Pathology Deterioration in a Pure β-zero Thalassemia Heterozygote After mRNA COVID-19 Vaccination: A Case Report and Literature Review
DOI:
https://doi.org/10.56098/y768gc33Keywords:
SARS-CoV-2 mRNA vaccine, β-zero-thalassaemia deterioration, hematological stress, pre-syncope syndrome, autophagy inhibition, chronic inflammationAbstract
Background: β-thalassemia heterozygotes produce sensitive levels of fetal hemoglobin and hemoglobin A2 to remain asymptomatic for life compared to β-thalassemia intermedia and β-thalassemia major patients. The asymptomatic β0 thalassemia minor individuals rarely deteriorate to the point of requiring a blood transfusion.
Case report: An asymptomatic individual with a pure β0-thalassemia trait, after his first and only Pfizer modified mRNA COVID-19 injection, immediately developed cardiological, neurological, and other clinically important symptoms. The patient’s severe physical impairments resembled a presyncope (about to feint) syndrome. Multiple hematological tests prior to and after the Pfizer injection revealed that the patient sustained a medically important rise in fetal hemoglobin and concurrently a remarkable drop of his hemoglobin A2 levels, compared to prior to mRNA injection. Moreover, the alterations in his life sustaining fetal hemoglobin and hemoglobin A2 levels was accompanied by a clinically significant lowering of blood hemoglobin concentration that required blood transfusion. The patient’s antibody response to the spike protein remains very high (> 10,000 AU/ml) even almost three years after the Pfizer injection. Furthermore, the elevated levels of C-reactive protein — through May 2024 — after the mRNA injection, apart from pointing to multi-organ systemic inflammation, are consistent with his elevated levels of anti-p53 autoantibodies.
Conclusions: The simultaneous decrease of patient blood hemoglobin levels was consistent with the hematological readings of mean corpuscular volume, hematocrit, ferritin, folate, and zinc level deteriorations soon after the mRNA injection, which, apart from his double digit rise in C-reactive protein, resemble overall the pathological manifestations of a β-thalassemia worsening condition. By performing an investigative literature review we conclude that an autoimmune hematological disorder contributed to the patient’s severe hematological stress.
References
Aiba, T., Ishibashi, K., Hattori, K, Wada, M., Ueda, N., Miyazaki Y, Wakamiya A, Yamagata, K., Inoue, Y., Miyamoto, K., Nagase, S., & Kusano, K. (2021). Frequent premature ventricular contraction and non-sustained ventricular tachycardia after the SARS-CoV-2 vaccination in patient with implantable cardioverter defibrillator due to acquired long-QT syndrome. Circulation Journal 85(11), 2117. https://doi.org/10.1253/circj.CJ-21-0515
Akiki, N., Hodroj, M. H., Bou-Fakhredin, R., Matli, K., & Taher, A. T. (2023). Cardiovascular complications in β-thalassemia: getting to the heart of it. Thalassemia Reports 13, 38-50. https://doi.org/10.3390/thalassrep13010005
Alperin, J. B., Dow, P. A., & Petteway, M. B. (1977). Hemoglobin A2 levels in health and various hematologic disorders. American Journal of Clinical Pathology 67(3), 219-26. https://doi.org/10.1093/ajcp/67.3.219
Amato, A., Cappabianca, M. P., Perri, M., Zaghis, I., Grisanti, P., Ponzini, D., & Biagio, P. (2014). Interpreting elevated fetal hemoglobin in pathology and health at the basic laboratory level: new and known γ-gene mutations associated with hereditary persistence of fetal hemoglobin. International Laboratory Hematology 36(1), 13-9. https://doi.org/10.1111/ijlh.12094
Appelman, B., Charlton, B. T., Goulding, R. P., Kerkhoff, T. J., Breedveld, E. A., Noort, W., Offringa, C., Bloemers, F. W., van Weeghel, M., Schomakers, B. V., Coelho, P., Posthuma, J. J., Aronica, E., Joost Wiersinga, W., van Vugt, M., & Wüst, R. C. I. (2024). Muscle abnormalities worsen after post-exertional malaise in long COVID. Nature Communications 15, 17. https://doi.org/10.1038/s41467-023-44432-3
