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Rare thrombotic reactions to adenovirus-based COVID-19 vaccines

Undeniably, a global and coordinated COVID-19 vaccination effort is a prerequisite for taming the spread of emerging SARS-CoV-2 variants and achieving population-wide immunity that can thwart future viral surges. Ongoing vaccination programs have relied on both mRNA and adenoviral-based formulations eliciting potent humoral responses and showing safety in the majority of the population vaccinated so far. However, rare vaccine-related adverse events were recently reported in individuals who received the adenoviral-encoded ChAdOx1 nCov-19 and Ad26.COV2.S vaccines (1–3). Most of these cases developed acute thrombotic complications (cerebral venous thrombosis or disseminated intravascular coagulation) and severe thrombocytopenia following the first dose of the vaccine, without any prior history of heparin exposure or known risk factors for thrombophilia. This rare syndrome, termed vaccine-induced immune thrombotic thrombocytopenia (VITT), clinically resembles the hallmarks of autoimmune heparin-induced thrombocytopenia (autoimmune HIT) and is linked to the consistent presence of circulating autoantibodies against platelet factor 4 (PF4), which can directly activate platelets in the absence of heparin (2).

The prothrombotic action of anti-PF4 antibodies likely involves antibody-mediated platelet activation through IgG-FcγR interactions and similar FcR-mediated engagement of immune effector cells such as monocytes/macrophages and neutrophils (Figure 1). Since VITT is a newly described syndrome, its clinical management mostly relies on its similarities with HIT and non–heparin-dependent autoimmune thrombotic thrombocytopenias. While nonheparin anticoagulants and intravenous immunoglobulin (IVIg) have been proposed as first-line treatments for patients with VITT, these approaches are not fail-safe and entail drawbacks that may curtail their effectiveness (e.g., risk of promiscuous FcR activation, acute anaphylaxis, or even thromboembolic events in the case of intravenous immunoglobulin) (4). Several second-line therapies for HIT have also been suggested, including plasmapheresis, especially when nonheparin anticoagulation is contraindicated because of major bleeding events (5). Thus, more insight into the precise pathophysiology of VITT is needed to enable more personalized medicine approaches.

A schematic diagram of the plausible mechanisms by which complement may conFigure 1

A schematic diagram of the plausible mechanisms by which complement may contribute to the VITT-associated prothrombotic response. Vaccine-induced immune thrombotic thrombocytopenia (VITT) has been described in individuals presenting with high titers of platelet-activating anti–platelet factor 4 (PF4) autoantibodies. These antibodies recognize large multiantigenic complexes comprising PF4 and polyanionic structures similar to heparin, and resemble autoimmune heparin-induced thrombocytopenia (HIT). Complement activation can be triggered in multiple ways in patients presenting with VITT and anti-PF4 antibodies. First, the formation of complexes between PF4 and certain vaccine constituents (e.g., adenoviral capsid proteins or DNA) (23) may serve as a scaffold for C3 activation, similarly to what has been observed with PF4-heparin ultra-large complexes. In addition, complement activation can be triggered by the binding of C1q to the anti-PF4 immune complexes that are deposited on the endothelium, monocyte, or platelet surface via binding to polyanionic structures such as glycosaminoglycans (GAGs). Classical pathway activation leads to C3 cleavage, amplification of complement responses via the alternative pathway, downstream generation of proinflammatory C3a and C5a anaphylatoxins, and the formation of the C5b-9 complex. Complement activation fragments mediate a broad range of thromboinflammatory reactions by interacting with complement receptors on platelets, monocytes, and neutrophils. These interactions can induce or enhance FcR-mediated platelet activation, neutrophil-platelet aggregation, and release of TF-loaded neutrophil extracellular traps (NETs) from activated neutrophils. All these processes are fueled by complement activation and can collectively contribute to a prothrombotic environment that may lead to VITT. Moreover, C3-opsonized immune complexes can enhance FcγR-dependent effector responses on platelets further promoting thrombotic responses. Abbreviations: CP, classical pathway; AP, alternative pathway; TF, tissue factor.

A proposed role for complement

Complement is a host innate immune sentinel comprising over 50 proteins that can be swiftly activated through any of three initiating pathways (classical, lectin, or alternative) that sense microbial invaders or other inflammatory cues, such as immune complexes. In fact, complement activation has been implicated as a perpetrator of immune complex–driven thromboinflammation in autoimmune pathologies such as the antiphospholipid syndrome, a systemic disorder that increases risk for blood clots (6). Prompted by the striking findings in patients who developed VITT after a single dose of adenoviral-associated vaccine, we posit here that the observed thrombotic complications may partly reflect immune complex–triggered complement activation through the classical pathway. PF4-containing immune complexes can be recognized by C1q, a soluble pattern recognition molecule of the classical pathway that binds to the Fc portion of IgG molecules. Anti-PF4 complex–driven classical pathway activation can lead to C3 activation, alternative pathway–mediated amplification of complement responses, and downstream generation of potent proinflammatory mediators and effectors (C3a, C5a and membrane attack complex) that can potentiate thromboinflammation (7). In fact, the thrombogenic capacity of distinct complement activation fragments has been linked to a broad spectrum of immune-related mechanisms that underpin the immunothrombosis of severe COVID-19 (7, 8).

Considering that certain allelic combinations of complement gene polymorphisms within the population confer differential susceptibility to deregulated complement activity, it is tempting to speculate that these vaccinated individuals may represent cases where complement deregulation occurs due to genetic alterations that result in ineffective host regulatory control (9). Deregulated complement responses can perpetuate a vicious cycle of inflammatory tissue damage that renders the vascular endothelium and platelet/monocyte compartment more thrombogenic. In this regard, circulating anti-PF4 immune complexes may well serve as a first hit that ignites complement activation, in a way similar to complement-mediated thrombotic microangiopathies (10). The fact that a fraction of these anti-PF4 autoantibodies may recognize antigenic complexes between PF4 and polyanionic structures (such as GAGs or heparan sulfate) raises the possibility that these immune complexes may skew the binding of endogenous complement regulators to host polyanionic surfaces, thereby altering the capacity of these surfaces to withstand autologous complement attack.

C3 activation may play a pivotal pathogenic role in this vaccine-induced immunothrombotic phenotype. C3-opsonized anti-PF4 immune complexes can enhance the phagocytic and inflammatory properties of monocytes and neutrophils through the synergistic engagement of FcγR and complement receptors, thereby increasing the thrombogenic milieu in the vasculature (Figure 1). C3 fragment deposition on the endothelium and on platelets/neutrophils can potentiate thromboinflammatory responses by promoting CR3-dependent platelet-neutrophil interactions that favor platelet adhesion and clotting (11). Also, C3aR signaling on platelets can further drive thrombotic responses (12). Of note, it has been shown that PF4–heparin complexes, a hallmark of HIT pathology, can potently activate C3 in the fluid phase and C3 inhibitors such as Cp40 can abrogate C3 activation triggered by HIT-associated PF4–heparin complexes (13). In line with this, the Cp40-based drug candidate AMY-101 has been shown to effectively decrease both neutrophils and neutrophil extracellular trap (NET) formation, two major drivers of HIT-associated thrombosis, in patients with COVID-19 (7, 14–16).

Potential treatment approaches

In an analogy to HIT, clinical-stage complement C3 inhibitors may represent a novel therapeutic strategy for ameliorating the thrombotic complications elicited in VITT. On one hand, C3 inhibition may quench anti-PF4 antibody production by reducing antigen uptake or processing in the lymphoid tissue. On the other hand, it can broadly suppress multiple paths of immune complex–driven thromboinflammation in VITT (Figure 1). Moreover, C3 inhibition may offer broader therapeutic control of thromboembolic reactions mediated by pathogenic autoantibodies. In this regard, C3 activation, but not C5, was shown to be indispensable for antiphospholipid antibody-induced tissue factor (TF) activation and thrombosis in antiphospholipid syndrome (17). The recently reported resolution of vaccine-induced thrombotic microangiopathy in two patients following combined treatment with anticoagulants and the C5 inhibitor eculizumab further corroborates our hypothesis that therapeutic complement modulation may offer significant clinical benefits to patients with VITT (18). In this regard, C3 inhibitors may exert a broader therapeutic effect than anti-C5 agents by suppressing both terminal pathway activation and thrombogenic pathways operating upstream of C5 (14, 19).

