The European Journal of Contraception & Reproductive Health Care ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/iejc20 COVID-19, gender and estroprogestins, what do we know? Tiziana Fidecicchi, Franca Fruzzetti, Luis Ignacio Lete Lasa & Joaquim Calaf To cite this article: Tiziana Fidecicchi, Franca Fruzzetti, Luis Ignacio Lete Lasa & Joaquim Calaf (2022) COVID-19, gender and estroprogestins, what do we know?, The European Journal of Contraception & Reproductive Health Care, 27:1, 67-74, DOI: 10.1080/13625187.2021.2000959 To link to this article: https://doi.org/10.1080/13625187.2021.2000959 © 2021 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. Published online: 29 Nov 2021. Submit your article to this journal Article views: 2638 View related articles View Crossmark data Citing articles: 7 View citing articles Full Terms & Conditions of access and use can be found at https://www.tandfonline.com/action/journalInformation?journalCode=iejc20 THE EUROPEAN JOURNAL OF CONTRACEPTION & REPRODUCTIVE HEALTH CARE 2022, VOL. 27, NO. 1, 67–74 https://doi.org/10.1080/13625187.2021.2000959 REVIEW COVID-19, gender and estroprogestins, what do we know? Tiziana Fidecicchia , Franca Fruzzettia , Luis Ignacio Lete Lasab and Joaquim Calafc a Department of Obstetrics and Gynecology, Pisa University Hospital of S. Chiara, Azienda Ospedaliera Universitaria, Pisa, Italy; b Department of Obstetrics and Gynaecology, Araba University Hospital, Vitoria-Gasteiz, Spain; cHospital de la Santa Creu i Sant Pau. Universitat Autonoma de Barcelona, Barcelona, Spain ABSTRACT ARTICLE HISTORY The new coronavirus disease-19 (COVID-19) pandemic has rapidly spread all around the world, elic- Received 31 July 2021 iting many questions and doubts about the pathogenesis of the disease and treatment. Mortality Revised 24 October 2021 has been related to a prothrombotic state. Risk factors for the infection and for severe forms of Accepted 27 October 2021 COVID-19 have still to be defined. According to data collected, women appear to be less prone to KEYWORDS severe forms of the disease and their mortality was lower than for men. The role of female hor- SARS-CoV2; inflammation; mones in the modulation of inflammation may be the reason behind this gender gap. cytokine storm; combined Considering the prothrombotic state activated by the virus, hormone therapies have been placed hormonal contraceptives; under investigation as possible increasing risk factors for severe forms. Moreover, new vaccines vaccine-induced immune and their rare thrombotic side effects have increased the concern about this issue. thrombotic The goal of this review is to go over the mechanisms that lead up to thrombosis during COVID-19, thrombocytopenia trying to explain the possible reasons why women seem to be naturally protected. The expert opinions about whether to continue/discontinue hormonal therapies are reviewed. Moreover, avail- able data about the so-called ‘vaccine induced immune thrombotic thrombocytopaenia’ caused by vaccines against COVID-19 are discussed. Introduction Moreover, a comment on the thrombotic effect of the new vaccines will be given. The novel Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV2) has spread around the world since December 2019, causing the well-known coronavirus dis- Sex differences in the epidemiology of COVID-19 ease-2019 (COVID-19) pandemic. Since the outbreak of COVID-19 in December 2019 in Wuhan, China, the infection The mechanisms of death in COVID-19 remain to be clari- has rapidly become the biggest pandemic of the century, fied, but the most likely hypothesis relates to the activation with more than 185 million global cases and over 4 million of a dysregulated inflammatory reaction that leads to mul- deaths around the world by July 2021 [1]. tisystem organ pathology in a subset of patients [3]. This There are still many open questions about this new dis- mechanism may be at the basis of gender differences in ease, and the search for an effective therapy is actively morbidity and mortality of COVID-19. Men with COVID-19 ongoing. The pathogenesis of the disease and its different are more at risk for severe symptoms and death, independ- manifestations are also difficult to explain. By now, it is ent of age and other comorbidities such as diabetes, hyper- generally accepted that SARS-CoV2 causes a more severe tension, and cardiovascular diseases [4]. This observation illness and kills more men than women [2], and being a for COVID-19 is in line with previous results for other infec- pre-menopausal woman seems to be a protective factor for tions. The predilection of viral infections for men was COVID-19 infection. A significant number of deaths from already observed in