Athiyarath, R., Shaji, R., Ahmed, R., George, B., Mathews, V., Srivastava, A., & Edison, E. S. (2012). High expression of p53 and growth differentiation factor-15 in beta-thalassemia. Blood 120(21), 2130. https://doi.org/10.1182/blood.V120.21.2130.2130
Boros, L. G., Kyriakopoulos, A. M., Brogna, C. , Piscopo, M., McCullough, P. A., & Seneff, S. (2024) Long-lasting, biochemically modified mRNA and its frameshifted recombinant spike proteins in human tissues and circulation after COVID-19 vaccination. Pharmacology Research & Perspectives 12(13), e1218. https://doi.org/10.1002/PRP2.1218
Britze, J., Arngrim, N., Schytz, H. W., & Ashina, M. (2017). Hypoxic mechanisms in primary headaches. Cephalalgia 37(4), 372-384. https://doi.org/10.1177/0333102416647037
Báez-Negrón, L. & Vilá, L. M. (2022). New-onset systemic lupus erythematosus after mRNA SARS-CoV-2 vaccination. Case Reports in Rheumatology 2022, 6436839. https://doi.org/10.1155/2022/6436839
Carrocini, G. C., Zamaro, P. J., & Bonini-Domingos CR. (2011). Revista Brasileira de Hematologia e Hemoterapia 33(3), 231-6. https://doi.org/10.5581/1516-8484.20110059
Choi, E., Park, D. H., Yu, J. H., Ryu, S. H., & Ha, J. H. (2016). The severity of sleep disordered breathing induces different decrease in the oxygen saturation during rapid eye movement and non-rapid eye movement sleep. Psychiatry Investigation 13(6), 652-658. https://doi.org/10.4306/pi.2016.13.6.652
Choi, H. S., Kim, M.-H., Choi, M. G., Park, J. H., & Chun, E. M. (2023). Hematologic abnormalities after COVID-19 vaccination: A large Korean population-based cohort study. medRxiv Preprint. November 22. https://doi.org/10.1101/2023.11.15.23298565
Cisterna, B. A., Vargas, A. A., Puebla, C., Fernndez, P., Escamilla, R., Lagos, C. F., Matus, M. F., Vilos, C., Cea, L. A., Barnafi, E., Gaete, H., Escobar, D. F., Cardozo, C. P., & Sáez, J. C. (2020). Active acetylcholine receptors prevent the atrophy of skeletal muscles and favor reinnervation. Nature Communications 11(1), 1073. https://doi.org/10.1038/s41467-019-14063-8
Cocco, N., Leibundgut, G., Pelliccia, F., Cammalleri, V., Nusca, A., Mangiacapra, F., Cocco, G., Fanale, V., Ussia, G. P., & Grigioni, F. (2023). Arrhythmias after COVID-19 vaccination: Have we left all stones unturned? International Journal of Molecular Sciences 24(12), 10405. https://doi.org/10.3390/ijms241210405
Colaco, S., Colah, R., & Nadkarni, A. (2022). Significance of borderline hemoglobin A2 levels in β thalassemia carrier screening. Scientific Reports 12, 5414. https://doi.org/10.1038/s41598-022-09250-5
Cosenza, L. C., Marzaro, G., Zurlo, M., Gasparello, J., Zuccato, C., Finotti, A., & Gambari, R. (2024). Inhibitory effects of SARS-CoV-2 spike protein and BNT162b2 vaccine on erythropoietin-induced globin gene expression in erythroid precursor cells from patients with β-thalassemia. Experimental Hematology 129, 104128. https://doi.org/10.1016/j.exphem.2023.11.002
Ding, W. X. & Yin, X. M. (2012). Mitophagy: mechanisms, pathophysiological roles, and analysis. Biological Chemistry 393(7), 547-64. https://doi.org/10.1515/hsz-2012-0119
Ehteram, H., Bavarsad, M. S., Mokhtari, M., Saki, N., Soleimani, M., Parizadeh, S. M., & Mobarra, N. (2014). Prooxidant-antioxidant balance and hs-CRP in patients with beta-thalassemia major. Clinical Laboratory 60(2), 207-15. https://doi.org/10.7754/clin.lab.2013.130132
Farmakis, D., Porter, J., Taher, A., Domenica Cappellini, M., Angastiniotis, M., & Eleftheriou, A. (2022) Thalassemia International Federation guidelines for the management of transfusion-dependent thalassemia. Hemasphere 6(8), e732. https://doi.org/10.1097/HS9.0000000000000732
Fessas P, & Stamatoyannopoulos G. (1964). Hereditary persistence of fetal hemoglobin in Greece. A study and a comparison. Blood 24, 223-40. PMID: 14214133. https://pubmed.ncbi.nlm.nih.gov/14214133/
Finsterer, J. (2009). Mitochondriale Myopathien [Mitochondrial myopathies]. Fortschritte der Neurologie Psychiatrie 77(11), 631-8. German. https://doi.org/10.1055/s-0028-1109759
Fraidenburg, D. R. & Machado, R. F. (2016). Pulmonary hypertension associated with thalassemia syndromes. Annals of the New York Academy of Sciences 1368(1), 127-39. https://doi.org/10.1111/nyas.13037
