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Thrombosis Journal

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01-12-2021 | Thrombocytopenia | Review

Platelet factor 4 polyanion immune complexes: heparin induced thrombocytopenia and vaccine-induced immune thrombotic thrombocytopenia

Authors: Payel Datta, Fuming Zhang, Jonathan S. Dordick, Robert J. Linhardt

Published in: Thrombosis Journal | Issue 1/2021

Abstract

Background

This is a review article on heparin-induced thrombocytopenia, an adverse effect of heparin therapy, and vaccine-induced immune thrombotic thrombocytopenia, occurring in some patients administered certain coronavirus vaccines.

Main body/text

Immune-mediated thrombocytopenia occurs when specific antibodies bind to platelet factor 4 /heparin complexes. Platelet factor 4 is a naturally occurring chemokine, and under certain conditions, may complex with negatively charged molecules and polyanions, including heparin. The antibody-platelet factor 4/heparin complex may lead to platelet activation, accompanied by other cascading reactions, resulting in cerebral sinus thrombosis, deep vein thrombosis, lower limb arterial thrombosis, myocardial infarction, pulmonary embolism, skin necrosis, and thrombotic stroke. If untreated, heparin-induced thrombocytopenia can be life threatening. In parallel, rare incidents of spontaneous vaccine-induced immune thrombotic thrombocytopenia can also occur in some patients administered certain coronavirus vaccines. The role of platelet factor 4 in vaccine-induced thrombosis with thrombocytopenia syndrome further reinforces the importance the platelet factor 4/polyanion immune complexes and the complications that this might pose to susceptible individuals. These findings demonstrate, how auxiliary factors can complicate heparin therapy and drug development. An increasing interest in biomanufacturing heparins from non-animal sources has driven a growing interest in understanding the biology of immune-mediated heparin-induced thrombocytopenia, and therefore, the development of safe and effective biosynthetic heparins.

Short conclusion

In conclusion, these findings further reinforce the importance of the binding of platelet factor 4 with known and unknown polyanions, and the complications that these might pose to susceptible patients. In parallel, these findings also demonstrate how auxiliary factors can complicate the heparin drug development.

Linhardt RJ. 2003 Claude S. Hudson award address in carbohydrate chemistry. Heparin: structure and activity. J Med Chem. 2003;46(13):2551–64. https://doi.org/10.1021/jm030176m.CrossRefPubMed

Fareed J, Jeske W, Ramacciotti E. Porcine mucosal heparin shortage crisis! What are the options? Clin Appl Thromb. 2019;25:1–3 https://doi.org/10.1177/1076029619878786.CrossRef

Zhang F, Yang B, Ly M, Solakyildirim K, Xiao Z, Wang Z, et al. Structural characterization of heparins from different commercial sources. Anal Bioanal Chem. 2011;401(9):2793–803. https://link.springer.com/article/10.1007/s00216-011-5367-7.CrossRefPubMedPubMedCentral

Badri A, Williams A, Linhardt RJ, Koffas MA. The road to animal-free glycosaminoglycan production: current efforts and bottlenecks. Curr Opin Biotechnol. 2018;53:85–92 https://doi.org/10.1016/j.copbio.2017.12.018.CrossRefPubMed

Thacker BE, Sharfstein ST. Metabolic engineering of mammalian cells to produce heparan sulfates. Emerg Top Life Sci. 2018;2(3):443–52. https://doi.org/10.1042/ETLS20180007.CrossRefPubMed

Liu J, Linhardt RJ. Chemoenzymatic synthesis of heparan sulfate and heparin. Nat Prod Rep. 2014;31(12):1676–85. https://doi.org/10.1039/c4np00076e.CrossRefPubMedPubMedCentral

Xiong J, Bhaskar U, Li G, Fu L, Li L, Zhang F, et al. Immobilized enzymes to convert N-sulfo, N-acetyl heparosan to a critical intermediate in the production of bioengineered heparin. J Biotechnol. 2013;167(3):241–7. https://doi.org/10.1016/j.jbiotec.2013.06.018.CrossRefPubMedPubMedCentral

Lee S, Raw A, Yu L, Lionberger R, Ya N, Verthelyi D, et al. Scientific considerations in the review and approval of generic enoxaparin in the United States. Nat Biotechnol. 2013;3(3):220–6. https://doi.org/10.1038/nbt.2528.CrossRef

Baik JY, Gasimli L, Yang B, Datta P, Zhang F, Glass CA, et al. Metabolic engineering of Chinese hamster ovary cells: towards a bioengineered heparin. Metab Eng. 2012;14(2):81–90. https://doi.org/10.1016/j.ymben.2012.01.008.CrossRefPubMedPubMedCentral

10.