previous similar epidemics such as the COVID-19 infection have been attributed to a prothrom- severe acute respiratory syndrome (SARS) and the Middle botic state, thus to an increased risk of venous thrombo- East respiratory syndrome (MERS) [5]. embolism (VTE). For this reason, doubts about whether to Sex-disaggregated data at a global level (last update discontinue or limit the use of combined hormonal contra- June 2021) suggest that the ratio of positive cases between ceptives (CHC) during the pandemic has emerged. males and females is similar, but the number of men hospi- Much data has accumulated over the more than one talised is 1.1 times greater than women; intensive care unit year from the beginning of this pandemic. The goal of this (ICU) admissions are 1.8 times higher with males than with review is to make an update and to discuss how female females, and the confirmed cases of death are 1.5 times hormones can positively influence the inflammation mech- that of women of every age [6]. During the first months of anism triggered by viral infections, with particular attention the pandemic, many series of data were reported. In Italy, to the use of hormonal contraceptives during COVID-19. women represented 18% of all COVID-19 admissions to ICU CONTACT Tiziana Fidecicchi t.fidecicchi@gmail.com Department of Obstetrics and Gynecology, Pisa University Hospital of S. Chiara, Azienda Ospedaliera Universitaria, Pisa, Italy Joint first authors. ß 2021 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/licenses/by-nc- nd/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way. 68 T. FIDECICCHI ET AL. most likely current hypothesis is that SARS-CoV2 enters the cells and stimulates an early antiviral response with the activation of the innate and then the adaptive immune response. Inflammation leads to endothelial damage and to an hypercoagulative status (Figure 2(A)). SARS-CoV2 spike proteins have two domains. The first one binds the angiotensin-converting enzyme 2 (ACE2) expressed in the host cell surface; the second domain is cleaved by the host cell serine protease Transmembrane Protease Serine 2 (TMPRSS2). These two steps are necessary to allow the virus entry into the host cell [10,11]. ACE2 is encoded by the X chromosome [12]; SARS-CoV2 infection per se is capable of enhancing the ACE2 and TMPRSS2 mes- senger ribonucleic acid (mRNA) gene expression [13]. Figure 1. Sex- and age- disaggregated data on deaths from COVID-19 in Europe. Data on mortality in males and females in Europe is shown in the Severe COVID-19 outcomes are associated with delayed graph. Data are derived from a specific dataset available at https://global- and exaggerated innate immune responses: patients with health5050.org/the-sex-gender-and-covid-19-project/the-data-tracker [6]. As COVID-19 do not die from damage caused by the virus rep- a compromise between accurate age- and sex-stratification and sufficient data density, we included in the analyses only European countries with sex- lication; they die instead because of the effects induced by disaggregated data about number of deaths per 100,000 population divided the immune response that lead to the so-called ‘cytokine into 10-year age groups. The final selection included data from: Czech storm’ [3,14,15]. Immune cells infiltrate the lungs, causing Republic, Denmark, England, France, Hungary, Israel, Italy, Poland, Portugal, Spain, Switzerland, Wales. The mean about separate males and females’ mor- hyperactivation of monocytes and macrophages, with pro- tality of all the countries selected was done. Then, the ratio between males duction of pro-inflammatory cytokines, tumour necrosis fac- and females’ mortality per 100,000 population was calculated for every tor a (TNF-a) and chemokines. This situation causes 10-year age group. lymphopenia (which is related with COVID-19 severity) and lung injury [15], leading to acute respiratory distress syn- in the Lombardy region [7]. Among 1099 COVID-19 hospi- drome (ARDS) and multiorgan failure. talised cases in Wuhan, China, 42% were women; with only The cytokine storm may ultimately lead to the activation 32% of severe cases in females [2]. Other series of data in of the coagulation cascade, causing thrombotic phenom- different settings provided similar observations [8]. Marina ena (Figure 2(A)) [3]. Some indicators of these increased S. and Piemonti L. in 2020 analysed the data of six prothrombotic effects are the identification of fibrinous European countries about number of confirmed cases and thrombi in small pulmonary areas, regardless of their deaths stratified by age and sex. They found a clear age- involvement in lung injury, endothelial tumefaction and a dependent pattern of the