Sickle cell disease (SCD) is a complex disease that is characterized by the polymerization of deoxyhemoglobin S, altered red blood cell membrane biology, endothelial activation, hemolysis, a procoagulant state, acute and chronic inflammation, and vaso-occlusion. Among the physiological changes that occur during pregnancy, oxygen is consumed by fetal growth, and pregnant women with SCD are more frequently exposed to low oxygen levels. This might lead to red blood cells sickling, and, consequently, to vaso-occlusion. The mechanisms by which SCD affects placental physiology are largely unknown, and chronic inflammation might be involved in this process. This study aimed to evaluate the gene expression profile of inflammatory response mediators in the placentas of pregnant women with sickle cell cell anemia (HbSS) and hemoglobinopathy SC (HbSC). Our results show differences in a number of these genes. For the HbSS group, when compared to the control group, the following genes showed differential expression: IL1RAP (2.76-fold), BCL6 (4.49-fold), CXCL10 (−2.12-fold), CXCR1 (−3.66-fold), and C3 (−2.0-fold). On the other hand, the HbSC group presented differential expressions of the following genes, when compared to the control group: IL1RAP (4.33-fold), CXCL1 (3.05-fold), BCL6 (4.13-fold), CXCL10 (−3.32-fold), C3 (−2.0-fold), and TLR3 (2.38-fold). Taken together, these data strongly suggest a differential expression of several inflammatory genes in both SCD (HbSS and HbSC), indicating that the placenta might become an environment with hypoxia, and increased inflammation, which could lead to improper placental development.
This is a preview of subscription content, log in to check access.
We thank Dr. Fred Kraus for helping with the morphology analysis of the H&E stained samples and Dr. Nicola Conran for the careful review of the manuscript.
This study was supported by São Paulo Research Foundation (FAPESP) grant 2008/57441-0, grant 2014/00984-3 and grant 2014/01925-0 to MLC and by the Coordination for the Improvement of Higher Education Personnel (CAPES) and the National Council for Scientific and Technological Development (CNPq).
Compliance with ethical standards
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all patients for being included in the study.
Conflict of interest
The authors declare that they have no conflict of interest.
Supplementary Table 1mRNA expression profile of PCR Array for Human Inflammatory Response & Autoimmunity of 84 genes in placentas of SCD groups. (DOCX 17 kb)
Hoppe CC (2014) Inflammatory mediators of endothelial injury in sickle cell disease. Hematol Oncol Clin North Am 28(2):265–286CrossRefPubMedGoogle Scholar
Qari MH, Dier U, Mousa SA (2012) Biomarkers of inflammation, growth factor, and coagulation activation in patients with sickle cell disease. Clin Appl Thromb Hemost 18(2):195–200CrossRefPubMedGoogle Scholar
Goodman SR, Pace BS, Hansen KC, D’alessandro A, Xia Y, Daescu O et al (2016) Minireview: multiomic candidate biomarkers for clinical manifestations of sickle cell severity: early steps to precision medicine. Exp Biol Med (Maywood) 241(7):772–781CrossRefGoogle Scholar
Powars DR, Sandhu M, Niland-Weiss J, Johnson C, Bruce S, Manning PR (1986) Pregnancy in sickle cell disease. Obstet Gynecol 67(2):217–228CrossRefPubMedGoogle Scholar
Howard J, Oteng-Ntim E (2012) The obstetric management of sickle cell disease. Best Pract Res Clin Obstet Gynaecol 26(1):25–36CrossRefPubMedGoogle Scholar
Oteng-Ntim E, Meeks D, Seed PT, Webster L, Howard J, Doyle P et al (2015) Adverse maternal and perinatal outcomes in pregnant women with sickle cell disease: systematic review and meta-analysis. Blood 125(21):3316–3325CrossRefPubMedGoogle Scholar
De Montalembert M, Deneux-Tharaux C (2015) Pregnancy in sickle cell disease is at very high risk. Blood 125(21):3216–3217CrossRefPubMedGoogle Scholar
Andemariam B, Browning SL (2013) Current management of sickle cell disease in pregnancy. Clin Lab Med 33(2):293–310CrossRefPubMedGoogle Scholar
