3.4 Symptomatic crises in CAS patients are associated with formation of PMPs.
PMPs (also known as microvesicles) are particles of less than 1µm diameter which are split from platelet cell membranes under conditions of platelet activation or apoptosis, and interact with vascular endothelium to modulate both inflammatory changes and eventual (Pope et al. , 2016; Rosinska et al. , 2017). In our experiments (Fig. 4 ), plasma PMP content varied according to group of subjects/patients (ANOVA: p = 0.03), and increased significantly (p = 0.02, Bonferroni post hoc test) among patients evaluated during the acute phase of CAS (Fig. 4 ).

3.5 GTN/NAC infusion reverses both platelet resistance to NO and SD-1 release during acute phases of CAS.

Anti-aggregatory effects of SNP were studied in whole blood samples obtained from CAS patients in acute crises, before and during (2-12 hrs) GTN/NAC intravenous infusion (Fig. 5 ). Following the initiation of infusion of GTN/NAC, platelet aggregation in response to ADP decreased marginally from 10.6 ± 0.5 to 9.1 ± 0.5 ohms (p = 0.05). Furthermore, GTN/ NAC therapy significantly augmented anti-aggregatory responses to SNP (n = 11; p = 0.003, Fig. 5A ).
There was a substantial fall in plasma SD-1 concentrations post onset of GTN/NAC treatment (n = 6; p = 0.002; Fig. 5B ).