male to female ratio of cumula- large number of megakaryocytes in the pulmonary capilla- tive incidence of cases in all countries analysed: even if the ries [16]. Anticoagulant therapy may be associated with a rate of confirmed SARS-CoV2 infection among females better prognosis in severe COVID-19 patients with sepsis- compared to males between the age of 10 and 50 years induced coagulopathy [17]. was higher, a higher preliminary fatality rate among males compared to females emerged in all age groups above 20 years old (not peer reviewed article, available at: https:// Oestradiol and immune response in women papers.ssrn.com/sol3/papers.cfm?abstract_id=3576790). The immune response is likely to play a critical role in Interestingly, there is also an age-related pattern in COVID-19 disease and females usually develop heightened infection rate and fatality. Seeland et al. identified a sex- immune responses compared to males [14]. The X chromo- and age-specific distribution of the COVID-19 incidence some contains the largest number of immune-related genes rate: premenopausal women (in the 20-55-year age range) [18], and this may be related to sex-based differences in presented the highest frequency of SARS-CoV2 infection, immune responses. Females benefit from having two X chro- but their fatality rate compared to age-matched men was mosomes and being a mosaic of X-linked genes, randomly lower [9]. We collected sex- and age-disaggregated data expressing alleles inherited from their mother or father [19]. about the number of deaths for COVID-19 per 100,000 The outcome and survival rates from infections or sepsis are population in different European countries from an online usually better in females than in males. Females, however, dataset (https://globalhealth5050.org/the-sex-gender-and- respond more aggressively to self-antigens and they are covid-19-project/the-data-tracker) and we represented the more susceptible to autoimmune diseases [20]. calculated male to female mean death ratio for 10-year age The steroid hormones, oestradiol (E2) and progesterone groups in Figure 1. These results support the hypothesis of (P4), at high physiological concentrations are also powerful an important role for female hormones in this disease, sug- immunomodulators [21]. The variation in sex steroids con- gesting that biological sex differences may be at the basis centration that occurs during life contributes to differences of the different death rate. in immune profiles and disease susceptibility patterns at different ages [12]. Oestrogen receptors (ERs) are expressed in all immune cells, and different peripheral blood mono- COVID-19: from inflammation to venous nuclear cells express a different balance between ERa and thromboembolism ERb [21]. E2 can modulate innate immunity by suppressing The pathogenic mechanisms of this new disease have still the production of proinflammatory cytokines and interleu- to be clarified, but our knowledge increases daily. The kins (ILs), IL-6, IL-1b, tumour necrosis factor-a - TNF-a, by THE EUROPEAN JOURNAL OF CONTRACEPTION & REPRODUCTIVE HEALTH CARE 69 Figure 2. Mechanisms of tissue damage by SARS-CoV2 and sex-hormone defence mechanisms. (A) Severe acute respiratory syndrome coronavirus 2 (SARS- CoV2) spike proteins recognise the host cell via the angiotensin-converting enzyme 2 (ACE2) and the serine protease Transmembrane Protease Serine 2 (TMPRSS2), leading to virus entry. SARS-CoV2 infection can enhance the ACE2 and TMPRSS2 messenger ribonucleic acid (mRNA) gene expression. Immune cells infiltrate the lungs, causing hyperactivation of monocytes and macrophages, with production of pro-inflammatory cytokines, tissue necrosis factor-b (TNF-b) and chemokines. The exaggerated activation of the immune response leads to the so-called ‘cytokine storm’, and this situation causes lymphopenia and lung injury. Tissue damage ultimately leads to the activation of the extrinsic pathway of the coagulation cascade. (B) Both oestradiol (E2) and progesterone (P4) can modulate innate and adaptive immune response by binding their nuclear receptors. Both hormones can inhibit macrophage activation, thus reducing the secretion of pro-inflammatory cytokines and the migration of neutrophils and monocytes into inflamed tissues and can stimulate the production of anti-inflam- matory cytokines and the expansion of T regulatory (Treg) cells. Moreover, E2 can enhance the production of antibodies by B cells, and it inhibits the increas- ing expression of TMPRSS2 in infected cells, possibly reducing the virus content inside the cells. Created with BioRender.com. ERs: oestrogen receptors; PR: progesterone receptor; TF: tissue factor. monocytes and macrophages and the