Mechanisms and Prevention of Alloimmunization in Pregnancy

Abstract

Transfusion only occasionally gives rise to antibody production, because blood cells per se are not markedly immunogenic. However, the immunological changes that occur during pregnancy increase the risk of alloimmunization against red blood cells, platelets, and/or leukocytes. Fetal-maternal bleeding during pregnancy or in relation to delivery is the antigenic stimuli for immunization against red blood cells, whereas other mechanisms, such as trophoblast-derived microparticles, may also play a role in the production of antibodies against platelets. Antibody-mediated immune suppression has for 4 decades successfully been used for prevention of RhD immunization. Result from a mouse model of fetal and neonatal alloimmune thrombocytopenia (FNAIT) suggests that the same principle may be applied for the prevention of FNAIT. A European Union-funded consortium is presently in the process of developing a hyperimmune anti-human platelet antigen 1a (HPA-1a) immunoglobulin G. The idea is to prevent HPA-1a immunization by administering the drug to nonimmunized HPA-1a-negative women after delivery of an HPA-1a-positive child. The anti-HPA-1a will be purified from plasma collected from women who previously have given birth to a child with FNAIT caused by anti-HPA-1a. If the results of the planned phase III trial are favorable, it is possible that a product for prevention of FNAIT will be available within this decade.

Fatal delayed haemolytic transfusion reaction in a patient without previous transfusions but with an obstetric history of 13 pregnancies

“…However, the immunological changes that occur during pregnancy markedly increase the risk of alloimmunisation against RBCs, platelets and leucocytes. It seems that fetal–maternal bleeding during pregnancy or delivery is a major antigenic stimulus for immunisation against RBCs 14. We believe that the repetitive antigenic stimuli that occurred during the patient’s 13 pregnancies played a crucial role in her outcome.…”

Platelets and platelet alloantigens: Lessons from human patients and animal models of fetal and neonatal alloimmune thrombocytopenia

“…Antibody-mediated immune suppression (AMIS) has successfully been used for prevention of RhD immunization for the past 4 decades. 186 Results from a proof of concept study using our mouse model of FNAIT suggest that the same principle may be applied for the prevention of FNAIT. In our murine model of FNAIT, AMIS led to a 90% reduction in anti-platelet antibodies in maternal circulation, significantly elevated neonatal platelet counts and vastly improved pregnancy outcomes.…”

Recent progress in understanding the pathogenesis of fetal and neonatal alloimmune thrombocytopenia

“…In such cases, FNAIT prophylaxis might be effective if given soon after parturition. These seeming discrepancies have sparked debate about the true incidence of FNAIT in first pregnancies (Kjeldsen‐Kragh et al , ; Tiller et al , ; Kjeldsen‐Kragh & Skogen, ; Jin et al , ). Inherent differences between large prospective studies and smaller retrospective studies of FNAIT could provide a potential explanation.…”

“…Based on large prospective studies showing that a small percentage of first pregnancies are affected with FNAIT, and animal model studies (Tiller et al , ) showing administration of platelet antibodies induced AMIS and improved pregnancy outcome, a collaborative effort is underway to produce an effective FNAIT prophylaxis for human use (Kjeldsen‐Kragh et al , ). Beginning in 2011, a European Union consortium organized the PROFNAIT project (http://www.profnait.eu/) to develop and test the clinical effectiveness of a safe prophylactic agent for FNAIT within this decade (Kjeldsen‐Kragh et al , ; Kjeldsen‐Kragh & Skogen, ). The product, called ‘NAITgam’, will consist of anti‐HPA‐1a IgG prepared from the plasma of hundreds of women previously immunized by a FNAIT‐affected pregnancy.…”