COVID-19 Vaccines and Autoimmune Hematologic Disorders

Citation: Mingot-Castellano, M.E.; Butta, N.; Canaro, M.; del Carmen Gómez del Castillo Solano, M.; Sánchez-González, B.; Jiménez-Bárcenas, R.; Pascual-Izquierdo, C.; Caballero-Navarro, G.; Entrena Ureña, L.; González-López, T.; et al. COVID-19 Vaccines and Autoimmune Hematologic Disorders. Vaccines 2022,10, 961. https:// doi.org/10.3390/vaccines10060961 Academic Editor: S. Louise Cosby Received: 22 May 2022 Accepted: 15 June 2022 Published: 16 June 2022 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Copyright: © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). Review COVID-19 Vaccines and Autoimmune Hematologic Disorders María Eva Mingot-Castellano 1,*, Nora Butta 2, Mariana Canaro 3, María del Carmen Gómez del Castillo Solano 4, Blanca Sánchez-González 5, Reyes Jiménez-Bárcenas 6, Cristina Pascual-Izquierdo 7, Gonzalo Caballero-Navarro 8, Laura Entrena Ureña 9, Tomás JoséGonzález-López 10 and on behalf of the GEPTI 11,† 1Hematology Department, Hospital Universitario Virgen del Rocío, Instituto de Biomedicina de Sevilla (IBIS/CSIC), 41013 Sevilla, Spain 2Hospital Universitario La Paz-IdiPAZ, 28046 Madrid, Spain; [email protected] 3Hematology Department, Hospital Universitario Son Espases, 07210 Palma, Spain; [email protected] 4Hematology Department, Hospital General de la Coruña, 15006 A Coruña, Spain; [email protected] 5Hematology Department, Hospital del Mar, 08003 Barcelona, Spain; [email protected] 6Hematology Department, Hospital Serranía de Ronda, 29400 Ronsa, Spain; [email protected] 7SpainDepartment of Hematology, Gregorio Marañón General University Hospital (HGUGM) Madrid, Insti-tuto de Investigación Gregorio Marañón, 28009 Madrid, Spain; crisizquier[email protected] 8Hematology Department, Hospital Universitario Miguel Servet, 50009 Zaragoza, Spain; [email protected] 9Hematology Department, Hospital Universitario Virgen de las Nieves, 18014 Granada, Spain; [email protected] 10 Hematology Department, Hospital Universitario de Burgos, 09006 Burgos, Spain; [email protected] 11 Grupo Español de PTI, 28040 Madrid, Spain; [email protected] *Correspondence: [email protected] † All the authors from this group are included in Acknowledgments part. Abstract: Worldwide vaccination against SARS-CoV-2 has allowed the detection of hematologic autoimmune complications. Adverse events (AEs) of this nature had been previously observed in association with other vaccines. The underlying mechanisms are not totally understood, although mimicry between viral and self-antigens plays a relevant role. It is important to remark that, although the incidence of these AEs is extremely low, their evolution may lead to life-threatening scenarios if treatment is not readily initiated. Hematologic autoimmune AEs have been associated with both mRNA and adenoviral vector-based SARS-CoV-2 vaccines. The main reported entities are secondary immune thrombocytopenia, immune thrombotic thrombocytopenic purpura, autoimmune hemolytic anemia, Evans syndrome, and a newly described disorder, so-called vaccine-induced immune thrombotic thrombocytopenia (VITT). The hallmark of VITT is the presence of anti-platelet factor 4 autoantibodies able to trigger platelet activation. Patients with VITT present with thrombocytopenia and may develop thrombosis in unusual locations such as cerebral beds. The management of hematologic autoimmune AEs does not differ significantly from that of these disorders in a nonvaccine context, thus addressing autoantibody production and bleeding/thromboembolic risk. This means that clinicians must be aware of their distinctive signs in order to diagnose them and initiate treatment as soon as possible. Keywords: COVID-19; vaccines; ITP; VITT; TTP; AIHA and Evans syndrome; antiphospholipid syndrome; catastrophic antiphospholipid syndrome 1. Introduction The exceptional scenario conditioned by the sudden outbreak of SARS-CoV-2 infection all over the world prompted the search for vaccines that are efficient and easy to manufacture at huge scale. Extensive research led to the production of more than 20 compounds that successfully passed phase III trials and, thus, were deemed to be safe. Nevertheless, Vaccines 2022,10, 961. https://doi.org/10.3390/vaccines10060961 https://www.mdpi.com/journal/vaccines Vaccines 2022,10, 961 2 of 23 the extended use in the real-world of drugs that have successfully passed the test of clinical trials often involves the emergence of adverse events (AEs). Although these are infrequent and will not tip the balance towards product withdrawal, they can be serious and their occurrence has to be envisaged. Indeed, this phenomenon occurred when COVID-19 vaccines started being administered throughout the world. Statements documenting AEs started being reported. Although regular updates repeatedly demonstrate that the majority of these episodes are mild and transient, serious AEs (SAEs) are occasionally described that, albeit rarely, may be fatal. These SAEs are particularly of an autoimmune nature. This is not unexpected, since humoral immune response to vaccination involves the production of antibodies against foreign antigens that, occasionally, could mimic self-ones. Structures often affected by autoimmune disorders include platelets, RBCs and blood vessels. Thus, it is not surprising that hematologic autoimmune disorders are associated with SARS-CoV-2 vaccines, either the mRNA or adenoviral vector-based ones. When a hematologic autoimmune disorder develops following vaccination, a prompt and accurate diagnosis is essential to initiate the appropriate treatment and avoid bleeding or thromboembolic complications that may sometimes be life-threatening. The main autoimmune disorders of a hematologic nature that have been linked to SARS-CoV-2 vaccination are addressed herein. Commonly used therapies and outcomes are revised. Where suggested, potentially involved mechanisms linking vaccines and autoimmune pathology are described. Finally, guidelines to follow in order to promptly recognize and manage these complications are provided. 2. Methods In order to select the eligible studies whose results would be considered a comprehensive update about the AEs of hematologic autoimmune nature reported in the context of COVID-19 infection, the authors searched the PubMed registry and the regular updates of the European Database of Suspected Adverse Drug Reaction (EudraVigilance), United Kingdom Medicines & Healthcare Products Released Regulatory Agency (MHRA), Health-Infobase Government of Canada, and the Vaccine Adverse Events Reporting System (VAERS). The search criteria consisted of considering all reports regarding phase III clinical trials and the real-world use of vaccines, stating that any hematologic AE had occurred. The latest search date included was 9 May 2022. Although some reports were limited to enumerating AEs, the scarcity of available literature prompted us to consider all statements addressing the occurrence of hematologic AEs, even if the information was incomplete. The chosen keywords or word combinations to track the information of interest were COVID-19, vaccines, ITP, VITT, TTP, AIHA, Antiphospholipid and Evans syndrome, autoimmune disorder, thrombocytopenia, and anemia. 3. Commercially Available COVID-19 Vaccines More than 100 vaccines have been developed against SARS-CoV-2, 26 of which have been evaluated in phase III clinical trials according to the World Health Organization (WHO) [ 1 ]. These can be stratified into up to five different categories according to how they generate immunity. The classically used methods based on whole inactivated or live attenuated virus, although effective, have always raised concerns. Incomplete viral inactivation may not be discarded, and every batch needs to be checked [ 2 ]. The development of antibody disease enhancement (ADE) syndrome due to non-neutralizing antibodies may be a risk which, in the COVID-19 scenario, can increase lung pathology [ 3 ]. Furthermore, there was a need for quickly available, massively produced vaccines. Nucleic acid-based vaccines constituted an attractive alternative option. They are easier to manufacture, their lipid nanoparticle-based platform is robust and efficient, and can be rapidly produced at industrial scale. For these reasons, they are being widely used, at least in Western countries, in spite of the challenge raised by the poor stability of mRNA-based products that limits storage periods and may compromise in vivo activity [4]. Vaccines 2022,10, 961 3 of 23 The aforementioned categories are inactivated-virus vaccines, mRNA vaccines, DNA vaccines, viral vector vaccines and protein-based vaccines. Inactivated-virus vaccines consist of whole viruses that cannot infect cells and replicate. Viruses can be inactivated by formalin, heat irradiation or chemical treatment. Moderate immunogenicity can