migration of innate (HIV), hepatitis C virus (HCV), Ebola and human cyto- immune cells into inflamed areas (e.g., neutrophils and megalovirus [5,14]. monocytes). Moreover, E2 stimulates the production of P4 is another important immunomodulator and anti- anti-inflammatory cytokines (IL-4, IL-10 and interferon-c) by inflammatory hormone. Its receptors are widely distributed CD4þ T-helper cells and decreases the production of proin- in immune cells: it inhibits pro-inflammatory IL-12 and IL- flammatory IL-17. The expansion of regulatory T cells and 1b production by macrophages, and it favours anti-inflam- the production of antibodies by B cells are also enhanced matory actions of CD4þ T-helper cells, similarly to E2 by E2 (Figure 2(B)) [14,20]. (Figure 2(B)) [14]. Studies in mice have demonstrated that Several lines of research have shown that oestrogen luteal-phase levels of P4 could protect from influenza A exhibits antiviral properties, which have been studied virus pneumonia, reducing inflammation and promoting against influenza A virus, human immunodeficiency virus pulmonary tissue repair [22]. 70 T. FIDECICCHI ET AL. Thus, female sex hormones can enhance and modulate either among males or post-menopausal women present- innate and adaptive immunity, representing the major ing with any form of the disease. causing factor of the gender-bias existing in the infection and the course of the COVID-19 disease. Oestrogen signalling is critical for cellular protection What to do with combined hormonal from SARS-CoV2, too. A recent study showed that E2 was contraception during the COVID-19 pandemic? able to modulate ACE2 gene-expression levels in differenti- It is more complex to establish if what is known for natural ated airway epithelial cells [23]. However, preclinical evi- hormones is valid also for CHC in pre-menopausal women, dence that ACE2 expression is regulated in a sex- mainly due to the variability of oestrogens (natural and dependent manner has not yet been validated and further synthetic) and of routes of administration used. The magni- studies are needed [24]. Lemes et al. found that the tude of the protective effect of CHC usage among women in vitro activation of ERs in SARS-CoV2 infected cells may in reproductive age versus non-users seems to be small, cause the downregulation in TMPRSS2 gene expression mostly because circulating hormone levels are already (Figure 2(B)), suggesting that this mechanism may be high [9]. related to the reduction of virus content inside the cells Despite the apparent protective effect of female hor- found after the activation of ERs. This seems to be a defen- mones, in this last year, the safety of CHCs during COVID- sive mechanism activated by infected cells, considering 19 pandemic has been doubted due to their well-known that E2 didn’t cause changes in ACE2 and TMPRSS2 expres- pro-thrombotic effect. Many contradictory messages have sion in non-infected cells [13]. been given to the public by media and researchers. However, currently there are no studies that demonstrate an increased risk of VTE and of severe forms of COVID-19 Post-COVID-19 syndrome in CHC users versus non-users during SARS-CoV2 infection. A post-COVID-19 syndrome has recently attracted attention, In May 2020, the Italian Society of Contraception (SIC) pub- which consists of the persistence of symptoms after recov- lished their guidelines for the management of hormonal ering from the initial acute COVID-19 [25–28]. In particular, contraception during this pandemic. The aim was to avoid the most common symptoms are fatigue, dyspnoea, neuro- unnecessary discontinuation of pill intake, especially con- logical disorders, anosmia/dysgeusia, and they resulted to sidering that no data were available in support of an be significantly associated with disease severity at increased thromboembolic risk in this particular population. onset [27]. They recommended not to discontinue contraception (in Studies suggest that the overall incidence of post- particular CHCs) in asymptomatic and mild/moderate forms COVID-19 syndrome may range from 40% to 60% after of COVID-19 [31]. Moreover, the effect of pill discontinu- 6 months from recovery, but knowledge about this syn- ation on the normalisation of coagulation parameters drome is still poor. Curiously, first data suggest that this requires about two months to realise. Thus, some authors syndrome may have a higher prevalence in women [27,28]. suggested to add an anticoagulant therapy versus stopping However, sex-disaggregated data are lacking, as well as CHC usage in women with COVID-19 [32]. During hospital- information about the pathogenesis of this long-term syn- isation, CHCs must be interrupted, and re-initiation