Because this newly described immune syndrome is still poorly defined, it would be of great benefit to patients with VITT if the algorithm for VITT clinical management considered diagnostic monitoring of complement biomarkers as a means of validating the use of specific complement inhibitors. As a cautionary note, we should stress that plasma levels of complement proteins reflect both turnover and synthesis. Therefore, the accurate monitoring of complement activity should rely on markers of ongoing activation combined with corroborative functional assays that gauge the impact of complement activation on the tissue or cellular level.

mRNA vaccine reactions

In addition to these cases of VITT in individuals receiving adenovirus vectored vaccines, the rollout of COVID-19 mRNA vaccines has brought to the spotlight rare adverse events involving a maladaptive immune reaction to certain vaccine constituents. Rare cases of severe allergic reactions (anaphylaxis) were reported following the first dose of the Pfizer–BioNTech or Moderna SARS-CoV-2 mRNA vaccines (20). Such allergic reactions are likely triggered by the PEG or lipid moieties of these mRNA vaccines. They involve complement and mast cell activation in an IgE-independent manner and closely resemble the complement mediated pseudo-allergy reaction (CARPA) that has been described in the case of liposomal carriers (21). Complement activation in this case may be initiated by IgG or IgM directed against the PEGylated lipids of these vaccine formulations.

Concluding remarks

Taken together, these paradigms of vaccine-related adverse reactions highlight the potential contribution of complement activation to vaccine-related pathology, raise the importance of incorporating complement diagnostic monitoring in the early clinical management of such patients, and endorse complement inhibitors as potential treatment options. In addition to the complement-activating capacity of anti-PF4 antibodies, we cannot rule out the possibility that complement activation in VITT may also be fueled by preformed (natural IgM) or induced IgG antibodies against adenoviral capsid antigens or direct interaction of pattern recognition molecules with capsid elements (22). The relevance of these plausible mechanisms to VITT pathology warrants further investigation.

Footnotes

Conflict of interest: JDL is the founder of Amyndas Pharmaceuticals, which is developing complement inhibitors for therapeutic purposes. He is the inventor on patents or patent applications that describe the use of complement inhibitors for therapeutic purposes, some of which are developed by Amyndas Pharmaceuticals: US patents 8946145/9371365 (Modified compstatin with peptide backbone and C-terminal modifications), 9630992 (Compstatin analogs with improved pharmacokinetic properties), 9579360 (Methods of treating or preventing periodontitis and diseases associated with periodontitis). JDL is also the inventor of the compstatin technology licensed to Apellis Pharmaceuticals, i.e., 4(1MeW)7W/POT-4/APL-1 and PEGylated derivatives such as APL-2/pegcetacoplan/empaveli and APL-9: US patents 6319897 (Peptides which inhibit complement activation), 7989589 (Compstatin analogs with improved activity), 7888323 (Potent compstatin analogs).

Copyright: © 2021, American Society for Clinical Investigation.

Reference information: J Clin Invest. 2021;131(11):e151092. https://doi.org/10.1172/JCI151092.

References
  1. Muir K-L, et al. Thrombotic thrombocytopenia after Ad26.COV2.S vaccination. [published online April 14, 2021]. N Engl J Med. https://doi.org/10.1056/NEJMc2105869.
  2. Scully M, et al. Pathologic antibodies to platelet factor 4 after ChAdOx1 nCoV-19 vaccination. [published online April 16, 2021]. N Engl J Med. https://doi.org/10.1056/NEJMoa2105385.
  3. Schultz NH, et al. Thrombosis and thrombocytopenia after ChAdOx1 nCoV-19 vaccination. [published online April 9, 2021]. N Engl J Med. https://doi.org/10.1056/NEJMoa2104882.
  4. Kapoor M, et al. Thromboembolic risk with IVIg: incidence and risk factors in patients with inflammatory neuropathy. Neurology. 2020;94(6):e635–e638.
  5. Marchetti M, et al. Heparin-induced thrombocytopenia: a review of new concepts in pathogenesis, diagnosis, and management. J Clin Med. 2021;10(4):683.
  6. Chaturvedi S, et al. Complement in the pathophysiology of the antiphospholipid syndrome. Front Immunol. 2019;10:449.
  7. Skendros P, et al. Complement and tissue factor-enriched neutrophil extracellular traps are key drivers in COVID-19 immunothrombosis. J Clin Invest. 2020;130(11):6151–6157.
  8. Risitano AM, et al. Complement as a target in COVID-19? Nat Rev Immunol. 2020;20(6):343–344.
  9. Heurich M, et al. Common polymorphisms in C3, factor B, and factor H collaborate to determine systemic complement activity and disease risk. Proc Natl Acad Sci U S A. 2011;108(21):8761–8766.
  10. Gavriilaki E, Brodsky RA. Complementopathies and precision medicine. J Clin Invest. 2020;130(5):2152–2163.
  11. Hamad OA, et al. Contact activation of C3 enables tethering between activated platelets and polymorphonuclear leukocytes via CD11b/CD18. Thromb Haemost. 2015;114(6):1207–1217.
  12. Sauter RJ, et al. Functional relevance of the anaphylatoxin receptor C3aR for platelet function and arterial thrombus formation marks an intersection point between innate immunity and thrombosis. Circulation. 2018;138(16):1720–1735.
  13. Khandelwal S, et al. Novel immunoassay for complement activation by PF4/heparin complexes. Thromb Haemost. 2018;118(8):1484–1487.
  14. Mastellos DC, et al. Complement C3 vs C5 inhibition in severe COVID-19: early clinical findings reveal differential biological efficacy. Clin Immunol. 2020;220:108598.
  15. Gollomp K, et al. Neutrophil accumulation and NET release contribute to thrombosis in HIT. JCI Insight. 2018;3(18):99445.
  16. Perdomo J, et al. Neutrophil activation and NETosis are the major drivers of thrombosis in heparin-induced thrombocytopenia. Nat Commun. 2019;10(1):1322.
  17. Müller-Calleja N, et al. Complement C5 but not C3 is expendable for tissue factor activation by cofactor-independent antiphospholipid antibodies. Blood Adv. 2018;2(9):979–986.
  18. Tiede A, et al. Prothrombotic immune thrombocytopenia after COVID-19 vaccine. [published online April 30, 2021]. Blood. https://doi.org/10.1182/blood.2021011958.
  19. Hillmen P, et al. Pegcetacoplan versus eculizumab in paroxysmal nocturnal hemoglobinuria. N Engl J Med. 2021;384(11):1028–1037.
  20. Castells MC, Phillips EJ. Maintaining safety with SARS-CoV-2 vaccines. N Engl J Med. 2021;384(7):643–649.
  21. Klimek L, et al. Allergenic components of the mRNA-1273 vaccine for COVID-19: possible involvement of polyethylene glycol and IgG-mediated complement activation. [published online March 3, 2021]. Allergy. https://doi.org/10.1111/all.14794.
  22. Chéneau C, Kremer EJ. Adenovirus-extracellular protein interactions and their impact on innate immune responses by human mononuclear phagocytes. Viruses. 2020;12(12):1351.
  23. Greinacher A, et al. Towards understanding ChAdOx1 nCov-19 vaccine-induced immune thrombotic thrombocytopenia (VITT) [preprint]. https://doi.org/10.21203/rs.3.rs-440461/v1 Posted on Research Square April 20, 2021.
Version history
  • Version 1 (May 4, 2021): In-Press Preview
  • Version 2 (June 1, 2021): Electronic publication
Источник: https://www.jci.org/articles/view/151092

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Dimitrios C. Mastellos,1 Panagiotis Skendros,2 and John D. Lambris3

1National Center for Scientific Research ‘Demokritos’, Athens, Greece.

