Suspected Causes of the Specific Intolerance Profile of Spike-Based Covid-19 Vaccines (Review/Analysis)
Main Article Content
Abstract
The aim of this review is to provide explanations for many of the reported adverse reactions associated with spike-based Covid-19 vaccination and to draw appropriate conclusions.
Based on the comparatively disproportionate spectrum of adverse reactions of spike-based vaccines, an overwhelming body of evidence supports the consequences of the main mode of action of spike-based Covid-19 vaccines, namely the downregulation of angiotensin-converting enzyme 2 (ACE2) by spikes. This enzyme is a key protective counterregulator in the renin-angiotensin-aldosterone system. The renin-angiotensin-aldosterone system is not only responsible for cardiovascular homeostasis, but is also involved in pro-inflammatory, procoagulant, pro-fibrotic and immunological effects via its main vasoconstrictor effector, angiotensin II. This may explain the magnitude and diversity of the spectrum of side effects.
Other spike effects (cell fusion, binding to heparan sulphate, activation of Toll-like receptor 4), synergisms (increase in des-arg9-bradykinin, catecholamines) and impairment of intestinal amino acid uptake complement and multiply the already adverse effects of spike-related downregulation of ACE2 on tolerability.
Spike-based Covid-19 vaccines are characterised by a class-specific profile of adverse reactions. A causal relationship between an activated renin-angiotensin-aldosterone system and vasoconstrictive and ischaemic sequelae can be considered to be proven. Therefore, stimulation of the renin-angiotensin-aldosterone system and co-medication with vasoconstrictive, catecholaminergic or TLR4- and DABK-activating and heparan sulphate-inhibiting drugs should be avoided for the duration of spike efficacy.
It has been shown that vaccine spikes are distributed systemically and are detectable in the body for longer than previously thought. According to current knowledge, the time window for assessing a causal relationship between vaccination and adverse reactions can be extended to up to six months.
The variability of adverse effects is likely to be comparatively high, especially for spike-inducing vaccines, as the occurrence and severity of adverse reactions can be influenced by numerous individual factors and counter-regulatory mechanisms. There are no findings on this.
The exceptionally wide range, frequency and severity of reported adverse reactions associated with spike-based Covid-19 vaccination exceeds the known level of conventional vaccination and is a cause for serious concern. From a pharmacological point of view, spikes are highly potent substances, but they are not innocuous antigens. Therefore, they do not appear to be suitable for preventive immunisation against comparatively harmless infections.
Keywords:
Spike-based Covid-19 vaccination, spike induced adverse drug reactions, mode of action of spikes
Article Details
How to Cite
LEHMANN, Karla Johanna.
Suspected Causes of the Specific Intolerance Profile of Spike-Based Covid-19 Vaccines (Review/Analysis).
Medical Research Archives, [S.l.], v. 12, n. 9, oct. 2024.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/5704>. Date accessed: 14 oct. 2024.
doi: https://doi.org/10.18103/mra.v12i9.5704.
Section
Review Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
1. Ioannides JPA. Infection fatality rate of COVID-19 inferred from seroprevalence data. Bull World Health Organ 2021; 99:19–33F
2. Streeck H, Schulte B, Kümmerer BM, Richter E, Höller T, Fuhrmann Ch, et al. Infection fatality rate of SARS-CoV2 in a super-spreading event in Germany. Nature Comm 2020; 11: 5829
3. Covid-19 Forecasting Team: Variation in the COVID-19 infection-fatality ratio by age, time, and geography during the pre-vaccine era: a systematic analysis. Lancet 2022; 399: 1469-88
4. https://karla-lehmann.de/wp-content/uploads/2021/12/Das-Impfjahr-2021.pdf
5. Rancourt DG, Hickey J, Linard Ch. Spatiotemporal variation of excess all-cause mortality in the world (125 countries) during the Covid period 2020-2023 regarding socio-economic factors and public-health and medical interventions. correlation-canada.org; 2024
6. Lehmann KJ. The Global and Specific Cardiovascular Burden of Spike-Based COVID-19 Vaccination Int J Cardiol Res 2023; 12: 5
7. Lehmann KJ. Suspected Cardiovascular Side Effects of Two COVID-19 Vaccines. J. of Biology and Today‘s World 2021, 10(5): 001-006
8. Lehmann KJ. Spike-Induced Disturbances (SPAS*): An Analysis of Common Suspected Adverse Experiences Associated With Covid-19 Vaccines, I J Infectious Disea; 2022, 3(1): 1-19
9. https://www.adrreports.eu/en/search_subst.html
10. Lowe D. Spike Protein Behavior. Science ASCA Corporation; 4 May 2021
11. Ogata AF, Cheng CA, Desjardins M, Senussi Y, Sherman AC, Powell M et al. Circulating SARS-CoV-2 Vaccine Antigen Detected in the Plasma of mRNA-1273 Vaccine Recipients Clin Infect Dis 2021; ciab465, 1-4
12. Cognetti, JS, Miller BL. Monitoring Serum Spike Protein with Disposable Photonic Biosensors Following SARS-CoV-2 Vaccination. Sensors 2021; 21:5857
