PB1100 - Effects of COVID-19 vaccination on pro-coagulant state of a Protein S-deficient pediatric patient: new hope for treatment of the deficiency

Background: Protein S (PS) is a multifunctional vitamin K-dependent plasma protein associated with FIXa inhibition in the absence or presence of FVIIIa. Hereditary deficiencies of Protein S increase the thrombosis risk.

Aims: We present genetic and protein studies of a nine-year-old PS-deficient child with a history of neonatal stroke and describe how mRNA based COVID-19 vaccination reduced her coagulation levels and thrombin generation.

Methods: Before and after vaccination, the child’s plasma was analyzed by an activated partial thromboplastin time (aPTT) assay, a thrombin generation assay, immunoblotting, enzyme-linked immunosorbent assay, and mass spectrometry.

Results: The patient had a PROS1 genetic variation, a M643T missense mutation (rs750531364). We found that residues E435 and E437 of the PS LGI domain exclusively bind FIXa. The M643T mutation resides in the LG2 domain but close to the LG1-LG2 junction. This mutation can explain the child’s clinical condition. Prior to vaccination, she had low aPTT clotting times and high thrombin generation levels. Her concentration of free PS was considerably low. However, after COVID-19 vaccination she had a higher, essentially control level of antithrombin-III (normalized emPAI: 12.5; normalized iBAQ: 2,500,000,000) compared with a control sample (emPAI: 7.3; iBAQ: 1,900,000,000). Mass spectrometry showed normalization of her antithrombin after vaccination, which could have caused a decrease in her prothrombotic state. The child also had a significant reduction in thrombin. Patient coagulation Factor XII was only half of the factor level before vaccination.

Conclusion(s): The considerable reduction in thrombin post-vaccination supports the thesis of an important change in the child's symptoms caused by Protein S deficiency. The marked reduction of Factor XII minimizes its activation by contact phase with the blood vessel walls, thus reducing the possibility of activating FXI and promoting procoagulant action. These findings constitute a target for possible therapeutic studies of people with the same clinical condition.