be a drawback, and adjuvants and/or booster doses are required. mRNA vaccines [ 5 ] contain the mRNA of the antigen of interest, which enters cells and is translated into the corresponding protein to induce an immune response. DNA vaccines use a plasmid DNA vector to induce response and they are easier to store and the route of administration may not be exclusively intramuscular, but also intradermal or oral. Viral vector vaccines are based on viral delivery systems that contain a nucleic acid which encodes the antigen of interest. Adenoviruses, which are often employed, have also been used as non-enveloped double stranded DNA (dsDNA) for gene therapy purposes, because the encoded gene can be delivered into human cells without integrating in the human genome [ 6 ]. Finally, protein-based vaccines are made of fragments of proteins or polysaccharides. The source can be either the target virus, from which the protein is purified, a recombinant protein, virus-infected cells, or virus-like particles. Low immunogenicity can be one disadvantage, and adding an adjuvant might be needed [ 7 ]. Supplementary Table S1 shows which category each one of the 26 COVID-19 vaccines that have successfully passed phase III trials belongs to. Table 1shows the main features of the most widely used ones. Table 1. Characteristics, mechanism of production, storage, efficacy, and adverse events of vaccines against COVID-19. Compound (Trade Name) Manufacturer Mechanism Doses Needed Interval Storage (◦C) Efficacy (%) BNT162b2 (Comirnaty) Pfizer/BioNTech mRNA 2 21 d −70 95 mRNA-1273 (Spikevax) Moderna mRNA 2 28 d −20 94.5 ChAdOx1 nCoV-19 (Vaxzevria) AstraZeneca/Oxford AdV-vectored 2 4–12 wk 2–8 70 Ad26.CoV2.S Johnson & Johnson AdV-vectored 1 - 2–8 66.3 Gam-COVID-Vac (Sputnik V) Gamaleya Research Institute AdV-vectored 2 21 d −18 92 Ad5-nCoV (Convidecia) CanSino AdV-vectored 1 - −20 65.7 NVX-CoV2373 (Covovax) Novavax Protein subunit 2 21 d −20 89.3 EpiVacCorona (Aurora-CoV) Vector Institute Protein subunit 2 21 d 2–8 n.a. BBIBP-CorV (Covilo) Sinopharm (Beijing) Inactivated virus 2 21–28 d 2–8 79 WIBP-CorV Sinopharm (Wuhan) Inactivated virus 2 14–21 d 2–8 72.5 Vero cell (CoronaVac) Sinovac Biotech Inactivated virus 2 28 d 2–8 50–83.5 BBV152 (Covaxin) Bharat Biotech Inactivated virus 2 28 d 2–8 81 AdV, adenovirus; d, days; n.a., not available; wk, weeks. Key concepts •There are currently many different ways of producing vaccines. •Obstacles or disadvantages may be storage, stability, or low immunogenicity. 4. International Reports of Adverse Events Associated with COVID-19 Vaccines COVID-19 vaccination programmes are being rolled out globally. Nevertheless, the need for ready availability prompted the approval of vaccines whose studies regarding side effects and efficacy involved shorter than desirable follow-up periods. As time goes on, cases of moderate to severe adverse events (AEs) associated to SARS-CoV-2 vaccines in the real world are being documented. This information is being analyzed and updated regularly, and reports are being made available via databases and agencies such as the European Database of Suspected Adverse Drug Reaction (EudraVigilance), the United Kingdom Medicines & Healthcare Products Released Regulatory Agency (MHRA), the Health-Infobase Government of Canada, or the Vaccine Adverse Events Reporting System (VAERS). AEs are always classified according to the Common Toxicity Criteria (CTC) cate- Vaccines 2022,10, 961 4 of 23 gories [ 8 – 11 ]. Between December 2020 and March 2022, 1,114,386,127 doses of four different COVID-19 vaccines, two of them mRNA-based and the other two using adenovirus as vectors, were administered in the European Union, United Kingdom and Canada. Table 2depicts the amount of doses administered up to March 2022, including frequency and types of common AEs and serious AEs (SAEs) corresponding to each type of vaccine, according to the information released by the aforementioned databases and articles concerning clinical trials [ 8 – 15 ]. Global numbers of common AEs are not particularly remarkable [ 12 – 15 ]. On the other hand, the incidence of SAEs is not different than that expected in a worldwide campaign [ 8 – 11 ]. The SAEs reported so far include, among others, autoimmune disorders, predominantly of hematologic origin, which are addressed in detail below, venous or arterial thrombotic events, paroxysmal arrhythmias or anaphylactic reactions [ 8 – 11 ]. Reports regarding other vaccines less used in Western countries, such as Gam-COVID-Vac, Ad5-nCoV, NVX-CoV2373, EpiVacCorona, BBIBPCorV, WIBPCorV or CoronaVac, identify flu-like illness, injection site pain, headache, asthenia, pain, soreness, fatigue, headache, malaise, myalgia or fever among mild to moderate AEs. SAEs have not been reported except in the case of Gam-COVID-Vac, whose use has been associated with renal colic, deep venous thrombosis (DVT) or extremity abscess development [16]. Table 2. Adverse events associated with the most used vaccines in Western countries. Vaccine Number of Administered Doses * Incidence of SAEs (%) *,†Common AEs ‡SAEs § BNT162b2 770,897,374 0.13 (0.05–0.21) Local pain (>80%) fever (>10%) headache (>50%) fatigue (>60%) myalgia (>40%) arthralgia (>20%), lymphadenopathy (3%) chills (>30%) ATE/VTE, ITP, TTS, allergic reactions including anaphylaxis, paroxysmal ventricular arrhythmia, syncope, MIS, myocarditis, pericarditis mRNA-1273 203,315,870 0.18 (0.06–0.29) Local pain (92%) fever (16%) headache (65%) fatigue (70%) myalgia (61%) arthralgia (46%), lymphadenopathy (20%) chills (45%) nausea/vomiting (23%) ATE/VTE, ITP, TTS, allergic reactions including anaphylaxis, facial swelling, Bell’s palsy, myocarditis, pericarditis ChAdOx1 nCoV-19 120,953,207 0.42 (0.13–0.68) Local pain (58%) fever (8%) headache (53%) fatigue (53%) myalgia (44%) arthralgia (27%) chills (32%) nausea/vomiting (22%) ATE/VTE, TTS, ITP, Guillain-Barré syndrome, CLS, CVST without thrombocytopenia, capillary leak syndrome Ad26.CoV2.S 19,219,676 0.26 (0.23–0.29) Local pain (49%) fever (9%) headache (39%) fatigue (38%) myalgia (33%) nausea/vomiting (14%) ATE/VTE, TTS, ITP, Guillain-Barré syndrome, capillary leak syndrome * Until March 2022 in the European Union, United Kingdom and Canada [ 8 – 11 ]. † AEs are expressed as median (IQR). ‡ In >16 y.o. subjects in clinical trials [ 12 – 15 ]. § Information taken from post-authorization reports [ 8 – 11 ]. AEs, adverse events; ATE, arterial thromboembolism; CLS, capillary leak syndrome; CVST, cerebral venous sinus thrombosis; ITP, immune thrombocytopenia; MIS, multisystem inflammatory syndrome; SAEs, serious adverse events; TTS, thrombosis with thrombocytopenia syndrome; VTE, venous thromboembolism; y.o., years old. Key concepts •AEs are generally mild or moderate. •Albeit very infrequently, there can be SAEs that need to be paid attention to. Vaccines 2022,10, 961 5 of 23 4.1. Autoimmune Hematologic Disorders Subsequent to COVID-19 Vaccination Hematologic AEs subsequent to SARS-CoV-2 vaccine exposition are rare, and can be categorized into three types: autoimmunity exacerbations, AEs secondary to allergic reactions, and inflammatory syndromes triggered by complement activation (reviewed in [ 17 ]). Hematologic autoimmune phenomena of new onset, especially those involving platelets, are among the AEs that have been given more attention. Reports are being increasingly made that document secondary immune thrombocytopenia (ITP), vaccine-induced immune thrombotic thrombocytopenia (VITT), immune thrombotic thrombocytopenic purpura (iTTP), autoimmune hemolytic anemia (AIHA), Evans syndrome, aplastic anemia, antiphospholipid syndrome (APS), catastrophic APS (CAPS) or acquired coagulation disorders, subsequent to COVID-19 vaccination. Table 3shows the documented cases of some of these entities in the European Union, United Kingdom and Canada up to March 2022 [ 8 – 10 ]. Their extremely low incidence prevents us from understanding completely whether autoimmune manifestations are merely coincidental or are caused by vaccines’ active components or excipients [ 18 ]. What is known about the association between COVID-19 vaccines and autoimmune hematologic disorders is reviewed below. Table 3. Incidence of autoimmune hematologic AEs subsequent to COVID-19 vaccination until March 2022. Vaccine Doses, n ITP, n (inc) TTP, n (inc) ES, n (inc) AIHA, n (inc) BNT162b2 770,897,374 424 (0.55) 89 (0.11) 10 (0.01) 124 (0.16) mRNA-1273 203,315,870 24 (0.12) 38 (0.19) 7 (0.03) 46 (0.23) ChAdOx1 nCoV-19 120,953,207 254 (2.10) 51 (0.42) 5 (0.04) 123 (1.02) Ad26.CoV2.S 19,219,676 13 (0.68) 14 (0.73) 0 (0) 4 (0.21) The number of autoimmune hematologic AEs corresponding to the European Union, United Kingdom and Canada until March 2022 are shown [ 8 – 10 ]. AHAI, autoimmune haemolytic anaemia; ES, Evans syndrome; inc, incidence per million doses; ITP, immune thrombocytopenia; TTP, and thrombotic thrombocytopenic purpura. 