Xu Y, Masuko S, Takieddin M, Xu H, Liu R, Jing J, et al. Chemoenzymatic synthesis of homogeneous ultralow molecular weight heparins. Science (80- ). 2011:498–501. https://doi.org/10.1126/science.1207478.

11.

Wang Z, Yang B, Zhang Z, Ly M, Takieddin M, Mousa S, et al. Control of the heparosan N-deacetylation leads to an improved bioengineered heparin. Appl Microbiol Biotechnol. 2011;91(1):91–9. https://doi.org/10.1007/s00253-011-3231-5.CrossRefPubMedPubMedCentral

12.

Zhang Z, McCallum SA, Xie J, Nieto L, Corzana F, Jiménez-Barbero J, et al. Solution structures of chemoenzymatically synthesized heparin and its precursors. J Am Chem Soc. 2008;130(39):12998–3007. https://pubmed.ncbi.nlm.nih.gov/18767845/. https://doi.org/10.1021/ja8026345.CrossRefPubMedPubMedCentral

13.

Linhardt RJ, Dordick JS, Deangelis PL, Liu J. Enzymatic synthesis of glycosaminoglycan heparin. Semin Thromb Hemost. 2007:453–65 http://www.thieme-connect.de/DOI/DOI?10.1055/s-2007-982076.

14.

Lindahl U, Li JP, Kusche-Gullberg M, Salmivirta M, Alaranta S, Veromaa T, et al. Generation of “neoheparin” from E. coli K5 capsular polysaccharide. J Med Chem. 2005;48(2):349–52. https://doi.org/10.1021/jm049812m.CrossRefPubMed

15.

Glass CA. Recombinant heparin-New opportunities. Front Med. 2018;5:341 https://pubmed.ncbi.nlm.nih.gov/30564580/.CrossRef

16.

Sommers CD, Ye H, Liu J, Linhardt RJ, Keire DA. Heparin and homogeneous model heparin oligosaccharides form distinct complexes with protamine: light scattering and zeta potential analysis. J Pharm Biomed Anal. 2017;140:113–21. https://doi.org/10.1016/j.jpba.2017.03.010.CrossRefPubMed

17.

Fu L, Li K, Mori D, Hirakane M, Lin L, Grover N, et al. Enzymatic generation of highly anticoagulant bovine intestinal heparin. J Med Chem. 2017;60(20):8673–9. https://doi.org/10.1021/acs.jmedchem.7b01269.CrossRefPubMed

18.

Xu Y, Chandarajoti K, Zhang X, Pagadala V, Dou W, Hoppensteadt DM, et al. Synthetic oligosaccharides can replace animal-sourced low–molecular weight heparins. Sci Transl Med. 2017;9(406):5954. https://pubmed.ncbi.nlm.nih.gov/28878012/. https://doi.org/10.1126/scitranslmed.aan5954.CrossRef

19.

b Fu L, Suflita M, Linhardt RJ. Bioengineered heparins and heparan sulfates. Adv Drug Deliv Rev. 2016;97:237–49. https://doi.org/10.1016/j.addr.2015.11.002.

20.

Bhaskar U, Li G, Fu L, Onishi A, Suflita M, Dordick JS, et al. Combinatorial one-pot chemoenzymatic synthesis of heparin. Carbohydr Polym. 2015;122:399–407. https://doi.org/10.1016/j.carbpol.2014.10.054.CrossRefPubMed

21.

Fu L, Zhang F, Li G, Onishi A, Bhaskar U, Sun P, et al. Structure and activity of a new low-molecular-weight heparin produced by enzymatic ultrafiltration. J Pharm Sci. 2014;103(5):1375–83. https://doi.org/10.1002/jps.23939.CrossRefPubMedPubMedCentral

22.

Xu Y, Cai C, Chandarajoti K, Hsieh PH, Li L, Pham TQ, et al. Homogeneous low-molecular-weight heparins with reversible anticoagulant activity. Nat Chem Biol. 2014;10(4):248–50. https://www.nature.com/articles/nchembio.1459. https://doi.org/10.1038/nchembio.1459.CrossRefPubMedPubMedCentral

23.

Arepally GM, Cines DB. Pathogenesis of heparin-induced thrombocytopenia. Transl Res. 2020;225:131–40. https://pubmed.ncbi.nlm.nih.gov/32417430/. https://doi.org/10.1016/j.trsl.2020.04.014.CrossRefPubMedPubMedCentral

24.

