Clinical Trial Details
— Status: Recruiting
Administrative data
| NCT number |
NCT05128253 |
| Other study ID # |
6216 |
| Secondary ID |
|
| Status |
Recruiting |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
December 6, 2021 |
| Est. completion date |
August 31, 2023 |
Study information
| Verified date |
December 2021 |
| Source |
University of Roma La Sapienza |
| Contact |
Lucia Stefanini, PhD |
| Phone |
+390649972018 |
| Email |
lucia.stefanini[@]uniroma1.it |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational
|
Clinical Trial Summary
The primary objective of the study is to identify which features of platelet activation
promote the inflammatory response that underlies the progression from NAFL to NASH.
Therefore, the investigators plan:
1. To characterize and compare the platelet inflammatory phenotype in NAFL vs NASH patients
2. To study if and how the signaling pathways controlled by ITAM/ITIM-coupled receptors is
dysregulated in NAFL vs NASH As a secondary objective the investigators will analyze
platelet activation and inflammatory response in a subset of NAFL and NASH patients
after 2, 4 and 6 hours from consumption of a high fat meal to test if and how the
platelet inflammatory phenotype is promoted by post-prandial plasma lipids.
Description:
Background NonAlcoholic Fatty Liver Disease (NAFLD) is one of the most commonly encountered
liver disorders worldwide. NAFLD is a spectrum of liver disease including (i) simple hepatic
steatosis also called Non-Alcoholic Fatty Liver (NAFL) and (ii) Non-alcoholic SteatoHepatitis
(NASH).
When more than 5% hepatic steatosis is present, patients are considered to have NAFL. If
steatosis is present along with hepatocyte ballooning degeneration and lobular inflammation,
patients are considered to have NASH. About 20% of patients with NAFLD have NASH.
Over time, NAFLD may progress to cirrhosis and ultimately to hepatocellular carcinoma (HCC)
with a greater proportion of NASH patients (20%).
Platelets are specialized blood cells that continuously monitor and preserve the integrity of
the cardiovascular system. Beyond their well-established role in hemostasis, platelets have
been recently shown to actively participate in the inflammatory response and in tissue
remodeling, by releasing bioactive molecules and by interacting with leukocytes.
The liver-platelet relationship is very complex. In physiological conditions the liver
regulates platelet number by producing thrombopoietin and platelet lifespan by clearing aged
platelets. In pathological conditions, increasing evidence demonstrate that platelets have an
important role in regulating liver inflammation and chronic disease. Platelet-derived
cytokines, such as TGF-β, platelet-derived growth factor-β (PDGF-β), and CXCL4, promote
hepatic fibrosis, and platelet count has been used for many years as a surrogate marker of
liver fibrosis (FIB-4 index). Recent studies demonstrate that platelet number and platelet
aggregation are increased in liver sinusoids of NASH patients. Mechanistic insights provided
by mouse models suggest that the role of platelets in NAFLD progression is mediated through
the interaction with immune cells. Platelet colonization of the liver is mediated through the
interaction with specialized macrophages lining the liver sinusoids (Kupffer cells) and it is
a critical step for the recruitment of CD8+ T cells and NKT cells, which drive NASH
progression through the release of cytokines and the metabolic reprogramming of hepatocytes.
The importance of platelets in the development of NASH and subsequent progression to
cirrhosis and HCC has been confirmed in humans by inhibiting platelets with a combination of
aspirin and clopidogrel in a small pilot case study.
There is mounting evidence suggesting that distinct signaling pathways regulate the
hemostatic and the inflammatory function of platelets. For instance, the platelet ITAM-
(GPVI, CLEC2) and ITIM- (PECAM-1, TLT-1) coupled receptors regulate the platelet inflammatory
response but have a minor role in hemostasis. Thus, one could envisage targeting the platelet
inflammatory response as a strategy to limit the progression of NAFLD, without undermining
hemostasis.
Hypotheses The overarching hypothesis of the proposed project is that platelets amplify the
inflammatory state that drives the progression from NAFL to NASH.
Platelets participate in the inflammatory response by releasing bioactive compounds and
establishing heterotypic interactions with leukocytes. However, these mechanisms in the
context of chronic liver disease are poorly understood and have been studied mainly in mice.
Our working model is that platelets docked in the liver of NAFLD patients amplify the
inflammatory state by releasing pro-inflammatory cytokines, which in turn recruit and
activate leukocytes in the liver sinusoids. Combined stimuli from leukocytes and platelets
would then lead to metabolic reprogramming of hepatocytes and progression to NASH. In this
context the investigators expect to identify an important role of GPVI and CLEC-2 and their
inhibitory counterparts PECAM-1 and TLT-1, which are critically implicated in the regulation
of platelet activation at sites of inflammation.
The investigators anticipate that features of the platelet inflammatory response could be
both sensitive and sex-specific biomarkers for NASH progression and novel therapeutic
targets.