4.2. Risk of Secondary ITP 4.2.1. Historical Perspective Vaccines activate immune-mediated mechanisms that induce protective immunity but, as well as infections, they may trigger an autoimmune response that in some cases leads to ITP. This is an autoimmune disorder that causes a decrease in platelet counts due to their accelerated destruction and impaired production. A significant high risk of suffering ITP was found after hepatitis A, varicella, and diphtheria-tetanus-acellular pertussis vaccination [ 19 – 21 ]. Moreover, several cases of ITP related to poliomyelitis and influenza vaccines (reviewed in [ 20 ]), and after Gardasil 9 vaccination for human papillomavirus (HPV) [ 22 ], have been published. The trivalent vaccine, containing attenuated strains of measles, rubella, and mumps viruses (MMR), is also associated with ITP, although the risk is smaller than that induced by natural infection with these viruses [23–25]. The temporal relationship between vaccination and autoimmunity phenomena seems to be dependent on the specific vaccine. Vaccines may induce ITP by several mechanisms. The most likely one involves virally induced molecular mimicry, although the participation of others such as those associated with T cell immune-mediated pathways cannot be ruled out. Furthermore, not only the main compound of the product, i.e., mRNA, viral vector, attenuated virus or viral protein, may be involved in activating autoimmune pathways. Other constituents, such as yeast proteins, adjuvants or preservative diluents, may also play a role. Nevertheless, it is important to remark that the risk of ITP after vaccination is smaller than that of those patients exposed to viruses after natural infection [26–30]. Subjects developing ITP after vaccination usually have a favorable outcome. The presentation is acute and mild, and the percentage of remissions is high. It has been shown to be close to 95% in the period of six months after new onset of ITP subsequent to Vaccines 2022,10, 961 6 of 23 MMR vaccination, with no long-term sequelae, although therapy with corticosteroids or intravenous immunoglobulins (IVIG) may be required [ 19 ]. On the other hand, whether or not vaccination can exacerbate thrombocytopenia in patients who already have ITP is less understood, and remains a concern. Importantly, 65 children who had developed ITP after receiving the first dose of the MMR vaccine did not have a recurrence upon receipt of the second one. Nevertheless, it is advisable to delay vaccination until resolution of acute ITP [31–33]. 4.2.2. COVID-19, COVID-19 Vaccination and ITP COVID-19 infection is associated with the generation of autoantibodies and the new onset of autoimmune diseases, among which ITP has been reported [ 34 – 37 ]. Thrombocytopenia, albeit usually mild, has been identified in up to 36% of COVID-19 patients [ 37 ]. An important proportion of the infrequent cases of severe thrombocytopenia corresponds to patients who develop ITP upon infection [38]. Although thrombocytopenia secondary to COVID-19 vaccination had not been reported as a frequent AE in the clinical trials that led to the approval of vaccines [ 12 , 39 ], soon afterwards, regular updates of databases highlighted occasional secondary thrombocytopenia appearance in previously healthy recipients when vaccines started being used widely in the general population (Table 3). Several of these cases, which also included fatalities, were reported [ 40 – 42 ]. One of the largest series was taking data from up to four different sources: seventy-seven new cases of ITP were reported in March 2021. Thirty-seven and 40 of these subjects had been administered BNT162b2 and mRNA-1273, respectively. The overall incidence was calculated to be ~1 case per million doses. Seventy-seven percent of these subjects developed ITP after receiving the first dose of the vaccine, while 23% developed it after the second one. The median (IQR) platelet count was 3 × 10 9 /L [ 1 – 9 ], at a median (IQR) of eight days after vaccination [ 3 – 13 ]. Nevertheless, about 90% of subjects responded to the usual first-line treatments [42]. The association between the use of BNT162b2 or mRNA-1273 with the sporadic onset of ITP may be explained by the fact that these are mRNA-based vaccines. mRNA is known to be a potent activator of autoimmunity. mRNA is taken up by cellular RNA receptors, which leads to the upregulation of toll-like receptors (TLR) 7 and 8, and the subsequent activation and maturation of immune cells, as well as the secretion of cytokines and chemokines. The lipid nanoparticle component of mRNA-based COVID-19 vaccines further contributes to immune activation [ 43 , 44 ]. Nevertheless, non-mRNA vaccines might also induce ITP, whose onset could be partly contributed to by residual traces from the manufacturing process, whether adjuvants or preservatives [ 45 , 46 ]. In fact, a new syndrome has been described, so called autoimmune/autoinflammatory syndrome, which is induced by adjuvants (ASIA). It is hypothesized that ITP onset after immunization may be an epiphenomenon of such an entity [ 47 ]. In any case, the association of SARS-CoV-2 vaccination with ITP of new onset should not constitute a concern. A study carried out in the USA identified 15 and 13 cases of thrombocytopenia after administration of 18,841,309 and 16,260,102 doses of BNT162b2 and mRNA-1273 vaccines, respectively, which yields a rate of thrombocytopenia of 0.80 per million doses for both of them. Since the annual incidence rate of ITP is 3.3 cases per 100,000 adults, the observed number of thrombocytopenia cases, which includes ITP, among those subjects administered mRNA-based COVID-19 vaccines is not greater than the number of ITP cases expected [48]. Finally, the concern remains that patients with chronic ITP may suffer exacerbations upon SARS-CoV-2 vaccination. Cases have been documented in several reports [ 33 , 42 , 49 ]. In a case-series that recruited 52 consecutive chronic ITP patients, thrombocytopenia exacerbations were documented in 12% of them, mainly within two to five days post-vaccination and with new bleeding symptoms. ITP exacerbation occurred independently of remission status, concurrent ITP treatment and, importantly, vaccine type [ 33 ]. More recently, the analysis of more than 200 previously diagnosed ITP patients that were administered either BNT162b2, mRNA-1273 or ChAdOx1 nCoV-19 vaccine, revealed ITP exacerbations Vaccines 2022,10, 961 7 of 23 in nearly 14% of cases, bleeding episodes being reported in 2% of patients. Apparently, the type of vaccine did not influence the outcome, although the limited size of the cohort precluded firm conclusions regarding this topic [49]. 4.2.3. Management of ITP Patients with ITP concomitant with COVID-19 infection whose platelet counts fall severely should be administered IVIGs. Platelet transfusion should be given in cases of critical bleeding. On the other hand, there is no evidence suggesting that early treatment with corticosteroids worsens the course of COVID-19 infection. Treatment with dexamethasone in case of severe COVID-19 illness should be given as appropriate. Nevertheless, rituximab and other immunosuppressive agents could impair the ability of the patient to generate their own anti-SARS-CoV2 antibodies. Thrombopoietic agents (TPO-RA) and fostamatinib can also be used in this scenario, and their concomitant administration could be considered. Finally, tromboprophylaxis should be initiated in hospitalized patients with platelet counts above 20–30,000/ µ L, or with lower counts in the case of a high risk of thromboembolism [50]. Subjects with ITP subsequent to vaccination respond appropriately to canonical firstline therapy. Figure 1shows the main steps that may be recommended to follow in the light of current knowledge. In one of the aforementioned studies, 26 out of 28 patients responded to treatment with corticosteroids and/or IVIGs, and/or platelet transfusion. In the same cohort, 19 out of 109 patients with preexisting ITP had exacerbations upon SARS-CoV-2 vaccination. Seven of them were administered rescue therapy with either corticosteroids, TPO-RA, IVIG or a combination of IVIG, steroids, rituximab and cyclosporine, together with the increased dosing of ongoing ITP treatment. All of them responded appropriately, and platelets returned to prevaccination ranges within two to four weeks, with no major bleeding events documented [42]. Key concepts • Cases of ITP associated with SARS-CoV-2 infection have been reported. Although infrequently, severe thrombocytopenia has been documented among these subjects. • ITP onset subsequent to vaccination against SARS-CoV-2 has been documented. The overall incidence is extremely low. Exacerbations have been observed in a low proportion of previously diagnosed ITP patients. • Treatment of secondary ITP or ITP exacerbations subsequent to vaccination is essentially similar to that used in patients with primary ITP. The outcome is usually favorable. 