Hematology in the post-COVID era: spotlight on vaccine-induced immune thrombotic thrombocytopenia and a conceptual framework (the 4P’s) for anti-PF4 diseases

References

• Klok FA, Pai M, Huisman MV, et al. Vaccine-induced immune thrombotic thrombocytopenia. Lancet Haematol. 2022 Jan;9(1):e73–e80. doi: 10.1016/S2352-3026(21)00306-9. Epub 2021 Nov 11. PMID: 34774202; PMCID: PMC8585488.
   PubMed Web of Science ®Google Scholar
• Greinacher A, Thiele T, Warkentin TE, et al. Thrombotic thrombocytopenia after ChAdOx1 nCov-19 vaccination. N Engl J Med. 2021 Jun 3;384(22):2092–2101. doi: 10.1056/NEJMoa2104840. Epub 2021 Apr 9. PMID: 33835769; PMCID: PMC8095372.
   PubMed Web of Science ®Google Scholar
• Gabarin N, Arnold DM, Nazy I, et al. Treatment of vaccine-induced immune thrombotic thrombocytopenia (VITT). Semin Hematol. 2022 Apr;59(2):89–96. doi: 10.1053/j.seminhematol.2022.03.002. Epub 2022 Mar 7. PMID: 35512906; PMCID: PMC8898785
   PubMed Web of Science ®Google Scholar
• Huynh A, Kelton JG, Arnold DM, et al. Antibody epitopes in vaccine-induced immune thrombotic thrombocytopaenia. Nature. 2021 Aug;596(7873):565–569. doi: 10.1038/s41586-021-03744-4. Epub 2021 Jul 7. PMID: 34233346
   PubMed Web of Science ®Google Scholar
• Huynh A, Arnold DM, Michael JV, et al. Characteristics of VITT antibodies in patients vaccinated with Ad26.COV2.S. Blood Adv. 2023 Jan 24;7(2): 246–250. 10.1182/bloodadvances.2022007336. PMID: 35377937; PMCID: PMC9860431
   PubMed Web of Science ®Google Scholar
• Cines DB, Greinacher A. Vaccine-induced immune thrombotic thrombocytopenia. Blood. 2023 Apr 6;141(14):1659–1665. doi: 10.1182/blood.2022017696. PMID: 36669155; PMCID: PMC9870607
   PubMed Web of Science ®Google Scholar
• Bissola AL, Daka M, Arnold DM, et al. The clinical and laboratory diagnosis of vaccine-induced immune thrombotic thrombocytopenia. Blood Adv. 2022 Jul 26;6(14): 4228–4235. 10.1182/bloodadvances.2022007766. PMID: 35609563; PMCID: PMC9132380
   PubMed Web of Science ®Google Scholar
• Pavord S, Scully M, Hunt BJ, et al. Clinical features of vaccine-induced immune thrombocytopenia and thrombosis. N Engl J Med. 2021 Oct 28;385(18):1680–1689. doi: 10.1056/NEJMoa2109908. Epub 2021 Aug 11. PMID: 34379914
   PubMed Web of Science ®Google Scholar
• Greinacher A, Langer F, Makris M, et al. Vaccine-induced immune thrombotic thrombocytopenia (VITT): update on diagnosis and management considering different resources. J Thromb Haemost. 2022 Jan;20(1):149–156. doi: 10.1111/jth.15572. Epub 2021 Nov 10. PMID: 34693641; PMCID: PMC8646430
   PubMed Web of Science ®Google Scholar
• Scully M, Singh D, Lown R, et al. Pathologic Antibodies to platelet factor 4 after ChAdOx1 nCoV-19 vaccination. N Engl J Med. 2021 Jun 10;384(23):2202–2211. doi: 10.1056/NEJMoa2105385. Epub 2021 Apr 16. PMID: 33861525; PMCID: PMC8112532
   PubMed Web of Science ®Google Scholar
• Warkentin TE, Baskin-Miller J, Raybould AL, et al. Adenovirus-associated thrombocytopenia, thrombosis, and VITT-like antibodies. N Engl J Med. 2023 Aug 10;389(6):574–577. doi: 10.1056/NEJMc2307721. PMID: 37590457.
   PubMed Web of Science ®Google Scholar
• Schultz NH, Sørvoll IH, Michelsen AE, et al. Thrombosis and 39 thrombosis and thrombocytopenia after ChAdOx1 nCoV-19 vaccination. N Engl J Med. 2021 Jun 3;384(22):p. 2124–2130. doi: 10.1056/NEJMoa2104882. Epub 2021 Apr 9. PMID: 33835768; PMCID: PMC8112568.