Frontzek, K., Pfammatter, M., Sorce, S., Senatore, A., Schwarz, P., Moos, R., Frauenknecht, K., Hornemann, S., & Aguzzi, A. (2016). Neurotoxic antibodies against the prion protein do not trigger prion replication. PLoS One 11(9), e0163601. https://doi.org/10.1371/journal.pone.0163601
Fucharoen, S. (2023). Molecular basis of a high Hb A2/Hb Fβ-thalassemia trait: A retrospective analysis, genotype-phenotype interaction, diagnostic implication, and identification of a novel interaction with α-globin gene triplication. PeerJ 11, e15308. https://doi.org/10.7717/peerj.15308
Gaignard, M. E., Lieberherr, S., Schoenenberger, A., & Benz, R. (2021). Autoimmune hematologic disorders in two patients after mRNA COVID-19 vaccine. Hemasphere 5(8), e618. https://doi.org/10.1097/HS9.0000000000000618
Galanello, R. & Origa, R. (2010). Beta-thalassemia. Orphanet Journal of Rare Diseases 5, 11. https://doi.org/10.1186/1750-1172-5-11
Gamberini, M. R., Zuccato, C., Zurlo, M., Cosenza, L. C., Finotti, A., & Gambari, R. (2023). Effects of Sirolimus treatment on fetal hemoglobin production and response to SARS-CoV-2 vaccination: A case report study. Hematology Reports 15(3), 432-439. https://doi.org/10.3390/hematolrep15030044
Gavidel, A. (2019). Celiac disease associated with beta thalassemia minor, coincidence or not: A case report. Journal of Analytical Research in Clinical Medicine 7(1), 37-40. https://doi.org/10.15171/jarcm.2019.007
Gawaz, A., Schindler, M., Hagelauer, E., Blanchard, G., Riel, S., Vollert, A., Gilliet, M., Unterluggauer, L., Stary, G., Pospischil, I., Hoetzenecker, W., Fehrenbacher, B., Schaller, M., Guenova, E., & Forchhammer, S. (2024). SARS-CoV-2-induced vasculitic skin lesions are associated with massive spike protein depositions in autophagosomes. Journal of Investigative Dermatology 144(2), 369-377.e4. https://doi.org/10.1016/j.jid.2023.07.018
Ghosh, S., Salot, S., Sengupta, S., Navalkar, A., Ghosh, D., Jacob, R., Das, S., Kumar, R., Jha, N. N., Sahay, S., Mehra, S., Mohite, G. M., Ghosh, S. K., Kombrabail, M., Krishnamoorthy, G., Chaudhari, P., & Maji, S. K. (2017). p53 amyloid formation leading to its loss of function: implications in cancer pathogenesis. Cell Death & Differentiation 24(10), 1784-1798. https://doi.org/10.1038/cdd.2017.105
Gluba-Brzózka, A., Franczyk, B., Rysz-Górzyńska, M., Rokicki, R., Koziarska-Rościszewska, M., & Rysz, J. (2021). Pathomechanisms of immunological disturbances in β-thalassemia. International Journal of Molecular Sciences 22(18), 9677. https://doi.org/10.3390/ijms22189677
Gogo, P. B., Jr., Schneider, D. J., Terrien, E. F., Watkins, M. W., Sobel, B. E., & Dauerman, H. L. (2005). Relation of leukocytosis to C-reactive protein and interleukin-6 among patients undergoing percutaneous coronary intervention. American Journal of Cardiology 96(4), 538-42. https://doi.org/10.1016/j.amjcard.2005.04.016
Gray, L. R, (2014). Tompkins SC, Taylor EB. Regulation of pyruvate metabolism and human disease. Cellular and Molecular Life Sciences 71(14), 2577-604. https://doi.org/10.1007/s00018-013-1539-2
Green, D. R. & Kroemer, G. (2009). Cytoplasmic functions of the tumour suppressor p53. Nature 458(7242), 1127-30. https://doi.org/10.1038/nature07986
Halma, M. T. J., Marik, P. E., & Saleeby, Y. M. (2024). Exploring autophagy in treating SARS-CoV-2 spike protein-related pathology. Endocrine and Metabolic Science 14, 100163. https://doi.org/10.1016/j.endmts.2024.100163
Heckmann, J. G. & Lang, C. J. G. (2006). Neurological causes of taste disorders. Advances in Oto-Rhino-Laryngology 63, 255-264. https://doi.org/10.1159/000093764
Heiner, D. C. (1988). IgG4 immunodeficiency. New England and Regional Allergy Proceedings 9(1), 43-50. https://doi.org/10.2500/108854188778984509
Henningsen, K. M., Manzini, V., Magerhans, A., Gerber, S., & Dobbelstein, M. (2021). MDM2-driven ubiquitination rapidly removes p53 from its cognate promoters. Biomolecules 12(1), 22. https://doi.org/10.3390/biom12010022
Herkel, J., Mimran, A., Erez, N., Kam, N., Lohse, A. W., Märker-Hermann, Rotter, V., & Cohen, I. R. (2001). Autoimmunity to the p53 protein is a feature of systemic lupus erythematosus (SLE) related to anti-DNA antibodies. J Autoimmunity 17(1), 63-9. https://doi.org/10.1006/jaut.2001.0518