4.3. Risk of VITT 4.3.1. Newly Described Autoimmune Disorder VITT (vaccine-induced immune thrombocytopenia with thrombosis), also known as thrombosis with thrombocytopenia syndrome (TTS) and vaccine-induced prothrombotic immune thrombocytopenia (VIPIT), is a newly described disorder that has been associated with the use of SARS-CoV-2 vaccines. Cases of thrombocytopenia accompanied by unusual thrombotic events have been described to occur 5 to 20 days after vaccination, especially with adenoviral vector-based vaccines. The first report in Europe identified 11 patients in Germany and Austria who had received the ChAdOx1 nCoV-19 vaccine [ 51 ]. On the other hand, 12 cases were documented in the USA after the administration of approximately seven million doses [ 52 ]. Cases have also been described with mRNA-based BNT162b2 and mRNA-1273, albeit less frequently [ 53 , 54 ]. VITT has not been reported with other adenoviral vectored COVID-19 vaccines such as Gam-COVID-Vac or Ad5-nCoV, although available data are more limited with these compounds. The incidence rate of VITT ranges between one in 125,000 to one in a million vaccinated people [ 55 ]. It is important to note that the risk of development of VITT after vaccination against SARS-CoV-2 is lower than the thrombotic risk caused by the disease itself [56]. Vaccines 2022,10, 961 8 of 23 The vaccine-induced response against SARS-CoV-2 spike protein is not involved in VITT development [ 57 ]. In fact, the hallmark of VITT is the presence of high-titer immunoglobulin G (IgG) antibodies directed against the cationic platelet chemokine platelet factor 4 (PF4), which is able to activate platelets. Thrombi are formed in atypical locations, such as the cerebral and splenic vascular beds, and patients often show laboratory signs of disseminated intravascular coagulation (DIC) with severe thrombocytopenia [51,58]. Vaccines 2022, 10, x FOR PEER REVIEW 8 of 23 •ITP onset subsequent to vaccination against SARS-CoV-2 has been documented. The overall incidence is extremely low. Exacerbations have been observed in a low proportion of previously diagnosed ITP patients. •Treatment of secondary ITP or ITP exacerbations subsequent to vaccination is essentially similar to that used in patients with primary ITP. The outcome is usually favorable. Figure 1. Management of ITP in the context of COVID-19 vaccination; Abs, antibodies; CTCs, corticosteroids; iTTP, immune thrombotic thrombocytopenic purpura; IVIGs, intravenous immunoglobulins; TPO-RA, thrombopoetin receptor agonists. 4.3. Risk of VITT 4.3.1. Newly Described Autoimmune Disorder VITT (vaccine-induced immune thrombocytopenia with thrombosis), also known as thrombosis with thrombocytopenia syndrome (TTS) and vaccine-induced prothrombotic immune thrombocytopenia (VIPIT), is a newly described disorder that has been associated with the use of SARS-CoV-2 vaccines. Cases of thrombocytopenia accompanied by SARS-CoV-2 vaccination Active bleeding, platelet counts <30,000/µL If required, ADAMTS-13 testing to discard iTTP ITP highly suspected (may be confirmed by anti-platelet Abs testing) ITP suspected Prompt treatment 3–20 days CTCs and/or IVIGs + platelet transfusion if severe bleeding If exacerbations, rescue with CTCs, IVIGs and/or TPO-RA Consider suspending second dose Not preexisting ITP Preexisting ITP Platelet count control Normal levels Low levels Consider delaying vaccination If negative Figure 1. Management of ITP in the context of COVID-19 vaccination ; Abs, antibodies; CTCs, corticosteroids; iTTP, immune thrombotic thrombocytopenic purpura; IVIGs, intravenous immunoglobulins; TPO-RA, thrombopoetin receptor agonists. 4.3.2. VITT and Heparin-Induced Thrombocytopenia VITT shows similarities with heparin-induced thrombocytopenia (HIT), both disorders being associated with the presence of autoantibodies against PF4, thrombocytopenia and thrombosis. PF4 is a positively charged protein found in the α -granules of platelets, which is released into plasma when platelets are activated. Although HIT also presents with venous and arterial ischemic events, it differs from VITT in that it is triggered by a recent Vaccines 2022,10, 961 9 of 23 exposure to heparin, and the autoimmune component is not exactly the same [ 59 ]. When PF4 binds to heparin, conformational changes in PF4 occur and a new antigen is exposed, resulting in the development of IgG autoantibodies against the complex formed by heparin and PF4. Once autoantibodies are incorporated into the complex, this crosslinks with Fc γ RIIa receptors on platelets, resulting in intracellular signaling, platelet activation, and aggregation. In turn, activated platelets degranulate and release more PF4 molecules and procoagulant microparticles into the plasma, thus increasing thrombin generation. The participation of neutrophil extracellular traps, red blood cells, von Willebrand factor, and tissue factor generates a positive feedback loop which results in a hypercoagulable state [60]. Patients with VITT have also high levels of circulating anti-PF4 antibodies that induce variable degrees of platelet activation. However, unlike what happens in HIT, such activation has been shown to be inhibited by low-molecular-weight heparin. It is hypothesized that PF4 would bind to an unidentified polyanion present in adenoviral vaccines. PF4 may also bind to free nucleic acids, since the ability of DNA and RNA to form multimolecular complexes with PF4 has been reported [ 61 ]. The formed complexes would be targeted by autoantibodies [60]. 4.3.3. Management of VITT Basically, management should address modulation of the autoimmune phenomenon and non-heparin anticoagulation [ 62 ]. Figure 2summarizes the management of VITT subsequent to SARS-CoV-2 vaccination, from first suspicion to treatment start. Treatment should be promptly initiated in those patients with suspected or confirmed VITT. The International Society on Thrombosis and Haemostasis Scientific Subcommittee (ISTH SSC) on Platelet Immunology has provided recommendations on how to recognize, diagnose, and manage these patients [ 63 ]. Early diagnosis and management is important to prevent fatalities, especially when VITT presents with cerebral venous sinus thrombosis (CVST). The documented mortality due to CVST with thrombocytopenia after vaccination with adenoviral vector-based COVID-19 vaccines has experienced a relevant decrease over time. A study carried out with information provided by the EudraVigilance database of the European Medicines Agency involved 270 cases of CVST with thrombocytopenia occurring after adenoviral vector SARS-CoV-2 vaccination. The reported mortality before and after 28 March 2021 was 47% and 22%, respectively, which suggests a positive effect of early recognition and improved treatment on VITT outcomes [64]. The diagnosis procedure should start when the subject presents with thrombocytopenia and altered coagulation, with or without thrombosis, in the four weeks after vaccination. In addition to determining blood cell count, prothrombin time (PT), activated partial thromboplastin time (aPTT), fibrinogen, and D-dimer (DD), the following guidelines should be considered: • all samples for testing for VITT must be collected prior to administration of any treatment, especially IVIGs and danaparoid. • assessment of anti-PF4 antibodies should be performed by enzyme-linked immunosorbent assay (ELISA), since rapid tests and chemiluminescence immunoassays can yield false negatives. •the ability of a patient´s serum to activate platelets must be tested. •the clinical picture of the individual must be taken into account: • thrombocytopenia, bleeding, and normal coagulation parameters may indicate ITP. In this case, the bleeding risk has to be considered. High-dose IVIGs without anticoagulation is recommended, as well as testing for autoantibodies against platelet glycoproteins via monoclonal antibody immobilization of platelet antigens (MAIPA), monoclonal antigen capture ELISA (MACE), platelet antibody bead array (PABA), or flow cytometry. Platelet-associated IgGs are not often measured because of the low sensitivity of the usually available methods. Vaccines 2022,10, 961 16 of 23 Vaccines 2022, 10, x FOR PEER REVIEW 16 of 23 Figure 4. Management of AIHA in the context of COVID-19 vaccination; * In case of previous history of Evans syndrome, platelet and neutrophil counts should also be assessed before vaccination. AIHA, autoimmune hemolytic anemia; CTCs, corticosteroids; Hb, hemoglobin; LDH, lactate dehydrogenase; RBCs, red blood cells; RTX, rituximab. AIHA secondary to COVID-19 vaccination was managed with immunosuppressive agents, especially corticosteroids and occasionally rituximab [103,106,107]. A young woman whose case was