to the Editor:

Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a prothrombotic antagonistic impact of vaccination towards extreme acute respiratory syndrome coronavirus 2 (SARS-CoV-2), an essential measure within the prevention of extreme coronavirus illness 2019 (Covid-19). VITT is attributable to immunoglobulin G class platelet-activated antiplatelet issue 4 (PF4) antibodies, which hardly ever happen in two adenovirus vector-based COVID-19 vaccines, ChAdOx1 nCoV-19 (AstraZeneca) and Ad26.COV2.S (Johnson et al. ) are impressed by. Johnson/Janssen).1

All obtainable COVID-19 vaccines induce an immune response towards the SARS-CoV-2 spike protein, elevating issues that VITT could also be triggered by cross-reactivity between PF4 and the spike protein,2 A view that has been additional strengthened by the detection of antibodies towards PF4 in some sufferers with COVID-19.3 Regardless of encouraging in vitro research, which supplied no proof of a hyperlink between anti-SARS-CoV-2 and anti-PF4 immune responses,4 The investigators couldn’t present in vivo proof to exclude such a hyperlink as a result of lack of animal fashions. Nonetheless, if the 2 immune responses are certainly linked, then VITT survivors who subsequently contract COVID-19 ought to have elevated anti-Pf4 antibodies, probably additionally reversing thrombocytopenia or thrombosis.

Traits of 11 sufferers with a historical past of VITT with subsequent covid-19.

We carried out a periodic evaluation of VITT antibody standing (Research Registry, EUPAS45098) in a bunch of 69 sufferers with a historical past of VITT who had acquired the adenovirus vector COVID-19 vaccine. Of those sufferers, 24 didn’t obtain any subsequent dose of the COVID-19 vaccine; The remaining 45 sufferers acquired subsequent doses of messenger RNA (mRNA) vaccine (both BNT162B2.) [Pfizer–BioNTech] or mRNA-1273 [Moderna] Vaccination). Of those sufferers, 31 acquired the second dose and 14 acquired the third dose. The traits of the sufferers are supplied in Desk S1 within the Supplementary Appendix obtainable with the total textual content of this paper at NEJM.org. Of the 69 sufferers, COVID-19 developed in 11 (16%), all of whom had delicate signs (Desk 1) COVID-19 occurred extra ceaselessly in sufferers who acquired solely adenovirus vector vaccine than in those that subsequently acquired one or two doses of mRNA vaccine (7 out of 24 sufferers) [29%] versus 4 out of 45 sufferers [9%], P = 0.04 by Fisher’s actual check). This low frequency of symptomatic COVID-19 helps the idea of providing vaccination with an mRNA-based SARS-CoV-2 vaccine to sufferers with a historical past of VITT.5

In all sufferers who contracted COVID-19, a follow-up blood pattern obtained after their restoration was obtainable as early as 2 weeks after the onset of an infection. There was no important improve in developed PF4-antibody ranges after restoration from COVID-19. In most sufferers, the repeat optical density readings have been decrease than within the final pattern obtained earlier than the onset of COVID-19, a discovering that was in keeping with the inherent pure decline in anti-Pf4 antibodies.5 No affected person had recurrent thrombocytopenia, new or recurrent thrombosis, or relapse for a constructive platelet-activation assay. Our observations present in vivo proof that confirms our earlier in vitro findings4 that the immune responses towards SARS-CoV-2 spike protein (induced by COVID-19 or any COVID-19 vaccines) and PF4 (induced in affiliation with VITT) are impartial. Our discovering that COVID-19 doesn’t re-stimulate anti-Pf4 antibodies in sufferers with a historical past of VITT supplies additional perception into the pathogenesis of the dysfunction and additional data on sufferers’ COVID-19 vaccination with mRNA vaccine. Counseling could also be useful.

Linda Schönborn, MD
Sabrina E. Sec, B.Sc.
Thomas Thiele, MD
College Drugs Greifswald, Greifswald, Germany

Theodore E. Warkentin, MD
McMaster College, Hamilton, ON, Canada

Andreas Grenacher, MD
College Drugs Greifswald, Greifswald, Germany
[email protected]

Supported by a grant from (374031971-TRR240) German Analysis Basis, Dr. Schönborn was supported beneath the Gerhard Domagk Analysis Program by College Drugs Greifswald, A part of the outcomes of the research was obtained beneath a service contract (EMA/2021/17/TDA) with College Drugs Greifswald,

Disclosure types supplied by the authors together with the total textual content of this letter can be found at NEJM.org.

