Possible Role of P-selectin Adhesion in Long-COVID: A Comparative Analysis of a Long-COVID Case Versus an Asymptomatic Post-COVID Case

Abstract

Background: Long-term outcomes of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are now recognized as an emerging public health challenge - a condition termed Long-COVID. The pathophysiology of Long-COVID remains to be established. Functional P-selectin activity, implicated in COVID-19 sequalae, was measured between two convalescent COVID-19 subjects, one with (Long-COVID subject) and another without Long-COVID symptoms. Methods: Flow adhesion of whole blood or isolated white blood cells to P-selectin (FA-WB-Psel and FA-WBC-Psel) was measured using a standardized microfluidics clinical assay; impedance aggregometry with a collagen agonist was measured using model 590 Chrono-Log impedance aggregometer; standard laboratory assays were performed to evaluate changes in blood chemistries. Results: For both subjects, hemoglobin, WBC, platelet counts, electrolytes and ferritin were within normal reference ranges, with FA-WB-Psel significantly elevated compared to healthy controls (p<0.01). In vitro treatment of whole blood samples with crizanlizumab (anti-p-selectin monoclonal antibody) within the clinical dose range (10 μg/ml) mL) inhibited FA-WB-Psel only in samples from asymptomatic post-COVID subject, with the Long-COVID subject sample requiring close to 5-fold elevated dose to achieve a response. Pronounced inhibition of P-selectin adhesion of isolated leukocytes was observed for both subjects in autologous platelet-poor plasma and buffer. Impedance aggregometry showed greater baseline platelet aggregation to collagen in the Long-COVID sample, although both samples responded similarly to aspirin-induced platelet inhibition. Conclusions: Presented results suggest that elevated platelet activation in Long-COVID subject may be associated with increased P-Selectin activity. The results are discussed in terms of possible use on P-selectin inhibition therapies in treating Long-COVID.

Possible Role of P-selectin Adhesion in Long-COVID: A Case of Recovery After Long-COVID

“…Supplementation of i-WBC with crizanlizumab showed nearly complete (down to 99% at high dose) inhibition of cell adhesion. Similar to what was observed for the subject when Long-COVID symptoms were present [20], such strong adhesion inhibition occurred even at 1 µg/mL of crizanlizumab, which is ten times lower than the standard clinical drug dose (Figure 2).…”

“…After the resolution of the infection, LC experienced a wide range of symptoms including, extreme fatigue, brain fog, hair loss, headaches, and migraines, which are typical for those reported in Long-COVID cases. While some symptoms started to alleviate, many of them remained severe beyond 5 months after the infection [20]. At 68 weeks post-infection, she considered herself recovered and does not report any lingering symptoms.…”

“…It remains to be determined to what extent changes in leukocyte adhesion to P-selectin may represent a new risk factor for or a mechanism driving Long-COVID syndrome. As reported previously [20] 3 Significance: t-test comparison between the results obtained at 20 weeks (5 months) when severe Long-COVID symptoms had been present and 68 weeks (17 months) when symptoms had been resolved.…”

“…This subject presented platelet hyperactivity that was associated with increased P-selectin activity and seemingly with alteration in the functionality of PSGL-1 leukocyte receptors. These features were not observed in an asymptomatic post-COVID subject [20]. At 20 weeks, when severe Long-COVID symptoms were present, crizanlizumab, an anti-P-selectin monoclonal antibody, was found to be less potent in whole blood based on cell adhesion to immobilized P-selectin.…”

The potential role of ischaemia–reperfusion injury in chronic, relapsing diseases such as rheumatoid arthritis, Long COVID, and ME/CFS: evidence, mechanisms, and therapeutic implications

“…These interactions not only drive pathological clotting, but can also perpetuate endothelial damage and immunothrombosis [ 648 , 649 ], not only in COVID-19 as Long COVID, but also in all inflammatory diseases [ 647 , 650–660 ]. P-selectin is a well-known inflammatory molecule that may be found inside the granules of healthy platelets, on the membrane of the activated platelet where it acts as a binding receptor, or in circulation, as a soluble inflammatory molecule [ 82 , 301 , 646 , 661 , 662 ], Levels were raised in both participants in a small study [ 663 ]. Figure 10 shows selected platelet receptors and Figure 11 examples of platelet hyperactivation in individuals with Long COVID.…”