Hockin, B. C. D., Heeney, N. D., Whitehurst, D. G. T., & Claydon, V. E. (2022). Evaluating the impact of orthostatic syncope and presyncope on quality of life: A systematic review and meta-analysis. Frontiers in Cardiovascular Medicine 9, 834879. https://doi.org/10.3389/fcvm.2022.834879
Ismail, D. K., El-Tagui, M. H., Hussein, Z. A., Eid, M. A., & Aly, S. M. (2018). Evaluation of health-related quality of life and muscular strength in children with beta thalassemia major. The Egyptian Journal of Medical Human Genetics 19(4), 353-357. https://doi.org/10.1016/j.ejmhg.2018.04.005
Jameel, T., Baig, M., Ahmed, I., Hussain, M. B., & Alkhamaly, M. B. D. (2017). Differentiation of beta thalassemia trait from iron deficiency anemia by hematological indices. Pakistan Journal of Medical Sciences 33(3), 665-669. https://doi.org/10.12669/pjms.333.12098
Jeong, J. K. & Park, S. Y. (2015). Neuroprotective effect of cellular prion protein (PrPC) is related with activation of alpha7 nicotinic acetylcholine receptor (7nAchR)-mediated autophagy flux. Oncotarget 6(28), 24660-74. https://doi.org/10.18632/oncotarget.4953
Ju, J. Y. & Zhao, Q. (2018). [Regulation of γ-globin gene expression and its clinical applications]. Yi Chuan 40(6), 429-444. Chinese. https://pubmed.ncbi.nlm.nih.gov/29959116/
Karadag, F., Kirdar, S., Karul, A. B., & Ceylan, E. (2008). The value of C-reactive protein as a marker of systemic inflammation in stable chronic obstructive pulmonary disease. European Journal of Internal Medicine 19(2), 104-8. https://doi.org/10.1016/j.ejim.2007.04.026
Kattamis, C., Metaxotou-Mavromati, A., Wood, W. G., Nash, J. R., & Weatherall, D. J. (1979). The heterogeneity of normal Hb A2-beta thalassemia in Greece. British Journal of Hematology 42(1), 109-23. https://doi.org/10.1111/j.1365-2141.1979.tb03703.x
Khan, K. M. & Jialal, I. (2024). Folic acid deficiency. [Updated 2023 Jun 26]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; Available from: https://www.ncbi.nlm.nih.gov/books/NBK535377/
Khan, S., Shafiei, M. S., Longoria, C., Schoggins, J. W., Savani, R. C., & Zaki, H. (2021). SARS-CoV-2 spike protein induces inflammation via TLR2-dependent activation of the NF-B pathway. eLife 10, e68563. https://doi.org/10.7554/eLife.68563
Kim, Y., Ryu, J., Ryu, M. S., Lim, S., Han, K. O., Lim, I. K., & Han, K. H. (2014). C-reactive protein induces G2/M phase cell cycle arrest and apoptosis in monocytes through the upregulation of B-cell translocation gene 2 expression. FEBS Letters 588(4), 625-31. https://doi.org/10.1016/j.febslet.2014.01.008
Kuhn, H. M., Kromminga, A., Flammann, H. T., Frey, M., Layer, P., & Arndt, R. (1999). p53 autoantibodies in patients with autoimmune diseases: a quantitative approach. Autoimmunity 31(4), 229-35. https://doi.org/10.3109/08916939908994068
Kyriakopoulos, A. M. & McCullough, P. A. (2021). Synthetic mRNAs; Their analogue caps and contribution to disease. Diseases 9(3), 57. https://doi.org/10.3390/diseases9030057
Kyriakopoulos, A. M., Nigh, G., McCullough, P. A., & Seneff, S. (2022). Mitogen activated protein kinase (MAPK) activation, p53, and autophagy inhibition characterize the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein induced neurotoxicity. Cureus 14(12), e32361. https://doi.org/10.7759/cureus.32361
Langer, H. T., Mossakowski, A. A., Sule, R., Gomes, A., & Baar, K. (2022). Dominant-negative p53-overexpression in skeletal muscle induces cell death and fiber atrophy in rats. Cell Death & Disease 13, 716. https://doi.org/10.1038/s41419-022-05160-6
Lavin, M. & Gueven, N. (2006). The complexity of p53 stabilization and activation. Cell Death & Differentiation 13, 941-950. https://doi.org/10.1038/sj.cdd.4401925
Leitzke, M. (2023). Is the post-COVID-19 syndrome a severe impairment of acetylcholine-orchestrated neuromodulation that responds to nicotine administration? Bioelectronic Medicine 9, 2. https://doi.org/10.1186/s42234-023-00104-7