Arnold DM, Nazi I, Warkentin TE, Smith JW, Toltl LJ, George JN, et al. Approach to the diagnosis and management of drug-induced immune thrombocytopenia. Transfus Med Rev. 2013;27(3):137–45. https://pubmed.ncbi.nlm.nih.gov/23845922/. https://doi.org/10.1016/j.tmrv.2013.05.005.CrossRefPubMedPubMedCentral

25.

Zhang F, Zhang Z, Linhardt, RJ. Glycosaminoglycans. In Handb Glycomics. 2010;59–80. https://www.sciencedirect.com/science/article/pii/B9780123736000000032.

26.

Kim SY, Jin W, Sood A, Montgomery DW, Grant OC, Fuster MM, et al. Characterization of heparin and severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) spike glycoprotein binding interactions. Antivir Res. 2020;181:104873 https://doi.org/10.1016/j.antiviral.2020.104873.CrossRefPubMed

27.

Magro G. COVID-19: review on latest available drugs and therapies against SARS-CoV-2. Coagulation and inflammation cross-talking. Virus Res. 2020;286:198070. https://doi.org/10.1016/j.virusres.2020.198070.CrossRefPubMedPubMedCentral

28.

Kwon PS, Oh H, Kwon SJ, Jin W, Zhang F, Fraser K, et al. Sulfated polysaccharides effectively inhibit SARS-CoV-2 in vitro. Cell Discov. 2020:50 https://doi.org/10.1038/s41421-020-00192-8.

29.

Soares da Costa D, Reis RL, Pashkuleva I. Sulfation of glycosaminoglycans and its implications in human health and disorders. Annu Rev Biomed Eng. 2017;19:1–26 http://www.annualreviews.org/doi/10.1146/annurev-bioeng-071516-044610.CrossRefPubMed

30.

Xiong A, Kundu S, Forsberg-Nilsson K. Heparan sulfate in the regulation of neural differentiation and glioma development. FEBS J. 2014;281(22):4993–5008. http://doi.wiley.com/10.1111/febs.13097.CrossRefPubMed

31.

Capila I, Linhardt RJ. Heparin - protein interactions. Angew Chem. 2002;41(3):391–412. https://doi.org/10.1002/1521-3773(20020201)41:3%3C390::AID-ANIE390%3E3.0.CO;2-B.CrossRef

32.

Onishi A, St Ange K, Dordick JS, Linhardt RJ. Heparin and anticoagulation. Front Biosci - Landmark. 2016;21(7):1372–92. https://doi.org/10.2741/4462.CrossRef

33.

Arepally GM. Heparin-induced thrombocytopenia. Blood. 2017:2864–72. https://doi.org/10.1182/blood-2016-11-709873.

34.

Chudasama SL, Espinasse B, Hwang F, Qi R, Joglekar M, Afonina G, et al. Heparin modifies the immunogenicity of positively charged proteins. Blood. 2010;116(26):6046–53. https://doi.org/10.1182/blood-2010-06-292938.CrossRefPubMedPubMedCentral

35.

Ong CS, Marcum JA, Zehr KJ, Cameron DE. A century of heparin. Ann Thorac Surg. 2019;108(3):955–8. https://pubmed.ncbi.nlm.nih.gov/31077659/. https://doi.org/10.1016/j.athoracsur.2019.03.104.CrossRefPubMed

36.

Jin W, Zhang F, Linhardt RJ. Bioengineered production of glycosaminoglycans and their analogues. Syst Microbiol Biomanufacturing. 2020;1(2):123–30. https://doi.org/10.1007/s43393-020-00011-x.CrossRef

37.

Zhang F, Datta P, Dordick JS, Linhardt RJ. Evaluating heparin products for heparin-induced thrombocytopenia using surface plasmon resonance. J Pharm Sci. 2020;109(2):975–80. https://doi.org/10.1016/j.xphs.2019.10.040.CrossRefPubMed

38.

Martel N, Lee J, Wells PS. Risk for heparin-induced thrombocytopenia with unfractionated and low-molecular-weight heparin thromboprophylaxis: a meta-analysis. Blood. 2005;106(8):2710–5. https://doi.org/10.1182/blood-2005-04-1546.CrossRefPubMed

39.

Warkentin TE, Levine MN, Hirsh J, Horsewood P, Roberts RS, Gent M, et al. Heparin-induced thrombocytopenia in patients treated with low-molecular-weight heparin or unfractionated heparin. N Engl J Med. 1995;332(20):1330–6. https://doi.org/10.1056/NEJM199505183322003.CrossRefPubMed

40.

Morris TA, Castrejon S, Devendra G, Gamst AC. No difference in risk for thrombocytopenia during treatment of pulmonary embolism and deep venous thrombosis with either low-molecular-weight heparin or unfractionated heparin: a metaanalysis. Chest. 2007;132(4):1131–9. https://doi.org/10.1378/chest.06-2518.CrossRefPubMed

41.

