Compound heterozygosity of HLA-DRB301:01 and HLA-DRB401:01 as a potential predictor of fetal neonatal alloimmune thrombocytopenia

Authors

  • Ron Loewenthal,

    1. From the Tissue Typing Laboratory, the Fetal Medicine Unit Department of Obstetrics and Gynecology, and the Amalia Biron Research Institute of Thrombosis and Hemostasis, Sheba Medical Center, Tel Hashomer, Israel; the Department of Statistics and Operations Research, Raymond and Beverly Sackler Faculty of Exact Sciences, and the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; and the National Blood Services Center, Tel Hashomer, Israel.
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    • Contributed equally as first authors.

  • Nurit Rosenberg,

    1. From the Tissue Typing Laboratory, the Fetal Medicine Unit Department of Obstetrics and Gynecology, and the Amalia Biron Research Institute of Thrombosis and Hemostasis, Sheba Medical Center, Tel Hashomer, Israel; the Department of Statistics and Operations Research, Raymond and Beverly Sackler Faculty of Exact Sciences, and the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; and the National Blood Services Center, Tel Hashomer, Israel.
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    • Contributed equally as first authors.

  • Rivka Kalt,

    1. From the Tissue Typing Laboratory, the Fetal Medicine Unit Department of Obstetrics and Gynecology, and the Amalia Biron Research Institute of Thrombosis and Hemostasis, Sheba Medical Center, Tel Hashomer, Israel; the Department of Statistics and Operations Research, Raymond and Beverly Sackler Faculty of Exact Sciences, and the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; and the National Blood Services Center, Tel Hashomer, Israel.
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  • Rima Dardik,

    1. From the Tissue Typing Laboratory, the Fetal Medicine Unit Department of Obstetrics and Gynecology, and the Amalia Biron Research Institute of Thrombosis and Hemostasis, Sheba Medical Center, Tel Hashomer, Israel; the Department of Statistics and Operations Research, Raymond and Beverly Sackler Faculty of Exact Sciences, and the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; and the National Blood Services Center, Tel Hashomer, Israel.
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  • Meytal Landau,

    1. From the Tissue Typing Laboratory, the Fetal Medicine Unit Department of Obstetrics and Gynecology, and the Amalia Biron Research Institute of Thrombosis and Hemostasis, Sheba Medical Center, Tel Hashomer, Israel; the Department of Statistics and Operations Research, Raymond and Beverly Sackler Faculty of Exact Sciences, and the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; and the National Blood Services Center, Tel Hashomer, Israel.
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  • Vered Yahalom,

    1. From the Tissue Typing Laboratory, the Fetal Medicine Unit Department of Obstetrics and Gynecology, and the Amalia Biron Research Institute of Thrombosis and Hemostasis, Sheba Medical Center, Tel Hashomer, Israel; the Department of Statistics and Operations Research, Raymond and Beverly Sackler Faculty of Exact Sciences, and the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; and the National Blood Services Center, Tel Hashomer, Israel.
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  • Ofelia Avishai,

    1. From the Tissue Typing Laboratory, the Fetal Medicine Unit Department of Obstetrics and Gynecology, and the Amalia Biron Research Institute of Thrombosis and Hemostasis, Sheba Medical Center, Tel Hashomer, Israel; the Department of Statistics and Operations Research, Raymond and Beverly Sackler Faculty of Exact Sciences, and the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; and the National Blood Services Center, Tel Hashomer, Israel.
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  • Orit Frenkel,

    1. From the Tissue Typing Laboratory, the Fetal Medicine Unit Department of Obstetrics and Gynecology, and the Amalia Biron Research Institute of Thrombosis and Hemostasis, Sheba Medical Center, Tel Hashomer, Israel; the Department of Statistics and Operations Research, Raymond and Beverly Sackler Faculty of Exact Sciences, and the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; and the National Blood Services Center, Tel Hashomer, Israel.
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  • Ephraim Gazit,