   PubMed Web of Science ®Google Scholar
• Gabarin N, Patterson S, Pai M, et al. Venous thromboembolism and mild thrombocytopenia after ChAdOx1 nCoV-19 vaccination. Thromb Haemost. 2021 Dec;121(12):1677–1680. doi: 10.1055/a-1585-6182 Epub 2021 Sep 23. PMID: 34384129; PMCID: PMC8632250
   PubMed Web of Science ®Google Scholar
• Kim AY, Woo W, Yon DK, et al. Thrombosis patterns and clinical outcome of COVID-19 vaccine-induced immune thrombotic thrombocytopenia: a systematic review and meta-analysis. Int J Infect Dis. 2022 Jun;119:130–139. doi: 10.1016/j.ijid.2022.03.034. Epub 2022 Mar 24. Erratum in: Int J Infect Dis. 2022 Oct;123:(166). PMID: 35339716; PMCID: PMC8942584
   PubMed Web of Science ®Google Scholar
• Devasagayam S, Wyatt B, Leyden J, et al. Cerebral venous sinus thrombosis incidence is higher than Previously thought: a retrospective population-based study. Stroke. 2016 Sep;47(9):2180–2. doi: 10.1161/STROKEAHA.116.013617. Epub 2016 Jul 19. PMID: 27435401
   PubMed Web of Science ®Google Scholar
• Coutinho JM, Zuurbier SM, Aramideh M, et al. The incidence of cerebral venous thrombosis: a cross-sectional study. Stroke. 2012 Dec;43(12):3375–7. doi: 10.1161/STROKEAHA.112.671453. Epub 2012 Sep 20. PMID: 22996960
   PubMed Web of Science ®Google Scholar
• De Michele M, Iacobucci M, Chistolini A, et al. Malignant cerebral infarction after ChAdOx1 nCov-19 vaccination: a catastrophic variant of vaccine-induced immune thrombotic thrombocytopenia. Nat Commun. 2021 Aug 2;12(1):4663. doi: 10.1038/s41467-021-25010-x
   PubMed Web of Science ®Google Scholar
• De Michele M, Kahan J, Berto I, et al. Cerebrovascular Complications of COVID-19 and COVID-19 Vaccination. Circ Res. 2022 Apr 15;130(8):1187–1203. doi: 10.1161/CIRCRESAHA.122.319954
   PubMed Web of Science ®Google Scholar
• van Kammen M S, Heldner MR, Brodard J, et al. Frequency of thrombocytopenia and platelet factor 4/Heparin antibodies in patients with cerebral venous sinus thrombosis prior to the COVID-19 pandemic. JAMA. 2021 Jul 27;326(4):332–338. doi: 10.1001/jama.2021.9889. PMID: 34213527; PMCID: PMC8317004
   PubMed Web of Science ®Google Scholar
• [cited 2023 Oct 1]. Available from: https://brightoncollaboration.us/wp-content/uploads/2021/11/TTS-Updated-Brighton-Collaboration-Case-Defintion-Draft-Nov-11-2021.pdf, https://www.canada.ca/en/public-health/services/immunization/vaccine-safety/advisory-committee-causality-assessment/thrombosis-thrombocytopenia-syndrome-findings.html
   Google Scholar
• Demma LJ, Winkler AM, Levy JH. A diagnosis of heparin-induced thrombocytopenia with combined clinical and laboratory methods in cardiothoracic surgical intensive care unit patients. Anesth Analg. 2011 Oct;113(4):697–702. doi: 10.1213/ANE.0b013e3182297031. Epub 2011 Jul 25. PMID: 21788317
   PubMed Web of Science ®Google Scholar
• Lee GM, Arepally GM. Heparin-induced thrombocytopenia. Hematology Am Soc Hematol Educ Program. 2013;2013(1):668–674. PMID: 24319250; PMCID: PMC4153428. doi: 10.1182/asheducation-2013.1.668
   PubMedGoogle Scholar
• Greinacher A, Juhl D, Strobel U, 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 Aug;5(8):1666–73. doi: 10.1111/j.1538-7836.2007.02617.x. Epub 2007 May 7. PMID: 17488345
   PubMed Web of Science ®Google Scholar
• Sachs UJ, Cooper N, Czwalinna A, et al. PF4-dependent immunoassays in patients with Vaccine-Induced Immune Thrombotic Thrombocytopenia: results of an interlaboratory comparison. Thromb Haemost. 2021 Dec;121(12):1622–1627. doi: 10.1055/a-1535-9002. Epub 2022 Jul 19. PMID: 34169493
