction. Higher VCAM-1 and ICAM-3 and lower P-selectin at an earlier time-point were linked to higher MELD score at a later time-point.

Conclusion: In chronic HCV, progressive decline in platelets and growth factors with fibrosis and their associations suggest that platelets are an important source of circulating GFs and influence GF decline with fibrosis. Enhanced markers of vascular injury in patients with early fibrosis suggest an earlier onset of endothelial dysfunction preceding cirrhosis. Associations of VIMs with platelets suggest a critical link between platelets and vascular homeostasis. Circulating markers of vascular injury may not only have prognostic importance but emphasize the role of vascular dysfunction in liver disease pathogenesis (NCT00001971).

Keywords: Growth factors; Hepatitis C virus (HCV); Platelets; Vascular injury.

Conflict of interest statement

Conflicts of Interest

None of the authors has financial interests or conflicts of interest related to this research.

Figures

Figure 1:. Changes in Circulating Platelet Counts and Growth factors (GFs) in HCV Patients

Growth factors mirror platelet counts in their circulating levels with disease progression to cirrhosis. At time-point B, platelet numbers (A) were lower in HCV patients compared to controls, and lower in the cirrhotic group compared to early fibrosis group. Among growth factors, PDGF-AA, PDGF-BB, TGFβ1, EGF, (B-E) were also lower in HCV patients compared to controls, and lower in the cirrhotics compared to early fibrosis. VEGF (F) showed no difference between HCV patients and controls or between disease stages. For all boxplot figures, the central horizontal line denotes the median and the length of the box indicates the interquartile range (IQR) from 75th to 25th range. P value was calculated with Mann-Whitney test and significant <0.05.

Figure 2.. Enhanced Levels of Circulating Vascular Injury Markers (VIMs) with Fibrosis in HCV Patients

HCV patients displayed enhanced vascular injury in both early stages of fibrosis and then a progressive increase with cirrhosis. E-selectin, ICAM-1, ICAM-3 and VCAM-1 and TM showed higher levels in both early fibrosis and cirrhosis when compared to controls. (A-E). ICAM-3 and VCAM-1 also showed higher levels with worsening stage of fibrosis. In contrast, P-selectin showed no difference between HCV patients and controls or between disease stages (F). For all boxplot figures, the central horizontal line denotes the median and the length of the box indicates the interquartile range (IQR) from 75th to 25th range. P value was calculated with Mann-Whitney test and significant <0.05. TM, Thrombomodulin.