13. Trougakos IP, Terpos E, Alexopoulos H, Politou M, Paraskevis D, Scorilas A et al. Adverse effects of COVID-19 mRNA vaccines: the spike hypothesis. Trends Mol Med. 2022; 28(7):542–554
14. Brogna C, Cristoni S, Marino G, Montano L, Viduto V, Fabrowski M et al. Detection of recombinant spike protein in the blood of individuals vaccinated against SARS-CoV-2: possible molecular mechanims. Proteomics 2023; 17/6: 2300048
15. Nakahara T, Iwabucchi Y, Miyazawa R, Tonda K, Shiga T, Strauss HW et al. Assessment of Myocardial 18F-FDG Uptake at PET/CT in Asymptomatic SARS-CoV-2–vaccinated and Nonvaccinated Patients. Radiology 2023; 308(3):e230743
16. Röltgen K, Nielsen SCA, Silva O, Pinsky BA, Nadeau KC, Boyd SD et al. Immune imprinting, breadth of variant recognition, and germinal center response in human SARS-CoV-2 infection and vaccination. Cell 2022; 185(6):1025-1040
17. Castruita JAS, Schneider UV, Mollerup S, Leineweber ThD, Weis N, Bukh J et al. SARS-CoV-2 spike mRNA vaccine sequences circulate in blood up to 28 days after COVID-19 vaccination. J Path Microbiol Immunol 2023;131/3: 128-132
18. Krauson AJ, Casimero FV, Siddiquee Z, and Stonde JB: Duration of SARS-COV-2 mRNA vaccine persistence and factors associated with cardiac involvement in recently vaccinated patients. npjVaccines 2023;8/141
19. Marquez-Martinez S, Khan S, van der Lubbe J, Solforosi L, Costes LM, Choi L. The Biodistribution of the Spike Protein after Ad26.COV2.S Vaccination Is Unlikely to Play a Role in Vaccine-Induced Immune Thrombotic Thrombocytopenia. Vaccines 2024; 12(5): 559
20. Rong Z, Mai H, Kapoor S, Puelles VG, Czogalla J, Schädler J et al. SARS-CoV-2 Spike Protein Accumulation in the Skull-Meninges-Brain Axis: Potential Implications for Long-Term Neurological Complications in post-COVID-19. 2023; doi:https://doi.org/10.1101/2023.04.04.535604
21. Yonker LM, Swank Z, Bartsch YC, Burns MD, Kane A, Boribong BP et al. Circulating Spike Protein Detected in Post–COVID-19 mRNA Vaccine Myocarditis. Circulation 2023; 147/11: 867-876
22. Hikmet F, Mear L, Edvinsson A, Micke P, Uhlen M, and Lindskog C. The protein expression profile of ACE2 in human tissue. Mol Syst Biol 2020;16:e9610
23. Gupta A, Madhavan MV, Sehgal K, Nair N, Mahajan S, Sehrawat TS et al. Extrapulmonary manifestations of COVID-19. Nat Med 2020: 26: 1017-1032
24. Verdecchia P, Cavallini C, Spanevello A, and Angeli F: The pivotal link between ACE2 deficiency and SARSCov-2 infection. Eur J Intern Med 2020; 76: 14-20
25. Lehmann KJ: SARS-CoV-2-Spike Interactions with the Renin-Angiotensin-Aldosterone System – Consequences of Adverse Reactions of Vaccination. J Biol Today’s World 2023; 12/4: 001-013; https://doi.org/10.31219/osf.io/27g5h
26. Lehmann KJ: Impact of SARS-CoV-2 Spikes on Safety of Spike-Based COVID-19 Vaccinations. Immunome Res. 2024; 20:267.
27. Osman IO, Melenotte C, Brouqui Ph, Stein A, La Scola B, Meddeb L et al. Expression of ACE2, soluble ACE2, Angiotensin I, Angiotensin II and Angiotensin (1-7) is modulated in Covid-19 Patients. Front Immunol 2021; 12. https://doi.org/10.3389/fimmu.2021.625732
28. Imai Y, Kuba K and Penninger JM: The discovery of angiotensin‐converting enzyme 2 and its role in acute lung injury in mice. Exp Physiol. 2008; 93(5): 543–548.
29. Kuba K, Imai Y and Penninger JM: Angiotensin-converting enzyme in lung diseases. Curr Opin Pharmacol. 2006; 6(3): 271–276.
30. Patra T, Meyer K, Geerling L, Scott Isbel T, Hoft DF, Brien J et al. SARS-CoV-2 spike protein promotes IL-6 trans-signaling by activation of angiotensin II receptor signaling in epithelial cells. PLoS Pathog 2020; 16(12): e1009128. https://journals.plos.org/plos-pathogens/article?id=10.1371/journal.ppat.1009128
31. Lei Y, Zhang J, Schiavon CR, He M, Chen L, Shen H et al. SARS-CoV-2 spike protein impairs endothelial function via downregulation of ACE2. Circulation Research 2021; 128:1323–1326
32. Nuovo G, Magro C, Shaffer T, Awad H, Suster D, Mikhail S et al. Endothelial cell damage is the central part of COVID-19 and a mouse model induced by injection of the S1 subunit of the spike protein. Ann Diagn Pathol. 2021; 51: 151682
33. Zhang S, Liu Y, Wang X, Yang L, Li H, Wang Y et al. SARS-CoV-2 binds platelet ACE2 to enhance thrombosis in COVID-19. J Hematol Oncol 2020; 13(1):120
34. Lesgard JF, Cerdan D, Perrone Ch, Sabatier JM, Azalbert X, Rodgers E et al. Toxicity of SARS-CoV-2 Spike Protein from the Virus and Produced from COVID-19 mRNA or Adenoviral DNA Vaccines. Arch Microbiol Immun 2023; 7: 121- 138.
35. Tabassum A, Iqbal MS, Sultan S, Alhuthali RA, Alshubaili DI, Sayyam RS et al. Dysregulated Bradykinin: Mystery in the Pathogenesis of COVID-19. Mediators of inflammation 2022; Article ID 7423537
36. Rostamzadeh F, Najafipour H, Nakhaei S, Yazdani R and Langari AA. Low Ang (1–7) and high des-Arg9 bradykinin serum levels are correlated with cardiovascular risk factors in patients with COVID-19. Open Medicine https://doi.org/10.1515/med-2023-0741
37. Lazebnik Y: Cell fusion as a link between the SARS-CoV-2 spike protein, COVID-19 complications, and vaccine side effects. Oncotarget. 2021; 12(25): 2476–2488.