can be drome. Currently, no conclusions about these gender differ- performed immediately after recovery [31]. These sugges- ences may be drawn. tions were corroborated by the fact that recent meta-analy- ses didn’t find an association between COVID-19 and an increased risk of VTE in the general population. In the Female natural hormones: potential benefit of review by Mai et al., seven studies (41,768 patients) eval- their administration uated VTE in COVID-19 cohorts compared to non-COVID-19 Considering that the natural protection against severe cohorts. The overall risk of VTE (RR 1.18; 95% CI 0.79–1.77; forms of the disease derives from mechanisms elicited by p ¼ 0.42; I2¼54%), pulmonary embolism (RR 1.25; 95% CI female hormones, some researchers tried to assess the pos- 0.77–2.03; p ¼ 0.36; I2 ¼ 52%) and deep venous thrombosis sible benefits of administering E2 during COVID-19 infec- (RR 0.92; 95% CI 0.52–1.65; p ¼ 0.78; I2 ¼ 0%) did not sig- tion. Seeland et al. [9] analysed real-world evidence in a nificantly differ between COVID-19 and non-COVID-19 subset of 16,891 post-menopausal women classified cohorts. An increased risk of VTE among COVID-19 versus according to the use of oestradiol therapy. They found a non-COVID-19 cohorts emerged when only patients hospi- significant difference in death rates among post-meno- talised within the ICU were considered (RR 3.10; 95% CI pausal women receiving hormone-replacement therapy 1.54–6.23), which was not observed in cohorts of predom- with E2 versus non-users: the fatality risk for women inantly non-ICU patients (RR 0.95; 95% CI 0.81–1.11) [33]. >50 years receiving E2 treatment is reduced by more than Moreover, according to a study by Jimenez et al. [34], the 50%, from 6.6 to 2.3%. These data suggest a protective clinical characteristics associated with a higher risk of VTE role of oestrogens. Other authors have suggested using during COVID-19 were older age and having a history oestrogens in the treatment of COVID-19 after analysing of VTE, recent surgery/immobilisation and hypertension; experimental evidence of well-established actions of this D-dimer >5000 ng/mL was also a strong predictor. The use hormone in the immune modulation mechanisms [29,30]. of hormonal contraceptives was not reported [34]. All this However, up to this review, we have not been able to iden- evidence confirms the hypothesis that women can con- tify any prospective, randomised study evaluating the tinue to use their hormonal contraceptive without the effect of oestrogen treatment on the severity of the disease need to move to a progestogen-only contraception. THE EUROPEAN JOURNAL OF CONTRACEPTION & REPRODUCTIVE HEALTH CARE 71 In agreement with the World Health Organisation guide- of women, more than 30% went through unexpected preg- lines [35], the SIC maintains that the coronavirus pandemic nancies, all of them requiring voluntary termination of has not changed the indications and the contraindications pregnancy [41]. for the use of the different hormonal contraceptive meth- In recent months, other articles and guidelines were ods. Where it is not possible to collect an appropriate med- published about this issue, the majority of them confirming ical history and conduct a physical examination, the the fact that clinicians can continue to prescribe and use physician may consider prescribing a progesterone only pill CHCs, including those containing EE, during this pandemic (POP) until an outpatient visit is possible. [42,43]. By now, all these recommendations reflect the The recommendations from the Spanish Menopause opinions of expert groups, but scientific studies designed Society, Sociedad Espan ~ola de Ginecologıa y Obstetricia to define whether and when continuing, discontinuing, or and Sociedad Espan ~ ola de Trombosis y Haemostasia are switching to another type of contraceptive during COVID- more restrictive [36]. For perimenopausal women using 19 disease are still lacking. CHC, they suggest withdrawing CHC, also in women with mild symptoms and confirmed COVID-19 infection and The dilemma about COVID-19 vaccines and adding prophylactic low molecular weight heparin when combined hormonal contraceptives there are persistent respiratory symptoms, also if there are not criteria for hospitalisation. If contraception is required In recent months, new concerns have arisen since the for medical reasons, they suggest to switching to proges- worldwide diffusion of the novel COVID-19 vaccines. At terone-only methods [36]. However, even if COVID-19 may present, the European Medicines Agency (EMA) has be a risk factor for VTE, as previously described data does approved four vaccines against COVID-19, and more than not support the need to