Thromboses and Hemostasis Disorders Associated with COVID-19: The Possible Causal Role of Cross-Reactivity and Immunological Imprinting
Darja Kanduc
Thromboses and Hemostasis Disorders Associated with COVID-19: The Possible Causal Role of Cross-Reactivity and Immunological Imprinting
By examining the issue of the thromboses and hemostasis disorders associated with severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) through the lens of cross-reactivity, it was found that 60 pentapeptides are shared by SARS-CoV-2 spike glycoprotein (gp) and human proteins that— when altered, mutated, deficient or, however, improperly functioning— cause vascular diseases, thromboembolic complications, venous thrombosis, thrombocytopenia, coagulopathies, and bleeding, inter alia. The peptide commonality has a relevant immunological potential as almost all of the shared sequences are present in experimentally validated SARS-CoV-2 spike gp-derived epitopes, thus supporting the possibility of cross-reactions between the viral gp and the thromboses-related human proteins. Moreover, many of the shared peptide sequences are also present in pathogens to which individuals have previously been exposed following natural infection or vaccinal routes, and of which the immune system has stored imprint. Such an immunological memory might rapidly trigger anamnestic secondary cross-reactive responses of extreme affinity and avidity, in this way explaining the thromboembolic adverse events that can associate with SARS-CoV-2 infection or active immunization.
COVID-19 / SARS-CoV-2 spike gp / cross-reactivity / immunological imprinting / thromboses-related proteins / thromboses / vascular diseases / bleeding
[1] |
Ng JJ, Choong AMTL.Thromboembolic events in patients with SARS-CoV-2. J Vasc Surg 2020;72(02):760-761
|
[2] |
Cui S, Chen S, Li X, Liu S, Wang F.Prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia. J Thromb Haemost 2020;18(06):1421-1424
|
[3] |
Klok FA, Kruip MJHA, van der Meer NJM. et al. Incidence of thrombotic complications in critically ill ICU patients with COVID-19. Thromb Res 2020;191:145-147
|
[4] |
Lucchese G, Capone G, Kanduc D.Peptide sharing between influenza A H1N1 hemagglutinin and human axon guidance proteins. Schizophr Bull 2014;40(02):362-375
|
[5] |
Lucchese G, Kanduc D.Potential crossreactivity of human immune responses against HCMV glycoprotein B. Curr Drug Discov Technol 2016;13(01):16-24
|
[6] |
Lucchese G, Kanduc D.Zika virus and autoimmunity: From microcephaly to Guillain-Barré syndrome, and beyond. Autoimmun Rev 2016;15(08):801-808
|
[7] |
Kanduc D.Pentapeptides as minimal functional units in cell biology and immunology. Curr Protein Pept Sci 2013;14(02): 111-120
|
[8] |
Kanduc D.Homology, similarity, and identity in peptide epitope immunodefinition. J Pept Sci 2012;18(08):487-494
|
[9] |
UniProt Consortium. UniProt: a worldwide hub of protein knowledge. Nucleic Acids Res 2019;47(D1):D506-D515
|
[10] |
Vita R,Mahajan S, Overton JA, et al.The Immune Epitope Database (IEDB): 2018 update. Nucleic Acids Res 2019;47(D1):D339-D343
|
[11] |
Lupu C, Zhu H, Popescu NI, Wren JD, Lupu F.Novel protein ADTRP regulates TFPI expression and function in human endothelial cells in normal conditions and in response to androgen. Blood 2011; 118(16):4463-4471
|
[12] |