particularly severe was transfused with 13 units of packed RBCs, and administered corticosteroids, rituximab, mycophenolate mofetil, and immune globulin [108]. Finally, the patient who presented with Evans syndrome and SLE after having received the BNT162b2 vaccine was administered prednisolone to rapidly restore hemoglobin levels and platelet count [110]. Key concepts •Cases of AIHA subsequent to COVID-19 infection and COVID-19 vaccination, although uncommon, may be severe and life-threatening. •Corticosteroids and, when required, RBCs transfusion is a usually successful combination to treat patients with AIHA in the context of COVID-19 infection or vaccination. Additional boosts with agents such as rituximab may be occasionally needed. •Evans syndrome is a rare entity, usually associated with other immune disorders or infection. Information regarding new-onset or exacerbations subsequent to COVIDSARS-CoV-2 vaccination Normocytic or macrocytic anemia; reticulocytosis, increased indirect bilirubin and LDH; low haptoglobin AIHA suspected Direct Antiglobulin Test If positive Hemolytic anemia AHAI confirmed Prompt treatment 5–90 days CTCs + RBCs (additional immunosuppression [RTX] may be required) Consider suspending second dose Not preexisting AIHA Preexisting AIHA* RBC count, Hb testing Normal Low Consider delaying vaccination Figure 4. Management of AIHA in the context of COVID-19 vaccination ; * In case of previous history of Evans syndrome, platelet and neutrophil counts should also be assessed before vaccination. AIHA, autoimmune hemolytic anemia; CTCs, corticosteroids; Hb, hemoglobin; LDH, lactate dehydrogenase; RBCs, red blood cells; RTX, rituximab. 4.5.4. Antiphospholipid Syndrome and COVID-19 Vaccines Patients suffering from antiphospholipid syndrome (APS) have not been included in SARS-CoV-2 vaccination clinical studies, there for little data regarding this population is available [ 12 ]. Yu et al., showed that the SARS-CoV-2 spike protein, a key molecule in COVID-19 mRNA vaccine immunogenicity, could be responsible for thrombotic manifestations during COVID-19 disease since it directly activates the alternative complement cascade [ 111 ]. Adenoviral vector-based vaccines can bind platelets and induce their destruction in the reticuloendothelial organs. Liposomal mRNA-based vaccines may instead favour the activation of coagulation factors and confer a prothrombotic phenotype to endothelial cells and platelets. Furthermore, both formulations may trigger a type I interferon response associated with the generation of antiphospholipid antibodies (aPLs). They may lead to aberrant activation of the immune response with the participation of innate immune cells, cytokines and the complement cascade. NETosis, monocyte recruitment and cytokine release may further support endothelial dysfunction and promote platelet aggregation. These considerations suggest that aPLs may represent a thrombotic risk factor Vaccines 2022,10, 961 17 of 23 following COVID-19 vaccination [ 112 ]. These data could support mRNA vaccine as a trigger for APS and catastrophic antiphospholipid syndrome (CAPS), although several case reports of both conditions after SARS-CoV-2 vaccination have been published [ 113 – 116 ], other serie do not confirm this hypothesis [ 117 ]. In this series of high risk APS patients (triple-positive aPL confirmed 12 weeks apart), out of 161 patients interviewed, 18 (11%) had COVID-19. All of them recovered fully without any progression to severe disease or thromboembolic event. One-hundred-forty-six patients received the first (92%) and 129 (80%) received the second dose of vaccine and fifteen patients (9%) were unvaccinated. The vaccines used by these patients were the mRNA-based vaccine by Pfizer-BioNTech (BNT162b2) in 121 patients, the mRNA-based vaccine Moderna (mRNA-1273) in 20 of them and the adenovirus-vectored vaccine produced by Oxford-AstraZeneca (ChAdOx1 nCoV-19) in the last five. No thromboembolic event was described and no increase in APLs levels was detected. No other relevant adverse event has been communicated. Of the 15 (9%) unvaccinated patients, 13 refused vaccination and two were waiting for the booster dose as they were recently affected by the SARS-CoV-2 infection. Among the 13 patients who did not undergo vaccination, 10 refused vaccinations against SARS-CoV-2 due to fear and vaccine disbelief, one patient with associated SLE followed the treating physician 0 s recommendation against vaccination, one refused vaccination because of high titre positivity for IgM anti spike protein of SARS-CoV-2 despite having never got the infection, and one refused because of the onset of a serious illness. From a laboratory point of view, it is common that acute viral infections and some vaccines induce false positivity in serologic assays. By now, there is little information about vaccines against SARS-CoV-2 and serologic assays reactivity. In a serie of 35 subjects, Korentzelos et al., described no change in reactivity of β 2-glycoprotein IgA and IgG, cardiolipin IgA and IgG for over the course of samples of patients before vaccination, two weeks after each vaccine dose, and monthly thereafter for up to five months. The used assays were Sure-Vue rapid plasma reagin (RPR) test, (Thermo Fisher Scientific, Waltham, MA, USA) and Macro-Vue RPR test (Becton Dickinson) [ 118 ]. These data have been validated by other groups, including no modification in previous positive intensity before and after vaccination in patients suffering from APS [ 119 , 120 ]. Despite this, larger longitudinal studies are needed to determine the incidence and window of false reactivity. Key concepts: • Adenoviral vector-based vaccines can bind platelets, activate complement and induce APLs. • In patients suffering from APS, there has not been reported a worse evolution after COVID-19 vaccination. • Phospholipid serologic assays seem to not be influenced by SARS-CoV-2 vaccines. Despite this, in case of results that do not fit the clinical picture following SARS-CoV-2, vaccination should be repeated. 5. Conclusions Vaccines against SARS-CoV-2, like other ones, are able to induce antibodies against vaccinated subjects self-antigens that trigger mechanisms leading to hematologic autoimmune disease development. Treatments indicated for secondary ITP, iTTP, AIHA or Evans Syndrome are similar to those used when the vaccine is not the trigger, except for the recommendation to avoid rituximab to warrant the proper immunization against SARSCoV-2. When a hematologic autoimmune disorder develops following vaccination, a prompt and accurate diagnosis is essential to initiate the appropriate treatment and avoid life-threatening bleeding or thromboembolic complications such as VITT. To go on working on registries and the publication of case series, it is crucial to know the incidence of these AEs, learn about their pathophysiology and plan a suitable vaccine schedule for the affected patients. Vaccines 2022,10, 961 18 of 23 Supplementary Materials: The following supporting information can be downloaded at: https: //www.mdpi.com/article/10.3390/vaccines10060961/s1, Table S1: Categories SARS-CoV-2 vaccines that successfully passed phase III trials belong to. Author Contributions: Conceptualization, methodology and style has been developed by M.E.M.-C. Bibliography revision and writing original draft preparation, have been elaborated by all the authors. M.E.M.-C., antiphospholipid syndrome; N.B., Thrombocytopenia physiopathology; M.d.C.G.d.C.S., vaccines characteristics; M.C., registries and general adverse events; B.S.-G. and T.G.-L.; R.J.-B. and G.C.-N., Evans Syndrome; C.P.-I. and L.E.U. All authors have read and agreed to the published version of the manuscript. Funding: This research received no external funding. Institutional Review Board Statement: Not applicable. Informed Consent Statement: Not applicable. Data Availability Statement: The study did not report any data. Conflicts of Interest: The authors declare that they have no conflict of interest. References 1. Fiolet, T.; Kherabi, Y.; MacDonald, C.J.; Ghosn, J.; Peiffer-Smadja, N. Comparing COVID-19 vaccines for their characteristics, efficacy and effectiveness against SARS-CoV-2 and variants of concern: A narrative review. Clin. Microbiol. Infect. 2022 ,28, 202–221. [CrossRef] [PubMed] 2. Ghasemiyeh, P.; Mohammadi-Samani, S.; Firouzabadi, N.; Dehshahri, A.; Vazin, A. A focused review on technologies, mechanisms, safety, and efficacy of available COVID-19 vaccines. Int. Immunopharmacol. 2021,100, 108162. [CrossRef] 3. Palatnik-De-Sousa, C.B. What Would Jenner and Pasteur Have Done About COVID-19 Coronavirus? The Urges of a Vaccinologist. Front. Immunol. 