The views expressed on this paper are these of the authors and don’t essentially mirror the views of the European Medicines Company or any of its committees or working teams.

This paper was printed on NEJM.org on June 27, 2022.

  1. 1. Greencher A, Thiel T, Warkentin Tee, to visor, Kiral PA, etchinger sleep, Thrombotic thrombocytopenia after ChAdOx1 nCov-19 vaccination. en eng j medi 2021;384:2092,2101,

  2. 2. passarillo m, waitrei c, Amato F, di lorenzo c, Interplay of spike-RBD of SARS-CoV-2 and platelet issue 4: new insights into the etiopathogenesis of thrombosis. Int J Mol Sci 2021;22:8562,8562,

  3. 3. Brodard J, Kramer Hovinga JA, drink fontana, stud jedi, gruel you, Greencher A, Sufferers with COVID-19 usually present high-titer non-platelet-activating anti-PF4/heparin IgG antibodies. J Thromb Hemostay 2021;19:1294,1298,

  4. 4. Greencher A, to Seleng, Mayerle J, and others. Anti-platelet issue 4 antibodies, which trigger VITT, don’t cross-react with the SARS-CoV-2 spike protein. Blood 2021;138:1269,1277,

  5. 5. shonborn lee, Thiel T, Kaderli Lee, and others. Most anti-Pf4 antibodies in vaccine-induced immune thrombotic thrombocytopenia are transient. Blood 2022;139:1903,1907,

Traits of 11 sufferers with a historical past of VITT with subsequent covid-19.*

affected person quantity age in years, gender Scientific VITT Presentation Vaccine dosage earlier than covid-19 VITT to Kovid-19 time Anti-PF4-antibody standing† COVID-19 early anticoagulation
earlier than the onset of covid-19 after recovering from covid-19
quantity value (time)
1 34, M DVT 2 7 mo 3.27; PAA constructive (28 weeks) 2.26; PAA destructive (8 weeks) none
2 41, M CVST, portal-vein thrombosis, left jugular-vein thrombosis 1 10 mo 1.97; PAA constructive (16 weeks) 1.48; PAA constructive (1 week) Apixaban (5 mg twice every day)
3 48, m arterial stroke 1 3 mo 1.81; PAA destructive (3 weeks) 1.70; PAA destructive (1 week) aspirin (100 mg) plus apixaban (2.5 mg) twice every day
4 53, F CVST, DVT 1 10 mo 1.72; PAA destructive (5 days) 1.05; PAA destructive (9 weeks) none
5 51, F thrombocytopenia, elevated D-dimmer, headache (“pre-VITT”) 1 12 months 1.26; PAA destructive (3 weeks) 0.65; PAA destructive (2 weeks) Rivaroxaban (20 mg as soon as a day)
6 36, M CVST 3 9 mo 0.77; PAA destructive (4 weeks) 0.63; PAA destructive (2 weeks) Dabigatran (150 mg twice a day)
7 52, F pulmonary embolism 1 14 mo 0.97; PAA destructive (5 weeks) 0.8; PAA destructive (2 weeks) none
8 31, F thrombocytopenia, elevated D-dimmer, headache (“pre-VITT”) 2 10 mo 0.28; PAA destructive (10 weeks) 0.14; PAA destructive (3 weeks) none,
then dalteparin (5000 U every day) for six weeks postpartum
9 31, M CVST 1 12 months 0.85; PAA destructive (1 week) 1.07; PAA destructive (1 week) none
10 40, m CVST 1 9 mo 0.59; PAA constructive (1 week) 0.54; PAA constructive (4 weeks) Phenprocoumon (INR Adjusted)
1 1 31, F CVST with secondary bleeding 2 13 mo 0.35; PAA destructive (6 weeks) 0.21; PAA destructive (4 weeks) none



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