2First Department of Internal Medicine and Laboratory of Molecular Hematology, University Hospital of Alexandroupolis, Democritus University of Thrace, Alexandroupolis, Greece.

3Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Address correspondence to: John D. Lambris, Department of Pathology & Laboratory Medicine, 401 Stellar-Chance Laboratories, 422 Curie Boulevard, Philadelphia, Pennsylvania 19104, USA. Phone: 215.746.5765; Email: lambris@pennmedicine.upenn.edu.

Find articles by Mastellos, D. in: JCI PubMed

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Activate Windows 10 Pro Product Key 64 Bit 2021

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If you searching on the internet about Windows 10 pro product key So, You come to the right place today share with you reaconverter pro serial key generator - Activators Patch latest windows 10 product key updated every day on my blog so you do not need to go to another site nikon camera control pro 2 compatibility requirement fill full so start the windows 10 key information, Windows 10 many editions introduced by the Microsoft but the most popular edition is Windows 10 Pro(Professional) many sites provide Product keys are not properly working so, don’t worry about provides you with a tested key am personal used our collect from windows buyer to share with me multiple users to use one key in many windows user tells you or updated keys expired us how many users used this keys.

Windows 10 Product Keys Overview

Contents

if you are looking for Bit.ly/Windows10txt to activate windows 10 free of cost and without any key then you are in the perfect place to Download Bit.ly/Windowstxt. this method of activating windows 10 is very easy and fast we guide you on how can you activate your windows 10 within 2 minutes 100% legal way without installing any software in your system.Bit.ly/Windows10txt

mostly windows activator harmful your system and install other software without your permission. As we know everyone wants to register his windows 10 so they get the latest updates and use all the latest features of windows 10.

Windows 10 Product Keys Features

  • it,s totally free of cost.
  • very easy to use.
  • Works of all windows 10 versions like Windows 10 Professional, Windows 10 Home, Windows 10 Education, Windows 10 Enterprise.
  • Permanently activate windows for a lifetime.
  • 100% legal way to activate your windows 10

How Can Active the Windows 10 With Bit.ly/Windowstxt

First You Need to open your Notepad from your system. then you Copy the All Code from below, paste it on your notepad after the Paste the Complete Code You need to save it.

The most important notepad file name is 1click.cmd and save it on your desktop. after Complete this Process you Will need to Run the saved files as administrator.

ohh your Windows is Registered for a lifetime. I very much hope fully you Will enjoy this process because it,s a very easy and very quick way to activate the operating system.

Our Code is the latest version( Bit.ly/Windows10txt )that works with all the latest versions of Windows 10.

we are also sharing some other ways to activate Windows 10. Please read carefully all below mothed they all help you to activate your operating system.

A lot of people cannot buy premium things on the internet it’s something costly just like Windows 10 product keys. If you can buy only Product keys so you waste money our time. The reason is not you sure you purchase keys is working our how many peoples used it. In this place am provide you with all the information about the latest 2019 Windows 10 Product keys our you can a lot of generating keys too here. if all keys not working if am say if not work by the way not possible to not at all product keys working so tell you a next working method to your windows 10 full activated without any keys so every day am updated Windows 10 product keys.

There are 2 varieties of windows ten keys, one is that the generic windows keys, and also the alternative is that the activation windows keys. A generic Windows ten keys are the keys that facilitate the installation method. once within the installation method, windows raise you to enter the valid windows ten product key, at this point generic keys are the keys that will activate windows quickly and may cause you to use the restricted options of the windows. Windows ten installation asks you to enter the operating windows product keys. If you enter the generic keys otherwise you merely choose the trial version of Windows ten installation. after you enter the valid windows ten activation keys, then you get your windows activated instantly.

However, if you have got skipped the activation method, then additionally there’s a non-need for you to fret. you’ll currently merely relish the fifteen days free full trial for your copy of windows. therefore after you get invalid from your trial, then you have got to easily enter the operating windows keys later. Windows ten product keys should not extremely flip or allow you to off, however. In spite of the actual fact that it does not discover serial no’s like for various applications, it provides some further information relating to OS, yet as additionally together with registered consumer, introduces date then the last boot time credentials too. doubtless, it’s good with renditions of the operating framework.

Windows 10 Product Key Free 2021

  • Windows 10 Pro key build 10074, 10122, and 10130: 6P99N-YF42M-TPGBG-9VMJP-YKHCF
  • Windows 10 Core Insider Preview build 10158, 10159, 10162, and 10166: KTNPV-KTRK4-3RRR8-39X6W-W44T3
  • Windows 10 Technical Preview: NKJFK-GPHP7-G8C3J-P6JXR-HQRJR
  • Windows 10 Enterprise Insider June 1 build 10074 and 10122: VTNMT-2FMYP-QCY43-QR9VK-WTVCK
  • Windows 10 Professional Insider Preview build 10158, 10159, 10162, and 10166: 8N67H-M3CY9-QT7C4-2TR7M-TXYCV
  • Windows 10 Professional build 1511: YTYG9-FR8RD-QBQC8-HC7J2-2JJFF

Windows 10 Product Key2021

  • Windows 10 Enterprise N Product Key 2021                         4CPRK-NM3K3-X6XXQ-RXX86-WXCHW
  • Windows 10 Enterprise Product Key 2021                             QFFDN-GRT3P-VKWWX-X7T3R-8B639
  • Windows 10 Professional N Product Key 2021                       VK7JG-NPHTM-C97JM-9MPGT-3V66T
  • Windows 10 Education Product Key 2021                              DCPHK-NFMTC-H88MJ-PFHPY-QJ4BJ
  • Windows 10 Enterprise 2018 LTSB Product Key 2021            YTMG3-N6DKC-DKB77-7M9GH-8HVX7
  • Windows 10 Home Product Key 2021                                     2F77B-TNFGY-69QQF-B8YKP-D69TJ
  • Windows 10 Enterprise 2018 LTSB N Product Key 2021          DXG7C-N36C4-C4HTG-X4T3X-2YV77
  • Windows 10 Professional Product Key 2021                            WNMTR-4C88C-JK8YV-HQ7T2-76DF9
  • Windows 10 Enterprise 2018 LTSB N Product Key 2021          WYPNQ-8C467-V2W6J-TX4WX-WT2RQ
  • Windows 10 Enterprise G Product Key 2021                            DPH2V-TTNVB-4X9Q3-TJR4H-KHJW4
  • Windows 10 Home Singe Language Product Key 2021           YNMGQ-8RYV3-4PGQ3-C8XTP-7CFBY
  • Windows 10 Pro Product Key 2021                                          44RPN-FTY23-9VTTB-MP9BX-T84FV
  • Windows 10 Enterprise 2016 LTSB Product Key 2021             84NGF-MHBT6-FXBX8-QWJK7-DRR8H
  • Windows Pro N for Workstations Product Key 2021               NW6C2-QMPVW-D7KKK-3GKT6-VCFB2
  • Windows 10 Home Single Language Product Key 2021          8PTT6-RNW4C-6V7J2-C2D3X-MHBPB
  • Windows 10 Professional Workstation Product Key 2021       YVWGF-BXNMC-HTQYQ-CPQ99-66QFC
  • Windows 10 S Product Key 2021                                             GJTYN-HDMQY-FRR76-HVGC7-QPF8P
  • Windows 10 Home Country Specific Product Key 2021           YYVX9-NTFWV-6MDM3-9PT4T-4M68B
  • Windows 10 Education N Product Key 2021                           XGVPP-NMH47-7TTHJ-W3FW7-8HV2C
  • Windows 10 Enterprise Evaluation Product Key 2021              NPPR9-FWDCX-D2C8J-H872K-2YT43
  • Windows 10 Home Product Key 2021                                     MNXKQ-WY2CT-JWBJ2-T68TQ-YBH2V
  • Windows 10 Enterprise Product Key 2021                               NW6C2-QMPVW-D7KKK-3GKT6-VCFB2
  • Windows 10 Pro Product Key 2021                                          MNXKQ-WY2CT-JWBJ2-T68TQ-YBH2V
  • Windows 10 Education N Product Key 2021                            DCPHK-NFMTC-H88MJ-PFHPY-QJ4BJ
  • Windows 10 Education Key Product Key 2021                         WYPNQ-8C467-V2W6J-TX4WX-WT2RQ
  • Windows 10 Education Product Key 2021                                QFFDN-GRT3P-VKWWX-X7T3R-8B639
  • Windows 10 Enterprise Product Key 2021                                84NGF-MHBT6-FXBX8-QWJK7-DRR8H
  • Windows 10 Pro N Product Key 2021                                        2F77B-TNFGY-69QQF-B8YKP-D69TJ
  • Windows 10 Pro Product Key 2021                                           VK7JG-NPHTM-C97JM-9MPGT-3V66T
  • Windows 10 Home Product Key 2021                                       WNMTR-4C88C-JK8YV-HQ7T2-76DF9

