Murine models for studying treatment, prevention and pathogenesis of FNAIT

Abstract

Maternal alloimmunization to paternally inherited antigens on fetal/neonatal platelets can cause fetal/neonatal alloimmune thrombocytopenia (FNAIT) after antibody-mediated removal of platelets from the fetal circulation. The complications vary from mild bleeding symptoms to severe intracranial hemorrhage and subsequent neurological impairment or death. Studies on in vivo mechanisms are challenging to measure directly in pregnant women, rendering murine models as valuable and attractive alternatives, despite some critical differences between mice and men affecting the translational value. Here we present and discuss, the different murine models that substantially have increased our knowledge and understanding of FNAIT pathogenesis -as well as preclinical evaluation of therapeutic and preventive strategies.

Characterization of glycoprotein IIb/IIIa‐specific alloantibodies induced by cross‐strain platelet immunization in mice

“…The ease with which such antibodies can be induced in selected mouse strains and the limited numbers of AA differences that occur naturally between strains (Table 1) suggest that it might not be particularly difficult to characterize immunogenic AA differences in mice that mimic the HPA antigen systems of humans. FNAIT, a significant cause of morbidity and mortality in newborns 31–34 has been studied in mice under experimental conditions that deviate markedly from those found naturally in human patients with this condition 35–38 . Our findings raise the possibility that further studies of cross‐strain immunogenicity of GPIIb/IIIa in mice, could identify strains in which pregnancy leads to “natural” maternal alloimmunization against epitopes on GPIIb/IIIa and recapitulates the human disorder FNAIT.…”

“…FNAIT, a significant cause of morbidity and mortality in newborns [31][32][33][34] has been studied in mice under experimental conditions that deviate markedly from those found naturally in human patients with this condition. [35][36][37][38] Our findings raise the possibility that further studies of cross-strain immunogenicity of GPIIb/IIIa in mice, could identify strains in which pregnancy leads to "natural" maternal alloimmunization against epitopes on GPIIb/IIIa and recapitulates the human disorder FNAIT.…”

Reticulated Platelets—Which Functions Have Been Established by In Vivo and In Vitro Data?

“…Also, mouse platelets are smaller compared to human platelets (mean platelet volumes 4.7 ± 0.3 fl in mice vs. 7.5–10 fl in humans) [ 12 ]. Besides these structural differences, the circulating life-span of mouse platelets is markedly shorter than that of human platelets (3–4 days in mice vs. 8–12 days in humans) [ 13 ]. Since part of the murine thrombopoiesis takes part in megakaryocytes in the spleen, this could further add to the higher platelet turnover observed in mice [ 14 ].…”

“…Using different automated analyzers, the values in human blood were stable within 6 h after blood collection at room temperature [ 30 ], while for Mindray BC-6800 stability was shown within 8 h [ 31 ]. When platelets collected from one animal are not sufficient in number, it may be necessary to collect blood from multiple animals [ 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 ] for one experiment. Platelets are isolated from whole blood for most of the assays in the form of platelet-rich plasma (PRP).…”