38. Braga L, Ali H, Secco I, Chiavacci E, Neves G, Goldhill D et al. Drugs that inhibit TMEM16 proteins block SARS-CoV-2 spike-induced syncytia. Nature 2021; 594: 88-93
39. PEI (03/2021): Messen, was verbindet – Gewebeschäden durch Zellfusion in COVID-19 und die Rolle des Spikeproteins https://www.pei.de/DE/newsroom/pm/jahr/2021/03-gewebeschaeden-zellfusion-covid-19-rolle-spikeprotein.html
40. Theuerkauf SA, Michels A, Riechert V, Maier TJ, Flory E, Cichutek K et al. Quantitative assays reveal cell fusion at minimal levels of SARS-CoV-2 spike protein and fusion from without. iScience 2021; 24: 102170
41. Liu X, Wei L, Xu F, Zhao F, Gui F et al. SARS-CoV-2 spike protein–induced cell fusion activates the cGAS-STING pathway and the interferon response Sci Signal 12 apr 2022;15, Issue 729
42. Murphy WJ, and Longo DL. A Possible Role for Anti-idiotype Antibodies in SARS-CoV-2 Infection and Vaccination. N Engl J Med 2022; 386:394-396
43. Tsoi JYH, Cai J, Situ J, Lam WJ, Shun EHK, Leung JKY et al. Autoantibodies against angiotensin-converting enzyme 2 (ACE2) after COVID-19 infection or vaccination. J Medical Virology 2023; 95/12: e29313
44. Lai Y-Ch, Cheng Y-W, Chao Ch-H, Chang Y-Y, Chen Ch-D, Tsai W-J et al. Antigenic Cross-Reactivity Between SARS-CoV-2 S1-RBD and Its Receptor ACE2. Front Immunol. 2022; 13: 868724
45. Zhang Z, Li L, Li M, Wang X. The SARS-CoV-2 host cell receptor ACE2 correlates positively with immunotherapy response and is a potential protective factor for cancer progression. Computational and Structural Biotechnology Journal 2020; 18:2438-2444
46. Benigni A, Cassis P and Remuzzi G. Angiotensin II revisited: new roles in inflammation, immunology and aging. EMBO Mol Med 2010; 2:247-257; https://doi.org/10.1002/emmm.201000080
47. Ekholm M, Kahan T. The Impact of the Renin-Angiotensin-Aldosterone System on Inflammation, Coagulation, and Atherothrombotic Complications, and to Aggravated COVID-19. Front Pharmacol. 2021; 12: 640185
48. Kaschina E, Unger Th. Angiotensin AT1/AT2 Receptors: Regulation, Signalling and Function. Blood pressure 2003; 12: 70-88
49. Padia SH, and Carey RM. AT2 receptors: beneficial counter-regulatory role in cardiovascular and renal function. Pfluegers Arch. 2013; 465(1):99-110; Publ. online 2012 Sep 5 doi: 10.1007/s00424-012-1146-3
50. Satou R, Penrose H and Navar LG. Inflammation as a Regulator of the Renin-Angiotensin System and Blood Pressure. Curr Hypertens Rep. 2018; 20(12): 100. doi: 10.1007/s11906-018-0900-0
51. Mehta PK and Griendling KK. Angiotensin II cell signaling: physiological and pathological effects in the cardiovascular system. Am J Physiol Cell Physiol 2007; 292: C82–C97; doi:10.1152/ajpcell.00287.2006.
52. Gong S, Deng F. Renin-angiotensin system: The underlying mechanisms and promising therapeutical target for depression and anxiety. Front. Immunol 2023; 13: 1053136
53. Hallaj S, Ghorbani A, Mousavi-Aghdas SA, Mirza-Aghazadeh-Attari M, Sevbitov A, Hashemi V et al. Angiotensin-converting enzyme as a new immunologic target for the new SARS-CoV-2. Immun Cell Biol 2021; 99/2: 192-205; https://doi.org/10.1111/imcb.12396
54. Crowley SD and Rudemiller NP. Immunologic Effects of the Renin-Angiotensin System. J Am Soc Nephrol. 2017; 28(5):1350–1361.
55. Gomez RA, Norling LL, Wilfong N, Isakson P, Lynch KR, Hock R and Quesenberry P. Leukocytes Synthesize Angiotensinogen. Hypertension 1993; 21:470-47
56. Weinstock JV and Blum AM. Granuloma macrophages in murine schistosomiasis mansoni generate components of the angiotensin system. Cell Immunol 1984 a; 89(1):39-45.
57. Nataraj Ch, Oliverio MI, Mannon RB,Mannon PJ, Audoly LP, Amuchastegui CS, Ruiz P et al. Angiotensin II regulates cellular immune responses through a calcineurin-dependent pathway. Clin. Invest. 1999; 104:1693–1701
58. Inuzuka T, Fujioka Y, Tsuda M, Fujioka M, Satoh AO, Horiuchi K. Attenuation of ligand-induced activation of angiotensin II type 1 receptor signaling by the type 2 receptor via proteinkinase C. Scientific Reports 2016; 6: 21613
59. Terenzi R, Manetti M, Rosa I, Romano E, Galluccio F, Guiducci S et al. Angiotensin II type 2 receptor (AT2R) as a novel modulator of inflammation in rheumatoid arthritis synovium. Scientific Reports 2017; 7: 13293
60. Pei N, Mao Y, Wan P, Chen X, Li A, Chen H et al. Angiotensin II type 2 receptor promotes apoptosis and inhibits angiogenesis in bladder cancer. Journal of Experimental & Clinical Cancer Research 2017; 36: 77
61. Ni, J, Yang F, Huang XR, Meng J, Chen J, Bader M. Dual deficiency of angiotensin-converting enzyme-2 and Mas receptor enhances angiotensin II-induced hypertension and hypertensive nephropathy. J. Cell. Mol. Med. 2020; 24:13093–13103
62. Penninger JM, Grant MB, Sung JJY. The role of angiotensin converting enzyme 2 in modulating gut microbiota, intestinal inflammation, and coronavirus infection. Gastroenterology. 2021;160(1):39-46.
63. Badi SA, Khatami S, Siadat SD. Tripartite communication in COVID-19 infection: SARS-CoV-2 pathogenesis, gut microbiota and ACE2. Future Virol. 2022;17(11):773-776.
64. Hashimoto T, Perlot Th,Rehman A, Trichereau J,Ishiguro H, Paolino M, et al. ACE2 links amino acid malnutrition to microbial ecology and intestinal inflammation. Nature. 2012;487(7408):477- 481.
65. Yan R, Zhang Y, Li Y, Xia L, Guo Y, Zhou Q. Structural basis for the recognition of SARS-CoV-2 by full-length human ACE2. Science. 2021;367(6485):1444-1448.
66. Guo Y, Wang B, Gao H, Gao L, Hua R, Xu D. ACE2 in the gut: The center of the 2019-nCoV infected pathology. Front Mol Biosci. 2021; 8:708336
67. Singer D, Camargo SMR, RamadanT, Schäfer M, Mariotta L, Herzog B, et al. Defective intestinal amino acid absorption in Ace2 null mice. Am J Physiol Gastrointest Liver Physiol. 2012; 303(6):G686-G695.
68. Wong AC, Devason AS, Umana IC, Cox TO, Dohnalová L, Litichevskiy L, et al. Serotonin reduction in post-acute sequelae of viral infection. Cell. 2023;186(22): 4851-4867.
69. Ng SC, Peng Y,Zhang L, Mok ChKP, Zhao S,Li A, et al. Gut microbiota composition is associated with SARS-CoV-2 vaccine immunogenicity and adverse events. Gut. 2022;71(6):1106-1116.
70. Zhao Y, Kuang M, Li J, Zhu L, Jia Z, Guo X, et al. SARSCoV-2 spike protein interacts with and activates TLR41. Cell Res. 2021;31(7):818-820.