Trampont P, Roudier M, Andrea AM et al (2004) The placental-umbilical unit in sickle cell disease pregnancy: a model for studying in vivo functional adjustments to hypoxia in humans. Hum Pathol 35(11):1353–1359CrossRefPubMedGoogle Scholar
Pantanowitz L, Schwartz R, Balogh K (2000) The placenta in sickle cell disease. Arch Pathol Lab Med 124:1565–1567PubMedGoogle Scholar
Yu CK, Stasiowska E, Stephens A, Awogbade M, Davies A (2009) Outcome of pregnancy in sickle cell disease patients attending a combined obstetric and haematology clinic. J Obstet Gynaecol 29:512–516CrossRefPubMedGoogle Scholar
Naik RP, Lanzkron S (2012) Baby on board: what you need to know about pregnancy in the hemoglobinopathies. Hematol Am Soc Hematol Educ Program 2012:208–214Google Scholar
Benites BD, Benevides TCL, Valente IS, Marques JF, Gilli SCO, Saad STO (2016) The effects of exchange transfusion for prevention of complications during pregnancy of sickle hemoglobin C disease patients. Transfusion 56(1):119–124.Google Scholar
Lanaro C, Franco-Penteado CF, Albuqueque DM, Saad ST, Conran N, Costa FF (2009) Altered levels of cytokines and inflammatory mediators in plasma and leukocytes of sickle cell anemia patients and effects of hydroxyurea therapy. J Leukoc Biol 85:235–242CrossRefPubMedGoogle Scholar
Goncalves MS, Nechtman JF, Figueiredo MS, Kerbauy J, Arruda VR, Sonati MF et al (1994) Sickle cell disease in a Brazilian population from Sao Paulo: a study of the beta s haplotypes. Hum Hered 44(6):322–327CrossRefPubMedGoogle Scholar
Burton GJ, Sebire NJ, Myatt L, Tannetta D, Wang Y-L, Sadovsky Y et al (2014) Optimising sample collection for placental research. Placenta 35(1):9–22CrossRefPubMedGoogle Scholar
Schmittgen TD, Livak KJ (2008) Analyzing real-time PCR data by the comparative C(T) method. Nat Protoc 3(6):1101–1108CrossRefPubMedGoogle Scholar
Kadyrov M, Kosanke G, Kingdom J, Kaufmann P (1998) Increased fetoplacental angiogenesis during first trimester in anaemic women. Lancet 352(9142):1747–1749CrossRefPubMedGoogle Scholar
Morey JS, Ryan JC, Van Dolah FM (2006) Microarray validation: factors influencing correlation between oligonucleotide microarrays and real-time PCR. Biol Proced Online 8:175–193CrossRefPubMedPubMedCentralGoogle Scholar
Silva-Pinto AC, de Oliveira Domingues Ladeira S, Brunetta DM, De Santis GC, de Lucena Angulo I, Covas DT (2014) Sickle cell disease and pregnancy: analysis of 34 patients followed at the Regional Blood Center of Ribeirão Preto, Brazil. Rev Bras Hematol Hemoter 36(5):329–333CrossRefPubMedPubMedCentralGoogle Scholar
Orsi NM (2008) Cytokine networks in the establishment and maintenance of pregnancy. Hum Fertil (Camb) 11:222–230CrossRefGoogle Scholar
Tjoa ML, Oudejans CB, van Vugt JM, Blankenstein MA, van Wijk IJ (2004) Markers for presymptomatic prediction of preeclampsia and intrauterine growth restriction. Hypertens Pregnancy 23:171–189CrossRefPubMedGoogle Scholar
Orsi NM, Tribe RM (2008) Cytokine networks and the regulation of uterine functionin pregnancy and parturition. J Neuroendocrinol 20:462–469CrossRefPubMedGoogle Scholar
Basso K, Dalla-Favera R (2012) Roles of BCL6 in normal and transformed germinal center B cells. Immunol Rev 247:172–183CrossRefPubMedGoogle Scholar
Louwen F, Muschol-Steinmetz C, Friemel A, Kämpf AK, Töttel E, Reinhard J et al (2014) Targeted gene analysis: increased B-cell lymphoma 6 in preeclamptic placentas. Hum Pathol 45(6):1234–1242CrossRefPubMedGoogle Scholar
Barish GD, Yu RT, Karunasiri M, Ocampo CB, Dixon J, Benner C et al (2010) Bcl-6 and NF-kappaB cistromes mediate opposing regulation of the innate immune response. Genes Dev 24(24):2760–2765CrossRefPubMedPubMedCentralGoogle Scholar
Dent AL, Shaffer AL, Yu X, Allman D, Staudt LM (1997) Control of inflammation, cytokine expression, and germinal center formation by BCL-6. Science 276(5312):589–592CrossRefPubMedGoogle Scholar
Hassell K. Pregnancy and sickle cell disease. Hematol Oncol Clin North Am 2005; 19(5):903–16, vii – viii.Google Scholar
Hanna J, Goldman-Wohl D, Hamani Y, Avraham I, Greenfield C, Natanson-Yaron S et al (2006) Decidual NK cells regulate key developmental processes at the human fetal-maternal interface. Nat Med 12(9):1065–1074CrossRefPubMedGoogle Scholar