Stein PD, Hull RD, Matta F, Yaekoub AY, Liang J. Incidence of thrombocytopenia in hospitalized patients with venous thromboembolism. Am J Med. 2009;122(10):919–30. https://doi.org/10.1016/j.amjmed.2009.03.026.CrossRefPubMed

42.

Mohamed S, Coombe DR. Heparin mimetics: Their therapeutic potential. Pharmaceuticals. 2017;10(4):78 https://pubmed.ncbi.nlm.nih.gov/28974047/.CrossRefPubMedCentral

43.

Linkins LA, Hu G, Warkentin TE. Systematic review of fondaparinux for heparin-induced thrombocytopenia: when there are no randomized controlled trials. Res Pract Thromb Haemost. 2018;2(4):678–83. http://doi.wiley.com/10.1002/rth2.12145.CrossRefPubMedPubMedCentral

44.

Biosynthetic heparin. https://patents.google.com/patent/US20190225998A1/en. Accessed 9 Sept 2021.

45.

Datta P, Linhardt RJ, Sharfstein ST. An ‘omics approach towards CHO cell engineering. Biotechnol Bioeng. 2013;110(5):1255–71. http://doi.wiley.com/10.1002/bit.24841.CrossRefPubMed

46.

Datta P, Linhardt RJ, Sharfstein ST. Industrial production of glycosaminoglycans. Encycl Microbiol. 2019:681–90. https://doi.org/10.1016/B978-0-12-809633-8.12224-1.

47.

Nguyen T, Xu Y, Brandt S, Mandelkow M, Raschke R, Strobel U, et al. Characterization of the interaction between platelet factor 4 and homogeneous synthetic low molecular weight heparins. J Thromb Haemost. 2020;18(2):390–8. https://onlinelibrary.wiley.com/doi/abs/10.1111/jth.14657.CrossRefPubMed

48.

Datta P, Yang B, Linhardt RJ, Sharfstein ST. Modulation of heparan sulfate biosynthesis by sodium butyrate in recombinant CHO cells. Cytotechnology. 2015;67(2):223–35. https://doi.org/10.1007/s10616-013-9677-9.CrossRefPubMed

49.

Baik JY, Dahodwala H, Oduah E, Talman L, Gemmill TR, Gasimli L, et al. Optimization of bioprocess conditions improves production of a CHO cell-derived, bioengineered heparin. Biotechnol J. 2015;10(7):1067–81. http://doi.wiley.com/10.1002/biot.201400665.CrossRefPubMedPubMedCentral

50.

Zhao X, Yang B, Linkens K, Datta P, Onishi A, Zhang F, et al. Microscale separation of heparosan, heparan sulfate, and heparin. Anal Biochem. 2013;434(2):215–7. https://doi.org/10.1016/j.ab.2012.12.009.CrossRefPubMed

51.

Datta P, Li G, Yang B, Zhao X, Baik JY, Gemmill TR, et al. Bioengineered Chinese hamster ovary cells with golgi-targeted 3-O-sulfotransferase-1 biosynthesize heparan sulfate with an antithrombin-binding site. J Biol Chem. 2013;288(52):37308–18. https://doi.org/10.1074/jbc.M113.519033.CrossRefPubMedPubMedCentral

52.

Stringer SE, Gallagher JT. Specific binding of the chemokine platelet factor 4 to heparan sulfate. J Biol Chem. 1997;272(33):20508–14. https://doi.org/10.1074/jbc.272.33.20508.CrossRefPubMed

53.

Kashoki M, Hanaizi Z, Yordanova S, Veselý R, Bouygues C, Llinares J, et al. A comparison of EMA and FDA decisions for new drug marketing applications 2014-2016: concordance, discordance, and why. Clin Pharmacol Ther. 2020;107(1):195–202. https://doi.org/10.1002/cpt.1565.CrossRefPubMed

54.

Curtis B. Drug-induced immune thrombocytopenia: incidence, clinical features, laboratory testing, and pathogenic mechanisms. Immunohematology. 2014;30(2):55–65. https://pubmed.ncbi.nlm.nih.gov/25247620/. https://doi.org/10.21307/immunohematology-2019-099.CrossRefPubMed

55.

Krauel K, Pötschke C, Weber C, Kessler W, Fürll B, Ittermann T, et al. Platelet factor 4 binds to bacteria, inducing antibodies cross-reacting with the major antigen in heparin-induced thrombocytopenia. Blood. 2011;117(4):1370–8. https://doi.org/10.1182/blood-2010-08-301424.CrossRefPubMed

56.