71. Halajian EA, Leblanc EV, Gee K, Colpitts ChC. Activation of TLR4 by viral glycoproteins: A double-edged sword? Front Microbiol. 2022;13:1007081.
72. Ye R, Liu Z. ACE2 exhibits protective effects against LPS-induced acute lung injury in mice by inhibiting the LPS-TLR4 pathway. Exp Mol Pathol. 2020;113:104350
73. Nakashima T, Umemoto S, Yoshimura K, Matsuda S, Itoh S, Murata T, et al. TLR4 is a critical regulator of angiotensin II induced vascular remodelling: The roles of extracellular SOD and NADPH oxidase. Hypertens Res. 2015;38(10):649-655.
74. Theobald D, Nair AR, Sriramula S, Francis J. Cardiomyocytespecific deletion of TLR4 attenuates angiotensin II-induced hypertension and cardiac remodelling. Front Cardiovasc Med. 2023; 10: 1074700.
75. Biancardi VC, Bomfim GF, Reis WL, Al-Gassimi S, Nunes KP. The interplay between Angiotensin II, TLR4 and hypertension. Pharmacol Res. 2017;120:88-96.
76. Feng Q, Liu D, Lu Y, Liu Z. The interplay of renin-angiotensin system and toll-like receptor 4 in the inflammation of diabetic nephropathy. J Immunol Res. 2020;6193407.
77. Aboudounya MM, Heads RJ. COVID-19 and toll-like receptor 4 (TLR4): SARS-CoV-2 may bind and activate TLR4 to increase ACE2 expression, facilitating entry and causing hyper inflammation. Mediators Inflamm. 2021; 8874339
78. Frank MG, Nguyen KH, Ball JB, Hopkins S, Kelley T, Baratta MV, et al. SARS-CoV-2 spike S1 subunit induces neuroinflammatory, microglial and behavioral sickness responses: Evidence of PAMPlike properties. Brain Behav Immun. 2022;100:267-277.
79. Fontes-Dantas L, Fernandes GG, Gutman EG, de Lima EV, Antonio LS, Hammerle MB, et al. SARS-CoV-2 spike protein induces TLR4-mediated long-term cognitive dysfunction recapitulating postCOVID-19 syndrome in mice. Cell Rep. 2023;42(3):112189.
80. Collins LE, Troeberg L. Heparan sulfate as a regulator of inflammation and immunity. J Leukoc Biol. 2018:105(1):81-92.
81. Davis DA, Parish ChR. Heparan sulfate: A ubiquitous glycosaminoglycan with multiple roles in immunity. Front Immunol. 2013;4:470.
82. Ling J, Li J, Khan A, Lundkvist A, Li JP. Is heparan sulfate a target for inhibition of RNA virus infection? Am J Physiol Cell Physiol. 2022;322(4): C605-C613
83. Clausen TM, Sandoval DR, Spliid ChB, Pihl J, Perrett HR, Painter CD, et al. SARS-CoV-2 infection depends on cellular heparan sulfate and ACE2. Cell. 2020;183(4):1047-1057; P1043-1057.
84. Zheng Y, Zhao J, Li J, Guo Z, Sheng J, Ye X, et al. SARS-CoV-2 spike protein causes blood coagulation and thrombosis by competitive binding to heparan sulfate. Int J Biol Macromol. 2021;193:1124-1129.
85. Zerebrale Vaskulitis und zerebrale Beteiligung bei systemischen Vasculitiden und rheumatischen Grunderkrankungen, AWMF online, AWMF-Register-Nu.:030/085, Leitlinien für Diagnostik und Therapie in der Neurologie, DGN 2018
86. Arandela K, Samudrala S, Abdelkader M, Anand P, Daneshmand A, Dasenbrock H et al. Reversible Cerebral Vasoconstriction Syndrome in Patients with Coronavirus Disease: A Multicenter Case Series. J Stroke Cerebrovasc Dis. 2021; 30(12): 106118
87. Finsterer J. First reported Case of reversible cerebral vasoconstriction syndrome after a SARS-CoV-2 Vaccine. Cureus 2021; 13(11): e19987
88. Lund AM, Al-Karagholi MAM. Covid-19 Vaccination Might Induce Reversible Cerebral Vasoconstrictio Syndrome Attacks: A Case report Vaccines 2022; 10(5): 823
89. Srichawla B. Reversible Cerebral Vasoconstriction Syndrome (RCVS) After COVID-19 Vaccination: An Analysis of VAERS (P2-7.004) Neurology 2023; 100 17/2
90. McCullough J, Ahmad M, Tam I, Portnoy R, Ng J Zachary K et al. Posterior Reversible Encephalopathy Syndrome Onset Within 24 Hours following Moderna mRNA Booster COVID-19 Vaccination: Vaccine Adverse Event Vs. Hypertension? Cureus 2022 14/5: e24919
91. Patone M, Handunnetthi L, Saatci D, Pan J, Katikiredc SV, Razvi S et al. Neurological complications after first dose of Covid-19 vaccines and SARS-CoV-2 infection. nature medicines, https://doi.org/10.1038/ s41591-021-01556-7.
92. Mentzer D, Oberle D, Streit R, Weisser K, and Keller-Stanislawski B. Sicherheitsprofil der COVID-19 Impfstoffe – Sachstand 31.03.2023 PEI Ausgabe 2, Juni 2023
93. Tawakul AA, Al-Doboke AW, Altayyar SA, Alsulami SA, Alfahmi AM and Nooh RT. Guillain-Barré Syndrome in the COVID-19 Pandemic Neurol. Int. 2022; 14, 34–48.
94. Satou, R, Penrose H and Navar LG. Inflammation as a regulator of the Renin-Angiotensin system and blood pressure. Curr Hypertens Rep. 2018; 20:100.
95. Xia H. and Lazartigues F. Angiotensin-converting enzyme 2 in the brain: properties and future directions. J Neurochemistry 2008; 107: 1482-1494
96. Robinson FA, Mihealsick RP, Wagener BM, Hanna P, Poston MD, Efimov IR et al. Role of angiotensin-converting enzyme 2 and pericytes in cardiac complications of COVID-19 infection. Am J Physiol Heart Circ Physiol. 2020; 319:H1059–H1068
97. Gill JR, Tashjian R, and Duncanson E. Autopsy Histopathologic cardiac findings in two adolescents following the second COVID-19 vaccine dose. Arch Pathol Lab Med. 2022; 146: 925-929.
