Case Control Study
Copyright ©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Oct 14, 2020; 26(38): 5849-5862
Published online Oct 14, 2020. doi: 10.3748/wjg.v26.i38.5849
Longitudinal decrease in platelet counts as a surrogate marker of liver fibrosis
Neta Gotlieb, Naama Schwartz, Shira Zelber-Sagi, Gabriel Chodick, Varda Shalev, Oren Shibolet
Neta Gotlieb, Shira Zelber-Sagi, Oren Shibolet, Department of Gastroenterology and Hepatology, Tel-Aviv Sourasky Medical Center, Tel Aviv 6423906, Israel
Neta Gotlieb, Oren Shibolet, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel
Naama Schwartz, Shira Zelber-Sagi, School of Public Health, University of Haifa, Haifa 3498838, Israel
Gabriel Chodick, Varda Shalev, Institute for Research and Innovation, Maccabi Health Services, Tel Aviv 6812509, Israel
Author contributions: Gotlieb N collected the data and wrote the manuscript; Schwartz N analyzed the results and performed the statistical analysis; Zelber-Sagi S, Chodick G and Shalev V were involved in critical revision of the paper; Shibolet O conceived the idea of the paper and was involved in writing and critical revision of the paper.
Institutional review board statement: The study was reviewed and approved by institutional review board (IRB) at the Maccabi Health Services (MHS).
Informed consent statement: Since this is a retrospective study in which anonymized administrative data from electronic medical records was retrieved, exemption from informed consent was granted by the IRB committee.
Conflict-of-interest statement: There was no conflict of interest to be reported.
Data sharing statement: None.
STROBE statement: The authors have read the STROBE Statement-checklist of items, and the manuscript was prepared and revised according to the STROBE Statement-checklist of items.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Corresponding author: Oren Shibolet, MD, Academic Research, Director, Professor, Department of Gastroenterology and Hepatology, Tel-Aviv Sourasky Medical Center, No. 6 Weizmann Street, Tel-Aviv 6423906, Israel.
Received: May 22, 2020
Peer-review started: May 21, 2020
First decision: May 29, 2020
Revised: June 10, 2020
Accepted: August 26, 2020
Article in press: August 26, 2020
Published online: October 14, 2020

Liver cirrhosis is a significant source of morbidity and mortality worldwide. The disease is usually indolent and asymptomatic early in its course while many cirrhotic patients are diagnosed late when severe complications occur. A major challenge is to diagnose advanced fibrosis as early as possible, using simple and non-invasive diagnostics tools. Thrombocytopenia represents advanced fibrosis and portal hypertension (HTN) and most non-invasive scores that predict liver fibrosis incorporate platelets as a strong risk factor. However, little is known about the association between longitudinal changes in platelet counts (PTC), when still within the normal range, and the risk of cirrhosis.


To explore whether platelet counts trajectories over time, can predict advanced liver fibrosis across the different etiologies of liver diseases.


A nested case-control study utilizing a large computerized database. Cirrhosis cases (n = 5258) were compared to controls (n = 15744) matched for age and sex at a ratio of 1:3. All participants had multiple laboratory measurements prior to enrollment. We calculated the trends of PTC, liver enzymes, bilirubin, international normalized ratio, albumin and fibrosis scores (fibrosis-4 and aspartate transaminase-to-platelet ratio index) throughout the preceding 20 years prior to cirrhosis diagnosis compared to healthy controls. The association between PTC, cirrhosis complications and fibrosis scores prior to cirrhosis diagnosis was investigated.


The mean age in both groups was 56 (SD 15.8). Cirrhotic patients were more likely to be smokers, diabetic with chronic kidney disease and had a higher prevalence of HTN. The leading cirrhosis etiologies were viral, alcoholic and fatty liver disease. The mean PTC decreased from 240000/μL to 190000/μL up to 15 years prior to cirrhosis diagnosis compared to controls who’s PTC remained stable around the values of 240000/μL. This trend was consistent regardless of sex, cirrhosis etiology and was more pronounced in patients who developed varices and ascites. Compared to controls whose values remained in the normal range, in the cirrhosis group aspartate aminotransferase and alanine aminotransferase, increased from 40 U/L to 75 U/L and FIB-4 increased gradually from 1.3 to 3 prior to cirrhosis diagnosis. In multivariable regression analysis, a decrease of 50 units in PTC was associated with 1.3 times odds of cirrhosis (95%CI 1.25-1.35).


In the preceding years before the diagnosis of cirrhosis, there is a progressive decline in PTC, within the normal range, matched to a gradual increase in fibrosis scores.

Keywords: Cirrhosis, Platelets, Count, Trend, Prediction, Range

Core tip: Cirrhosis is usually asymptomatic thus often diagnosed late when complications occur. Most non-invasive hepatic fibrosis scores (fibrosis-4, aspartate transaminase-to-platelet ratio index) incorporate platelets as a strong risk factor. However, the association between platelets average trends within the normal range and the risk of cirrhosis development is unknown. We found that up to 15 years before the diagnosis of cirrhosis, a progressive decline in platelet counts occurs, within the normal limits along with a gradual incline in FIB-4. The decline in platelet counts may alert of an early liver disease and may enable early therapeutic and preventive interventions before complications occur.