   PubMed Web of Science ®Google Scholar
• Warkentin TE, Arnold DM, Sheppard JI, et al. Investigation of anti-PF4 versus anti-PF4/heparin reactivity using fluid-phase enzyme immunoassay for 4 anti-PF4 disorders: classic heparin-induced thrombocytopenia (HIT), autoimmune HIT, vaccine-induced immune thrombotic thrombocytopenia, and spontaneous HIT. J Thromb Haemost. 2023 Aug;21(8):2268–2276. doi: 10.1016/j.jtha.2023.04.034. Epub 2023 May 12. PMID: 37182698
   PubMed Web of Science ®Google Scholar
• Bankova A, Andres Y, Horn MP, et al. Rapid immunoassays for diagnosis of heparin-induced thrombocytopenia: comparison of diagnostic accuracy, reproducibility, and costs in clinical practice. Epub 20170608 PubMed PMID: 28594835; PubMed Central PMCID: PMC5464550 PLoS One. 2017;12(6):e0178289. doi: 10.1371/journal.pone.0178289
   PubMed Web of Science ®Google Scholar
• Nagler M, Bakchoul T. Clinical and laboratory tests for the diagnosis of heparin-induced thrombocytopenia. Thromb Haemost. 2016;116(5):823–834. doi: 10.1160/TH16-03-0240. Epub 20160908 PubMed PMID: 27604316.
   PubMed Web of Science ®Google Scholar
• Platton S, Bartlett A, MacCallum P, et al. Evaluation of laboratory assays for anti-platelet factor 4 antibodies after ChAdOx1 nCOV-19 vaccination. J Thromb Haemost. 2021;19(8):2007–13. doi: 10.1111/jth.15362. Epub 20210705 PubMed PMID: 33973336; PubMed Central PMCID: PMC8236994.
   PubMed Web of Science ®Google Scholar
• Warkentin TE COVID-19: vaccine-induced immune thrombotic thrombocytopenia (VITT) uptodate2023 [cited 2023 feb 7]. Available from: https://www.uptodate.com/contents/covid-19-vaccine-induced-immune-thrombotic-thrombocytopenia-vitt#topicContent
   Google Scholar
• Warkentin TE, Greinacher A. Laboratory testing for VITT antibodies. Semin Hematol. 2022;59(2):80–8. Epub 20220307 PubMed PMID: 35512905. doi: 10.1053/j.seminhematol.2022.03.003
   PubMed Web of Science ®Google Scholar
• Uzun G, Althaus K, Hammer S, et al. Diagnostic performance of a particle gel immunoassay in vaccine-induced immune thrombotic thrombocytopenia. Hamostaseologie. 2023;43(1):22–27. doi: 10.1055/a-1986-1556. Epub 20230220 PubMed PMID: 36807823.
   PubMedGoogle Scholar
• Warkentin TE, Arnold DM, Nazi I, et al. The platelet serotonin-release assay. Am J Hematol. 2015 Jun;90(6):564–72. doi: 10.1002/ajh.24006. Epub 2015 May 3. PMID: 25775976
   PubMed Web of Science ®Google Scholar
• Greinacher A, Michels I, Kiefel V, et al. A rapid and sensitive test for diagnosing heparin-associated thrombocytopenia. Thromb Haemost. 1991 Dec 2;66(6): 734–6. 10.1055/s-0038-1646493. PMID: 1796420
   PubMed Web of Science ®Google Scholar
• Padmanabhan A, Jones CG, Curtis BR, et al. A novel PF4-dependent platelet activation assay identifies patients likely to have heparin-induced Thrombocytopenia/Thrombosis. Chest. 2016 Sep;150(3):506–15. doi: 10.1016/j.chest.2016.02.641. Epub 2016 Feb 19. PMID: 26905366; PMCID: PMC5028397.
   PubMed Web of Science ®Google Scholar
• Fratantoni JC, Pollet R, Gralnick HR. Heparin-induced thrombocytopenia: confirmation of diagnosis with in vitro methods. Blood. 1975 Mar;45(3):395–401. doi: 10.1182/blood.V45.3.395.395. PMID: 1115835
   PubMed Web of Science ®Google Scholar
• Nazi I, Arnold DM, Warkentin TE, et al. Distinguishing between anti-platelet factor 4/heparin antibodies that can and cannot cause heparin-induced thrombocytopenia. J Thromb Haemost. 2015 Oct;13(10):1900–1907. doi: 10.1111/jth.13066 Epub 2015 Aug 29. PMID: 26291604.