98. Simpson CR, Shi T, Vasileiou E, Katikireddi SV, Kerr S, Moore E. First-dose ChAdOx1 and BNT162b2 COVID-19 vaccines and thrombocytopenic, thromboembolic and hemorrhagic events in Scotland. Nature Medicine 2021; 27: 1290–1297
99. Matzdorff A, Meyer O, Ostermann H, Kiefel V, Eberl W, Kühne T, Pabinger H et al. Immune Thrombocytopenia - Current Diagnostics and Therapy: Recommendations of a Joint Working Group of DGHO, ÖGHO, SGH, GPOH, and DGTI Oncol Res Treat 2018;41(suppl 5):1-30; https://doi.org/10.1159/000492187
100. EMA: 24 March 2021 EMA/PRAC/157045/2021 Pharmacovigilance Risk Assessment Committee (PRAC): Signal assessment report on embolic and thrombotic events (SMQ) with COVID-19 Vaccine (ChAdOx1-S [recombinant]) – COVID-19 Vaccine AstraZeneca (Other viral vaccines) EPITT no:19683
101. Schultz NH, Sorvoll IH, Michelsen AE, Munthe LA, Lund-Johansen F, Ahlen MT et al. Thrombosis and Thrombocytopenia after ChAdOx1 nCoV-19 Vaccination. N Engl J Med 2021; 384:2124-2130
102. Scully M, Singh D, Lown R, Poles A, Solomon T, Levi M et al. Pathologic Antibodies to Platelet Factor 4 after ChAdOx1 nCoV-19 Vaccination. N Engl J Med. 2021; NEJMoa2105385
2. Streeck H, Schulte B, Kümmerer BM, Richter E, Höller T, Fuhrmann Ch, et al. Infection fatality rate of SARS-CoV2 in a super-spreading event in Germany. Nature Comm 2020; 11: 5829
3. Covid-19 Forecasting Team: Variation in the COVID-19 infection-fatality ratio by age, time, and geography during the pre-vaccine era: a systematic analysis. Lancet 2022; 399: 1469-88
4. https://karla-lehmann.de/wp-content/uploads/2021/12/Das-Impfjahr-2021.pdf
5. Rancourt DG, Hickey J, Linard Ch. Spatiotemporal variation of excess all-cause mortality in the world (125 countries) during the Covid period 2020-2023 regarding socio-economic factors and public-health and medical interventions. correlation-canada.org; 2024
6. Lehmann KJ. The Global and Specific Cardiovascular Burden of Spike-Based COVID-19 Vaccination Int J Cardiol Res 2023; 12: 5
7. Lehmann KJ. Suspected Cardiovascular Side Effects of Two COVID-19 Vaccines. J. of Biology and Today‘s World 2021, 10(5): 001-006
8. Lehmann KJ. Spike-Induced Disturbances (SPAS*): An Analysis of Common Suspected Adverse Experiences Associated With Covid-19 Vaccines, I J Infectious Disea; 2022, 3(1): 1-19
9. https://www.adrreports.eu/en/search_subst.html
10. Lowe D. Spike Protein Behavior. Science ASCA Corporation; 4 May 2021
11. Ogata AF, Cheng CA, Desjardins M, Senussi Y, Sherman AC, Powell M et al. Circulating SARS-CoV-2 Vaccine Antigen Detected in the Plasma of mRNA-1273 Vaccine Recipients Clin Infect Dis 2021; ciab465, 1-4
12. Cognetti, JS, Miller BL. Monitoring Serum Spike Protein with Disposable Photonic Biosensors Following SARS-CoV-2 Vaccination. Sensors 2021; 21:5857
13. Trougakos IP, Terpos E, Alexopoulos H, Politou M, Paraskevis D, Scorilas A et al. Adverse effects of COVID-19 mRNA vaccines: the spike hypothesis. Trends Mol Med. 2022; 28(7):542–554
14. Brogna C, Cristoni S, Marino G, Montano L, Viduto V, Fabrowski M et al. Detection of recombinant spike protein in the blood of individuals vaccinated against SARS-CoV-2: possible molecular mechanims. Proteomics 2023; 17/6: 2300048
15. Nakahara T, Iwabucchi Y, Miyazawa R, Tonda K, Shiga T, Strauss HW et al. Assessment of Myocardial 18F-FDG Uptake at PET/CT in Asymptomatic SARS-CoV-2–vaccinated and Nonvaccinated Patients. Radiology 2023; 308(3):e230743
16. Röltgen K, Nielsen SCA, Silva O, Pinsky BA, Nadeau KC, Boyd SD et al. Immune imprinting, breadth of variant recognition, and germinal center response in human SARS-CoV-2 infection and vaccination. Cell 2022; 185(6):1025-1040
17. Castruita JAS, Schneider UV, Mollerup S, Leineweber ThD, Weis N, Bukh J et al. SARS-CoV-2 spike mRNA vaccine sequences circulate in blood up to 28 days after COVID-19 vaccination. J Path Microbiol Immunol 2023;131/3: 128-132
18. Krauson AJ, Casimero FV, Siddiquee Z, and Stonde JB: Duration of SARS-COV-2 mRNA vaccine persistence and factors associated with cardiac involvement in recently vaccinated patients. npjVaccines 2023;8/141
19. Marquez-Martinez S, Khan S, van der Lubbe J, Solforosi L, Costes LM, Choi L. The Biodistribution of the Spike Protein after Ad26.COV2.S Vaccination Is Unlikely to Play a Role in Vaccine-Induced Immune Thrombotic Thrombocytopenia. Vaccines 2024; 12(5): 559
20. Rong Z, Mai H, Kapoor S, Puelles VG, Czogalla J, Schädler J et al. SARS-CoV-2 Spike Protein Accumulation in the Skull-Meninges-Brain Axis: Potential Implications for Long-Term Neurological Complications in post-COVID-19. 2023; doi:https://doi.org/10.1101/2023.04.04.535604
21. Yonker LM, Swank Z, Bartsch YC, Burns MD, Kane A, Boribong BP et al. Circulating Spike Protein Detected in Post–COVID-19 mRNA Vaccine Myocarditis. Circulation 2023; 147/11: 867-876
22. Hikmet F, Mear L, Edvinsson A, Micke P, Uhlen M, and Lindskog C. The protein expression profile of ACE2 in human tissue. Mol Syst Biol 2020;16:e9610
23. Gupta A, Madhavan MV, Sehgal K, Nair N, Mahajan S, Sehrawat TS et al. Extrapulmonary manifestations of COVID-19. Nat Med 2020: 26: 1017-1032
24. Verdecchia P, Cavallini C, Spanevello A, and Angeli F: The pivotal link between ACE2 deficiency and SARSCov-2 infection. Eur J Intern Med 2020; 76: 14-20
25. Lehmann KJ: SARS-CoV-2-Spike Interactions with the Renin-Angiotensin-Aldosterone System – Consequences of Adverse Reactions of Vaccination. J Biol Today’s World 2023; 12/4: 001-013; https://doi.org/10.31219/osf.io/27g5h