Krauel K, Weber C, Brandt S, Zähringer U, Mamat U, Greinacher A, et al. Platelet factor 4 binding to lipid a of gram-negative bacteria exposes PF4/heparin-like epitopes. Blood. 2012;120(16):3345–52. https://doi.org/10.1182/blood-2012-06-434985.CrossRefPubMed

57.

Tsilingiris D, Vallianou NG, Karampela Ι, Dalamaga Μ. Vaccine induced thrombotic thrombocytopenia: the shady chapter of a success story. Metab Open. 2021;11:100101. https://doi.org/10.1016/j.metop.2021.100101.CrossRef

58.

Geeraerts T, Montastruc F, Bonneville F, Mémier V, Raposo N, Darcourt J, et al. Oxford-AstraZeneca COVID-19 vaccine-induced cerebral venous thrombosis and thrombocytopaenia: a missed opportunity for a rapid return of experience. Anaesth Crit Care Pain Med. 2021;40(4):100889. https://doi.org/10.1016/j.accpm.2021.100889.CrossRefPubMedPubMedCentral

59.

Ferro JM, de Sousa DA, Coutinho JM, Martinelli I. European stroke organization interim expert opinion on cerebral venous thrombosis occurring after SARS-CoV-2 vaccination. Eur Stroke J. 2021:23969873211030840 https://doi.org/10.1177/23969873211030842.

60.

Gessler F, Schmitz AK, Dubinski D, Bernstock JD, Lehmann F, Won S-Y, et al. Neurosurgical considerations regarding decompressive craniectomy for intracerebral hemorrhage after SARS-CoV-2-vaccination in vaccine induced thrombotic thrombocytopenia—VITT. J Clin Med. 2021; https://pubmed.ncbi.nlm.nih.gov/34202817/.

61.

McGonagle D, De Marco G, Bridgewood C. Mechanisms of immunothrombosis in vaccine-induced thrombotic thrombocytopenia (VITT) compared to natural SARS-CoV-2 infection. J Autoimmun. 2021;121:102662. https://pubmed.ncbi.nlm.nih.gov/34051613/. https://doi.org/10.1016/j.jaut.2021.102662.CrossRefPubMedPubMedCentral

62.

Vayne C, Rollin J, Gruel Y, Pouplard C, Galinat H, Huet O, et al. PF4 immunoassays in vaccine-induced thrombotic thrombocytopenia. N Engl J Med. 2021;385(4):376–8. https://www.nejm.org/doi/full/10.1056/NEJMc2106383.CrossRefPubMed

63.

Schultz NH, Sørvoll 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(22):2124–30. https://doi.org/10.1056/NEJMoa2104882.CrossRefPubMed

64.

McDonald I, Murray SM, Reynolds CJ, Altmann DM, Boyton RJ. Comparative systematic review and meta-analysis of reactogenicity, immunogenicity and efficacy of vaccines against SARS-CoV-2. NPJ Vaccines. 2021;6(1):74. https://doi.org/10.1038/s41541-021-00336-1.CrossRefPubMedPubMedCentral

65.

Mayo KH, Ilyina E, Roongta V, Dundas M, Joseph J, Lai CK, et al. Heparin binding to platelet factor-4 an NMR and site-directed mutagenesis study: arginine residues are crucial for binding. Biochem J. 1995;312(2):357–65. https://doi.org/10.1042/bj3120357.CrossRefPubMedPubMedCentral

66.

Greinacher A, Alban S, Omer-Adam MA, Weitschies W, Warkentin TE. Heparin-induced thrombocytopenia: a stoichiometry-based model to explain the differing immunogenicities of unfractionated heparin, low-molecular-weight heparin, and fondaparinux in different clinical settings. Thromb Res. 2008;122(2):211–20. https://doi.org/10.1016/j.thromres.2007.11.007.CrossRefPubMed

67.

D’Angelo A, Della Valle P, Fattorini A, Crippa L. Disappearance of anti-PF4/heparin antibodies under prolonged fondaparinux administration in a patient with DVT associated with LMWH-induced thrombocytopenia. Thromb Haemost. 2006;95(3):573–5. https://pubmed.ncbi.nlm.nih.gov/16525590/. https://doi.org/10.1160/TH05-11-0722.CrossRefPubMed

68.

Greinacher A, Juhl D, Strobel U, Wessel A, Lubenow N, Selleng K, et al. Heparin-induced thrombocytopenia: a prospective study on the incidence, platelet-activating capacity and clinical significance of antiplatelet factor 4/heparin antibodies of the IgG, IgM, and IgA classes. J Thromb Haemost. 2007;5(8):1666–73. https://doi.org/10.1111/j.1538-7836.2007.02617.x.CrossRefPubMed

69.