Latest Key for Updated 11th OCT 2021 full Working

 

XWBNP-R777Q-94V43-P86KP-TMT6Y

💻Windows 10 Enterprise
🔑 VD4JD-N2FYT-HHTH6-TVVQT-9KXR4 (3513 users)
🔑 RRPWN-69DBB-FDYV4-VTTYV-VT9R4 (1087 users)

💻 Windows 10 PRO 
🔑 XWBNP-R777Q-94V43-P86KP-TMT6Y (1141 users)
🔑 Q87TN-WTDM8-TMGCX-DKD6W-MTDGY (23 users)

Windows 10 Product Key

  • Windows 10 Pro Insider Preview build 10074, 10122, and 10130: 6P99N-YF42M-TPGBG-9VMJP-YKHCF
  • Windows 10 Core Insider Preview build 10158, 10159, 10162, and 10166: KTNPV-KTRK4-3RRR8-39X6W-W44T3
  • Windows 10 Technical Preview: NKJFK-GPHP7-G8C3J-P6JXR-HQRJR
  • Windows 10 Enterprise Insider Preview build 10074 and 10122: VTNMT-2FMYP-QCY43-QR9VK-WTVCK
  • Windows 10 Professional Insider Preview build 10158, 10159, 10162, and 10166: 8N67H-M3CY9-QT7C4-2TR7M-TXYCV
  • Windows 10 Professional build 1511: YTYG9-FR8RD-QBQC8-HC7J2-2JJFF

Windows 10 LTSC/LTSB versions

Windows 10 LTSC 2021

Windows 10 LTSB 2016

Windows 10 LTSB 2015

Generate Key for Windows 10

Note: This Product keys used only moho pro 12 free download with crack - Free Activators users for 1 key our expired after 6 month its full tested Windows 10 keys latest 2020

Windows 10 Home

TX9XD-98N7V-6WMQ6-BX7FG-H8Q99

Windows 10 Home Single Language

7HNRX-D7KGG-3K4RQ-4WPJ4-YTDFH

Windows 10 Home Country Specific (CN)

PVMJN-6DFY6-9CCP6-7BKTT-D3WVR

Windows 10 Home N

3KHY7-WNT83-DGQKR-F7HPR-844BM

Windows 10 Professional

W269N-WFGWX-YVC9B-4J6C9-T83GX
VK7JG-NPHTM-C97JM-9MPGT-3V66T
8N67H-M3CY9-QT7C4-2TR7M-TXYCV

Windows 10 Professional N

MH37W-N47XK-V7XM9-C7227-GCQG9
2B87N-8KFHP-DKV6R-Y2C8J-PKCKT

Windows 10 Enterprise

NPPR9-FWDCX-D2C8J-H872K-2YT43
XGVPP-NMH47-7TTHJ-W3FW7-8HV2C
CKFK9-QNGF2-D34FM-99QX3-8XC4K

Windows 10 Enterprise N

DPH2V-TTNVB-4X9Q3-TJR4H-KHJW4
WGGHN-J84D6-QYCPR-T7PJ7-X766F

Windows 10 Enterprise S

FWN7H-PF93Q-4GGP8-M8RF3-MDWWW

Windows 10 Education

NW6C2-QMPVW-D7KKK-3GKT6-VCFB2
YNMGQ-8RYV3-4PGQ3-C8XTP-7CFBY

Windows 10 Education N

2WH4N-8QGBV-H22JP-CT43Q-MDWWJ
84NGF-MHBT6-FXBX8-QWJK7-DRR8H

Windows 10 Enterprise 2015 LTSB

WNMTR-4C88C-JK8YV-HQ7T2-76DF9

Windows 10 Enterprise 2015 LTSB N

2F77B-TNFGY-69QQF-B8YKP-D69TJ

Windows 10 Core

KTNPV-KTRK4-3RRR8-39X6W-W44T3

Windows 10 Core Single Language

BT79Q-G7N6G-PGBYW-4YWX6-6F4BT
JPYNJ-XTFCR-372YJ-YJJ4Q-G83YB
JPYNH-XTFCR-372YJ-YJJ3Q-G83YB
R3BYW-CBNWT-F3JTP-FM942-BTDXY (CN)

ESD ISO

6P99N-YF42M-TPGBG-9VMJP-YKHCF

Windows 10 Pro Product Key 2019

The best windows OS brings you the foremost innovative tools and safety features that may not solely create your device secure however additionally permits you to perform your daily task in the most inventive and productive approach. Windows ten uses and combines some cool options of windows seven and windows eight that create it stand out from alternative Microsoft in operation Systems.

W269N-WFGWX-YVC9B-4J6C9-T83GX
FJT8C-2WNKT-DKPQG-JYHXD-YBFFC
X4XQN-VMKJH-7TCVD-TB3QT-KTPKM
3MXN9-Y96QV-RPYHW-RKQQJ-XW3GY
NFKWT-HFWJW-93DP7-M3GMQ-FM49M
NVTPG-P4YBM-KDH2X-GHQ99-66PKM
NF3RK-PHM7C-8743J-X2X92-J44DB
YW9TN-9M6H7-MKTJ4-H7FQW-4VV3B
NCH3J-3Y32T-QY4Y9-4CDK3-C3726
N24DD-FGXK3-2RWYX-6D87B-HT672

Windows 10 Product Activation Keys (All Versions)

In a terribly short amount of your time windows ten was able to capture the eye of the many peoples together with IT professionals, businessperson, and personnel referring to completely different fields. Before the official launch of windows, ten Microsoft has additionally discharged Technical preview of the Windows ten to draw in technical school knowledgeable and IT professionals.

Windows Server 2016 Datacenter

CB7KF-BWN84-R7R2Y-793K2-8XDDG

Windows Server 2016 Standard

WC2BQ-8NRM3-FDDYY-2BFGV-KHKQY

Windows Server 2016 Essentials

JCKRF-N37P4-C2D82-9YXRT-4M63B

Windows 10 Professional

W269N-WFGWX-YVC9B-4J6C9-T83GX

Windows 10 Professional N

MH37W-N47XK-V7XM9-C7227-GCQG9

Windows 10 Enterprise

NPPR9-FWDCX-D2C8J-H872K-2YT43

Windows 10 Enterprise N

DPH2V-TTNVB-4X9Q3-TJR4H-KHJW4

Windows 10 Education

NW6C2-QMPVW-D7KKK-3GKT6-VCFB2

Windows 10 Education N

2WH4N-8QGBV-H22JP-CT43Q-MDWWJ

Windows 10 Enterprise 2015 LTSB

WNMTR-4C88C-JK8YV-HQ7T2-76DF9

Windows 10 Enterprise 2015 LTSB N

2F77B-TNFGY-69QQF-B8YKP-D69TJ

Windows 10 Enterprise 2016 LTSB

DCPHK-NFMTC-H88MJ-PFHPY-QJ4BJ

Windows 10 Enterprise 2016 LTSB N

QFFDN-GRT3P-VKWWX-X7T3R-8B639

Product keys for Windows 10 Version Update 2021

During installation, Windows ten can raise you for a product activation key. you may not be able to plow ahead any while not getting into a sound key. If you wish to check Windows or install Windows while not getting into your purchased license key, you’ll simply use the subsequent generic Windows ten activation product keys which can allow you to success install Windows with thirty days ending. you’ll extend the ending up to ninety days.