Thiel C, Schwarz M, Peng J, et al.A new type of congenital disorders of glycosylation (CDG-Ii) provides new insights into the early steps of dolichol-linked oligosaccharide biosynthesis. J Biol Chem 2003;278(25):22498-22505
|
[13] |
Schollen E, Frank CG, Keldermans L, et al.Clinical and molecular features of three patients with congenital disorders of glycosylation type Ih (CDG-Ih) (ALG8 deficiency). J Med Genet 2004;41(07):550-556
|
[14] |
Yoshizaki H, Mizoguchi T, Arai K, Shiratsuchi M, Shidara Y, Maki M.Structure and properties of calphobindin II, an anticoagulant protein from human placenta. J Biochem 1990;107(01):43-50
|
[15] |
Huizing M, Malicdan MCV, Wang JA, et al.Hermansky-Pudlak syndrome: mutation update. Hum Mutat 2020;41(03):543-580
|
[16] |
Xu F, Previti ML, Nieman MT, Davis J, Schmaier AH, Van Nostrand WE.AbetaPP/APLP2 family of Kunitz serine proteinase inhibitors regulate cerebral thrombosis. J Neurosci 2009;29(17):5666-5670
|
[17] |
Chang WA, Sheu CC, Liu KT, Shen JH, Yen MC, Kuo PL.Identification of mutations in SLC4A1, GP1BA and HFE in a family with venous thrombosis of unknown cause by next-generation sequencing. Exp Ther Med 2018;16(05):4172-4180
|
[18] |
Hansske B, Thiel C, Lübke T, et al.Deficiency of UDP-galactose:Nacetylglucosamine beta-1,4-galactosyltransferase I causes the congenital disorder of glycosylation type IId. J Clin Invest 2002; 109(06):725-733
|
[19] |
Blom AM, Villoutreix BO, Dahlbäck B.Functions of human complement inhibitor C4b-binding protein in relation to its structure. Arch Immunol Ther Exp (Warsz) 2004;52(02):83-95
|
[20] |
Buil A, Trégouët DA, Souto JC, et al.C4BPB/C4BPA is a new susceptibility locus for venous thrombosiswith unknown protein S-independent mechanism: results from genome-wide association and gene expression analyses followed by case-control studies. Blood 2010;115(23):4644-4650
|
[21] |
Sikora M, Lewandowska I, Marczak Ł, Bretes E, Jakubowski H.Cystathionine β-synthase deficiency: different changes in proteomes of thrombosis-resistant Cbs-/- mice and thrombosisprone CBS-/- humans. Sci Rep 2020;10(01):10726
|
[22] |
Nuytinck L, Freund M, Lagae L, Pierard GE, Hermanns-Le T, De Paepe A.Classical Ehlers-Danlos syndrome caused by a mutation in type I collagen. Am J Hum Genet 2000;66(04):1398-1402
|
[23] |
Malfait F, Symoens S, De Backer J, et al.Three arginine to cysteine substitutions in the pro-alpha (I)-collagen chain cause Ehlers- Danlos syndrome with a propensity to arterial rupture in early adulthood. Hum Mutat 2007;28(04):387-395
|
[24] |
Foulquier F, Vasile E, Schollen E, et al.Conserved oligomeric Golgi complex subunit 1 deficiency reveals a previously uncharacterized congenital disorder of glycosylation type II. Proc Natl Acad Sci U S A 2006;103(10):3764-3769
|
[25] |
Kodera H, Ando N, Yuasa I, et al.Mutations in COG2 encoding a subunit of the conserved oligomeric golgi complex cause a congenital disorder of glycosylation. Clin Genet 2015;87(05): 455-460
|
[26] |
Paesold-Burda P, Maag C, Troxler H, et al.Deficiency in COG5 causes a moderate form of congenital disorders of glycosylation. Hum Mol Genet 2009;18(22):4350-4356
|
[27] |
Kaczmarek E, Koziak K, Sévigny J, et al.Identification and characterization of CD39/vascular ATP diphosphohydrolase. J Biol Chem 1996;271(51):33116-33122
|
[28] |
Savio LEB, Robson SC, Longhi MS.Ectonucleotidasemodulation of lymphocyte function in gut and liver. Front Cell Dev Biol 2021; 8:621760
|
[29] |
