Placenta and FNAIT
The research group has several ongoing projects related to the condition fetal neonatal alloimmune thrombocytopenia (FNAIT). FNAIT is a rare disease affecting the fetus and newborn, and it may occur if the mother and fetus has different platelet types. When there is incompatibility between the mother and fetus in platelet alloantigens (human platelet antigens – HPAs), the mother can develop an alloimmune response with antibodies targeting fetal platelets. Clinically this may cause low platelet count in the fetus or newborn, with severe brain bleedings as the most severe complication.
It is primarily Heidi Tiller and Nora Hersoug Nedberg performing the FNAIT research in the group. The projects are local, national and we participate in extensive international research collaboration. The FNAIT- research is carried out in close collaboration with our colleagues at the Immunology Research Group, led by prof Tor Stuge at IMB, UiT. We are interested in clinical follow-up and treatment of pregnant women at risk of having a fetus/newborn with FNAIT, one example being development and implementation of an antibody-mediated anti-HPA-1a antibody prophylaxis to prevent the mother from becoming immunized. No country has so far implemented antenatal screening to identify the 2% pregnant women who are at risk of having a baby with FNAIT, but this is an ongoing discussion and research focus in several countries, including Norway. In collaboration with Department of Laboratory Medicine at the University Hospital of North Norway, the group with Tiller as local site PI is participating in an ongoing sponsored clinical international multicenter study (IPA2002, «Natural history study to assess the occurrence of HPA-1a alloimmunization in women identified at higher risk for Fetal and Neonatal Alloimmune Thrombocytopenia»). Tiller is also hired by Janssen Pharmaceuticals as research consultant since August 2021, to assist in preparing for a new clinical trial testing a new drug to prevent severe FNAIT in HPA-1a alloimmunized pregnant women.
A current research focuses is how anti-HPA-1a antibodies, in addition to causing thrombocytopenia and brain bleedings, may affect development and function of the placenta. Placenta research, related to FNAIT, is highly prioritized in the group. We have found a significantly higher frequency of chronic placental inflammations in pregnancies where the mother had anti-platelet antibodies (anti-HPA-1a antibodies) during pregnancy. In collaboration with The Nanoscopy Group at UiT led by prof Balpreet Singh Ahluwalia, we are currently exploring how various super-resolution microscopy applications can be used to further understand the intricate interplay between platelet antibodies and the placenta up close. As basis for this research, we have established a unique FNAIT placenta biobank in Tromsø, in close collaboration with Polen. Tiller is also work package leader for placenta research related to an ongoing international collaboration study (PLATONIC). We are also studying if placental biomarkers in maternal blood from HPA-1a alloimmunized pregnancies may be useful to predict placental function and whether fetal growth and placental function measured by fetal ultrasound in pregnant women with anti-HPA-1a antibodies may be clinically relevant to assess.
Tiller participates in preparing national clinical guidelines for FNAIT (https://www.legeforeningen.no/foreningsledd/fagmed/norsk-gynekologisk-forening/veiledere/veileder-i-fodselshjelp/Allomimmunisering-mot-trombocyttantigener) as well as co-authoring a book-chapter on FNAIT in a nordic texbook in obstetrics and gynecology for medical students (www.nfog.org)
National and international collaborators
Prof Prof Anne Cathrine Staff, Oslo University Hospital (placenta biomarkers)
MD PhD Gitta Turowski, Oslo University Hospital (placenta histopathology)
MD PhD Vasilis Sitras and MD Dagmar Julia Paulik, Fetal Medicine Department, Oslo Universitetssykehus (ultrasound fetal growth, PLATONIC)
Leiden University Medical Center, Leiden, Nederland, MD PhD Joanne Verweij and colleagues
Sanquin Research, Amsterdam, Nederland, prof Masha de Haas and colleagues
Institute of Hematology and Transfusion Medicine, Warsaw, Poland, dr Guz Katarzyna and colleagues
Publications
1. Tiller H, Killie MK, Husebekk A, Skogen B, Ni H, Kjeldsen-Kragh J, Øian P. Platelet antibodies and fetal growth: maternal antibodies against fetal platelet antigen 1a are strongly associated with reduced birthweight in boys. Acta Obst Gyn Scand. 2011;91(1):79-86
2. Tiller H, Kamphuis MM, Flodmark O, Papadogiannakis N, David A, Sainio S, Koskinen S, Javela K, Wikman AT, Kekomaki R, Kanhai HHH, Oepkes D, Husebekk A and Westgren M: Fetal intracranial haemorrhage caused by fetal and neonatal alloimmune thrombocytopenia: an observational cohort study of 43 cases from an international multicentre registry. BMJ open 2013
3. Issaka Yougbare,* Sean Lang,* Hong Yang, Pingguo Chen, Xu Zhao, Wei-She Tai, Darko Zdravic, Brian Vadasz, Conglei Li, Siavash Piran, Alexandra Marshall, Guangheng Zhu, Heidi Tiller, Mette Kjaer Killie, Shelley Boyd, Howard Leong-Poi, Bjorn Skogen, S. Lee Adamson, John Freedman, and Heyu Ni: Maternal anti-platelet β3 integrins impair angiogenesis and cause intracranial hemorrhage, J Clin Invest. 2015 Apr;125(4):1545-56. doi: 10.1172/JCI77820. Epub 2015 Mar 16.