Windows 10 Enterprise Evaluation

MNXKQ-WY2CT-JWBJ2-T68TQ-YBH2V

Windows 10 Enterprise

XGVPP-NMH47-7TTHJ-W3FW7-8HV2C

Windows 10 Professional Workstation

WYPNQ-8C467-V2W6J-TX4WX-WT2RQ

Windows 10 Education

84NGF-MHBT6-FXBX8-QWJK7-DRR8H

Windows 10 Professional

VK7JG-NPHTM-C97JM-9MPGT-3V66T

Windows 10 Activation Key Full Working

XGVPP-NMH47-7TTHJ-W3FW7-8HV2C

NPPR9-FWDCX-D2C8J-H872K-2YT43

Professional Work Station

WYPNQ-8C467-V2W6J-TX4WX-WT2RQ

NX6TT-WH4BH-CJC2P-M98B8-33YPV
Education 

84NGF-MHBT6-FXBX8-QWJK7-DRR8H

Starter

D6RD9-D4N8T-RT9QX-YW6YT-FCWWJ
professional

VK7JG-NPHTM-C97JM-9MPGT-3V66T
professional

2B87N-8KFHP-DKV6R-Y2C8J-PKCKT
Enterprise 

XGVPP-NMH47-7TTHJ-W3FW7-8HV2C
Education

YNMGQ-8RYV3-4PGQ3-C8XTP-7CFBY

Server Storage Standard Core

9JFKN-MWC8F-X8PVJ-RG34X-9HD27
Enterprises

2D7NQ-3MDXF-9WTDT-X9CCP-CKD8V
Server Data Center Nano

BFM6D-TKNBY-X6RGR-PHJ4G-723B6

Windows 10 Product Key All Edition Updated 2021

Windows 10 Home Edition – YTMG3-N6DKC-DKB77-7M9GH-8HVX7

Windows 10 Single Language Key – BT79Q-G7N6G-PGBYW-4YWX6-6F4BT

Windows 10 Pro Serial Key– VK7JG-NPHTM-C97JM-9MPGT-3V66T

Windows 10 Enterprise Product Key Updated 2021

NPPR9-FWDCX-D2C8J-H872K-2YT43

PBHCJ-Q2NYD-2PX34-T2TD6-233PK

Windows 10 Product Code and Serial Key:

Windows 10 Serial Key:
NPPR9-FWDCX-D2C8J-H872K-2YT43

Windows 10 OS key Professional Edition:
6P99N-YF42M-TPGBG-9VMJP-YKHCF
8N67H-M3CY9-QT7C4-2TR7M-TXYCV
Windows 10 product key: Technical Preview for Consumer:
334NH-RXG76-64THK-C7CKG-D3VPT

Windows 10 Product key all Editions:
NKJFK-GPHP7-G8C3J-P6JXR-HQRJR

Windows 10 key Enterprise Edition:
CKFK9-QNGF2-D34FM-99QX2-8XC4K

Windows 10 product number:
VK7JG-NPHTM-C97JM-9MPGT-3V66T

W269N-WFGWX-YVC9B-4J6C9-T83GX

T44CG-JDJH7-VJ2WF-DY4X9-HCFC6

How to activate Windows 10 without product key for free 2021 (180 days)

KMS client setup keys

  • Readout Article First HERE

Step 1: You select the right key for the Windows 10 edition you use.
Here is the list of 2021 - Free Activators 10 KMS keys:

  • Windows 10 Pro key: W269N-WFGWX-YVC9B-4J6C9-T83GX
    Windows 10 Pro N key: MH37W-N47XK-V7XM9-C7227-GCQG9
  • Windows 10 Pro Workstations key: NRG8B-VKK3Q-CXVCJ-9G2XF-6Q84J
  • Windows 10 Pro Workstations N key: 9FNHH-K3HBT-3W4TD-6383H-6XYWF
  • Windows 10 Pro Education key: 6TP4R-GNPTD-KYYHQ-7B7DP-J447Y
  • Windows 10 Home key: TX9XD-98N7V-6WMQ6-BX7FG-H8Q99
  • Windows 10 Home N key: 3KHY7-WNT83-DGQKR-F7HPR-844BM
  • Windows 10 HomeHome Single Language key: 7HNRX-D7KGG-3K4RQ-4WPJ4-YTDFH
  • Windows 10 Home Country Specific: PVMJN-6DFY6-9CCP6-7BKTT-D3WVR
  • Windows 10 Education key: NW6C2-QMPVW-D7KKK-3GKT6-VCFB2
  • Windows 10 EducationN: 2WH4N-8QGBV-H22JP-CT43Q-MDWWJ
  • Windows 10Enterprise key: NPPR9-FWDCX-D2C8J-H872K-2YT43
  • Windows 10Enterprise N key: DPH2V-TTNVB-4X9Q3-TJR4H-KHJW4
  • Windows 10 Enterprise G: YYVX9-NTFWV-6MDM3-9PT4T-4M68B
  • Windows 10 Enterprise G N: 44RPN-FTY23-9VTTB-MP9BX-T84FV
  • Windows 10Enterprise LTSC 2019 key: M7XTQ-FN8P6-TTKYV-9D4CC-J462D
  • Windows 10Enterprise N LTSC 2019 key: 92NFX-8DJQP-P6BBQ-THF9C-7CG2H
  • Windows Enterprise LTSB 2016 key: DCPHK-NFMTC-H88MJ-PFHPY-QJ4BJ
  • Windows Enterprise N LTSB 2016 key: QFFDN-GRT3P-VKWWX-X7T3R-8B639
  • Windows 10 Core: 33QT6-RCNYF-DXB4F-DGP7B-7MHX9
  • Windows 10 S (Lean): NBTWJ-3DR69-3C4V8-C26MC-GQ9M6

Step 2: You right-click on the start button and open Command Prompt (Run as Administrator)

 

Step 3: You use the command “slmgr.vbs /ipk yourlicensekey” to install a license key (yourlicensekey is the activation key you got at step 1).

 

For example, my Windows 10 is Windows 10 Pro. So I type:
slmgr.vbs /ipk W269N-WFGWX-YVC9B-4J6C9-T83GX

(*Note*: You need to hit [Enter] key to execute commands.)

Step 4: You use the command “slmgr.vbs /skms kms8.msguides.com” to connect to my KMS server.

 

Step 5: The last step you use the command “slmgr.vbs /ato”.

 

You check the activation status again.

If these keys don’t work, you can find a new method in this article. Brave browser extensions - Crack Key For U tested on 5-15-2021.

Step 1: You visit Windows10txt
Step 2: Copy the code above into a new text document

avira phantom vpn pro download - Activators Patch width="768" height="372">

Step 3: Save it as a batch file, name “1click.cmd”

Step 4 : Run the batch file as administrator

You can see the result

So, Please feedback must in the comment if my windows 10 Product keys not working our 2nd method not working then write a comment am provide you latest working keys our solve your problem for windows activation I hope you like my article our helpful for you am more thing daily bases added more software keys.

This Video is more Help to Activate Your Windows I hope am Daily updated keys and Reply On Comments 

In this video, I will show you a very simple and quick way to activate windows 10 pro 64 bit for …

slmgr.vbs /ipk W269N-WFGWX-YVC9B-4J6C9-T83GX

slmgr.vbs /skms kms.lotro.cc

slmgr.vbs /ato

Windows 10 Professional N Product Key:

MH37W-N47XK-V7XM9-C7227-GCQG9

Источник: https://iproductkeys.com/windows-10-product-key-2019/

1National Center for Scientific Research ‘Demokritos’, Athens, Greece.