Lentz, T. L., Burrage, T. G., Smith, A. L., Crick, J., & Tignor, G. H. (1982). Is the acetylcholine receptor a rabies virus receptor? Science 215(4529), 182-184. https://doi.org/10.1126/science.7053569
Liang, S., Bao, C., Yang, Z., Liu, S., Sun, Y., Cao, W., Wang, T., Schwantes-An, T.-H., Choy, J. S., Naidu, S., Luo, A., Yin, W., Black, S. M., Wang, J., Ran, P., Desai, A. A. & Tang, H. (2023). SARS-CoV-2 spike protein induces IL-18-mediated cardiopulmonary inflammation via reduced mitophagy. Signal Transduction and Targeted Therapy 8, 108. https://doi.org/10.1038/s41392-023-01368-w
Li, F., Li, J., Wang, P. H., Yang, N., Huang, J., Ou, J., Xu, T., Zhao, X., Liu, T., Huang, X., Wang, Q., Li, M., Yang, L., Lin, Y., Cai, Y., Chen, H., & Zhang, Q. (2021). SARS-CoV-2 spike promotes inflammation and apoptosis through autophagy by ROS-suppressed PI3K/AKT/mTOR signaling. Biochimica et Biophysica Acta: Molecular Basis of Disease 1867(12), 166260. https://doi.org/10.1016/j.bbadis.2021.166260
Liu, J. J., Hou, S. C., & Shen, C. K. (2003). Erythroid gene suppression by NF-kB. Journal of Biological Chemistry 278, 1953440. https://doi.org/10.1074/jbc.M212278200
Maacke, H., Kessler, A., Schmiegel, W., Roeder, C., Vogel, I., Deppert, W., & Kalthoff, H. (1997). Overexpression of p53 protein during pancreatitis. British Journal of Cancer 75(10), 1501-4. https://doi.org/10.1038/bjc.1997.256
Mank, V., Azhar, W., & Brown, K. (2024). Leukocytosis. National Library of Medicine. https://www.ncbi.nlm.nih.gov/books/NBK560882/
Mashhadi, M. A., Sepehri, Z., Heidari, Z., Shirzaee, E., & Kiani, Z. (2014). The prevalence of zinc deficiency in patients with thalassemia in South East of Iran, Sistan and Baluchistan province. Iranian Red Crescent Medical Journal 16(8), e6243. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4222021/
Matta, A., Kallamadi, R., Matta, D., & Bande, D. (2021). Post-mRNA COVID-19 vaccination myocarditis. European Journal of Case Reports in Internal Medicine 8(8), 002769. https://doi.org/10.12890/2021_002769
Mazzola, A., Todesco, E., Drouin, S., Hazan, F., Marot, S., Thabut, D., Varnous, S., Soulié, C., Barrou, B., Marcelin, A. G., & Conti, F. (2022). Poor antibody response after two doses of severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2) vaccine in transplant recipients. Clinical Infectious Diseases 74(6), 1093-1096. https://doi.org/10.1093/cid/ciab580
Moftah, W. M., Mohammed, E. K., Morsy, A. A., & Ibrahim, A. A. (2020). Ischemia modified albumin and C-reactive protein in children with β-thalassemia major. Open Journal of Pediatrics 10(3). https://doi.org/10.4236/ojped.2020.103046
Musallam, K. M., Sankaran, V. G., Cappellini, M. D., Duca, L., Nathan, D. G., & Taher, A. T. (2012). Fetal hemoglobin levels and morbidity in untransfused patients with β-thalassemia intermedia. Blood 119(2), 364-7. https://doi.org/10.1182/blood-2011-09-382408
Musallam, K. M., Taher, A. T., Cappellini, M. D., Hermine, O., Kuo, K. H. M., Sheth, S., Viprakasit, V., & Porter, J. B. (2022). Untreated anemia in nontransfusion-dependent β-thalassemia: Time to sound the alarm. Hemasphere 6(12), e806. https://doi.org/10.1097/HS9.0000000000000806
Naeimzadeh, Y., Tajbakhsh, A., & Fallahi, J. (2024). Understanding the prion-like behavior of mutant p53 proteins in triple-negative breast cancer pathogenesis: The current therapeutic strategies and future directions. Heliyon 10(4), e26260. https://doi.org/10.1016/j.heliyon.2024.e26260
Nasouhipur, H., Banihashemi, A., Youssefi Kamangar, R., & Akhavan-Niaki, H. (2014). Hb Knossos: HBB:c.82G>T associated with HBB:c.315+1G>A beta zero mutation causes thalassemia intermedia. Indian Journal of Hematology and Blood Transfusion 30 (Suppl 1), 243-5. https://doi.org/10.1007/s12288-014-0343-y
National Institute of Neurological disorders and stroke. (ND) Peripheral Neuropathy. Accessed: February 6, 2024. https://www.ninds.nih.gov/health-information/disorders/peripheral-neuropathy
Ng, X. L., Betzler, B. K., Testi, I., Ho, S. L., Tien, M., Ngo, W. K., Zierhut, M., Chee, S. P., Gupta, V., Pavesio, C. E., de Smet, M. D., & Agrawal, R. (2021). Ocular adverse events after COVID-19 vaccination. Ocular Immunology and Inflammation 29(6), 1216-1224. https://doi.org/10.1080/09273948.2021.1976221