Alsaleh KA, Al-Nasser SMA, Bates SM, Patel A, Warkentin TE, Arnold DM. Delayed-onset HIT caused by low-molecular-weight heparin manifesting during fondaparinux prophylaxis. Am J Hematol. 2008;83(11):876–8. https://pubmed.ncbi.nlm.nih.gov/18803278/. https://doi.org/10.1002/ajh.21273.CrossRefPubMed

70.

Warkentin TE, Pai M, Sheppard JI, Schulma S, Spyropoulos AC, Eikelboom JW. Fondaparinux treatment of acute heparin-induced thrombocytopenia confirmed by the serotonin-release assay: a 30-month, 16-patient case series. J Thromb Haemost. 2011;9(12):2389–96. http://doi.wiley.com/10.1111/j.1538-7836.2011.04487.x.CrossRefPubMed

71.

Peshattiwar V. The fondaparinux paradox: fondaparinux-related heparin-induced thrombocytopenia. Indian J Crit Care Med. 2018;22(2):116–8. https://www.ijccm.org/doi/10.4103/ijccm.IJCCM_189_17.CrossRefPubMedPubMedCentral

72.

Manji F, Warkentin TE, Sheppard JAI, Lee A. Fondaparinux cross-reactivity in heparin-induced thrombocytopenia successfully treated with high-dose intravenous immunoglobulin and rivaroxaban. Platelets. 2020;31(1):124–7. https://pubmed.ncbi.nlm.nih.gov/31397594/. https://doi.org/10.1080/09537104.2019.1652263.CrossRefPubMed

73.

Dulicek P, Ivanova E, Kostal M, Fiedlerova Z, Sadilek P, Hirmerova J. Heparin-induced thrombocytopenia treated with fondaparinux: single center experience. Int Angiol. 2020;39(1):76–81. https://pubmed.ncbi.nlm.nih.gov/31782283/. https://doi.org/10.23736/S0392-9590.19.04247-0.CrossRefPubMed

74.

Krečak I, Tomac G, Škugor J, Gverić-Krečak V, Pulanić D. In vivo and in vitro cross-reactivity to fondaparinux in a stroke patient with IgG-PF4/heparin antibody-negative delayed-onset heparin-induced thrombocytopenia. Blood Transfus. 2020;18(4):322–5. https://pubmed.ncbi.nlm.nih.gov/32530398. https://doi.org/10.2450/2020.0037-20.CrossRefPubMedPubMedCentral

75.

Nguyen TH, Medvedev N, Delcea M, Greinacher A. Anti-platelet factor 4/polyanion antibodies mediate a new mechanism of autoimmunity. Nat Commun. 2017;8(1):14945. https://doi.org/10.1038/ncomms14945.CrossRefPubMedPubMedCentral

76.

Juhl D, Eichler P, Lubenow N, Strobel U, Wessel A, Greinacher A. Incidence and clinical significance of anti-PF4/heparin antibodies of the IgG, IgM, and IgA class in 755 consecutive patient samples referred for diagnostic testing for heparin-induced thrombocytopenia. Eur J Haematol. 2006;76(5):420–6. https://doi.org/10.1111/j.1600-0609.2005.00621.x.CrossRefPubMed

77.

Amiral J, Wolf M, Fischer AM, Boyer-Neumann C, Vissac AM, Meyer D. Pathogenicity of IgA and/or IgM antibodies to heparin-PF4 complexes in patients with heparin-induced thrombocytopenia. Br J Haematol. 1996;92(4):954–9. https://doi.org/10.1046/j.1365-2141.1996.407945.x.CrossRefPubMed

78.

Denomme GA, Warkentin TE, Horsewood P, Sheppard JA, Warner MN, Kelton JG. Activation of platelets by sera containing IgG1 heparin-dependent antibodies: an explanation for the predominance of the fc gammaRIIa “low responder” (his131) gene in patients with heparin-induced thrombocytopenia. J Lab Clin Med. 1997;130(3):278–84. http://www.ncbi.nlm.nih.gov/pubmed/9341987. https://doi.org/10.1016/S0022-2143(97)90022-6.CrossRefPubMed

79.

Nevzorova TA, Mordakhanova ER, Daminova AG, Ponomareva AA, Andrianova IA, Le Minh G, et al. Platelet factor 4-containing immune complexes induce platelet activation followed by calpain-dependent platelet death. Cell Death Dis. 2019;5(1):106. https://doi.org/10.1038/s41420-019-0188-0.CrossRef

80.