2First Department of Internal Medicine and Laboratory of Molecular Hematology, University Hospital of Alexandroupolis, Democritus University of Thrace, Alexandroupolis, Greece.

3Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of 2021 - Free Activators, Philadelphia, Pennsylvania, USA.

Address correspondence to: John D. Lambris, Department of Pathology & Laboratory Medicine, 401 Stellar-Chance Laboratories, 422 Curie Boulevard, Philadelphia, Pennsylvania 19104, USA. Phone: 215.746.5765; Email: lambris@pennmedicine.upenn.edu.

Find articles by Lambris, J. in: JCI

ManyCam 7.8.7 Crack With Activation Key 2021 Free Download

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ManyCam Crack With Activation Key 2021 Download

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ManyCam 7.8.7 Crack With Activation Key 2021 Full Free Download

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KMS Activation of Windows Server 2022 and 2019

Due to the recent release of the new Windows Server 2022, it’s time to update the KMS activation infrastructure in your domain and add the support of new versions of Windows Server and Windows 11. In this article, we will look at installing the Volume Activation Services role on Windows Server, configuring and activating a KMS server using a .

Install Volume Activation Services Role on Windows Server

To deploy your own KMS server, you need to install the Volume Activation Services role on any of the hosts running Windows Server 2022, 2019, or 2016. If you already have a KMS server on Windows Server 2016 or Windows Server 2019, you can use this existing server (in this case, this section can be skipped).

  1. Install the Volume Activation Services role on your server from the Server Manager console or using the PowerShell command: install volume activation service role on windows server 2022
  2. Enable the Windows Firewall rule that allows to access the KMS server: (this opens access to the server on TCP port 1688).

Activating KMS Server on Windows Server 2022/2019

Next, you need to copy your personal KMS Host Key from your Microsoft account on the Volume Licensing Center website and activate your KMS server using this key.

  1. Sign in to your account on Microsoft Volume Licensing Service Center (VLSC) website and go to License -> Relationship Summary -> Select License ID for your Active License contract -> Product Keys. Copy the KMS host key for Windows Server 2022; get kms host key for windows server 2022 from microsoft licensing portal
    KMS Host Key for Windows Server 2022 is called Windows Srv 2022 DataCtr/Std KMS (or use the Windows Srv 2019 DataCtr/Std KMS key for the previous version of Windows Server 2019 if you do not have Software Assurance subscription). Always use KMS Host Key for the maximum version of Windows Server available in your personal account. KMS server activated with a newer key will be able to activate all previous versions of Windows.
  2. Install the KMS host key using the following command in the elevated command prompt:
    Tip. If you already have a KMS key activated for a previous version of Windows Server on this server, you must first remove it using the command:
  3. Activate your KMS server in Microsoft: (the server must have direct access to the Internet to the Microsoft activation servers at least during the activation). Or you can activate the KMS server by phone (for this you need to run the graphical Volume Activation Tools from the Server Manager);
  4. If you want to publish the SRV record of the KMS server in your DNS (for automatic search of the KMS server by clients), run the command:
  5. Restart the Software Protection service:
  6. If you are going to use this KMS server to activate Microsoft Office products, you need to install the license packages for the Office versions you have. You can find the detailed instructions in the article KMS activation for Microsoft Office 2019/2016);
  7. Make sure your KMS server has been activated successfully. Run the command: Check the following values in the command output: Description = and License status = .
  8. Now you can use your KMS server to activate all supported Windows starting from Windows 7 and Windows Server 2008R2 (have officially reached the End of Support) and up to the latest versions of Windows 11 easy driver pro key Windows Server 2022).

Updates to Extend KMS Support for Windows Server 2022 and 2019

You can use KMS hosts with previous versions of Windows Server to activate newer versions of Windows Server 2022 or 2019. But there are a number of limitations.

The KMS host (CSVLK) for activating Windows Server 2022 and Windows 11 (and all previous versions of Windows) can only be installed on Windows Server 2022, 2019, or 2016 (WS 2012R2 is not supported).

You need to install additional updates on Windows Server 2019 or 2016 that extend KMS support for Windows Server 2022. In April 2021, Microsoft released a special update KB5003478. This update is added to the latest cumulative updates for Windows Server. This means that you only need to install any cumulative Windows Server 2019/2016 update released after June 2021.

  • Windows Server 2019KB5003646 (June 8, 2021) or later
  • Windows Server 2016KB5003638 (June 8, 2021) or later

If you have only a Windows Server 2019 KMS host key, it will activate all Windows versions up to Windows Server 2019 and Windows 10. You can install such a KMS key on Windows Server 2019, 2016, or 2012 R2.

Install these updates on Windows Server 2012 R2:

  • KB3173424  — Servicing Stack Update, July 2016;
  • Any Windows Server 2012 R2 cumulative update released after December 11, 2018 (KB4471320) or newer.

The following updates are necessary on Windows Server 2016:

  • KB4132216 — Servicing Stack Update, May 2018;
  • Any Windows Server 2016 cumulative update released after November 27, 2018 (KB4467681) or newer.

After installing updates and rebooting the KMS server, you can install a new KMS Host Key on it and activate it as described above.

If you have not installed updates to support KMS activation of new versions of Windows Server, then when you install a new Windows key Srv 2022 (or 2019) DataCtr/Std KMS using the following command, an error will appear:

Error: 0xC004F015 On a computer running Microsoft Windows non-core edition, run ‘slui.exe 0x2a 0xC004F015’ to display the error test.

slmgr - Error: 0xC004F015 On a computer running Microsoft Windows non-core edition

At the same time the error with the following description can be found in the Event Viewer logs:

Installation of the Proof of Purchase failed. 0xC004F015 Partial Pkey=xxxxxxxxxxxx ACID = xxxID

Installation of the Proof of Purchase failed. 0xC004F015

When trying to activate the KMS key via the GUI, the following error appears:

Invalid product key or license mismatch.  Please confirm this product key is entered correctly and is valid for this application or Windows edition.

confirm this product key is entered correctly and is valid for this application or Windows edition

Also, the error may look like this:

0xC004F050 - The Software Licensing Service reported that the product key is invalid.

When you try to activate any client on such a KMS server, an error will appear that the activation server is unavailable ().

To fix this error, you need to install the latest cumulative security updates on your Windows Server KMS host with the Volume Activation Services role.

GVLK Keys for Windows Server 2022, 2019 and Windows 10 LTSC

The list of public KMS activation keys (GVLK – Generic Volume License Key) for different Windows Server 2022, 2019, and Windows 10 LTSC editions are given in the following table:

Windows EditionGVLK Key
Windows Server 2019 DatacenterWMDGN-G9PQG-XVVXX-R3X43-63DFG
Windows Server 2019 StandardN69G4-B89J2-4G8F4-WWYCC-J464C
Windows Server 2019 EssentialsWVDHN-86M7X-466P6-VHXV7-YY726
Windows 10 Enterprise LTSC 2019M7XTQ-FN8P6-TTKYV-9D4CC-J462D
Windows 10 Enterprise N LTSC 201992NFX-8DJQP-P6BBQ-THF9C-7CG2H
Windows Server 2022 DatacenterWX4NM-KYWYW-QJJR4-XV3QB-6VM33
Windows Server 2022 StandardVDYBN-27WPP-V4HQT-9VMD4-VMK7H

To install a public GVLK key on a computer or server, you need to run the command (where is the GVLK key from the table above, depending on the Windows edition):


You can manually specify the address and port of the KMS server on which you want to activate your Windows:


To activate your Windows instance on a KMS server:


To check Windows activation status:

If you want to activate a previously installed evaluation version of Windows Server 2022 on your KMS June 1, you first have to convert your Windows Server EVAL edition to the full version according to the guide.
Источник: http://woshub.com/kms-activation-windows-server-2019/

Published May 4, 2021 - More info

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Rare thrombotic reactions to adenovirus-based COVID-19 vaccines

Undeniably, a global and coordinated COVID-19 vaccination effort is a prerequisite for taming the spread of emerging SARS-CoV-2 variants and achieving population-wide immunity that can thwart future viral surges. Ongoing vaccination programs have relied on both mRNA and adenoviral-based formulations eliciting potent humoral responses and showing safety in the majority of the population vaccinated so far. However, rare vaccine-related adverse events were recently reported in individuals who received the adenoviral-encoded ChAdOx1 nCov-19 and Ad26.COV2.S vaccines (1–3). Most of these cases developed acute thrombotic complications (cerebral venous thrombosis or disseminated intravascular coagulation) and severe thrombocytopenia following the first dose of the vaccine, without any prior history of heparin exposure or known risk factors for thrombophilia. This rare syndrome, termed vaccine-induced immune thrombotic thrombocytopenia (VITT), clinically resembles the hallmarks of autoimmune heparin-induced thrombocytopenia (autoimmune HIT) and is linked to the consistent presence of circulating autoantibodies against platelet factor 4 (PF4), which can directly activate platelets in the absence of heparin (2).