26. Lehmann KJ: Impact of SARS-CoV-2 Spikes on Safety of Spike-Based COVID-19 Vaccinations. Immunome Res. 2024; 20:267.
27. Osman IO, Melenotte C, Brouqui Ph, Stein A, La Scola B, Meddeb L et al. Expression of ACE2, soluble ACE2, Angiotensin I, Angiotensin II and Angiotensin (1-7) is modulated in Covid-19 Patients. Front Immunol 2021; 12. https://doi.org/10.3389/fimmu.2021.625732
28. Imai Y, Kuba K and Penninger JM: The discovery of angiotensin‐converting enzyme 2 and its role in acute lung injury in mice. Exp Physiol. 2008; 93(5): 543–548.
29. Kuba K, Imai Y and Penninger JM: Angiotensin-converting enzyme in lung diseases. Curr Opin Pharmacol. 2006; 6(3): 271–276.
30. Patra T, Meyer K, Geerling L, Scott Isbel T, Hoft DF, Brien J et al. SARS-CoV-2 spike protein promotes IL-6 trans-signaling by activation of angiotensin II receptor signaling in epithelial cells. PLoS Pathog 2020; 16(12): e1009128. https://journals.plos.org/plos-pathogens/article?id=10.1371/journal.ppat.1009128
31. Lei Y, Zhang J, Schiavon CR, He M, Chen L, Shen H et al. SARS-CoV-2 spike protein impairs endothelial function via downregulation of ACE2. Circulation Research 2021; 128:1323–1326
32. Nuovo G, Magro C, Shaffer T, Awad H, Suster D, Mikhail S et al. Endothelial cell damage is the central part of COVID-19 and a mouse model induced by injection of the S1 subunit of the spike protein. Ann Diagn Pathol. 2021; 51: 151682
33. Zhang S, Liu Y, Wang X, Yang L, Li H, Wang Y et al. SARS-CoV-2 binds platelet ACE2 to enhance thrombosis in COVID-19. J Hematol Oncol 2020; 13(1):120
34. Lesgard JF, Cerdan D, Perrone Ch, Sabatier JM, Azalbert X, Rodgers E et al. Toxicity of SARS-CoV-2 Spike Protein from the Virus and Produced from COVID-19 mRNA or Adenoviral DNA Vaccines. Arch Microbiol Immun 2023; 7: 121- 138.
35. Tabassum A, Iqbal MS, Sultan S, Alhuthali RA, Alshubaili DI, Sayyam RS et al. Dysregulated Bradykinin: Mystery in the Pathogenesis of COVID-19. Mediators of inflammation 2022; Article ID 7423537
36. Rostamzadeh F, Najafipour H, Nakhaei S, Yazdani R and Langari AA. Low Ang (1–7) and high des-Arg9 bradykinin serum levels are correlated with cardiovascular risk factors in patients with COVID-19. Open Medicine https://doi.org/10.1515/med-2023-0741
37. Lazebnik Y: Cell fusion as a link between the SARS-CoV-2 spike protein, COVID-19 complications, and vaccine side effects. Oncotarget. 2021; 12(25): 2476–2488.
38. Braga L, Ali H, Secco I, Chiavacci E, Neves G, Goldhill D et al. Drugs that inhibit TMEM16 proteins block SARS-CoV-2 spike-induced syncytia. Nature 2021; 594: 88-93
39. PEI (03/2021): Messen, was verbindet – Gewebeschäden durch Zellfusion in COVID-19 und die Rolle des Spikeproteins https://www.pei.de/DE/newsroom/pm/jahr/2021/03-gewebeschaeden-zellfusion-covid-19-rolle-spikeprotein.html
40. Theuerkauf SA, Michels A, Riechert V, Maier TJ, Flory E, Cichutek K et al. Quantitative assays reveal cell fusion at minimal levels of SARS-CoV-2 spike protein and fusion from without. iScience 2021; 24: 102170
41. Liu X, Wei L, Xu F, Zhao F, Gui F et al. SARS-CoV-2 spike protein–induced cell fusion activates the cGAS-STING pathway and the interferon response Sci Signal 12 apr 2022;15, Issue 729
42. Murphy WJ, and Longo DL. A Possible Role for Anti-idiotype Antibodies in SARS-CoV-2 Infection and Vaccination. N Engl J Med 2022; 386:394-396
43. Tsoi JYH, Cai J, Situ J, Lam WJ, Shun EHK, Leung JKY et al. Autoantibodies against angiotensin-converting enzyme 2 (ACE2) after COVID-19 infection or vaccination. J Medical Virology 2023; 95/12: e29313
44. Lai Y-Ch, Cheng Y-W, Chao Ch-H, Chang Y-Y, Chen Ch-D, Tsai W-J et al. Antigenic Cross-Reactivity Between SARS-CoV-2 S1-RBD and Its Receptor ACE2. Front Immunol. 2022; 13: 868724
45. Zhang Z, Li L, Li M, Wang X. The SARS-CoV-2 host cell receptor ACE2 correlates positively with immunotherapy response and is a potential protective factor for cancer progression. Computational and Structural Biotechnology Journal 2020; 18:2438-2444
46. Benigni A, Cassis P and Remuzzi G. Angiotensin II revisited: new roles in inflammation, immunology and aging. EMBO Mol Med 2010; 2:247-257; https://doi.org/10.1002/emmm.201000080
47. Ekholm M, Kahan T. The Impact of the Renin-Angiotensin-Aldosterone System on Inflammation, Coagulation, and Atherothrombotic Complications, and to Aggravated COVID-19. Front Pharmacol. 2021; 12: 640185
48. Kaschina E, Unger Th. Angiotensin AT1/AT2 Receptors: Regulation, Signalling and Function. Blood pressure 2003; 12: 70-88
49. Padia SH, and Carey RM. AT2 receptors: beneficial counter-regulatory role in cardiovascular and renal function. Pfluegers Arch. 2013; 465(1):99-110; Publ. online 2012 Sep 5 doi: 10.1007/s00424-012-1146-3
50. Satou R, Penrose H and Navar LG. Inflammation as a Regulator of the Renin-Angiotensin System and Blood Pressure. Curr Hypertens Rep. 2018; 20(12): 100. doi: 10.1007/s11906-018-0900-0
51. Mehta PK and Griendling KK. Angiotensin II cell signaling: physiological and pathological effects in the cardiovascular system. Am J Physiol Cell Physiol 2007; 292: C82–C97; doi:10.1152/ajpcell.00287.2006.