Litvinov RI, Yarovoi SV, Rauova L, Barsegov V, Sachais BS, Rux AH, et al. Distinct specificity and single-molecule kinetics characterize the interaction of pathogenic and non-pathogenic antibodies against platelet factor 4-heparin complexes with platelet factor. J Biol Chem. 2013;288(46):33060–70. https://doi.org/10.1074/jbc.M113.481598.CrossRefPubMedPubMedCentral

81.

Ziporen L, Li ZQ, Park KS, Sabnekar P, Liu WY, Arepally G, et al. Defining an antigenic epitope on platelet factor 4 associated with heparin-induced thrombocytopenia. Blood. 1998;92(9):3250–9. https://doi.org/10.1182/blood.v92.9.3250.CrossRefPubMed

82.

Cai Z, Yarovoi SV, Zhu Z, Rauova L, Hayes V, Lebedeva T, et al. Atomic description of the immune complex involved in heparin-induced thrombocytopenia. Nat Commun. 2015;6(1):8277. https://doi.org/10.1038/ncomms9277.CrossRefPubMed

83.

Arepally GM, Kamei S, Park KS, Kamei K, Li ZQ, Liu W, et al. Characterization of a murine monoclonal antibody that mimics heparin-induced thrombocytopenia antibodies. Blood. 2000;95(5):1533–40. https://doi.org/10.1182/blood.V95.5.1533.005k01_1533_1540.CrossRefPubMed

84.

Vayne C, Guéry E-A, Rollin J, Baglo T, Petermann R, Gruel Y. Pathophysiology and diagnosis of drug-induced immune thrombocytopenia. J Clin Med. 2020;9(7):2212. https://pubmed.ncbi.nlm.nih.gov/32668640/. https://doi.org/10.3390/jcm9072212.CrossRefPubMedCentral

85.

Parren PWHI, Warmerdam PAM, Boeije LCM, Arts J, Westerdaal NAC, Vlug A, et al. On the interaction of IgG subclasses with the low affinity FcγRIIa (CD32) on human monocytes, neutrophils, and platelets. Analysis of a functional polymorphism to human IgG2. J Clin Invest. 1992;90(4):1537–46. https://doi.org/10.1172/JCI116022.CrossRefPubMedPubMedCentral

86.

Pouplard C, Iochmann S, Renard B, Herault O, Colombat P, Amiral J, et al. Induction of monocyte tissue factor expression by antibodies to heparin-platelet factor 4 complexes developed in heparin-induced thrombocytopenia. Blood. 2001;97(10):3300–2. https://pubmed.ncbi.nlm.nih.gov/11342462/. https://doi.org/10.1182/blood.V97.10.3300.CrossRefPubMed

87.

Cines DB, Tomaski A, Tannenbaum S. Immune endothelial-cell injury in heparin-associated thrombocytopenia. N Engl J Med. 1987;316(10):581–9. https://doi.org/10.1056/NEJM198703053161004.CrossRefPubMed

88.

Padmanabhan A, Jones CG, Curtis BR, Bougie DW, Sullivan MJ, Peswani N, et al. A novel PF4-dependent platelet activation assay identifies patients likely to have heparin-induced thrombocytopenia/thrombosis. Chest. 2016;150(3):506–15. https://doi.org/10.1016/j.chest.2016.02.641.CrossRefPubMedPubMedCentral

89.

Warkentin TE. Laboratory diagnosis of heparin-induced thrombocytopenia. Int J Lab Hematol. 2019;41(Suppl 1):15–25. https://doi.org/10.1111/ijlh.12993.CrossRefPubMed

90.

Nagler M, Bachmann LM, Ten Cate H, Ten Cate-Hoek A. Diagnostic value of immunoassays for heparin-induced thrombocytopenia: a systematic review and meta-analysis. Blood. 2016;127(5):546–57. https://doi.org/10.1182/blood-2015-07-661215.CrossRefPubMed

91.

Železnik K, Rožman P, Kocjan E, Maličev E. Heparin-induced thrombocytopenia: ELISA optical density value and 4T score in correlation with panel donor platelets activation in functional flow cytometric assay. Blood Transfus. 2021;19(1):77–84. https://pubmed.ncbi.nlm.nih.gov/33085589/. https://doi.org/10.2450/2020.0120-20.CrossRefPubMedPubMedCentral

92.

Brodard J, Alberio L, Angelillo-Scherrer A, Nagler M. Accuracy of heparin-induced platelet aggregation test for the diagnosis of heparin-induced thrombocytopenia. Thromb Res. 2020;185:27–30. https://pubmed.ncbi.nlm.nih.gov/31739198/. https://doi.org/10.1016/j.thromres.2019.11.004.CrossRefPubMed

93.