   PubMed Web of Science ®Google Scholar
• Warkentin TE, Arnold DM, Kelton JG, et al. Platelet-Activating Antibodies are Detectable at the earliest onset of heparin-induced thrombocytopenia, with implications for the operating characteristics of the Serotonin-Release Assay. Chest. 2018 Jun;153(6):1396–1404. doi: 10.1016/j.chest.2018.01.001 Epub 2018 Jan 8. PMID: 29325985.
   PubMed Web of Science ®Google Scholar
• Warkentin TE, Sheppard JA, Moore JC, et al. Studies of the immune response in heparin-induced thrombocytopenia. Blood. 113(20):4963–4969. 2009 May 14. 10.1182/blood-2008-10-186064 Epub 2009 Jan 14. PMID: 19144981.
   PubMed Web of Science ®Google Scholar
• Cuker A, Cines DB. How I treat heparin-induced thrombocytopenia. Blood. 2012 Mar 8;119(10):2209–18. doi: 10.1182/blood-2011-11-376293 Epub 2012 Jan 13. PMID: 22246036.
   PubMed Web of Science ®Google Scholar
• Cuker A. Clinical and laboratory diagnosis of heparin-induced thrombocytopenia: an integrated approach. Semin Thromb Hemost. 2014 Feb;40(1):106–114. doi: 10.1055/s-0033-1363461 Epub 2013 Dec 21. PMID: 24363239.
   PubMed Web of Science ®Google Scholar
• Reilly-Stitt C, Jennings I, Kitchen S, et al. Anti-PF4 testing for vaccine-induced immune thrombocytopenia and thrombosis (VITT): results from a NEQAS, ECAT and SSC collaborative exercise in 385 centers worldwide. J Thromb Haemost. 2022 Aug;20(8):1875–1879. doi: 10.1111/jth.15766 Epub 2022 Jun 6. PMID: 35603519.
   PubMed Web of Science ®Google Scholar
• Günther A, Brämer D, Pletz MW, et al. Complicated long term vaccine induced thrombotic immune thrombocytopenia-A case report. Vaccines (Basel). 2021 Nov 17;9(11): 1344. 10.3390/vaccines9111344 PMID: 34835275; PMCID: PMC8622649.
   PubMed Web of Science ®Google Scholar
• Roberge G, Carrier MLV. Long VITT: a case report. Thromb Res. 2023 Mar;223:78–79. doi: 10.1016/j.thromres.2023.01.017 Epub 2023 Jan 24. PMID: 36709677; PMCID: PMC9870606.
   PubMed Web of Science ®Google Scholar
• Schonborn L, Seck SE, Thiele T, et al. Long-term outcome in vaccine-induced immune thrombocytopenia and thrombosis. J Thromb Haemost. 2023 Sep;21(9):2519–2527.
   PubMed Web of Science ®Google Scholar
• Kanack AJ, Singh B, George G, et al. Persistence of Ad26.COV2.S-associated vaccine-induced immune thrombotic thrombocytopenia (VITT) and specific detection of VITT antibodies. Am J Hematol. 2022 May;97(5):519–526.
   PubMed Web of Science ®Google Scholar
• Singh A, Toma F, Uzun G, et al. The interaction between anti-PF4 antibodies and anticoagulants in vaccine-induced thrombotic thrombocytopenia. Blood. 2022 Jun 9;139(23):3430–3438. doi: 10.1182/blood.2021013839 PMID: 35679071; PMCID: PMC8949646.
   PubMed Web of Science ®Google Scholar
• Uzun G, Althaus K, Singh A, et al. The use of IV immunoglobulin in the treatment of vaccine-induced immune thrombotic thrombocytopenia. Blood. 2021 Sep 16;138(11):992–996. doi: 10.1182/blood.2021012479 PMID: 34166507; PMCID: PMC8444699.
   PubMed Web of Science ®Google Scholar
• Bourguignon A, Arnold DM, Warkentin TE, et al. Adjunct Immune Globulin for Vaccine-Induced Immune Thrombotic Thrombocytopenia. N Engl J Med. 2021 Aug 19;385(8):720–728. doi: 10.1056/NEJMoa2107051 Epub 2021 Jun 9. PMID: 34107198; PMCID: PMC8362588.
   PubMed Web of Science ®Google Scholar
• Major A, Carll T, Chan CW, et al. Refractory vaccine-induced immune thrombotic thrombocytopenia (VITT) managed with delayed therapeutic plasma exchange (TPE). J Clin Apheresis. 2022 Feb;37(1):117–121. doi: 10.1002/jca.21945 Epub 2021 Oct 21. PMID: 34672380.