Noureldine, M. H. A., Taher, A. T., Haydar, A. A., Berjawi, A., Khamashta, M. A., & Uthman, I. (2018). Rheumatological complications of beta-thalassemia: An overview. Rheumatology (Oxford) 57(1), 19-27. https://doi.org/10.1093/rheumatology/kex058
Oliveira, A. S. F., Ibarra, A. A., Bermudez, I., Casalino, L., Gaieb, Z., Shoemark, D. K., Gallagher, T., Sessions, R. B., Amaro, R. E., & Mulholland, A. J. (2020). Simulations support the interaction of the SARS-CoV-2 spike protein with nicotinic acetylcholine receptors. bioRxiv Preprint. 2020.07.16.206680. https://doi.org/10.1101/2020.07.16.206680
Oppenheim, A., Yaari, A., Rund, D., Rachmilewitz, E. A., Nathan, D., Wong, C., Kazazian, H. H. Jr., & Miller, B. (1990). Intrinsic potential for high fetal hemoglobin production in a Druz family with beta-thalassemia is due to an unlinked genetic determinant. Human Genetics 86(2), 175-80. https://doi.org/10.1007/BF00197701
Pari, B., Babbili, A., Kattubadi, A., Thakre, A., Thotamgari, S., Gopinathannair, R. Olshansky, B., & Dominic, P. (2023). COVID-19 vaccination and cardiac arrhythmias: A review. Current Cardiology Reports 25(9), 925-940. https://doi.org/10.1007/s11886-023-01921-7
Park, S. K., Park, S., Pentek, C., & Liebman, S. W. (2020). Tumor suppressor protein p53 expressed in yeast can remain diffuse, form a prion, or form unstable liquid-like droplets. iScience 24(1), 102000. https://doi.org/10.1016/j.isci.2020.102000
Patone, M., Mei, X. W., Handunnetthi, L., Dixon, S., Zaccardi, F., Shankar-Hari, M., Watkinson, P., Khunti, K., Harnden, A., Coupland, C. A. C., Channon, K. M., Mills, N. L., Sheikh, A., & Hippisley-Cox, J. (2022). Risks of myocarditis, pericarditis, and cardiac arrhythmias associated with COVID-19 vaccination or SARS-CoV-2 infection. Nature Medicine 28, 410–422. https://doi.org/10.1038/s41591-021-01630-0
Paulson, R. F., Hariharan, S., & Little, J. A. (2020). Stress erythropoiesis: definitions and models for its study. Experimental Hematology 89, 43-54.e2. https://doi.org/10.1016/j.exphem.2020.07.011
Pearson, T. A., Mensah, G. A., Alexander, R. W., Anderson, J. L., Cannon, R. O., Criqui, M., Fadl, Y. Y., Fortmann, S. P., Hong, Y., Myers, G. L., Rifai, N., Smith, S. C., Taubert, K., Tracy, R. P., & Vinicor, F. (2003). Markers of inflammation and cardiovascular disease. Circulation, 107(3), 499–511. https://doi.org/10.1161/01.CIR.0000052939.59093.45
Perez, J.-C., Moret-Chalmin, C., Montagnier, L. (2023). Emergence of a new Creutzfeldt-Jakob disease: 26 cases of the human version of mad-cow disease, days after a COVID-19 injection. International Journal of Vaccine Theory, Practice, and Research 3(1), 727-770. https://doi.org/10.56098/ijvtpr.v3i1.66
Porter, P., Gown, A., Kramp, S., & Coltrera, M. (1992). Widespread p53 overexpression in human malignant tumors. An immunohistochemical study using methacarn-fixed, embedded tissue. The American Journal of Pathology 140(1), 145-53. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1886248/
Rivella, S. (2009). Ineffective erythropoiesis and thalassemias. Current Opinion in Hematology 16(3), 187-94. https://doi.org/10.1097/MOH.0b013e32832990a4
Rodríguez-Núñez, I., Torres, G., Luarte-Martinez, S., Manterola, C., & Zenteno, D. (2020). Respiratory muscle impairment evaluated with MEP/MIP ratio in children and adolescents with chronic respiratory disease. Revista Paulista de Pediatria 39, e2019414. https://doi.org/10.1590/1984-0462/2021/39/2019414
Rose MS, Koshman ML, Ritchie D, & Sheldon R. (2009). The development and preliminary validation of a scale measuring the impact of syncope on quality of life. EP Europace 11(10), 1369-74. https://doi.org/10.1093/europace/eup106
Roth, I. L., Lachover, B., Koren, G., Levin, C., Zalman, L., & Koren, A. (2018). Detection of β-thalassemia carriers by red cell parameters obtained from automatic counters using mathematical formulas. Mediterranean Journal of Hematology and Infectious Diseases 10(1), e2018008. https://doi.org/10.4084/MJHID.2018.008