2020,11, 2173. [CrossRef] [PubMed] 4. Pushparajah, D.; Jimenez, S.; Wong, S.; Alattas, H.; Nafissi, N.; Slavcev, R.A. Advances in gene-based vaccine platforms to address the COVID-19 pandemic. Adv. Drug Deliv. Rev. 2021,170, 113–141. [CrossRef] [PubMed] 5. Wolff, J.A.; Malone, R.W.; Williams, P.; Chong, W.; Acsadi, G.; Jani, A.; Felgner, P.L. Direct gene transfer into mouse muscle in vivo . Science 1990,247, 1465–1468. [CrossRef] [PubMed] 6. Mendonça, S.A.; Lorincz, R.; Boucher, P.; Curiel, D.T. Adenoviral vector vaccine platforms in the SARS-CoV-2 pandemic. NPJ Vaccines 2021,6, 97. [CrossRef] 7. Azmi, F.; Fuaad, A.A.H.A.; Skwarczynski, M.; Toth, I. Recent progress in adjuvant discovery for peptide-based subunit vaccines. Hum. Vaccines Immunother. 2014,10, 778–796. [CrossRef] 8. European Medicines Agency. Guide on the Interpretation of Spontaneous Case Reports of Suspected Adverse Reactions to Medicines; European Medicines Agency: London, UK, 2017. 9. Medicines & Healthcare Products Regulatory Agency. Coronavirus Vaccine Weekly Summary of Yellow Card Reporting. gov.uk. 2021. Available online: https://www.gov.uk/government/publications/coronavirus-covid-19-vaccine-adverse-reactions/ coronavirus-vaccine-summary-of-yellow-card-reporting (accessed on 6 September 2021). 10. Reported Side Effects Following COVID-19 Vaccination in Canada. Available online: https://health-infobase.canada.ca/covid-19 /vaccine-safety/#a4 (accessed on 2 May 2022). 11. The Vaccine Adverse Event Reporting System (VAERS). Available online: https://wonder.cdc.gov/controller/datarequest/D8 ;jsessionid=426D8ABB1739155E11D06093CA0D (accessed on 2 May 2022). 12. Polack, F.P.; Thomas, S.J.; Kitchin, N.; Absalon, J.; Gurtman, A.; Lockhart, S.; Perez, J.L.; Marc, G.P.; Moreira, E.D.; Zerbini, C.; et al. Safety and efficacy of the BNT162b2 mRNA COVID-19 vaccine. N. Engl. J. Med. 2020,383, 2603–2615. [CrossRef] 13. Baden, L.R.; El Sahly, H.M.; Essink, B.; Kotloff, K.; Frey, S.; Novak, R.; Diemert, M.D.; Spector, S.A.; Rouphael, N.; Creech, B.; et al. Efficacy and Safety of the mRNA-1273SARS-CoV-2 Vaccine. N. Engl. J. Med. 2021,384, 403–416. [CrossRef] 14. Folegatti, P.M.; Ewer, K.J.; Aley, P.K.; Angus, B.; Becker, S.; Belij-Rammerstorfer, S.; Bellamy, D.; Bibi, S.; Bittaye, M.; Clutterbuck, E.A.; et al. Safety and immunogenicity of the ChAdOx1 nCoV-19 vaccine against SARS-CoV-2: A preliminary report of a phase 1/2, single-blind, randomised controlled trial. Lancet 2020,396, 467–478. [CrossRef] 15. Sadoff, J.; Gray, G.; Vandebosch, A.; Cárdenas, V.; Shukarev, G.; Grinsztejn, B.; Goepfert, P.A.; Truyers, C.; Fennema, H.; Spiessens, B.; et al. Safety and Efficacy of Single-Dose Ad26.COV2.S Vaccine against Covid-19. N. Engl. J. Med. 2021 ,384, 2187–2201. [CrossRef] [PubMed] 16. Logunov, D.Y.; Dolzhikova, I.V.; Shcheblyakov, D.V.; Tukhvatulin, A.I.; Zubkova, O.V.; Dzharullaeva, A.S.; Kovyrshina, A.V.; Lubenets, N.L.; Grousova, D.M.; Gam-COVID-Vac Vaccine Trial Group; et al. Safety and efficacy of an rAd26 and rAd5 vectorbased heterologous prime-boost COVID-19 vaccine: An interim analysis of a randomised controlled phase 3 trial in Russia. Lancet 2021,397, 671–681. [CrossRef] Vaccines 2022,10, 961 19 of 23 17. Al-Ali, D.; Elshafeey, A.; Mushannen, M.; Kawas, H.; Shafiq, A.; Mhaimeed, N.; Mhaimeed, O.; Mhaimeed, N.; Zeghlache, R.; Salameh, M.; et al. Cardiovascular and haematological events post COVID-19 vaccination: A systematic review. J. Cell. Mol. Med. 2021,26, 636–653. [CrossRef] 18. Chen, Y.; Xu, Z.; Wang, P.; Li, X.M.; Shuai, Z.W.; Ye, D.Q.; Pan, H.F. New-onset autoimmune phenomena post-COVID-19 vaccination. Immunology 2022,165, 386–401. [CrossRef] [PubMed] 19. O’Leary, S.T.; Glanz, J.M.; McClure, D.L.; Akhtar, A.; Daley, M.F.; Nakasato, C.; Baxter, R.; Davis, R.L.; Izurieta, H.S.; Lieu, T.A.; et al. The Risk of Immune Thrombocytopenic Purpura After Vaccination in Children and Adolescents. Pediatrics 2012 ,129, 248–255. [CrossRef] [PubMed] 20. Perricone, C.; Ceccarelli, F.; Nesher, G.; Borella, E.; Odeh, Q.; Conti, F.; Shoenfeld, Y.; Valesini, G. Immune thrombocytopenic purpura (ITP) associated with vaccinations: A review of reported cases. Immunol. Res. 2014,60, 226–235. [CrossRef] 21. Schmidt, N.; Maitland, H. Acute Immune Thrombocytopenia following administration of Shingrix recombinant zoster vaccine. Am. J. Hematol. 2021,96, E136–E137. [CrossRef] 22. Johansen, S.; Lægreid, I.J.; Ernstsen, S.L.; Azrakhsh, N.A.; Kittang, A.O.; Lindås, R.; Gjertsen, B.T.; Vetti, N.; Mørtberg, T.V.; Sørvoll, I.H.; et al. Thrombosis and thrombocytopenia after HPV vaccination. J. Thromb. Haemost. 2021 ,20, 700–704. [CrossRef] [PubMed] 23. Di Pietrantonj, C.; Rivetti, A.; Marchione, P.; Debalini, M.G.; Demicheli, V. Vaccines for measles, mumps, rubella, and varicella in children. Cochrane Database Syst. Rev. 2020,4, CD004407. [PubMed] 24. Andrews, N.; Stowe, J.; Miller, E.; Svanström, H.; Johansen, K.; Bonhoeffer, J.; Hviid, A.; VAESCO consortium. A collaborative approach to investigating the risk of thrombocytopenic purpura aMer measles–mumps–rubella vaccination in England and Denmark. Vaccine 2012,30, 3042–3046. [CrossRef] 25. Perez-Vilar, S.; Weibel, D.; Sturkenboom, M.; Black, S.; Maure, C.; Castro, J.L.; Bravo-Alcántara, P.; Dodd, C.N.; Romio, S.A.; de Ridder, M.; et al. Enhancing global vaccine pharmacovigilance: Proof-of-concept study on aseptic meningitis and immune thrombocytopenic purpura following measles-mumps containing vaccination. Vaccine 2017,36, 347–354. [CrossRef] [PubMed] 26. Catani, L.; Fagioli, M.E.; Tazzari, P.L.; Ricci, F.; Curti, A.; Rovito, M.; Preda, P.; Chirumbolo, G.; Amabile, M.; Lemoli, R.M.; et al. Dendritic cells of immune thrombocytopenic purpura (ITP) show increased capacity to present apoptotic platelets to T lymphocytes. Exp. Hematol. 2006,34, 879–887. [CrossRef] [PubMed] 27. Gu, D.; Chen, Z.; Zhao, H.; Du, W.; Xue, F.; Ge, J.; Sui, T.; Wu, H.; Liu, B.; Lu, S.; et al. Th1 (CXCL10) and Th2 (CCL2) chemokine expression in patients with immune thrombocytopenia. Hum. Immunol. 2010,71, 586–591. [CrossRef] 28. Sakakura, M.; Wada, H.; Tawara, I.; Nobori, T.; Sugiyama, T.; Sagawa, N.; Shiku, H. Reduced Cd4+Cd25+ T cells in patients with idiopathic thrombocytopenic purpura. Thromb. Res. 2007,120, 187–193. [CrossRef] [PubMed] 29. Yu, J.; Heck, S.; Patel, V.; LeVan, J.; Yu, Y.; Bussel, J.B.; Yazdanbakhsh, K. Defective circulating CD25 regulatory T cells in patients with chronic immune thrombocytopenic purpura. Blood 2008,112, 1325–1328. [CrossRef] 30. Zhang, J.; Ma, D.; Zhu, X.; Qu, X.; Ji, C.; Hou, M. Elevated profile of Th17, Th1 and Tc1 cells in patients with immune thrombocytopenic purpura. Haematologica 2009,94, 1326–1329. [CrossRef] 31. Black, C.; Kaye, J.A.; Jick, H. MMR vaccine and idiopathic thrombocytopaenic purpura. Br. J. Clin. Pharmacol. 2003 ,55, 107–111. [CrossRef] 32. Stowe, J.; Kafatos, G.; Andrews, N.; Miller, E. Idiopathic thrombocytopenic purpura and the second dose of MMR: Figure 1. Arch. Dis. Child. 2007,93, 182–183. [CrossRef] 33. Kuter, J.D. Exacerbation of immune thrombocytopenia following COVID-19 vaccination. Br. J. Haematol. 2021 ,195, 365–370. [CrossRef] [PubMed] 34. Dotan, A.; Muller, S.; Kanduc, D.; David, P.; Halpert, G.; Shoenfeld, Y. The SARS-CoV-2 as an instrumental trigger of autoimmunity. Autoimmun. Rev. 2021,20, 102792. [CrossRef] [PubMed] 35. Zulfiqar, A.-A.; Lorenzo-Villalba, N.; Hassler, P.; Andrès, E. Immune thrombocytopenic purpura in a patient with COVID-19. N. Engl. J. Med. 2020,382, e43. [CrossRef] [PubMed] 36. Levraut, M.; Ottavi, M.; Lechtman, S.; Mondain, V.; Jeandel, P. Immune thrombocytopenic purpura after COVID-19 infection. Int. J. Lab. Hematol. 2020,43, e28–e30. [CrossRef] 37. Murt, A.; Eskazan, A.E.; Yilmaz, U.; Ozkan, T.; Ar, M.C. COVID-19 presenting with immune thrombocytopenia: A case report and review of the literature. J. Med. Virol. 2020,93, 43–45. [CrossRef] 38. Guan, W.J.; Ni, Z.Y.; Hu, Y.; Liang, W.H.; Qu, C.Q.; He, J.X.; Liu, L.; Shan, H.; Lei, C.L.; Hui, D.S.C.; et al. China medical treatment expert group for COVID-19 2020. Clinical Characteristics of coronavirus disease in China. N. Engl. J. Med. 2020 ,382, 1708–1720. [CrossRef] [PubMed] 39. Thomas, S.J.; Moreira, E.D., Jr.; Kitchin, N.; Absalon, J.; Gurtman, A.; Lockhart, S.; Perez, J.L.; Pérez Marc, G.; Polack, F.P.; Zerbini, C.; et al. Safety and Efficacy of the BNT162b2 mRNA COVID-19 Vaccine through 6 Months. N. Engl. J. Med. 2021 ,385, 1761–1773. [CrossRef] [PubMed] 40. Lee, E.J.; Cines, D.B.; Gernsheimer, T.; Kessler, C.; Michel, M.; Tarantino, M.D.; Semple, J.W.; Arnold, D.M.; Godeau, B.; Lambert, M.P.; et al. Thrombocytopenia following Pfizer and Moderna SARS-CoV-2 vaccination. Am. J. Hematol. 