Tardy B, Lecompte T, Mullier F, Vayne C, Pouplard C. Detection of platelet-activating antibodies associated with heparin-induced thrombocytopenia. J Clin Med. 2020;9(4):1226. https://pubmed.ncbi.nlm.nih.gov/32344682/. https://doi.org/10.3390/jcm9041226.CrossRefPubMedCentral

94.

Marchetti M, Barelli S, Zermatten MG, Monnin-Respen F, Matthey-Guirao E, Nicolas N, et al. Rapid and accurate Bayesian diagnosis of heparin-induced thrombocytopenia. Blood. 2020;135(14):1171–84. https://pubmed.ncbi.nlm.nih.gov/31945147/. https://doi.org/10.1182/blood.2019002845.CrossRefPubMed

95.

Gruel Y, De Maistre E, Pouplard C, Mullier F, Susen S, Roullet S, et al. Diagnosis and management of heparin-induced thrombocytopenia. Anaesth Crit Care Pain Med. 2020;39(11):291–310. https://doi.org/10.5694/mja2.50213.CrossRefPubMed

96.

Pouplard C, Gueret P, Fouassier M, Ternisien C, Trossaert M, Régina S, et al. Prospective evaluation of the “4Ts” score and particle gel immunoassay specific to heparin/PF4 for the diagnosis of heparin-induced thrombocytopenia. J Thromb Haemost. 2007;5(7):1373–9. https://doi.org/10.1111/j.1538-7836.2007.02524.x.CrossRefPubMed

97.

Tardy-Poncet B, de Maistre E, Pouplard C, Presles E, Alhenc-Gelas M, Lasne D, et al. Heparin-induced thrombocytopenia: construction of a pretest diagnostic score derived from the analysis of a prospective multinational database, with internal validation. J Thromb Haemost https://doi.org/10.1111/jth.15344. 2021.

98.

Warkentin TE. Challenges in detecting clinically relevant heparin-induced thrombocytopenia antibodies. Hamostaseologie. 2020;40(04):472–84. https://doi.org/10.1055/a-1223-3329.CrossRefPubMedPubMedCentral

99.

Greinacher A, Thiele T, Warkentin TE, Weisser K, Kyrle PA, Eichinger S. Thrombotic thrombocytopenia after ChAdOx1 nCov-19 vaccination. N Engl J Med. 2021;384(22):2092–101. https://doi.org/10.1056/NEJMoa2104840.CrossRefPubMed

100.

Marchetti M, Zermatten MG, Bertaggia Calderara D, Aliotta A, Alberio L. Heparin-induced thrombocytopenia: a review of new concepts in pathogenesis, diagnosis, and management. J Clin Med. 2021;10(4):683. https://pubmed.ncbi.nlm.nih.gov/33578859/. https://doi.org/10.3390/jcm10040683.CrossRefPubMedPubMedCentral

101.

Sheridan D, Carter C, Kelton JG. A diagnostic test for heparin-induced thrombocytopenia. Blood. 1986;67(1):27–30. https://doi.org/10.1182/blood.v67.1.27.27.CrossRefPubMed

102.

Minet V, Dogné JM, Mullier F. Functional assays in the diagnosis of heparin-induced thrombocytopenia: a review. Molecules. 2017;22(4):617. https://doi.org/10.3390/molecules22040617.CrossRefPubMedCentral

103.

Warkentin TE, Nazy I, Sheppard JAI, Smith JW, Kelton JG, Arnold DM. Serotonin-release assay-negative heparin-induced thrombocytopenia. Am J Hematol. 2020;95(1):38–47. https://pubmed.ncbi.nlm.nih.gov/31621093/. https://doi.org/10.1002/ajh.25660.CrossRefPubMed

104.

Morel-Kopp M-C, Mullier F, Gkalea V, Bakchoul T, Minet V, Elalamy I, et al. Heparin-induced multi-electrode aggregometry method for heparin-induced thrombocytopenia testing: communication from the SSC of the ISTH. J Thromb Haemost. 2016;14(12):2548–52. https://doi.org/10.1111/jth.13516.CrossRefPubMed

Title: Platelet factor 4 polyanion immune complexes: heparin induced thrombocytopenia and vaccine-induced immune thrombotic thrombocytopenia
Authors: Payel Datta
Fuming Zhang
Jonathan S. Dordick
Robert J. Linhardt
Publication date: 01-12-2021
Publisher: BioMed Central
Keywords: Thrombocytopenia
Heparin
Heparin-Induced Thrombocytopenia
Fondaparinux
Published in: Thrombosis Journal / Issue 1/2021
Electronic ISSN: 1477-9560
DOI: https://doi.org/10.1186/s12959-021-00318-2

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