4. J Dahl, A Husebekk, G Acharya, K Flo, T B Stuge, B Skogen, B Straume, H Tiller: Maternal anti-HLA class I antibodies are associated with reduced birth weight in thrombocytopenic neonates. Accepted for publication in Journal of Reproductive Immunology October 19th 2015
5. Mariana Eksteen, Gøril Heide, Heidi Tiller, Yan Zhou, Nora Hersoug Nedberg, Inigo Martinez-Zubiaurre, Anne Husebekk, Bjørn Skogen, Tor Brynjar Stuge, Mette Kjær: Anti-human platelet antigen (HPA)-1a antibodies may affect trophoblast functions crucial for placental development: A laboratory study using an in vitro model. Reproductive Biology and Endocrinology 2017; Volum 15:28. s.1-8 DOI: 10.1186/s12958-017-0245-6
6. Jesper Dahl, Erle Refsum, Maria Therese Ahlen, Torstein Egeland, Tore Jensen, Marte K. Viken, Tor Brynjar Stuge, Ganesh Acharya, Anne Husebekk, Bjørn Skogen, Heidi Tiller: Unraveling the role of maternal anti-HLA class I antibodies in fetal and neonatal thrombocytopenia-Antibody specificity analysis using epitope data. Journal of Reproductive Immunology 2017; Volum 122. s.1-9 doi: 10.1016/j.jri.2017.06.003.
7. Heidi Tiller, Maria Therese Ahlen, Çiğdem Akalın Akkök and Anne Husebekk: Fetal and neonatal alloimmune thrombocytopenia – the Norwegian management model. Transfus Apher Sci. 2019 Dec 31:102711. doi: 10.1016/j.transci.2019.102711. [Epub ahead of print]
8. Nedberg NH, Turowski G, Guz K, Przytuła E, Uhrynowska M, Roald B, et al. Platelet alloimmunization is associated with low grade chronic histiocytic intervillositis - A new link to a rare placental lesion? Placenta. 2021; 112:89-96.
9. Siw L. Ernstsen, Maria T. Ahlen, Tiril Johansen, Eirin L. Bertelsen, Prof Jens Kjeldsen-kragh, Heidi Tiller: Antenatal intravenous immunoglobulins in pregnancies at risk of fetal and neonatal alloimmune thrombocytopenia: Comparison of neonatal outcome in treated and non-treated pregnancies. Accepted for publication in American Journal of Obstetrics and Gynecology 23.04.22.
10. Postnatal treatment in fetal and neonatal alloimmune thrombocytopenia: an international cohort study. Thijs de Vos; Dian Winkelhorst; Valgerdur Árnadóttir; Johanna G van der Bom; Carme Canals Suris; Camila Caram-Deelder; Emöke Deschmann; Helen E Haysom; Hem Birgit C Hverven; Jana Lozar Krivec; Zoe K McQuilten; Eduardo Muñiz Diaz; Núria Nogués; Dick Oepkes; Leendert Porcelijn; C Ellen van der Schoot; Matthew Saxonhouse; Martha Sola-Visner; Eleonor Tiblad; Heidi Tiller; Erica M Wood; Vanessa Young; Mojca Železnik; Masja de Haas; Enrico Lopriore. Accepted for publication in Lancet Hematology 140722
11. Pregnant Women at Low Risk of Having a Child with Fetal and Neonatal Alloimmune Thrombocytopenia Do Not Require Treatment with Intravenous Immunoglobulin (review). Jens Kjeldsen-Kragh, Gregor Bein and Heidi Tiller. J. Clin. Med. 2023, 12, 5492.
Heidi Tiller, Mette Killie, Bjørn Skogen, Paal Øian, and Anne Husebekk: "Neonatal alloimmune thrombocytopenia in Norway: Poor detection rate with non-screening versus a general screening program", BJOG An international journal of obstetrics and gynaecology 2009; 116(4):594-598
12. Tiller H, Killie MK, Chen P, Eksteen M, Husebekk A, Skogen B, Kjeldsen-Kragh J, Ni H. 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. Transfusion 2012, 52:1446-1457. Published with editorial by B. Kumpel