2021 ,96, 534–537. [CrossRef] [PubMed] 41. David, P.; Dotan, A.; Mahroum, N.; Shoenfeld, Y. Immune Thrombocytopenic Purpura (ITP) Triggered by COVID-19 Infection and Vaccination. Isr. Med. Assoc. J. 2021,23, 378–380. Vaccines 2022,10, 961 20 of 23 42. Lee, E.J.; Beltrami-Moreira, M.; Al-Samkari, H.; Cuker, A.; DiRaimo, J.; Gernsheimer, T.; Kruse, A.; Kessler, C.; Kruse, C.; Leavitt, A.D.; et al. SARS-CoV-2 vaccination and ITP in patients with de novo or preexisting ITP. Blood 2022,139, 1564–1574. [CrossRef] 43. Edwards, D.K.; Jasny, E.; Yoon, H.; Horscroft, N.; Schanen, B.; Geter, T.; Fotin-Mleczek, M.; Petsch, B.; Wittman, V. Adjuvant effects of a sequence-engineered mRNA vaccine: Translational profiling demonstrates similar human and murine innate response. J. Transl. Med. 2017,15, 1–18. [CrossRef] [PubMed] 44. Thi, T.; Suys, E.; Lee, J.; Nguyen, D.; Park, K.; Truong, N. Lipid-Based Nanoparticles in the Clinic and Clinical Trials: From Cancer Nanomedicine to COVID-19 Vaccines. Vaccines 2021,9, 359. [CrossRef] 45. Agmon-Levin, N.; Paz, Z.; Israeli, E.; Shoenfeld, Y. Vaccines and autoimmunity. Nat. Rev. Rheumatol. 2009 ,5, 648–652. [CrossRef] [PubMed] 46. Israeli, E.; Agmon-Levin, N.; Blank, M.; Shoenfeld, Y. Adjuvants and autoimmunity. Lupus 2009 ,18, 1217–1225. [CrossRef] [PubMed] 47. Shoenfeld, Y.; Agmon-Levin, N. ‘ASIA’-autoimmune/inflammatory syndrome induced by adjuvants. J. Autoimmun. 2011 ,36, 4–8. [CrossRef] [PubMed] 48. Welsh, K.J.; Baumblatt, J.; Chege, W.; Goud, R.; Nair, N. Thrombocytopenia including immune thrombocytopenia after receipt of mRNA COVID-19 vaccines reported to the Vaccine Adverse Event Reporting System (VAERS). Vaccine 2021 ,39, 3329–3332. [CrossRef] [PubMed] 49. Visser, C.; Swinkels, M.; van Werkhoven, E.D.; Croles, F.N.N.; Noordzij-Nooteboom, H.S.; Eefting, M.; Last-Koopmans, S.M.; Idink, C.; Westerweel, P.E.; Santbergen, B.; et al. COVID-19 vaccination in patients with immune thrombocytopenia. Blood Adv. 2022,6, 1637–1644. [CrossRef] 50. Bussel, J.; Cines, D.; Cooper, N.; Dunbar, C.; Michel, M.; Rodeghiero, F. COVID-19 and ITP: Frequently Asked Questions. In COVID-19 Resources of the American Society of Hematology. Available online: https://www.hematology.org/covid-19/covid19-and-itp (accessed on 5 May 2022). 51. Greinacher, A.; Thiele, T.; Warkentin, T.E.; Weisser, K.; Kyrle, P.A.; Eichinger, S. Thrombotic Thrombocytopenia after ChAdOx1 nCov-19 Vaccination. N. Engl. J. Med. 2021,384, 2092–2101. [CrossRef] 52. See, I.; Su, J.R.; Lale, A.; Woo, E.J.; Guh, A.Y.; Shimabukuro, T.T.; Streiff, M.B.; Rao, A.K.; Wheeler, A.P.; Beavers, S.F.; et al. US Case Reports of Cerebral Venous Sinus Thrombosis With Thrombocytopenia After Ad26.COV2.S Vaccination, March 2 to April 21, 2021. JAMA 2021,325, 2448–2456. [CrossRef] 53. Cines, D.B.; Bussel, J.B. SARS-CoV-2 Vaccine-Induced Immune Thrombotic Thrombocytopenia. N. Engl. J. Med. 2021 ,384, 2254–2256. [CrossRef] 54. Smadja, D.M.; Yue, Q.-Y.; Chocron, R.; Sanchez, O.; Louet, A.L.-L. Vaccination against COVID-19: Insight from arterial and venous thrombosis occurrence using data from VigiBase. Eur. Respir. J. 2021,58, 2100956. [CrossRef] 55. Afshar, Z.M.; Babazadeh, A.; Janbakhsh, A.; Afsharian, M.; Saleki, K.; Barary, M.; Ebrahimpour, S. Vaccine-induced immune thrombotic thrombocytopenia after vaccination against COVID-19: A clinical dilemma for clinicians and patients. Rev. Med. Virol. 2022,32, e2273. 56. Warkentin, T.E.; Cuker, A. COVID-19: Vaccine-Induced Immune Thrombotic Thrombocytopenia (VITT), UpToDate. 2022. Available online: https://www.uptodate.com/contents/covid-19-vaccine-induced-immune-thrombotic-thrombocytopenia-vitt (accessed on 8 May 2022). 57. Greinacher, A.; Selleng, K.; Mayerle, J.; Palankar, R.; Wesche, J.; Reiche, S.; Aebischer, A.; Warkentin, T.E.; Muenchhoff, M.; Immune-Response in COVID-19 Vaccination Study Group; et al. Anti-platelet factor 4 antibodies causing VITT do not cross-react with SARS-CoV-2 spike protein. Blood 2021,138, 1269–1277. [CrossRef] 58. Schultz, N.H.; Sørvoll, I.H.; Michelsen, A.E.; Munthe, L.A.; Lund-Johansen, F.; Ahlen, M.T.; Wiedmann, M.; Aamodt, A.-H.; Skattør, T.H.; Tjønnfjord, G.E.; et al. Thrombosis and Thrombocytopenia after ChAdOx1 nCoV-19 Vaccination. N. Engl. J. Med. 2021,384, 2124–2130. [CrossRef] [PubMed] 59. Greinacher, A.; Selleng, K.; Warkentin, T.E. Autoimmune heparin-induced thrombocytopenia. J. Thromb. Haemost. 2017 ,15, 2099–2114. [CrossRef] [PubMed] 60. Rizk, J.G.; Gupta, A.; Sardar, P.; Henry, B.M.; Lewin, J.C.; Lippi, G.; Lavie, C.J. Clinical Characteristics and Pharmacological Management of COVID-19 Vaccine-Induced Immune Thrombotic Thrombocytopenia With Cerebral Venous Sinus Thrombosis: A Review. JAMA Cardiol. 2021,6, 1451–1460. [CrossRef] [PubMed] 61. Jaax, M.E.; Krauel, K.; Marschall, T.; Brandt, S.; Gansler, J.; Fürll, B.; Appel, B.; Fischer, S.; Block, S.; Helm, C.A.; et al. Complex formation with nucleic acids and aptamers alters the antigenic properties of platelet factor 4. Blood 2013 ,122, 272–281. [CrossRef] [PubMed] 62. Klok, F.A.; Pai, M.; Huisman, M.V.; Makris, M. Vaccine-induced immune thrombotic thrombocytopenia. Lancet Haematol. 2022 ,9, e73–e80. [CrossRef] 63. Nazy, I.; Sachs, U.J.; Arnold, D.M.; McKenzie, S.E.; Choi, P.; Althaus, K.; Ahlen, M.T.; Sharma, R.; Grace, R.F.; Bakchoul, T. Recommendations for the clinical and laboratory diagnosis of VITT against COVID-19: Communication from the ISTH SSC Subcommittee on Platelet Immunology. J. Thromb. Haemost. 2021,19, 1585–1588. [CrossRef] 64. Van de Munckhof, A.; Krzywicka, K.; de Sousa, D.A.; van Kammen, M.S.; Heldner, M.R.; Jood, K.; Lindgren, K.; Tatlisumak, T.; Putaala, J.; Hovinga, J.A.K.; et al. Declining mortality of cerebral venous sinus thrombosis with thrombocytopenia after SARS-CoV-2 vaccination. Eur. J. Neurol. 2022,29, 339–344. [CrossRef] Vaccines 2022,10, 961 21 of 23 65. Sadler, J.E. What’s new in the diagnosis and pathophysiology of thrombotic thrombocytopenic purpura. Hematol. Am. Soc. Hematol. Educ. Program 2015,2015, 631–636. [CrossRef] 66. Yava¸so˘glu, I. Vaccination and Thrombotic Thrombocytopenic Purpura. Turk. J. Hematol. 2020,37, 218–219. [CrossRef] 67. Kadikoylu, G.; Yavasoglu, I.; Bolaman, Z. Rabies vaccine-associated thrombotic thrombocytopenic purpura. Transfus. Med. 2014 , 24, 428–429. [CrossRef] [PubMed] 68. Kojima, Y.; Ohashi, H.; Nakamura, T.; Nakamura, H.; Yamamoto, H.; Miyata, Y.; Iida, H.; Nagai, H. Acute thrombotic thrombocytopenic purpura after pneumococcal vaccination. Blood Coagul. Fibrinolysis 2014,25, 512–514. [CrossRef] [PubMed] 69. Ramakrishnan, N.; Parker, L.P. Thrombotic thrombocytopenic purpura following influenza vaccination—A brief case report. Connect. Med. 1998,62, 587–588. 70. Dias, P.J.; Gopal, S. Refractory thrombotic thrombocytopenic purpura following influenza vaccination. Anaesthesia 2009 ,64, 444–446. [CrossRef] [PubMed] 71. Hermann, R.; Pfeil, A.; Busch, M.; Kettner, C.; Kretzschmar, D.; Hansch, A.; La Rosée, P.; Wolf, G. Very severe thrombotic thrombocytopenic purpura (TTP) after H1N1 vaccination. Med. Klin. 2010,105, 663–668. [CrossRef] 72. Brown, R.C.; Blecher, T.E.; French, E.A.; Toghill, P.J. Thrombotic thrombocytopenic purpura after influenza vaccination. BMJ 1973 , 2, 303. [CrossRef] 73. Tehrani, H.A.; Darnahal, M.; Vaezi, M.; Haghighi, S. COVID-19 associated thrombotic thrombocytopenic purpura (TTP); A case series and mini-review. Int. Immunopharmacol. 2021,93, 107397. [CrossRef] 74. Hindilerden, F.; Yonal-Hindilerden, I.; Akar, E.; Kart-Yasar, K. Covid-19 associated autoimmune thrombotic thrombocytopenic purpura: Report of a case. Thromb. Res. 2020,195, 136–138. [CrossRef] 75. Capecchi, M.; Mocellin, C.; Abbruzzese, C.; Mancini, I.; Prati, D.; Peyvandi, F. Dramatic presentation of acquired thombotic thrombocytopenic purpura associated with COVID-19. Haematologica 2020,105, e540. [CrossRef] 76. Albiol, N.; Awol, R.; Martino, R. Autoimmune thrombotic thrombocytopenic purpura (TTP) associated with COVID-19. Ann. Hematol. 2020,99, 1673–1674. [CrossRef] 77. Giuffrida, G.; Condorelli, A.; Di Giorgio, M.A.; Markovic, U.; Sciortino, R.; Nicolosi, D.; Di Raimondo, F. Immune-mediated thrombotic thrombocytopenic purpura following administration of Pfizer-BioNTech COVID-19 vaccine. Haematologica 2022 ,107, 1008–1010. [PubMed] 78. De Bruijn, S.; Maes, M.B.; De Waele, L.; Vanhoorelbeke, K.; Gadisseur, A. First report of a de novo iTTP episode associated with an mRNA-based anti-COVID-19 vaccination. J. Thromb. Haemost. 2021,19, 2014–2018. [CrossRef] [PubMed] 79. Maayan, H.; Kirgner, I.; Gutwein, O.; Herzog-Tzarfati, K.; Rahimi-Levene, N.; Koren-Michowitz, M.; Blickstein, D. Acquired thrombotic thrombocytopenic purpura: A rare disease associated with BNT162b2 vaccine. J. Thromb. Haemost. 2021 ,19, 2314–2317. [CrossRef] [PubMed] 80. Ruhe, J.; Schnetzke, U.; Kentouche, K.; Prims, F.; Baier, M.; Herfurth, K.; Schlosser, M.; Busch, M.; Hochhaus, A.; Wolf, G. Acquired thrombotic thrombocytopenic purpura after first vaccination dose of BNT162b2 mRNA COVID-19 vaccine. Ann. Hematol. 