In the editor:
Vaccine-induced thrombotic immune thrombocytopenia (VITT) is a prothrombotic adverse effect of vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), an important measure in the prevention of severe coronavirus disease 2019 (Covid -19). VITT is caused by immunoglobulin G class antiplatelet factor 4 (PF4) antibodies that have rarely been induced by two Covid-19 vaccines based on adenovirus vectors, ChAdOx1 nCoV-19 (AstraZeneca) and Ad26.COV2. S (Johnson and Johnson / Janssen) .1
All available vaccines against Covid-19 generate an immune response against the SARS-CoV-2 ear protein, which raises concerns that VITT may be triggered by cross-reactivity between PF4 and the ear protein, 2 a view that has been enhanced by antibody detection. against PF4 in some patients with Covid-19.3 Despite encouraging in vitro studies that did not provide any evidence of a link between anti-SARS-CoV-2 and anti-PF4.4 immune responses, researchers were unable to provide evidence in I live to exclude this link due to the lack of an animal model. However, if the two immune responses are truly linked, VITT survivors who subsequently contract Covid-19 should have an increase in anti-PF4 antibodies, even reactivating thrombocytopenia or thrombosis.
Table 1. Table 1. Characteristics of 11 patients with a history of VITT with posterior Covid-19.
We performed a periodic evaluation of VITT antibody status (study record, EUPAS45098) in a cohort of 69 patients with a history of VITT who had received a Covid-19 adenovirus vector vaccine. Of these patients, 24 did not receive any subsequent dose of Covid-19 vaccine; the remaining 45 patients received subsequent doses of a messenger RNA (mRNA) (or BNT162b2) vaccine. [Pfizer–BioNTech] or mRNA-1273 [Moderna] vaccine). Of these patients, 31 received a second dose and 14 received a third dose. Patient characteristics are provided in Table S1 of the Supplementary Appendix, available with the full text of this letter at NEJM.org. Of the 69 patients, Covid-19 developed in 11 (16%), all of whom had mild symptoms (Table 1). Covid-19 occurred more frequently in patients who had only received the adenovirus vector vaccine than in those who had subsequently received one or two doses of an mRNA vaccine (7 of 24 patients). [29%] vs. 4 of 45 patients [9%]; P = 0.04 for Fisher’s exact test). This lower frequency of symptomatic Covid-19 supports the concept of offering patients with a history of VITT a subsequent vaccination with a mRNA-based SARS-CoV-2 vaccine.5
In all patients who had contracted Covid-19, a follow-up blood sample was obtained and obtained after recovery at an average of 2 weeks after the onset of infection. There was no significant increase in PF4 antibody levels after Covid-19 recovery. In most patients, repeated readings of optical density were lower than those of the last sample obtained before the appearance of Covid-19, a finding that was consistent with the inherent natural decrease in anti-PF4.5 antibodies. No patient had recurrent thrombocytopenia, new or recurrent thrombosis, or reversion to a positive platelet activation assay. Our observations provide in vivo evidence that corroborates our previous in vitro4 findings that immune responses against the SARS-CoV-2 ear protein (induced by Covid-19 or any of the Covid-19 vaccines) and against PF4 (induced by association with VITT). ) are independent. Our finding that Covid-19 does not re-stimulate anti-PF4 antibodies in patients with a history of VITT provides more information on the pathogenesis of this disorder and may be useful in advising patients on vaccination of Covid-19 with a vaccine. MRNA.
Linda Schönborn, MDSabrina E. Seck, BSc Thomas Thiele, MDUniversity Medicine Greifswald, Greifswald, Germany
Theodore E. Warkentin, MDMcMaster University, Hamilton, ON, Canada
Andreas Greinacher, PhD in University Medicine from Greifswald, Greifswald, Germany [email protected]
With the support of a grant (374031971 – TRR240) from the German Research Foundation. Dr. Schönborn received support from the Gerhard Domagk Research Program by Greifswald Medical University. Part of the results of the study were obtained under a service contract (EMA / 2021/17 / TDA) with University Medicine Greifswald.
The disclosure forms provided by the authors are available with the full text of this letter at NEJM.org.
The views expressed in this letter are those of the authors and do not necessarily reflect those of the European Medicines Agency or any of its committees or working groups.
This letter was published on June 27, 2022 on NEJM.org.
5 References
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1. 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: 2092-2101.
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2. Passariello M, Vetrei C, Amato F, De Lorenzo C. Spike-RBD interactions of SARS-CoV-2 and platelet factor 4: new insights into the etiopathogenesis of thrombosis. Int J Mol Sci 2021; 22: 8562-8562.
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3. Brodard J, Kremer Hovinga JA, Fontana P, Studt JD, Gruel Y, Greinacher A. Patients with COVID-19 often show high-titer anti-PF4 / heparin non-activating platelet IgG antibodies. J Thromb Haemost 2021; 19: 1294-1298.
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4. Greinacher A, Selleng K, Mayerle J, et al. Platelet anti-factor 4 antibodies that cause VITT do not cross-react with the SARS-CoV-2 ear protein. Sang 2021; 138: 1269-1277.
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5. Schönborn L, Thiele T, Kaderali L, et al. Most anti-PF4 antibodies in vaccine-induced immune thrombocytopenia thrombocytopenia are transient. Sang 2022; 139: 1903-1907.
10.1056 / NEJMc2206601-t1
Table 1. Characteristics of 11 patients with a history of VITT with posterior Covid-19. *
Num. patient Age in year, sex Clinical presentation VITTVaccine dose before Covid-19Time from VITT to Covid-19Anti-PF4 antibody status † Anticoagulation at the beginning of Covid-19Before the start of Covid-19After the recovery of Covid-19value (time) 134, MDVT27 month .27; PAA positive (28 weeks) 2.26; PAA negative (8 weeks) Cap241, MCVST, portal vein thrombosis, left jugular vein thrombosis110 mo1.97; PAA positive (16 weeks) 1.48; PAA positive (1 week) Apixaban (5 mg twice daily) 348, MAACerebral vascular accessory13 mo1.81; PAA negative (3 weeks) 1.70; PAA negative (1 week) Aspirin (100 mg) plus apixaban (2.5 mg) twice daily453, FCVST, DVT110 or 1.72; PAA negative (5 days) 1.05; PAA negative (9 weeks) Cap551, FThrombocytopenia, elevated dimer D, headache (“pre-VITT”) 112 mo1.26; Negative PAA (3 weeks) 0.65; PAA negative (2 weeks) Rivaroxaban (20 mg once daily) 636, MCVST39 mo0.77; PAA negative (4 weeks) 0.63; PAA negative (2 weeks) Dabigatran (150 mg twice daily) 752, FPulmonary embolism114 mo0.97; PAA negative (5 weeks) 0.8; PAA negative (2 weeks) Cap831, FThrombocytopenia, elevated dimer D, headache (“pre-VITT”) 210 mo0.28; PAA negative (10 weeks) 0.14; PAA negative (3 weeks) None, then dalteparin (5000 U daily) for 6 weeks after part931, MCVST112 or 0.85; PAA negative (1 week) 1.07; PAA negative (1 week) Cap1040, MCVST19 mo0.59; PAA positive (1 week) 0.54; PAA positive (4 weeks) Fenprocumon (adjusted INR) 1131, FCVST with secondary hemorrhage 213 mo0.35; PAA negative (6 weeks) 0.21; PAA negative (4 weeks) None