    1. From the Tissue Typing Laboratory, the Fetal Medicine Unit Department of Obstetrics and Gynecology, and the Amalia Biron Research Institute of Thrombosis and Hemostasis, Sheba Medical Center, Tel Hashomer, Israel; the Department of Statistics and Operations Research, Raymond and Beverly Sackler Faculty of Exact Sciences, and the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; and the National Blood Services Center, Tel Hashomer, Israel.
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  • David M. Steinberg,

    1. From the Tissue Typing Laboratory, the Fetal Medicine Unit Department of Obstetrics and Gynecology, and the Amalia Biron Research Institute of Thrombosis and Hemostasis, Sheba Medical Center, Tel Hashomer, Israel; the Department of Statistics and Operations Research, Raymond and Beverly Sackler Faculty of Exact Sciences, and the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; and the National Blood Services Center, Tel Hashomer, Israel.
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  • Shlomo Lipitz,

    1. From the Tissue Typing Laboratory, the Fetal Medicine Unit Department of Obstetrics and Gynecology, and the Amalia Biron Research Institute of Thrombosis and Hemostasis, Sheba Medical Center, Tel Hashomer, Israel; the Department of Statistics and Operations Research, Raymond and Beverly Sackler Faculty of Exact Sciences, and the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; and the National Blood Services Center, Tel Hashomer, Israel.
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  • Ophira Salomon

    Corresponding author
    1. From the Tissue Typing Laboratory, the Fetal Medicine Unit Department of Obstetrics and Gynecology, and the Amalia Biron Research Institute of Thrombosis and Hemostasis, Sheba Medical Center, Tel Hashomer, Israel; the Department of Statistics and Operations Research, Raymond and Beverly Sackler Faculty of Exact Sciences, and the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; and the National Blood Services Center, Tel Hashomer, Israel.
      Ophira Salomon, The Amalia Biron Research Institute of Thrombosis and Hemostasis, Sheba Medical Center, Tel Hashomer, 52621, Israel; e- mail: ophiras@sheba.health.gov.il.
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Ophira Salomon, The Amalia Biron Research Institute of Thrombosis and Hemostasis, Sheba Medical Center, Tel Hashomer, 52621, Israel; e- mail: ophiras@sheba.health.gov.il.

Abstract

BACKGROUND: Fetal neonatal alloimmune thrombocytopenia (FNAIT) is a life-threatening bleeding disorder in the fetus or neonate caused by maternal alloantibodies directed against fetal platelet (PLT) antigens inherited from the father. The immune-dominant antigen leading to severe FNAIT is the human PLT antigen (HPA)-1, whose polymorphism constitutes an epitope for human leukocyte antigens (HLAs), usually DRB3*0101 leading to an immune response.

STUDY DESIGN AND METHODS: In this study our aims were to find whether other allele variants of the β subunit of the HLA-DR family specifically focused on the HLA residues that bind Position 33 of the HPA-1 integrin contribute to FNAIT development and affect response to treatment and whether coexistence of both anti-HPA-1a and anti-HLA Class I specific against the father's antigens leads to a more severe thrombocytopenia in the newborn. We examine the genotype of 23 mothers to newborns with FNAIT compared to a control group.

RESULTS: Our results suggested that, when HPA-1 incompatibility with the husband is found, the presence of two HLA alleles (DRB3*01:01 and DRB4*01:01) in the mother increases the risk and severity of FNAIT and reduces the success of a preventive immunoglobulin G treatment. We provide a structural model for the molecular basis of the rational effects of the different HLA alleles. In addition, we found that the presence of both anti-HPA-1 and anti-HLAs did not aggravate FNAIT in comparison to mothers harboring only anti-HPA-1.

CONCLUSION: Overall, we suggest that a specific genotyping of the mother in relation to HLA-DRB as well as HPA-1 can serve as an antenatal diagnostic tool, particularly in siblings of women who gave birth to neonates with FNAIT.

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