change the contraceptive method 3 billion doses of vaccines had been administered globally in mild/moderate forms of COVID-19 [33,34]. by July 2021 [44]. If the goal is to use a combination with a low or no The main concern is about the vaccination with the impact on coagulation, we must be aware that prepara- recombinant adenoviral vector encoding the spike protein tions containing natural oestrogens induced similar or less antigen of SARS-CoV2 (ChAdOx1 nCov-19, Vaxzevria, previ- changes in the overall activity of the coagulation system ously AstraZeneca). Since the end of February 2021, rare than those containing ethinylestradiol (EE) [37,38]. This may cases of unusual thrombotic thrombocytopenia have been be a weapon for the clinician to address the problem of reported after ChAdOx1 nCoV-19 vaccination. the increased risk of VTE when anti-androgenic progestins At the beginning of this ‘vaccine era’, in Norway, this are needed. In a study comparing 17b-oestradiol (17bE2) þ vaccine was administered to healthcare professionals nomegestrol acetate (NOMAC) versus EE þ levonorgestrel younger than 65 years of age [45]. Within 10 days after (LNG), the first combination induced significantly fewer receiving a first immunisation with ChAdOx1 nCoV-19, five changes in the overall activity of the coagulation system. In health care workers, four of them women aged 32–54 years particular, mean changes in prothrombin fragment 1 þ 2 of age, presented with thrombosis in unusual sites and and antithrombin were close to zero, suggesting minimal concomitant severe thrombocytopenia, among a total of effects on thrombin turnover, while D-dimer levels, a deg- 132,686 first doses administered. Among these, four had radation product of fibrin which correlates with the throm- severe cerebral venous thrombosis with major cerebral bus burden, decreased rather than increased [39]. Similar haemorrhage, three with fatal outcomes [45]. A common results were observed with a preparation with oestradiol denominator in all five patients was a high level of anti- valerate (E2V) and dienogest [40]. In the study by Dinger bodies to platelet factor 4 (PF4)–polyanion complexes, simi- et al. the rate of VTE events with E2V þ dienogest was com- lar to those produced during ‘heparin-induced parable to other EE-containing CHCs (crude HR 0.8, 95% CI thrombocytopenia’ [46], even if none of these patients had 0.4–1.6), but the difference became significant when the received heparin before the onset of symptoms. These find- data were corrected for age, body mass index, duration ings suggest that a syndrome similar to autoimmune hep- of use, and family history of VTE (adjusted HR was 0.5 arin-induced thrombocytopenia may occur after [95% CI, 0.2–1.0]). However, the risk of VTE was similar to a administration of ChAdOx1 nCoV-19 [45]. The name pill containing EE and a second-generation progestin (LNG) ‘vaccine-induced immune thrombotic thrombocytopenia’ [37]. Recently, the study by Reed et al. showed that (VITT) has been proposed to call this emerging post-vaccin- 17bE2 þ NOMAC was not associated with a higher risk of ation syndrome [45,47]. VTE or arterial thromboembolism compared to a EE þ LNG Based on a report by the Society of Thrombosis and pill [38]. Haemostasis Research, it has been hypothesised that post- It is important to avoid unnecessary discontinuation vaccination antibodies are formed against platelet antigens because of the risk of undesired pregnancies, that could as a part of the immune stimulation process. These anti- represent a further risk factor for VTE. An Italian group bodies trigger massive platelet activation against PF4, investigated the effects of social distancing during SARS- resulting in immune thrombotic thrombocytopenia [48]. CoV2 pandemic, administering an online questionnaire to Cross-reaction between the vaccine and platelets or PF4 women taking long- or short-term hormonal contraceptives has also been highlighted as a potential contributing factor [41]. Women taking long-term contraceptives didn’t show in the pathogenesis of this syndrome especially knowing significant differences, while unmarried and non-cohabiting that adenovirus can bind to platelets resulting in platelet women regularly taking short-term contraceptives (CHC or activation [45]. POP) generally discontinued the treatment, despite con- A similar experience was reported in Austria and tinuing to have sexual intercourse. Among this latter group Germany. By March 2021, 11 patients were found to have 72 T. FIDECICCHI ET AL. one or more thrombotic complications beginning 5–16 days thus there is no indication to discontinue hormonal ther- after vaccination with ChAdOx1 nCov-19. The median age apy before the