Berrou E, Soukaseum C, Favier R, et al.A mutation of the human EPHB2 gene leads to a major platelet functional defect. Blood 2018;132(19):2067-2077
|
[30] |
Ivaskevicius V, Biswas A, Bevans C, et al.Identification of eight novel coagulation factor XIII subunit A mutations: implied consequences for structure and function. Haematologica 2010;95(06):956-962
|
[31] |
Castoldi E, Simioni P, Kalafatis M, et al.Combinations of 4 mutations (FV R506Q, FV H1299R, FV Y1702C, PT 20210G/A) affecting the prothrombinase complex in a thrombophilic family. Blood 2000;96(04):1443-1448
|
[32] |
Poursadegh Zonouzi A, Chaparzadeh N, Ghorbian S, et al.The association between thrombophilic gene mutations and recurrent pregnancy loss. J Assist Reprod Genet 2013;30(10): 1353-1359
|
[33] |
Casas JP, Hingorani AD, Bautista LE, Sharma P.Meta-analysis of genetic studies in ischemic stroke: thirty-two genes involving approximately 18,000 cases and 58,000 controls. Arch Neurol 2004;61(11):1652-1661
|
[34] |
Mumford AD, McVey JH, Morse CV, et al. Factor V I359T: a novel mutation associated with thrombosis and resistance to activated protein C. Br J Haematol 2003;123(03):496-501
|
[35] |
Al-Allaf FA, Taher MM, Abduljaleel Z, et al.Molecular analysis of factor VIII and factor IX genes in hemophilia patients: identification of novel mutations and molecular dynamics studies. J Clin Med Res 2017;9(04):317-331
|
[36] |
Asselta R, Platè M, Robusto M, et al.Clinical and molecular characterisation of 21 patients affected by quantitative fibrinogen deficiency. Thromb Haemost 2015;113(03):567-576
|
[37] |
Benson MD, Liepnieks J, Uemichi T, Wheeler G, Correa R.Hereditary renal amyloidosis associated with amutant fibrinogen alphachain. Nat Genet 1993;3(03):252-255
|
[38] |
Koopman J, Haverkate F, Grimbergen J, et al.Molecular basis for fibrinogen Dusart (A alpha 554 Arg->Cys) and its association with abnormal fibrin polymerization and thrombophilia. J Clin Invest 1993;91(04):1637-1643
|
[39] |
Wilberding JA, Castellino FJ.Characterization of the murine coagulation factor X promoter. Thromb Haemost 2000;84(06): 1031-1038
|
[40] |
Hung HL, Pollak ES, Kudaravalli RD, Arruda V, Chu K, High KA.Regulation of human coagulation factor X gene expression by GATA-4 and the Sp family of transcription factors. Blood 2001;97(04):946-951
|
[41] |
Li RG, Li L, Qiu XB, et al.GATA4 loss-of-function mutation underlies familial dilated cardiomyopathy. Biochem Biophys Res Commun 2013;439(04):591-596
|
[42] |
Almomani MH, Mangla A.Bernard soulier syndrome. In: Stat- Pearls. Treasure Island, FL: StatPearls Publishing; 2021
|
[43] |
Cheng YC, Stanne TM, Giese AK, et al; WTCCC-2 Consortium. Genome-wide association analysis of young-onset stroke identifies a locus on chromosome 10q25 near HABP2. Stroke 2016;47(02):307-316
|
[44] |
Anderson PD, Huizing M, Claassen DA, White J, Gahl WA.Hermansky- Pudlak syndrome type 4 (HPS-4): clinical and molecular characteristics. Hum Genet 2003;113(01):10-17
|
[45] |
Botero JP, Chen D, Majerus JA, et al.Hermansky-Pudlak syndrome subtype 5 (HPS-5) novel mutation in a 65 year-old with oculocutaneous hypopigmentation and mild bleeding diathesis: the importance of recognizing a subtle phenotype. Platelets 2018;29(01):91-94
|
[46] |
Xia G, Chen J, Tiwari V, et al.Heparan sulfate 3-O-sulfotransferase isoform 5 generates both an antithrombin-binding site and an entry receptor for herpes simplex virus, type 1. J Biol Chem 2002; 277(40):37912-37919
