Low-risk delisting strategy in highly sensitized patients without donor offers included in exchange donation programs. One single-center experience.

Donor exchange programs were designed to allocate organs for highly sensitized (HS) patients. The allocation algorithm differs slightly among countries and includes different strategies to improve access to transplants in HS patients. However, many HS patients with a calculated panel reactive of antibodies (cPRA) of 100 % remain on the waiting list for a long time. Some allocation algorithms assume immunological risk, including Imlifidase treatment, to increase the chance of transplantation in very HS patients. Here, we describe our unicenter experience of low-risk delisting strategy in 15 HS patients included in the Spanish donor exchange program without donor offers. After delisting, 7 out of 15 HS patients reduced the cPRA below 99.95 % and impacted the reduction of time on the waiting list (p = 0.01), where 5 out of 7 achieved transplantation. Within those HS that remained above 99.95 %, 1 out of 8 was transplanted. All the HS were transplanted with delisted DSA, and only one with DSA level rebounded early after transplantation. All HS transplanted after delisting maintain graft function. The transplant immunology laboratories are challenged to search intermediate risk assessment methods for delisting high HS patients.

Developmental Differences in Platelet Inhibition Response to Prostaglandin E1.

BACKGROUND: The mechanisms underlying neonatal platelets hyporesponsiveness are not fully understood. While previous studies have demonstrated developmental impairment of agonist-induced platelet activation, differences in inhibitory signaling pathways have been scarcely investigated. OBJECTIVE: To compare neonatal and adult platelets with regard to inhibition of platelet reactivity by prostaglandin E1 (PGE1). METHODS: Platelet-rich plasma from umbilical cord (CB) or adult blood was incubated with PGE1 (0-1 µM). We assessed aggregation in response to adenosine diphosphate (ADP), collagen, and thrombin receptor activating peptide as well as cyclic adenosine 3'5'-monophosphate (cAMP) levels (ELISA). Gαs, Gαi2, and total- and phospho-protein kinase A (PKA) were evaluated in adult and CB ultrapure and washed platelets, respectively, by immunoblotting. RESULTS: Neonatal (vs. adult) platelets display hypersensitivity to inhibition by PGE1 of platelet aggregation induced by ADP and collagen (PGE1 IC50: 14 and 117 nM for ADP and collagen, respectively, vs. 149 and 491 nM in adults). They also show increased basal and PGE1-induced cAMP levels. Mechanistically, PGE1 acts by binding to the prostanoid receptor IP (prostacyclin receptor), which couples to the Gαs protein-adenylate cyclase axis and increases intracellular levels of cAMP. cAMP activates PKA, which phosphorylates different target inhibitor proteins. Neonatal platelets showed higher basal and PGE1-induced cAMP levels, higher Gαs protein expression, and a trend to increased PKA-dependent protein phosphorylation compared to adult platelets. CONCLUSION: Neonatal platelets have a functionally increased PGE1-cAMP-PKA axis. This finding supports a downregulation of inhibitory when going from neonate to adult contributing to neonatal platelet hyporesponsiveness.