Toward a prophylaxis against fetal and neonatal alloimmune thrombocytopenia: induction of antibody-mediated immune suppression and prevention of severe clinical complications in a murine model

• Published in: Transfusion (Philadelphia, Pa.) Pa.), 2012-07, Vol.52 (7), p.1446-1457
• Main Authors: Tiller, Heidi, Killie, Mette Kjaer, Chen, Pingguo, Eksteen, Mariana, Husebekk, Anne, Skogen, Bjorn, Kjeldsen-Kragh, Jens, Ni, Heyu
• Format: Article
• Language: English
• Subjects: Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Animals; Antigens, Human Platelet - immunology; Biological and medical sciences; Blood Group Incompatibility - genetics; Blood Group Incompatibility - immunology; Blood Group Incompatibility - pathology; Blood Group Incompatibility - prevention & control; Blood. Blood and plasma substitutes. Blood products. Blood cells. Blood typing. Plasmapheresis. Apheresis; Disease Models, Animal; Drug toxicity and drugs side effects treatment; Female; Fetal Diseases - genetics; Fetal Diseases - immunology; Fetal Diseases - pathology; Fetal Diseases - prevention & control; Humans; Immunoglobulin G - immunology; Immunoglobulin G - pharmacology; Infant, Newborn; Integrin beta3 - genetics; Integrin beta3 - immunology; Isoantibodies - immunology; Isoantibodies - pharmacology; Male; Maternal-Fetal Exchange - immunology; Medical sciences; Pharmacology. Drug treatments; Pregnancy; Thrombocytopenia, Neonatal Alloimmune - genetics; Thrombocytopenia, Neonatal Alloimmune - immunology; Thrombocytopenia, Neonatal Alloimmune - pathology; Thrombocytopenia, Neonatal Alloimmune - prevention & control; Toxicity: blood; Transfusions. Complications. Transfusion reactions. Cell and gene therapy
• ISSN: 0041-1132; 1537-2995
• DOI: 10.1111/j.1537-2995.2011.03480.x

BACKGROUND: Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is a severe bleeding disorder caused by maternal antibody–mediated destruction of fetal or neonatal platelets (PLTs). Results from our recent large screening study suggest that the pathophysiology of FNAIT is more similar to hemolytic disease of the fetus and newborn (HDFN) than previously thought. Immunization against HPA‐1a might therefore be preventable by a prophylactic regimen of inducing antibody‐mediated immune suppression (AMIS), which has been documented to be a useful prophylaxis against HDFN. This preclinical proof‐of‐concept study investigated whether passive administration of anti‐β3 integrin could induce AMIS and thereby prevent clinical complications of FNAIT. STUDY DESIGN AND METHODS: A murine model of FNAIT using β3 integrin (GPIIIa)‐deficient (β3−/−) mice was employed for this study. AMIS in β3−/− mice was induced by intravenous administration of human anti‐HPA‐1a immunoglobulin G or murine anti‐β3 antisera given as prophylaxis after transfusion of HPA‐1a–positive human PLTs or murine wild‐type PLTs, respectively. RESULTS: AMIS against both human and murine PLT antigens was induced using this prophylactic approach, reducing the amount of maternal PLT antibodies by up to 90%. Neonatal PLT counts were significantly increased and pregnancy outcome was improved in a dose‐dependent manner. The incidence of intracranial hemorrhage, miscarriage, and dead‐born pups in mice receiving high‐dose prophylaxis was reduced to that of normal controls. We also observed that the severity of thrombocytopenia inversely correlated with birth weight. CONCLUSION: This work conceptually proves that prophylactic administration of PLT antibodies induces AMIS and prevents poor pregnancy outcome in FNAIT.