Ruangrai, W. & Jindadamrongwech, S. (2016). Genetic factors influencing hemoglobin F level in β-thalassemia/HB E disease. Southeast Asian Journal of Tropical Medicine and Public Health 47(1), 84-91. https://pubmed.ncbi.nlm.nih.gov/27086429/
Safary, A., Akbarzadeh-Khiavi, M., Barar, J., & Omidi, Y. (2023). SARS-CoV-2 vaccine-triggered autoimmunity: Molecular mimicry and/or bystander activation of the immune system. Bioimpacts 13(4), 269-273. https://doi.org/10.34172/bi.2023.27494
Sanchez-Villalobos, M., Blanquer, M., Moraleda, J. M., Salido, E. J., & Perez-Oliva, A. B. (2022). New insights into pathophysiology of β-thalassemia. Frontiers in Medicine (Lausanne) 9, 880752. https://doi.org/10.3389/fmed.2022.880752
Sawaya, R. A., Zahed, L., & Taher, A. (2006). Peripheral neuropathy in thalassemia. Annals of Saudi Medicine 26(5), 358-63. https://doi.org/10.5144/0256-4947.2006.358
Seneff, S., Kyriakopoulos, A. M., Nigh, G., & McCullough, P. A. (2023). A potential role of the spike protein in neurodegenerative diseases: A narrative review. Cureus 15(2), e34872. https://doi.org/10.7759/cureus.34872
Shapira, Y., Glick, B., Finsterbush, A., Goldfarb, A., & Rosenmann, E. (1990). Myopathological findings in thalassemia major. European Neurology 30(6), 324-7. https://doi.org/10.1159/000117365
Shukla, A. K., Spurrier, J., Kuzina, I., & Giniger, E. (2019). Hyperactive innate immunity causes degeneration of dopamine neurons upon altering activity of Cdk5 [Published erratum appears in Cell Reports 2021;35(10):109258]. Cell Reports 26(1), 131-144.e4. https://doi.org/10.1016/j.celrep.2018.12.025
Singh, N. & Bharara Singh, A. (2020). S2 subunit of SARS-nCoV-2 interacts with tumor suppressor protein p53 and BRCA: an in silico study. Translational Oncology 13(10), 100814. https://doi.org/10.1016/j.tranon.2020.100814
Smith, J. D., Moylan, J. S., Hardin, B. J., Chambers, M. A, Estus, S., Telling, G. C., & Reid M. B. (2011). Prion protein expression and functional importance in skeletal muscle. Antioxidants & Redox Signalling 15(9), 2465-2475. https://doi.org/10.1089/ars.2011.3945
Sobhani, N., Roviellod, G., D’Angelo, A., Roudi, R., Neeli, P., & Generali, D. (2021). p53 Antibodies as a diagnostic marker for cancer: A meta-analysis. Molecules 26(20), 6215. https://doi.org/10.3390/molecules26206215
Soontornpanawet, C., Singha, K., Srivorakun, H., Tepakhan, W., Fucharoen, G., & Fucharoen, S. (2023). Molecular basis of a high Hb A2/Hb Fβ-thalassemia trait: a retrospective analysis, genotype-phenotype interaction, diagnostic implication, and identification of a novel interaction with α-globin gene triplication. PeerJ 11, e15308. https://doi.org/10.7717/peerj.15308
Steinacker, P., Hawlik, A., Lehnert, S., Jahn, O., Meier, S., Görz, E., Braunstein, K. E., Krzovska, M., Schwalenstöcker, B., Jesse, S., Pröpper, C., Böckers, T., Ludolph, A., & Otto. M. (2010). Neuroprotective function of cellular prion protein in a mouse model of amyotrophic lateral sclerosis. American Journal of Pathology 176(3), 1409-20. https://doi.org/10.2353/ajpath.2010.090355
Steinberg, M. H., & Rodgers, G. P. (2015). hemoglobin A2: biology, clinical relevance and a possible target for ameliorating sickle cell disease. British Journal of Hematology 170(6), 781-7. https://doi.org/10.1111/bjh.13570
Suppiah, A. & Greenman, J. (2013). Clinical utility of anti-p53 auto-antibody: systematic review and focus on colorectal cancer. World Journal of Gastroenterology 19(29), 4651-70. https://doi.org/10.3748/wjg.v19.i29.4651
Swadźba, J., Panek, A., Wąsowicz, P., Anyszek, T., & Martin, E. (2024). High Concentration of anti-SARS-CoV-2 antibodies 2 years after COVID-19 vaccination stems not only from boosters but also from widespread, often unrecognized, contact with the virus. Vaccines 12(5), 471. https://doi.org/10.3390/vaccines12050471
Thilakarathne, S., Jayaweera, U. P., & Premawardhena, A. (2024). Unresolved laboratory issues of the heterozygous state of β-thalassemia: a literature review. Hematologica 109(1), 23-32. https://doi.org/10.3324/hematol.2022.282667
Tillman, T. S., Chen, Q., Bondarenko, V., Coleman, J. A., Xu, Y., & Tang, P. (2023). SARS-CoV-2 spike protein downregulates cell surface α7nAChR through a helical motif in the spike neck. ACS Chemical Neuroscience 14(4), 689-698. https://doi.org/10.1021/acschemneuro.2c00610
