# Evaluation of the podoplanin/C-type lectin-like receptor-2 (CLEC-2) pathway as a mediator of platelet and coagulation activation in sickle cell disease

## TL;DR

This study explores how the podoplanin/CLEC-2 pathway contributes to blood clotting and inflammation in sickle cell disease, especially in patients with the SS genotype.

## Contribution

The study is the first to evaluate the role of the PDPN/CLEC-2 pathway in sickle cell disease and its association with disease severity markers.

## Key findings

- SCD patients, especially those with SS genotype, have higher levels of PDPN and CLEC-2 compared to healthy individuals.
- Blocking PDPN in vitro reduced monocyte–platelet aggregate formation and platelet activation.
- PDPN expression in monocytes was higher in patients with a history of vaso-occlusive crises.

## Abstract

Sickle cell disease (SCD) is a condition characterized by a prothrombotic state attributed to the simultaneous activation of hemostasis and innate immunity, referred to as thromboinflammation. Previous studies have demonstrated that the podoplanin (PDPN)/C-type lectin-like receptor-2 (CLEC-2) pathway is an emerging and important element of the pathogenesis of conditions in which inflammation and thrombosis coexist, but no data is available regarding its role in SCD.

To explore the PDPN/CLEC-2 pathway in SCD and correlate it with parameters of disease severity.

Fifty SCD patients (35 with SS genotype; 15 with SC genotype) and 25 healthy individuals were recruited. PDPN and CLEC-2 were assessed for both soluble and surface expression on cells and cell aggregates, along with other classical parameters of hemostasis and platelet activation. An in vitro study was performed to analyze the effect of anti-PDPN antibody on the formation of monocyte–platelet aggregates.

Circulating levels and expression of PDPN and CLEC-2 were higher in patients with SCD, particularly in those with genotype SS. The number of CD41+CLEC+ monocytes correlated with hemoglobin, D-dimer, von Willebrand factor, and PDPN+ monocytes. In vitro, PDPN blockade reduced both monocyte–platelet aggregate formation and platelet activation. Finally, patients with a history of vaso-occlusive crises presented a trend toward increased PDPN expression in monocytes (P = .06).

Our findings suggest that the PDPN/CLEC-2 pathway may play an important role in the pathogenesis of thromboinflammation in SCD, especially in patients with the SS genotype.

•Thromboinflammation contributes to the hypercoagulable state in SCD.•We evaluated the PDPN/CLEC-2 pathway in patients with SCD and healthy individuals.•SS patients showed increased soluble and cellular PDPN/CLEC-2 expression.•PDPN/CLEC-2 pathway may be part to the thromboinflammatory cascade in SCD.

Thromboinflammation contributes to the hypercoagulable state in SCD.

We evaluated the PDPN/CLEC-2 pathway in patients with SCD and healthy individuals.

SS patients showed increased soluble and cellular PDPN/CLEC-2 expression.

PDPN/CLEC-2 pathway may be part to the thromboinflammatory cascade in SCD.