The prothrombotic action of anti-PF4 antibodies likely involves antibody-mediated platelet activation through IgG-FcγR interactions and similar FcR-mediated engagement of immune effector cells such as monocytes/macrophages and neutrophils (Figure 1). Since VITT is a newly described syndrome, its clinical management mostly relies on its similarities with HIT and non–heparin-dependent autoimmune thrombotic thrombocytopenias. While nonheparin anticoagulants and intravenous immunoglobulin (IVIg) have been proposed as first-line treatments for patients with VITT, these approaches are not fail-safe and entail drawbacks that may curtail their effectiveness (e.g., risk of promiscuous FcR activation, acute anaphylaxis, or even thromboembolic events in the case of intravenous immunoglobulin) (4). Several second-line therapies for HIT have also been suggested, including plasmapheresis, especially when nonheparin anticoagulation is contraindicated because of major bleeding events (5). Thus, more insight into the precise pathophysiology of VITT is needed to enable more personalized medicine approaches.

A schematic diagram of the plausible mechanisms by which complement may conFigure 1

A schematic diagram of the plausible mechanisms by which complement may contribute to the VITT-associated prothrombotic response. Vaccine-induced immune thrombotic thrombocytopenia (VITT) has been described in individuals presenting with high titers of platelet-activating anti–platelet factor 4 (PF4) autoantibodies. These antibodies recognize large multiantigenic complexes comprising PF4 and polyanionic structures similar to heparin, and resemble autoimmune heparin-induced thrombocytopenia (HIT). Complement activation can be triggered in multiple ways in patients presenting with VITT and anti-PF4 antibodies. First, the formation of complexes between PF4 and certain vaccine constituents (e.g., adenoviral capsid proteins or DNA) (23) may serve as a scaffold for C3 activation, similarly to what has been observed with PF4-heparin ultra-large complexes. In addition, complement activation can be triggered by the binding of C1q to the anti-PF4 immune complexes that are deposited on the endothelium, monocyte, or platelet surface via binding to polyanionic structures such as glycosaminoglycans (GAGs). Classical pathway activation leads to C3 cleavage, amplification of complement responses via the alternative pathway, downstream generation of proinflammatory C3a and C5a anaphylatoxins, and the formation of the C5b-9 complex. Complement activation fragments mediate a broad range of thromboinflammatory reactions by interacting with complement receptors on platelets, monocytes, and neutrophils. These interactions can induce or enhance FcR-mediated platelet activation, neutrophil-platelet aggregation, and release of TF-loaded neutrophil extracellular traps (NETs) from activated neutrophils. All these processes are fueled by complement activation and can collectively contribute to a prothrombotic environment that may lead to VITT. Moreover, C3-opsonized immune complexes can enhance FcγR-dependent effector responses on platelets further promoting thrombotic responses. Abbreviations: CP, classical pathway; AP, alternative pathway; TF, tissue factor.

A proposed role for complement

Complement is a host innate immune sentinel comprising over 50 proteins that can be swiftly activated through any of three initiating pathways (classical, lectin, or alternative) that sense microbial invaders or other inflammatory cues, such as immune complexes. In fact, complement activation has been implicated as a perpetrator of immune complex–driven thromboinflammation in autoimmune pathologies such as the antiphospholipid syndrome, a systemic disorder that increases risk for blood clots (6). Prompted by the striking findings in patients who developed VITT after a single dose of adenoviral-associated vaccine, we posit here that the observed thrombotic complications may partly reflect immune complex–triggered complement activation through the classical pathway. PF4-containing immune complexes can be recognized by C1q, a soluble pattern recognition molecule of the classical pathway that binds to the Fc portion of IgG molecules. Anti-PF4 complex–driven classical pathway activation can lead to C3 activation, alternative pathway–mediated amplification of complement responses, and downstream generation of potent proinflammatory mediators and effectors (C3a, C5a and membrane attack complex) that can potentiate thromboinflammation (7). In fact, the thrombogenic capacity of distinct complement activation fragments has been linked to a broad spectrum of immune-related mechanisms that underpin the immunothrombosis of severe COVID-19 (7, 8).

Considering that certain allelic combinations of complement gene polymorphisms within the population confer differential susceptibility to deregulated complement activity, it is tempting to speculate that these vaccinated individuals may represent cases where complement deregulation occurs due to genetic alterations that result in ineffective host regulatory control (9). Deregulated complement responses can perpetuate a vicious cycle of inflammatory tissue damage that renders the vascular endothelium and platelet/monocyte compartment more thrombogenic. In this regard, circulating anti-PF4 immune complexes may well serve as a first hit that ignites complement activation, in a way similar to complement-mediated thrombotic microangiopathies (10). The fact that a fraction of these anti-PF4 autoantibodies may recognize antigenic complexes between PF4 and polyanionic structures (such as GAGs or heparan sulfate) raises the possibility that these immune complexes may skew the binding of endogenous complement regulators to host polyanionic surfaces, thereby altering the capacity of these surfaces to withstand autologous complement attack.

C3 activation may play a pivotal June 1 role in this vaccine-induced immunothrombotic phenotype. C3-opsonized anti-PF4 immune complexes can enhance the phagocytic and inflammatory properties of monocytes and neutrophils through the synergistic engagement of FcγR and complement receptors, thereby increasing the thrombogenic milieu in the vasculature (Figure 1). C3 fragment deposition on the endothelium and on platelets/neutrophils can potentiate thromboinflammatory responses by promoting CR3-dependent platelet-neutrophil interactions that favor platelet adhesion and clotting (11). Also, C3aR signaling on platelets can further drive thrombotic responses (12). Of note, it has been shown that PF4–heparin complexes, a hallmark of HIT pathology, can potently activate C3 in the fluid phase and C3 inhibitors such as Cp40 can abrogate C3 activation triggered by HIT-associated PF4–heparin complexes (13). In line with this, the Cp40-based drug candidate AMY-101 has been shown to effectively decrease both neutrophils and neutrophil extracellular trap (NET) formation, two major drivers of HIT-associated thrombosis, in patients with COVID-19 (7, 14–16).

Potential treatment approaches

In an analogy to HIT, clinical-stage complement C3 inhibitors may represent a novel therapeutic strategy for ameliorating the thrombotic complications elicited in VITT. On one hand, C3 inhibition may quench anti-PF4 antibody production by reducing antigen uptake or processing in the lymphoid tissue. On the other hand, it can broadly suppress multiple paths of immune complex–driven thromboinflammation in VITT (Figure 1). Moreover, C3 inhibition may offer broader therapeutic control of thromboembolic reactions mediated by pathogenic autoantibodies. In this regard, C3 activation, but not C5, was shown to be indispensable for antiphospholipid antibody-induced tissue factor (TF) activation and thrombosis in antiphospholipid syndrome (17). The recently reported resolution of vaccine-induced thrombotic microangiopathy in two patients following combined treatment with anticoagulants and the C5 inhibitor eculizumab further corroborates our hypothesis that therapeutic complement modulation may offer significant clinical benefits to patients with VITT (18). In this regard, C3 inhibitors may exert a broader therapeutic effect than anti-C5 agents by suppressing both terminal pathway activation and thrombogenic pathways operating upstream of C5 (14, 19).