2021, 101, 717–719. [CrossRef] 81. Yoshida, K.; Sakaki, A.; Matsuyama, Y.; Mushino, T.; Matsumoto, M.; Sonoki, T.; Tamura, S. Acquired Thrombotic Thrombocytopenic Purpura Following BNT162b2 mRNA Coronavirus Disease Vaccination in a Japanese Patient. Intern. Med. 2022 ,61, 407–412. [CrossRef] 82. Alislambouli, M.; Victoria, A.V.; Matta, J.; Yin, F. Acquired thrombotic thrombocytopenic purpura following Pfizer COVID-19 vaccination. eJHaem 2021,3, 207–210. [CrossRef] 83. Yocum, A.; Simon, E.L. Thrombotic Thrombocytopenic Purpura after Ad26.COV2-S Vaccination. Am. J. Emerg. Med. 2021 ,49, 441.e3–441.e4. [CrossRef] 84. Waqar, S.H.B.; Khan, A.A.; Memon, S. Thrombotic thrombocytopenic purpura: A new menace after COVID bnt162b2 vaccine. Int. J. Hematol. 2021,114, 626–629. [CrossRef] 85. Al-Ahmad, M.; Al-Rasheed, M.; Shalaby, N.A.B. Acquired thrombotic thrombocytopenic purpura with possible association with AstraZeneca-Oxford COVID-19 vaccine. EJHaem 2021,2, 534–536. [CrossRef] 86. Lee, H.P.; Selvaratnam, V.; Rajasuriar, J.S. Thrombotic thrombocytopenic purpura after ChAdOx1 nCoV-19 vaccine. BMJ Case Rep. 2021,14, e246049. [CrossRef] 87. Kirpalani, A.; Garabon, J.; Amos, K.; Patel, S.; Sharma, A.P.; Ganesan, S.L.; Barton, M.; Cacciotti, C.; Leppington, S.; Bakovic, L.; et al. Thrombotic thrombocytopenic purpura temporally associated with BNT162b2 vaccination in an adolescent successfully treated with caplacizumab. Br. J. Haematol. 2021,196, e11–e14. [CrossRef] [PubMed] 88. Sissa, C.; Al-Khaffaf, A.; Frattini, F.; Gaiardoni, R.; Mimiola, E.; Montorsi, P.; Melara, B.; Amato, M.; Peyvandi, F.; Franchini, M. Relapse of thrombotic thrombocytopenic purpura after COVID-19 vaccine. Transfus. Apher. Sci. 2021 ,60, 103145. [CrossRef] [PubMed] 89. Deucher, W.; Sukumar, S.; Cataland, S.R. Clinical relapse of immune-mediated thrombotic thrombocytopenic purpura following COVID-19 vaccination. Res. Pr. Thromb. Haemost. 2022,6, e12658. [CrossRef] [PubMed] 90. Saluja, P.; Gautam, N.; Yadala, S.; Venkata, A.N. Thrombotic thrombocytopenic purpura (TTP) after COVID-19 vaccination: A systematic review of reported cases. Thromb. Res. 2022,214, 115–121. [CrossRef] [PubMed] 91. Barcellini, W.; Fattizzo, B. The Changing Landscape of Autoimmune Hemolytic Anemia. Front. Immunol. 2020 ,11, 946. [CrossRef] [PubMed] Vaccines 2022,10, 961 22 of 23 92. Audia, S.; Grienay, N.; Mounier, M.; Michel, M.; Bonnotte, B. Evans’ Syndrome: From Diagnosis to Treatment. J. Clin. Med. 2020 , 9, 3851. [CrossRef] 93. Seltsam, A.; Shukry-Schulz, S.; Salama, A. Vaccination-associated immune hemolytic anemia in two children. Transfusion 2000 ,40, 907–909. [CrossRef] 94. Downes, K.A.; Domen, R.E.; McCarron, K.F.; Bringelsen, K.A. Acute Autoimmune Hemolytic Anemia Following DTP Vaccination: Report of a Fatal Case and Review of the Literature. Clin. Pediatr. 2001,40, 355–358. [CrossRef] 95. Johnson, S.T.; McFarland, J.G.; Kelly, K.J.; Casper, J.T.; Gottschall, J.L. Transfusion support with RBCs from an Mk homozygote in a case of autoimmune hemolytic anemia following diphtheria-pertussis-tetanus vaccination. Transfusion 2002 ,42, 567–571. [CrossRef] 96. Montagnani, S.; Tuccori, M.; Lombardo, G.; Testi, A.; Mantarro, S.; Ruggiero, E.; Blandizzi, C. Autoimmune Hemolytic Anemia Following MF59-Adjuvanted Influenza Vaccine Administration: A Report of Two Cases. Ann. Pharmacother. 2010 ,45, 128. [CrossRef] 97. Gani, I.; Hinnant, G.; Kapoor, R.; Savage, N. Autoimmune Hemolytic Anemia in a Renal Transplant Patient Following Seasonal Influenza Vaccination. Case Rep. Hematol. 2019,2019, 1–4. [CrossRef] [PubMed] 98. Bowen, L.; LePage, N.; Lewandowska, M.; Waxman, D.A. Anti-Pr antibody induced cold autoimmune hemolytic anemia following pneumococcal vaccination. Clin. Case Rep. 2019,7, 1763–1765. [CrossRef] [PubMed] 99. Shlamovitz, G.Z.; Johar, S. A Case of Evans’ Syndrome Following Influenza Vaccine. J. Emerg. Med. 2013 ,44, e149–e151. [CrossRef] 100. Hsieh, Y.-L.; Lin, L.-H. Thrombocytopenic Purpura Following Vaccination in Early Childhood: Experience of a Medical Center in the Past 2 Decades. J. Chin. Med Assoc. 2010,73, 634–637. [CrossRef] 101. Lazarian, G.; Quinquenel, A.; Bellal, M.; Siavellis, J.; Jacquy, C.; Re, D.; Merabet, F.; Mekinian, A.; Braun, T.; Damaj, G.; et al. Autoimmune haemolytic anaemia associated with COVID-19 infection. Br. J. Haematol. 2020,190, 29–31. [CrossRef] [PubMed] 102. Finkenthal, T.A.; Aldaher, Z.; Ahmed, S.; DiValentin, L. Autoimmune Hemolytic Anemia Exacerbation Associated With COVID-19 Infection and Markedly Elevated Inflammatory Markers. Cureus 2021,13, e20416. [CrossRef] [PubMed] 103. Jacobs, J.W.; Booth, G.S. COVID-19 and Immune-Mediated RBC Destruction. Am. J. Clin. Pathol. 2021 ,157, 844–851. [CrossRef] [PubMed] 104. Taherifard, E.; Taherifard, E.; Movahed, H.; Mousavi, M.R. Hematologic autoimmune disorders in the course of COVID-19: A systematic review of reported cases. Hematology 2021,26, 225–239. [CrossRef] 105. Turgutkaya, A.; Bolaman, A.Z.; Yava¸so˘glu, ˙ I. COVID-19-associated Evans syndrome: A case report and review of the literature. Transfus. Apher. Sci. 2021,61, 103339. [CrossRef] 106. Jaydev, F.; Kumar, V.; Khatri, J.; Shahani, S.; Beganovic, S. A Case of Autoimmune Hemolytic Anemia after the First Dose of COVID-19 mRNA-1273 Vaccine with Undetected Pernicious Anemia. Case Rep. Hematol. 2022,2022, 2036460. [CrossRef] 107. Fatima, Z.; Reece, B.R.A.; Moore, J.S.; Means, R.T., Jr. Autoimmune Hemolytic Anemia After mRNA COVID Vaccine. J. Investig. Med. High Impact Case Rep. 2022,10, 23247096211073258. [CrossRef] [PubMed] 108. De Bruyne, S.; Van Landeghem, S.; Schauwvlieghe, A.; Noens, L. Life-threatening autoimmune hemolytic anemia following mRNA COVID-19 vaccination: Don’t be too prudent with the red gold. Clin. Chem. Lab. Med. 2022 ,60, 118. [CrossRef] [PubMed] 109. Angileri, F.; Légaré, S.; Gammazza, A.M.; de Macario, E.C.; Macario, A.J.L.; Cappello, F. Is molecular mimicry the culprit in the autoimmune haemolytic anaemia affecting patients with COVID-19? Br. J. Haematol. 2020,190, e92–e93. [CrossRef] 110. Hidaka, D.; Ogasawara, R.; Sugimura, S.; Fujii, F.; Kojima, K.; Nagai, J.; Ebata, K.; Okada, K.; Kobayashi, N.; Ogasawara, M.; et al. New-onset Evans syndrome associated with systemic lupus erythematosus after BNT162b2 mRNA COVID-19 vaccination. Int. J. Hematol. 2021,115, 424–427. [CrossRef] [PubMed] 111. Fattizzo, B.; Giannotta, J.A.; Cecchi, N.; Barcellini, W. SARS-CoV-2 vaccination in patients with autoimmune cytopenias: The experience of a reference center. Am. J. Hematol. 2021,96, E413–E416. [CrossRef] 112. Yu, J.; Yuan, X.; Chen, H.; Chaturvedi, S.; Braunstein, E.M.; Brodsky, R.A. Direct activation of the alternative complement pathway by SARS-CoV-2 spike proteins is blocked by factor D inhibition. Blood 2020,136, 2080–2089. [CrossRef] [PubMed] 113. Talotta, R.; Robertson, E.S. Antiphospholipid antibodies and risk of post-COVID-19 vaccination thrombophilia: The straw that breaks the camel’s back? Cytokine Growth Factor Rev. 2021,60, 52–60. [CrossRef] 114. Moreno-Torres, V.; Gutiérrez, Á.; Valdenebro, M.; Ortega, A.; Cítores, M.J.; Montero, E. Catastrophic antiphospholipid syndrome triggered by mRNA COVID-19 vaccine. Clin. Exp. Rheumatol. 2022,40, 1054–1055. [CrossRef] 115. Molina Rios, S.; Rojas Martinez, R.; Estévez Ramirez, G.M.; Medina, Y.F. Systemic Lupus Erythematosus and Antiphospholipid Syndrome After COVID-19 Vaccination. A Case Report. Mod. Rheumatol. Case Rep. 2022,4, rxac018. [CrossRef] [PubMed] 116. Jinno, S.; Naka, I.; Nakazawa, T. Catastrophic antiphospholipid syndrome complicated with essential thrombocythaemia after COVID-19 vaccination: In search of the underlying mechanism. Rheumatol. Adv. Pract. 2021,5, rkab096. [CrossRef] [PubMed] 117. Pengo, V.; Del Ross, T.; Tonello, M.; Andreoli, L.; Tincani, A.; Gresele, P.; Silvestri, E.; Simioni, P.; Campello, E.; Hoxha, A.; et al. Impact of COVID-19 and COVID-19 vaccination on high-risk patients with Antiphospholipid Syndrome: A nationwide survey. Rheumatology 2022,12, keac224. [CrossRef] [PubMed] 118. Korentzelos, D.; Baloda, V.; Jung, Y.; Wheeler, B.; Shurin, M.R.; Wheeler, S.E. COVID-19 mRNA Vaccines May Cause False Reactivity in Some Serologic Laboratory Tests, Including Rapid Plasma Reagin Tests. Am. J. Clin. Pathol. 2022 ,30, aqac025. [CrossRef] [PubMed] Vaccines 2022,10, 961 23 of 23 119. Signorelli, F.; Balbi, G.G.M.; Aikawa, N.E.; Silva, C.A.; Kupa, L.V.K.; Medeiros-Ribeiro, A.C.; Yuki, E.F.; Pasoto, S.G.; Saad, C.G.; Borba, E.F.; et al. Immunogenicity, safety, and antiphospholipid antibodies after SARS-CoV-2 vaccine in patients with primary antiphospholipid syndrome. Lupus 2022,20, 9612033221102073. [CrossRef] [PubMed] 120. Thurm, C.; Reinhold, A.; Borucki, K.; Kahlfuss, S.; Feist, E.; Schreiber, J.; Reinhold, D.; Schraven, B. Homologous and Heterologous Anti-COVID-19 Vaccination Does Not Induce New-Onset Formation of Autoantibodies Typically Accompanying Lupus Erythematodes, Rheumatoid Arthritis, Celiac Disease and Antiphospholipid Syndrome. Vaccines 2022 ,10, 333. [CrossRef] [PubMed]