|
[47] |
Liu H, Wang Y, Zheng J, et al.Platelet glycoprotein gene Ia C807T, HPA-3, and Ibα VNTR polymorphisms are associated with increased ischemic stroke risk: Evidence from a comprehensive meta-analysis. Int J Stroke 2017;12(01):46-70
|
[48] |
Reznik EV, Shcherbakova ES, Borisovskaya SV, et al.ST-elevation myocardial infarction, pulmonary embolism, and cerebral ischemic stroke in a patient with critically low levels of natural anticoagulants. J Cardiol Cases 2019;21(03):106-109
|
[49] |
French DL, Coller BS.Hematologically important mutations: Glanzmann thrombasthenia. Blood Cells Mol Dis 1997;23(01): 39-51
|
[50] |
Chung RT, Iafrate AJ, Amrein PC, Sahani DV, Misdraji J.Case records of the Massachusetts General Hospital. Case 15-2006. A 46-year-oldwomanwith sudden onset of abdominal distention.N Engl J Med 2006;354(20):2166-2175
|
[51] |
Stockklausner C, Duffert CM, Cario H, Knöfler R, Strei fW, Kulozik AETHROMKID-Plus Studiengruppe der Gesellschaft für Thrombose- und Hämostaseforschung (GTH) and of Gesellschaft für Pädiatrische Onkologie und Hämatologie (GPOH). Thrombocytosis in children and adolescents-classification, diagnostic approach, and clinical management. Ann Hematol 2021;100(07): 1647-1665
|
[52] |
Hayward CP, Rivard GE, Kane WH, et al.An autosomal dominant, qualitative platelet disorder associated with multimerin deficiency, abnormalities in platelet factor V, thrombospondin, von Willebrand factor, and fibrinogen and an epinephrine aggregation defect. Blood 1996;87(12):4967-4978
|
[53] |
Althaus K, Möller P, Uzun G, et al.Antibody-mediated procoagulant platelets in SARS-CoV-2-vaccination associated immune thrombotic thrombocytopenia. Haematologica 2021;106(08): 2170-2179
|
[54] |
Ichinose A, Espling ES, Takamatsu J, et al.Two types of abnormal genes for plasminogen in families with a predisposition for thrombosis. Proc Natl Acad Sci U S A 1991;88(01):115-119
|
[55] |
Boinot C, Borgel D, Kitzis A, Guicheteau M, Aiach M, Alhenc-Gelas M.Familial thrombophilia is an oligogenetic disease: involvement of the prothrombin G20210A, PROC and PROS gene mutations. Blood Coagul Fibrinolysis 2003;14(02):191-196
|
[56] |
Makris M, Leach M, Beauchamp NJ, et al.Genetic analysis, phenotypic diagnosis, and risk of venous thrombosis in families with inherited deficiencies of protein S. Blood 2000;95(06): 1935-1941
|
[57] |
Koren-Michowitz M, Eting E, Rahimi-Levene N, Garach-Jehoshua O, Volcheck Y, Kornberg A.Protein Z levels and central retinal vein or artery occlusion. Eur J Haematol 2005;75(05):401-405
|
[58] |
Senis YA, Tomlinson MG, Ellison S, et al. The tyrosine phosphatase CD148 is an essential positive regulator of platelet activation and thrombosis. Blood 2009;113(20):4942-4954
|
[59] |
Bogdanov VY, Balasubramanian V, Hathcock J, Vele O, Lieb M, Nemerson Y.Alternatively spliced human tissue factor: a circulating, soluble, thrombogenic protein. Nat Med 2003;9(04): 458-462
|
[60] |
Glenn KC, Frost GH, Bergmann JS, Carney DH.Synthetic peptides bind to high-affinity thrombin receptors and modulate thrombin mitogenesis. Pept Res 1988;1(02):65-73
|
[61] |
Ohlin AK, Norlund L,Marlar RA.Thrombomodulin gene variations and thromboembolic disease. Thromb Haemost 1997;78(01): 396-400
|
[62] |