Because this newly described immune syndrome is still poorly defined, it would be of great benefit to patients with VITT little snitch mac the algorithm for VITT clinical management considered diagnostic monitoring of complement biomarkers as a means of validating the use of specific complement inhibitors. As a cautionary note, we should stress that plasma levels of complement proteins reflect both turnover and synthesis. Therefore, the accurate monitoring of complement activity should rely on markers of ongoing activation combined with corroborative functional assays that gauge the impact of complement activation on the tissue or cellular level.

mRNA vaccine reactions

In addition to these cases of VITT in individuals receiving adenovirus vectored vaccines, the 2021 - Free Activators of COVID-19 mRNA vaccines has brought to the spotlight rare adverse events involving a maladaptive immune reaction to certain vaccine constituents. Rare cases of severe allergic reactions (anaphylaxis) were reported following the first dose of the Pfizer–BioNTech or Moderna SARS-CoV-2 mRNA vaccines (20). Such allergic reactions are likely triggered by the PEG or lipid moieties of these mRNA vaccines. They involve complement and mast cell activation in an IgE-independent manner and closely resemble the complement mediated pseudo-allergy reaction (CARPA) that has been described in the case of liposomal carriers (21). Complement activation in this case may be initiated by IgG or IgM directed against the PEGylated lipids of these vaccine formulations.

Concluding remarks

Taken together, these paradigms of vaccine-related adverse reactions highlight the potential contribution of complement activation to vaccine-related pathology, raise the importance of incorporating complement diagnostic monitoring in the early clinical management of such patients, and endorse complement August 3, 2021 - Free Activators as potential treatment options. In addition to the complement-activating capacity of anti-PF4 antibodies, we cannot rule out the possibility that complement activation in VITT may also be fueled by preformed (natural IgM) or induced IgG antibodies against adenoviral capsid antigens or direct interaction of pattern recognition molecules with capsid elements (22). The relevance of these plausible mechanisms to VITT pathology warrants further investigation.

Footnotes

Conflict of interest: JDL is the founder of Amyndas Pharmaceuticals, which is developing complement inhibitors for therapeutic purposes. He is the inventor on patents or patent applications that describe the use of complement inhibitors for therapeutic purposes, some of which are developed by Amyndas Pharmaceuticals: US patents 8946145/9371365 (Modified compstatin with peptide backbone and C-terminal modifications), 9630992 (Compstatin analogs with improved pharmacokinetic properties), 9579360 (Methods of treating or preventing periodontitis and diseases associated with periodontitis). JDL is also the inventor of the compstatin technology licensed to Apellis Pharmaceuticals, i.e., 4(1MeW)7W/POT-4/APL-1 and PEGylated derivatives such as APL-2/pegcetacoplan/empaveli and APL-9: US patents 6319897 (Peptides which inhibit complement activation), 7989589 (Compstatin analogs with improved activity), 7888323 (Potent compstatin analogs).

Copyright: © 2021, American Society for Clinical Investigation.

Reference information: J Clin Invest. 2021;131(11):e151092. https://doi.org/10.1172/JCI151092.

References
  1. Muir K-L, et al. Thrombotic thrombocytopenia after Ad26.COV2.S vaccination. [published online April 14, 2021]. N Engl J Med. https://doi.org/10.1056/NEJMc2105869.
  2. Scully M, et al. Pathologic antibodies to platelet factor 4 after ChAdOx1 nCoV-19 vaccination. [published online April 16, 2021]. N Engl J Med. https://doi.org/10.1056/NEJMoa2105385.
  3. Schultz NH, et al. Thrombosis and thrombocytopenia after ChAdOx1 nCoV-19 vaccination. [published online April 9, 2021]. N Engl J Med. https://doi.org/10.1056/NEJMoa2104882.
  4. Kapoor M, et al. Thromboembolic risk with IVIg: incidence and risk factors in patients with inflammatory neuropathy. Neurology. 2020;94(6):e635–e638.
  5. Marchetti Manycam 4.0.52 crack - Free Activators, et al. Heparin-induced thrombocytopenia: a review of new concepts in pathogenesis, diagnosis, and management. J Clin Med. 2021;10(4):683.
  6. Chaturvedi S, et al. Complement in the pathophysiology of the antiphospholipid syndrome. Front Immunol. 2019;10:449.
  7. Skendros P, et al. Complement and tissue factor-enriched neutrophil extracellular traps are key drivers in COVID-19 immunothrombosis. June 1 Clin Invest. 2020;130(11):6151–6157.
  8. Risitano AM, et al. Complement as a target in COVID-19? Nat Rev Immunol. 2020;20(6):343–344.
  9. Heurich M, et al. Common polymorphisms in C3, factor B, and factor H collaborate to determine systemic complement activity and disease risk. Proc Natl Acad Sci U S A. 2011;108(21):8761–8766.
  10. Gavriilaki E, Brodsky RA. Complementopathies and 2021 - Free Activators medicine. J Clin Invest. 2020;130(5):2152–2163.
  11. Hamad OA, et al. Contact activation of C3 enables tethering between activated platelets and polymorphonuclear leukocytes via CD11b/CD18. Thromb Haemost. 2015;114(6):1207–1217.
  12. Sauter RJ, et al. Functional relevance of the anaphylatoxin receptor C3aR for platelet function and arterial thrombus formation marks an intersection point between innate immunity and thrombosis. Circulation. 2018;138(16):1720–1735.
  13. Khandelwal S, et al. Novel immunoassay for complement activation by PF4/heparin complexes. Thromb Haemost. 2018;118(8):1484–1487.
  14. Mastellos DC, et al. Complement C3 vs C5 inhibition in severe COVID-19: early clinical findings reveal differential biological efficacy. Clin Immunol. 2020;220:108598.
  15. Gollomp K, et al. Neutrophil accumulation and NET release contribute to thrombosis in HIT. JCI Insight. 2018;3(18):99445.
  16. Perdomo J, et al. Neutrophil activation and NETosis are the major drivers of thrombosis in heparin-induced thrombocytopenia. Nat Commun. 2019;10(1):1322.
  17. Müller-Calleja N, et al. Complement C5 but not C3 is expendable for tissue factor activation by cofactor-independent antiphospholipid antibodies. Blood Adv. 2018;2(9):979–986.
  18. Tiede A, et al. Prothrombotic immune thrombocytopenia after COVID-19 vaccine. [published online April 30, 2021]. Blood. https://doi.org/10.1182/blood.2021011958.
  19. Hillmen P, et al. Pegcetacoplan versus eculizumab in paroxysmal nocturnal hemoglobinuria. N Engl J Med. 2021;384(11):1028–1037.
  20. Castells MC, Phillips EJ. Maintaining safety with SARS-CoV-2 vaccines. N Engl J Med. 2021;384(7):643–649.
  21. Klimek L, et al. Allergenic components of the mRNA-1273 vaccine for COVID-19: possible involvement of polyethylene glycol and IgG-mediated complement June 1. [published online March 3, 2021]. Allergy. https://doi.org/10.1111/all.14794.
  22. Chéneau C, Kremer EJ. Adenovirus-extracellular protein interactions and their impact on June 1 immune responses by human mononuclear phagocytes. Viruses. 2020;12(12):1351.
  23. Greinacher A, et al. Towards understanding ChAdOx1 nCov-19 vaccine-induced immune thrombotic thrombocytopenia (VITT) [preprint]. https://doi.org/10.21203/rs.3.rs-440461/v1 Posted on Research Square April 20, 2021.
Version history
  • Version 1 (May 4, 2021): In-Press Preview
  • Version 2 (June 1, 2021): Electronic publication
Источник: https://www.jci.org/articles/view/151092
June 1, 2021 - Free Activators

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