52. Gong S, Deng F. Renin-angiotensin system: The underlying mechanisms and promising therapeutical target for depression and anxiety. Front. Immunol 2023; 13: 1053136
53. Hallaj S, Ghorbani A, Mousavi-Aghdas SA, Mirza-Aghazadeh-Attari M, Sevbitov A, Hashemi V et al. Angiotensin-converting enzyme as a new immunologic target for the new SARS-CoV-2. Immun Cell Biol 2021; 99/2: 192-205; https://doi.org/10.1111/imcb.12396
54. Crowley SD and Rudemiller NP. Immunologic Effects of the Renin-Angiotensin System. J Am Soc Nephrol. 2017; 28(5):1350–1361.
55. Gomez RA, Norling LL, Wilfong N, Isakson P, Lynch KR, Hock R and Quesenberry P. Leukocytes Synthesize Angiotensinogen. Hypertension 1993; 21:470-47
56. Weinstock JV and Blum AM. Granuloma macrophages in murine schistosomiasis mansoni generate components of the angiotensin system. Cell Immunol 1984 a; 89(1):39-45.
57. Nataraj Ch, Oliverio MI, Mannon RB,Mannon PJ, Audoly LP, Amuchastegui CS, Ruiz P et al. Angiotensin II regulates cellular immune responses through a calcineurin-dependent pathway. Clin. Invest. 1999; 104:1693–1701
58. Inuzuka T, Fujioka Y, Tsuda M, Fujioka M, Satoh AO, Horiuchi K. Attenuation of ligand-induced activation of angiotensin II type 1 receptor signaling by the type 2 receptor via proteinkinase C. Scientific Reports 2016; 6: 21613
59. Terenzi R, Manetti M, Rosa I, Romano E, Galluccio F, Guiducci S et al. Angiotensin II type 2 receptor (AT2R) as a novel modulator of inflammation in rheumatoid arthritis synovium. Scientific Reports 2017; 7: 13293
60. Pei N, Mao Y, Wan P, Chen X, Li A, Chen H et al. Angiotensin II type 2 receptor promotes apoptosis and inhibits angiogenesis in bladder cancer. Journal of Experimental & Clinical Cancer Research 2017; 36: 77
61. Ni, J, Yang F, Huang XR, Meng J, Chen J, Bader M. Dual deficiency of angiotensin-converting enzyme-2 and Mas receptor enhances angiotensin II-induced hypertension and hypertensive nephropathy. J. Cell. Mol. Med. 2020; 24:13093–13103
62. Penninger JM, Grant MB, Sung JJY. The role of angiotensin converting enzyme 2 in modulating gut microbiota, intestinal inflammation, and coronavirus infection. Gastroenterology. 2021;160(1):39-46.
63. Badi SA, Khatami S, Siadat SD. Tripartite communication in COVID-19 infection: SARS-CoV-2 pathogenesis, gut microbiota and ACE2. Future Virol. 2022;17(11):773-776.
64. Hashimoto T, Perlot Th,Rehman A, Trichereau J,Ishiguro H, Paolino M, et al. ACE2 links amino acid malnutrition to microbial ecology and intestinal inflammation. Nature. 2012;487(7408):477- 481.
65. Yan R, Zhang Y, Li Y, Xia L, Guo Y, Zhou Q. Structural basis for the recognition of SARS-CoV-2 by full-length human ACE2. Science. 2021;367(6485):1444-1448.
66. Guo Y, Wang B, Gao H, Gao L, Hua R, Xu D. ACE2 in the gut: The center of the 2019-nCoV infected pathology. Front Mol Biosci. 2021; 8:708336
67. Singer D, Camargo SMR, RamadanT, Schäfer M, Mariotta L, Herzog B, et al. Defective intestinal amino acid absorption in Ace2 null mice. Am J Physiol Gastrointest Liver Physiol. 2012; 303(6):G686-G695.
68. Wong AC, Devason AS, Umana IC, Cox TO, Dohnalová L, Litichevskiy L, et al. Serotonin reduction in post-acute sequelae of viral infection. Cell. 2023;186(22): 4851-4867.
69. Ng SC, Peng Y,Zhang L, Mok ChKP, Zhao S,Li A, et al. Gut microbiota composition is associated with SARS-CoV-2 vaccine immunogenicity and adverse events. Gut. 2022;71(6):1106-1116.
70. Zhao Y, Kuang M, Li J, Zhu L, Jia Z, Guo X, et al. SARSCoV-2 spike protein interacts with and activates TLR41. Cell Res. 2021;31(7):818-820.
71. Halajian EA, Leblanc EV, Gee K, Colpitts ChC. Activation of TLR4 by viral glycoproteins: A double-edged sword? Front Microbiol. 2022;13:1007081.
72. Ye R, Liu Z. ACE2 exhibits protective effects against LPS-induced acute lung injury in mice by inhibiting the LPS-TLR4 pathway. Exp Mol Pathol. 2020;113:104350
73. Nakashima T, Umemoto S, Yoshimura K, Matsuda S, Itoh S, Murata T, et al. TLR4 is a critical regulator of angiotensin II induced vascular remodelling: The roles of extracellular SOD and NADPH oxidase. Hypertens Res. 2015;38(10):649-655.
74. Theobald D, Nair AR, Sriramula S, Francis J. Cardiomyocytespecific deletion of TLR4 attenuates angiotensin II-induced hypertension and cardiac remodelling. Front Cardiovasc Med. 2023; 10: 1074700.
75. Biancardi VC, Bomfim GF, Reis WL, Al-Gassimi S, Nunes KP. The interplay between Angiotensin II, TLR4 and hypertension. Pharmacol Res. 2017;120:88-96.
76. Feng Q, Liu D, Lu Y, Liu Z. The interplay of renin-angiotensin system and toll-like receptor 4 in the inflammation of diabetic nephropathy. J Immunol Res. 2020;6193407.