   PubMed Web of Science ®Google Scholar
• Patriquin CJ, Laroche V, Selby R, et al. Therapeutic plasma exchange in vaccine-induced immune thrombotic thrombocytopenia. N Engl J Med. 2021 Aug 26;385(9):857–859. doi: 10.1056/NEJMc2109465 Epub 2021 Jul 7. PMID: 34233107; PMCID: PMC8279091.
   PubMed Web of Science ®Google Scholar
• Kanack AJ, Schaefer JK, Sridharan M, et al. Monoclonal gammopathy of thrombotic/thrombocytopenic significance. Blood. 2023 Apr 6;141(14):1772–1776. doi: 10.1182/blood.2022018797 PMID: 36626584; PMCID: PMC10113173.
   PubMed Web of Science ®Google Scholar
• Johansen S, Laegreid IJ, Ernstsen SL, et al. Thrombosis and thrombocytopenia after HPV vaccination. J Thromb Haemost. 2022 Mar;20(3):700–704. doi: 10.1111/jth.15604 Epub 2021 Dec 7. PMID: 34817130; PMCID: PMC9906134.
   PubMed Web of Science ®Google Scholar
• Prechel MM, Walenga JM. Emphasis on the role of PF4 in the incidence, pathophysiology and treatment of heparin induced thrombocytopenia. Thromb J. 2013 Apr 5;11(1):7. doi: 10.1186/1477-9560-11-7 PMID: 23561460; PMCID: PMC3627638.
   PubMedGoogle Scholar
• De Michele M, Piscopo P, Crestini A, et al. Vaccine-induced immune thrombotic thrombocytopenia: a possible pathogenic role of ChAdOx1 nCoV-19 vaccine-encoded soluble SARS-CoV-2 spike protein. Haematologica. 2022 Jul 1;107(7):1687–1692. doi: 10.3324/haematol.2021.280180 PMID: 35172564; PMCID: PMC9244820.
   PubMed Web of Science ®Google Scholar
• Roytenberg R, García-Sastre A, Li W. Vaccine-induced immune thrombotic thrombocytopenia: what do we know hitherto? Front Med. 2023 May 16; 10:1155727. 10.3389/fmed.2023.1155727 PMID: 37261122; PMCID: PMC10227460.
   Web of Science ®Google Scholar
• Warkentin TE. HIT paradigms and paradoxes. J Thromb Haemost. 2011 Jul;9(1):105–117. doi: 10.1111/j.1538-7836.2011.04322.x PMID: 21781246.
   PubMedGoogle Scholar
• Jiang M, Väisänen E, Kolehmainen P, et al. COVID-19 adenovirus vector vaccine induces higher interferon and pro-inflammatory responses than mRNA vaccines in human PBMCs, macrophages and moDcs. Vaccine. 2023 Jun 13;41(26):3813–3823. doi: 10.1016/j.vaccine.2023.04.049 Epub 2023 Apr 25. PMID: 37142461; PMCID: PMC10126225.
   PubMed Web of Science ®Google Scholar
• Dhakal B, Kreuziger LB, Rein L, et al. Disease burden, complication rates, and health-care costs of heparin-induced thrombocytopenia in the USA: a population-based study. Lancet Haematol. 2018 May;5(5):e220–e231. doi: 10.1016/S2352-3026(18)30046-2 PMID: 29703336; PMCID: PMC6437775.
   PubMed Web of Science ®Google Scholar
• Pai M. Epidemiology of VITT. Semin Hematol. 2022 Apr;59(2):72–75. doi: 10.1053/j.seminhematol.2022.02.002 Epub 2022 Feb 8. PMID: 35512903; PMCID: PMC8820951.
   PubMed Web of Science ®Google Scholar
• Lieberman L, Greinacher A, Murphy MF, et al. International Collaboration for Transfusion Medicine Guidelines (ICTMG). Fetal and neonatal alloimmune thrombocytopenia: recommendations for evidence-based practice, an international approach. Br J Haematol. 2019 May;185(3):549–562. doi: 10.1111/bjh.15813 Epub 2019 Mar 3. PMID: 30828796.
   PubMed Web of Science ®Google Scholar
• Mwesigwa S, Moulds JM, Chen A, et al. Whole-exome sequencing of sickle cell disease patients with hyperhemolysis syndrome suggests a role for rare variation in disease predisposition. Transfusion. 2018 Mar;58(3):726–735. doi: 10.1111/trf.14431 Epub 2017 Dec 6. PMID: 29210071; PMCID: PMC5847445.
   PubMed Web of Science ®Google Scholar