administration of the vaccine. The mecha- was 36 years old and 9 out of 11 patients were female. nisms underlying thrombosis events in VITT, which are None of the patients had received heparin before the onset described above, are different from those described during of symptoms or the diagnosis of thrombosis. Also in these hormonal contraception. cases, VITT seemed to be at the basis of the thrombotic The EMA [54], the Agenzia Italiana del Farmaco (AIFA) events with thrombocytopenia [47]. [55] and the International Society on Thrombosis and A common denominator of the cases of VITT reported in Haemostasis (ISTH) [56] recently concluded that unusual these few published studies is the onset of thrombosis in blood clots with low blood platelet counts should be listed unusual sites. Currently, there are still few studies about as a very rare side effect of the vaccine. However, they this side effect and low patient numbers. The incidence of agree that currently no specific risk factors have been iden- this side effect has still to be quantified, but it is consid- tified, and that the benefits of the vaccine continue to out- ered very rare but obviously severe. weigh the risks for people who receive it. As for all Based on the EMA report of April 7th, 2021, there were vaccines, EMA will continue to monitor Vaxzevria’s safety 169 cases of thrombosis in the cerebral veins and 53 cases and effectiveness and to provide the public with the latest of thrombosis in the abdominal veins, with 18 fatal cases, information [54]. A study which may clarify the risk factors following the administration of 34 million doses of and the mechanisms beside the development of this rare Vaxzevria vaccine in Europe and United Kingdom (UK), i.e., side effect is necessary. 6.5 events/million subjects who received at least one dose of vaccine. The absolute estimated risk is 1/100,000 sub- jects who received the vaccine [49]. Conclusion In Italy by April 26th, 2021, 34 cases of venous throm- bosis in atypical areas have been reported, 18 of them There are currently few certainties in this complex situ- associated with thrombocytopenia. The estimated inci- ation. It is certain that the COVID-19 pandemic has revolu- dence was 0.45/100,000 people who received the vaccine: tionised people’s lives, so it is necessary to better identify this is a lower incidence than the one reported in UK and the risk and protective factors behind this disease. Women Europe, probably as a consequence of the lower number of seem to be relatively protected from the virus compared to doses of vaccine administered [50]. More recently, similar men, and it may be postulated that sex hormones may observations were done for the Ad26.COV.2.S vaccine contribute to this defence. However, no randomised studies (Janssen, Johnson & Johnson) [51]. are yet available to give answers to these questions. Why The mechanisms behind VITT are completely different some vaccines cause this very rare but severe thrombotic from those of COVID-19 itself, as described above. The side effect in some people is even less clear but mandatory majority of these VITT complications occurred within the to find out, figuring out a world where this vaccine will first five to twenty-one days following vaccination and become routine. occurred mainly in women under 55 years of age [52]. At the present time, the possible occurrence after the second dose cannot be ruled out. Moreover, why this situation Disclosure statement occurs with very high predominance in women has still not No potential conflict of interest was reported by the authors. been clarified. The thrombotic complication in unusual sites seems to be related to the production of autoantibodies. It may be of interest to observe that the incidence of auto- ORCID immune diseases is higher in women [14,53]. Tiziana Fidecicchi http://orcid.org/0000-0002-9191-6385 In this context, many doubts arose about the concomi- Franca Fruzzetti http://orcid.org/0000-0001-8273-0258 tant presence of other prothrombotic risk factors during Luis Ignacio Lete Lasa http://orcid.org/0000-0002-0266-3970 vaccination against COVID-19. A pre-existing hypercoagu- Joaquim Calaf http://orcid.org/0000-0002-2407-7884 lable or autoimmune condition may favour the onset of this particularly rare side effect, with the vector vaccine References serving as a trigger resulting in cascade of thrombosis and thrombocytopenia. Considering the small number of cases [1] Dong E, Du H, Gardner L. An interactive web-based dashboard to track COVID-19 in real time. Lancet Infect Dis. 2020;20(5): described in literature at this point, it’s hard to establish 533–534. real correlations. 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