77. Aboudounya MM, Heads RJ. COVID-19 and toll-like receptor 4 (TLR4): SARS-CoV-2 may bind and activate TLR4 to increase ACE2 expression, facilitating entry and causing hyper inflammation. Mediators Inflamm. 2021; 8874339
78. Frank MG, Nguyen KH, Ball JB, Hopkins S, Kelley T, Baratta MV, et al. SARS-CoV-2 spike S1 subunit induces neuroinflammatory, microglial and behavioral sickness responses: Evidence of PAMPlike properties. Brain Behav Immun. 2022;100:267-277.
79. Fontes-Dantas L, Fernandes GG, Gutman EG, de Lima EV, Antonio LS, Hammerle MB, et al. SARS-CoV-2 spike protein induces TLR4-mediated long-term cognitive dysfunction recapitulating postCOVID-19 syndrome in mice. Cell Rep. 2023;42(3):112189.
80. Collins LE, Troeberg L. Heparan sulfate as a regulator of inflammation and immunity. J Leukoc Biol. 2018:105(1):81-92.
81. Davis DA, Parish ChR. Heparan sulfate: A ubiquitous glycosaminoglycan with multiple roles in immunity. Front Immunol. 2013;4:470.
82. Ling J, Li J, Khan A, Lundkvist A, Li JP. Is heparan sulfate a target for inhibition of RNA virus infection? Am J Physiol Cell Physiol. 2022;322(4): C605-C613
83. Clausen TM, Sandoval DR, Spliid ChB, Pihl J, Perrett HR, Painter CD, et al. SARS-CoV-2 infection depends on cellular heparan sulfate and ACE2. Cell. 2020;183(4):1047-1057; P1043-1057.
84. Zheng Y, Zhao J, Li J, Guo Z, Sheng J, Ye X, et al. SARS-CoV-2 spike protein causes blood coagulation and thrombosis by competitive binding to heparan sulfate. Int J Biol Macromol. 2021;193:1124-1129.
85. Zerebrale Vaskulitis und zerebrale Beteiligung bei systemischen Vasculitiden und rheumatischen Grunderkrankungen, AWMF online, AWMF-Register-Nu.:030/085, Leitlinien für Diagnostik und Therapie in der Neurologie, DGN 2018
86. Arandela K, Samudrala S, Abdelkader M, Anand P, Daneshmand A, Dasenbrock H et al. Reversible Cerebral Vasoconstriction Syndrome in Patients with Coronavirus Disease: A Multicenter Case Series. J Stroke Cerebrovasc Dis. 2021; 30(12): 106118
87. Finsterer J. First reported Case of reversible cerebral vasoconstriction syndrome after a SARS-CoV-2 Vaccine. Cureus 2021; 13(11): e19987
88. Lund AM, Al-Karagholi MAM. Covid-19 Vaccination Might Induce Reversible Cerebral Vasoconstrictio Syndrome Attacks: A Case report Vaccines 2022; 10(5): 823
89. Srichawla B. Reversible Cerebral Vasoconstriction Syndrome (RCVS) After COVID-19 Vaccination: An Analysis of VAERS (P2-7.004) Neurology 2023; 100 17/2
90. McCullough J, Ahmad M, Tam I, Portnoy R, Ng J Zachary K et al. Posterior Reversible Encephalopathy Syndrome Onset Within 24 Hours following Moderna mRNA Booster COVID-19 Vaccination: Vaccine Adverse Event Vs. Hypertension? Cureus 2022 14/5: e24919
91. Patone M, Handunnetthi L, Saatci D, Pan J, Katikiredc SV, Razvi S et al. Neurological complications after first dose of Covid-19 vaccines and SARS-CoV-2 infection. nature medicines, https://doi.org/10.1038/ s41591-021-01556-7.
92. Mentzer D, Oberle D, Streit R, Weisser K, and Keller-Stanislawski B. Sicherheitsprofil der COVID-19 Impfstoffe – Sachstand 31.03.2023 PEI Ausgabe 2, Juni 2023
93. Tawakul AA, Al-Doboke AW, Altayyar SA, Alsulami SA, Alfahmi AM and Nooh RT. Guillain-Barré Syndrome in the COVID-19 Pandemic Neurol. Int. 2022; 14, 34–48.
94. Satou, R, Penrose H and Navar LG. Inflammation as a regulator of the Renin-Angiotensin system and blood pressure. Curr Hypertens Rep. 2018; 20:100.
95. Xia H. and Lazartigues F. Angiotensin-converting enzyme 2 in the brain: properties and future directions. J Neurochemistry 2008; 107: 1482-1494
96. Robinson FA, Mihealsick RP, Wagener BM, Hanna P, Poston MD, Efimov IR et al. Role of angiotensin-converting enzyme 2 and pericytes in cardiac complications of COVID-19 infection. Am J Physiol Heart Circ Physiol. 2020; 319:H1059–H1068
97. Gill JR, Tashjian R, and Duncanson E. Autopsy Histopathologic cardiac findings in two adolescents following the second COVID-19 vaccine dose. Arch Pathol Lab Med. 2022; 146: 925-929.
98. Simpson CR, Shi T, Vasileiou E, Katikireddi SV, Kerr S, Moore E. First-dose ChAdOx1 and BNT162b2 COVID-19 vaccines and thrombocytopenic, thromboembolic and hemorrhagic events in Scotland. Nature Medicine 2021; 27: 1290–1297
99. Matzdorff A, Meyer O, Ostermann H, Kiefel V, Eberl W, Kühne T, Pabinger H et al. Immune Thrombocytopenia - Current Diagnostics and Therapy: Recommendations of a Joint Working Group of DGHO, ÖGHO, SGH, GPOH, and DGTI Oncol Res Treat 2018;41(suppl 5):1-30; https://doi.org/10.1159/000492187
100. EMA: 24 March 2021 EMA/PRAC/157045/2021 Pharmacovigilance Risk Assessment Committee (PRAC): Signal assessment report on embolic and thrombotic events (SMQ) with COVID-19 Vaccine (ChAdOx1-S [recombinant]) – COVID-19 Vaccine AstraZeneca (Other viral vaccines) EPITT no:19683
101. Schultz NH, Sorvoll IH, Michelsen AE, Munthe LA, Lund-Johansen F, Ahlen MT et al. Thrombosis and Thrombocytopenia after ChAdOx1 nCoV-19 Vaccination. N Engl J Med 2021; 384:2124-2130
102. Scully M, Singh D, Lown R, Poles A, Solomon T, Levi M et al. Pathologic Antibodies to Platelet Factor 4 after ChAdOx1 nCoV-19 Vaccination. N Engl J Med. 2021; NEJMoa2105385