Microparticles (MPs) are submicron extracellular vesicles exposing phosphatidylserine (PS) detected in large quantities in the circulation of sickle cell anemia (SS) patients. Several groups studied the biological effects of MPs generated ex vivo. Here, we analyzed for the first time the impact of circulating MPs of 60 sickle cell disease (SCD) patients on endothelial cells (ECs). (1) SCD MPs were collected cross-sectionally, and compared to MPs isolated from healthy individuals (AA); whereas other plasma MPs were purified in a longitudinal manner, from SS patients (2) before and 2 years after hydroxyurea (HU) treatment onset, or (3) during a vaso-occlusive crisis and at steady state. SS MPs increased EC ICAM-1 mRNA and protein levels, as well as neutrophil adhesion, compared to AA MPs. We showed that ICAM-1 overexpression was mainly caused by MPs derived from erythrocytes, rather than from platelets, and that it was abolished by MPs PS capping using annexin V. MPs from SS patients treated with HU were less potent to induce a pro-inflammatory phenotype in ECs, compared to MPs collected before therapy. In contrast, MPs released during crisis increased ICAM-1 and neutrophil adhesion levels, in a PS-dependent manner, compared to MPs collected at steady state. Furthermore, neutrophil adhesion was abolished by a blocking anti-ICAM-1 antibody. Our study provides evidence that MPs play a key role in SCD pathophysiology by triggering a pro-inflammatory phenotype of endothelial cells. We also uncover a new mode of action for HU and identify potential therapeutics, namely annexin V and anti-ICAM-1 antibodies.

Summary: COVID‐19 has compelled scientists to better describe its pathophysiology to find new therapeutic approaches. While risk factors, such as older age, obesity, and diabetes mellitus, suggest a central role of endothelial cells (ECs), autopsies have revealed clots in the pulmonary microvasculature that are rich in neutrophils and DNA traps produced by these cells, called neutrophil extracellular traps (NETs.) Submicron extracellular vesicles, called microparticles (MPs), are described in several diseases as being involved in pro‐inflammatory pathways. Therefore, in this study, we analyzed three patient groups: one for which intubation was not necessary, an intubated group, and one group after extubation. In the most severe group, the intubated group, platelet‐derived MPs and endothelial cell (EC)‐derived MPs exhibited increased concentration and size, when compared to uninfected controls. MPs of intubated COVID‐19 patients triggered EC death and overexpression of two adhesion molecules: P‐selectin and vascular cell adhesion molecule‐1 (VCAM‐1). Strikingly, neutrophil adhesion and NET production were increased following incubation with these ECs. Importantly, we also found that preincubation of these COVID‐19 MPs with the phosphatidylserine capping endogenous protein, annexin A5, abolished cytotoxicity, P‐selectin and VCAM‐1 induction, all like increases in neutrophil adhesion and NET release. Taken together, our results reveal that MPs play a key role in COVID‐19 pathophysiology and point to a potential therapeutic: annexin A5.

Sickle cell disease (SCD) is the most common hemoglobinopathy worldwide. It is characterized by an impairment of shear stress-mediated vasodilation, a pro-coagulant, and a pro-adhesive state orchestrated among others by the depletion of the vasodilator nitric oxide, by the increased phosphatidylserine exposure and tissue factor expression, and by the increased interactions of erythrocytes with endothelial cells that mediate the overexpression of adhesion molecules such as VCAM-1, respectively. Extracellular vesicles (EVs) have been shown to be novel actors involved in SCD pathophysiological processes. Medium-sized EVs, also called microparticles, which exhibit increased plasma levels in this pathology, were shown to induce the activation of endothelial cells, thereby increasing neutrophil adhesion, a key process potentially leading to the main complication associated with SCD, vaso-occlusive crises (VOCs). Small-sized EVs, also named exosomes, which have also been reported to be overrepresented in SCD, were shown to potentiate interactions between erythrocytes and platelets, and to trigger endothelial monolayer disruption, two processes also known to favor the occurrence of VOCs. In this review we provide an overview of the current knowledge about EVs concentration and role in SCD.

Background and Objectives: Pain management poses a significant challenge for patients experiencing vaso-occlusive crisis (VOC) in sickle cell disease (SCD). While opioid therapy is highly effective, its efficacy can be impeded by undesirable side effects. Local regional anesthesia (LRA), involving the deposition of a perineural anesthetic, provides a nociceptive blockade, local vasodilation and reduces the inflammatory response. However, the effectiveness of this therapeutic approach for VOC in SCD patients has been rarely reported up to now. The objective of this study was to assess the effectiveness of a single-shot local regional anesthesia (LRA) in reducing pain and consequently enhancing the management of severe vaso-occlusive crisis (VOC) in adults with sickle cell disease (SCD) unresponsive to conventional analgesic therapy. Materials and Methods: We first collected consecutive episodes of VOC in critical care (ICU and emergency room) for six months in 2022 in a French University hospital with a large population of sickle cell patients in the West Indies population. We also performed a systematic review of the use of LRA in SCD. The primary outcome was defined using a numeric pain score (NPS) and/or percentage of change in opioid use. Results: We enrolled nine SCD adults (28 years old, 4 females) for ten episodes of VOC in whom LRA was used for pain management. Opioid reduction within the first 24 h post block was −75% (50 to 96%). Similarly, the NPS decreased from 9/10 pre-block to 0–1/10 post-block. Five studies, including one case series with three patients and four case reports, employed peripheral nerve blocks for regional anesthesia. In general, local regional anesthesia (LRA) exhibited a reduction in pain and symptoms, along with a decrease in opioid consumption post-procedure. Conclusions: LRA improves pain scores, reduces opioid consumption in SCD patients with refractory pain, and may mitigate opioid-related side effects while facilitating the transition to oral analgesics. Furthermore, LRA is a safe and effective procedure.

Severity of coronavirus disease 2019 (COVID‐19) is often associated with thrombotic complications and cytokine storm leading to intensive are unit (ICU) admission. Platelets are known to be responsible for abnormal hemostasis parameters (thrombocytopenia, raised D‐dimers, and prolonged prothrombin time) in other viral infections through the activation of the nucleotide‐binding domain leucine repeat rich containing protein 3 inflammasome induced by signaling pathways driven by Bruton tyrosine kinase (BTK) and leading to caspase‐1 activation. We hypothesized that caspase‐1 activation and the phosphorylation of BTK could be associated with the severity of the disease and that ibrutinib, a BTK inhibitor, could inhibit platelet activation. We studied caspase‐1 activation by flow cytometry and the phosphorylation of BTK by Western blot in a cohort of 51 Afro‐Carribean patients with COVID‐19 disease (19 not treated in ICU and 32 treated in ICU). Patients with a platelet count of 286.7 × 10⁹/L (69–642 × 10⁹/L) were treated by steroids and heparin preventive anticoagulation. Caspase‐1 and BTK activation were associated with the severity of the disease and with the procoagulant state of the patients. Furthermore, we showed in vitro that the plasma of ICU patients with COVID‐19 was able to increase CD62P expression and caspase‐1 activity of healthy platelets and that ibrutinib could prevent it. Our results show that caspase‐1 and BTK activation are related to disease severity and suggest the therapeutic hope raised by ibrutinib in the treatment of COVID‐19 by reducing the procoagulant state of the patients.