Treisman, R., Orkin, S. H., & Maniatis, T. (1983). Specific transcription and RNA splicing defects in five cloned beta-thalassemia genes. Nature 302(5909), 591-6. https://doi.org/10.1038/302591a0
Tzetis, M., Traeger-Synodinos, J., Kanavakis, E., Metaxotou-Mavromati, A., & Kattamis, C. (1994). The molecular basis of normal hemoglobin A2 (type 2) beta-thalassemia in Greece. Hematologic Pathology 8(1-2), 25-34. https://pubmed.ncbi.nlm.nih.gov/8034555/
Whitledge, J. D., Ali, N., Basit, H., & Grossman, S. A. (2024). Presyncope. [Updated 2023 Jul 17]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing. Available from: https://www.ncbi.nlm.nih.gov/books/NBK459383/
Williams, A. B. & Schumacher, B. (2016). p53 in the DNA-damage-repair process. Cold Spring Harbor Perspectives in Medicine 6(5), a026070. https://doi.org/10.1101/cshperspect.a026070
Yamsri, S., Singha, K., Prajantasen, T., Taweenan, W., Fucharoen, G., Sanchaisuriya, K., & Fucharoen, S. (2015). A large cohort of β(+)-thalassemia in Thailand: molecular, hematological and diagnostic considerations. Blood Cells, Molecules and Diseases 54(2), 164-9. https://doi.org/10.1016/j.bcmd.2014.11.008
Yang, Y. & Du, L. (2021). SARS-CoV-2 spike protein: a key target for eliciting persistent neutralizing antibodies. Signal Transduction Targeted Therapy 6, 95. https://doi.org/10.1038/s41392-021-00523-5
Yang, Z. & Klionsky, D. J. (2009). An overview of the molecular mechanism of autophagy. Current Topics in Microbiology and Immunology 335, 1-32. https://doi.org/10.1007/978-3-642-00302-8
Yang, Z., Goronzy, J. J., & Weyand, C. M. (2015). Autophagy in autoimmune disease. Journal of Molecular Medicine (Berl) 93(7), 707-17. https://doi.org/10.1007/s00109-015-1297-8
Yao, H., Zhao, D., Khan, S. H., & Yang, L. (2013). Role of autophagy in prion protein-induced neurodegenerative diseases. Acta Biochimica et Biophysica Sinica 45(6), 494-502. https://doi.org/10.1093/abbs/gmt022
Zambalde, É. P., Dias, T. L., Maktura, G. C., Amorim, M. R., Brenha, B., Santos, L. N., Buscaratti, L., Elston, J. G. A., Mancini, M. C. S., Pavan, I. C. B., Toledo-Teixeira, D. A., Bispo-Dos-Santos, K., Parise, P. L., Morelli, A. P., Silva, L. G. S. D., Castro, Í. M. S., Saccon, T. D., Mori, M. A., Granja, F., Nakaya, H. I., Proenca-Modena, J. L., Marques-Souza, H., & Simabuco, F. M. (2022). Increased mTOR signaling and impaired autophagic flux are hallmarks of SARS-CoV-2 infection. Current Issues in Molecular Biology 45(1), 327-336. https://doi.org/10.3390/cimb45010023
Zhang, J. &Chen, X. (2019). p53 tumor suppressor and iron homeostasis. The FEBS Journal 286(4), 620-629. https://doi.org/10.1111/febs.14638
Zhang, Q., Shan, K. S., Ogunnaike, B. A., Amewuame-Kpehor, A., & Nace, T. (2020). An exceedingly rare presentation of severe folate deficiency-induced non-immune hemolytic anemia. Cureus 12(6), e8570. https://doi.org/10.7759/cureus.8570
Zhang, S. & El-Deiry, W. S. (2024). SARS-CoV-2 spike S2 subunit inhibits p53 activation of p21(WAF1), TRAIL Death Receptor DR5 and MDM2 proteins in cancer cells. bioRxiv preprint. April 15. https://doi.org/10.1101/2024.04.12.589252
Zheng, H., You, H., Zhou, X. Z., Murray, S. A., Uchida, T., Wulf, G., Gu, L., Tang, X., Lu, K. P., Xiao, Z. X. (2002). The prolyl isomerase Pin1 is a regulator of p53 in genotoxic response. Nature 419(6909), 849-53. https://doi.org/10.1038/nature01116
Zivny, J. H., Gelderman, M P., Xu, F., Piper, J., Holada, K., Simak, J., & Vostal, J. G. (2008). Reduced erythroid cell and erythropoietin production in response to acute anemia in prion protein-deficient (Prnp-/-) mice. Blood Cells, Molecules and Diseases 40(3), 302-7. https://doi.org/10.1016/j.bcmd.2007.09.009
van Dijk, N., Boer, K. R., Wieling, W., Linzer, M., & Sprangers, M. A. (2007). Reliability, validity and responsiveness of the S functional status questionnaire. Journal of General Internal Medicine 22(9), 1280-5. https://doi.org/10.1007/s11606-007-0266-5
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