Vincent JL, Francois B, Zabolotskikh I, et al; SCARLET Trial Group. Effect of a recombinant human soluble thrombomodulin on mortality in patients with sepsis-associated coagulopathy: The SCARLET randomized clinical trial. JAMA 2019;321(20): 1993-2002
|
[63] |
Vincent JL, Ramesh MK, Ernest D, et al.A randomized, doubleblind, placebo-controlled, Phase 2b study to evaluate the safety and efficacy of recombinant human soluble thrombomodulin, ART-123, in patients with sepsis and suspected disseminated intravascular coagulation. Crit Care Med 2013;41(09):2069-2079
|
[64] |
Zhang XJ, Wei CY, Li WB, et al.Association between single nucleotide polymorphisms in thrombospondins genes and coronary artery disease: A meta-analysis. Thromb Res 2015;136(01): 45-51
|
[65] |
Allen S, Abuzenadah AM, Hinks J, et al.A novel von Willebrand disease-causing mutation (Arg273Trp) in the von Willebrand factor propeptide that results in defective multimerization and secretion. Blood 2000;96(02):560-568
|
[66] |
Horiuchi H, Doman T, Kokame K, Saiki Y, Matsumoto M. Acquired von Willebrand syndrome associated with cardiovascular diseases. J Atheroscler Thromb 2019;26(04):303-314
|
[67] |
Mital A.Acquired von Willebrand syndrome. Adv Clin Exp Med 2016;25(06):1337-1344
|
[68] |
Lucchese G, Kanduc D.The Guillain-Barrè peptide signatures: from Zika virus to campylobacter, and beyond. Virus Adaptation and Treatment 2017;9:1-11
|
[69] |
Lucchese G, Kanduc D.Minimal immune determinants connect Zika virus, human Cytomegalovirus, and Toxoplasma gondii to microcephaly-related human proteins. Am J Reprod Immunol 2017;77(02):e12608
|
[70] |
Kanduc D, Shoenfeld Y.Inter-pathogen peptide sharing and the original antigenic sin: solving a paradox. Open Immunol J 2018; 8:16-27
|
[71] |
Kanduc D.Anti-SARS-CoV-2 immune response and sudden death: titin as a link. Adv Stud Biol 2021;13:37-44
|
[72] |
Francis T, Salk JE, Quilligan JJ.Experiencewith vaccination against influenza in the spring of 1947: a preliminary report. Am J Public Health Nations Health 1947;37(08):1013-1016
|
[73] |
Davenport FM, Hennessy AV, Francis T Jr.Epidemiologic and immunologic significance of age distribution of antibody to antigenic variants of influenza virus. J Exp Med 1953;98(06): 641-656
|
[74] |
Halstead SB.Which dengue vaccine approach is the most promising, and should we be concerned about enhanced disease after vaccination? There is only one true winner. Cold Spring Harb Perspect Biol 2018;10(06):a030700. Doi: 10.1101/cshperspect.a030700
|
[75] |
Natale C, Giannini T, Lucchese A, Kanduc D.Computer-assisted analysis ofmolecular mimicry between human papillomavirus 16 E7 oncoprotein and human protein sequences. Immunol Cell Biol 2000;78(06):580-585
|
[76] |
Kanduc D.Peptide cross-reactivity: the original sin of vaccines. Front Biosci (Schol Ed) 2012;4:1393-1401
|
[77] |
Kanduc D.Immunogenicity, immunopathogenicity, and immunotolerance in one graph. Anticancer Agents Med Chem 2015;15(10):1264-1268
|
[78] |
Kanduc D.From anti-SARS-CoV-2 immune responses to COVID-19 via molecular mimicry. Antibodies (Basel) 2020; 9(03):33
|
[79] |
Kanduc D.Immunobiology: on the inexistence of a negative selection process. Adv Stud Biol 2020;12:19-28
|
[80] |
Kanduc D.Hydrophobicity and the physico-chemical basis of immunotolerance. Pathobiology 2020;87(04):268-276
|
[81] |
Kanduc D.The role of proteomics in defining autoimmunity. Expert Rev Proteomics 2021;18(03):177-184
|
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