Introduction

Coronavirus disease (COVID-19) due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has affected tens of millions of people [1] globally since it was declared a pandemic by the World Health Organization on March 11, 2020. The development of vaccines started as soon as the virus genome was published in early January 2021 [2]. Several types of COVID-19 vaccines have been produced with different techniques and consequently different mechanisms of action.

Even though the efficacy of the COVID-19 vaccine has been confirmed in the registration trial, some concerns regarding safety issues have been pointed out. One of the most frequently reported COVID-19 vaccines’ severe side effects (SAE) is thrombosis. Thromboembolic complications have been observed after administration of two adenovirus vector vaccines, namely ChAdOx1 nCoV-19 (Vaxzevria) and Janssen/Johnson &Johnson COVID-19 (Ad26.COV2.S) vaccines. In April 2021, among 34 million people vaccinated with ChAdOx1 nCoV-19 (Vaxzevria), the European Medicine Agency (EMA) has reviewed 163 cases of cerebral venous sinus thrombosis (CVST) and 53 in splanchnic veins, with an estimated incidence of 1:100,000 [3]. Similarly, 17 thromboembolic events were reported over 7.98 million people after Janssen/Johnson&Johnson COVID-19 (Ad26.COV2.S) vaccination, among which 14 were cases of CVST [4]. COVID-19 vaccine–induced thrombosis is characterized by an atypical localization of the thrombi (e.g., splanchnic and cerebral veins) and frequent association with thrombocytopenia. It has been supposed that Vaccine-induced thrombotic thrombocytopenia (VITT) develops as a consequence of an autoimmune mechanism, presumably due to an immune response to platelet-factor 4 (PF4), similar to heparin-induced thrombocytopenia (HIT). In this context, PF4 binds to polyanions such as heparin and undergoes a conformational change, forming an immunogenic complex that stimulates an anti-PF4-heparin IgG. The resulting immunocomplex causes a strong platelet activation and a decrease in platelet count due to consumption [5]. Since no reports of CVST with thrombocytopenia following authorized mRNA COVID-19 vaccines have been reported, a pro-thrombotic effect of the adenovirus vector has been supposed [6]. Indeed, it binds to PF4, resambling the action of heparin or an endogenous polyanion, and the resulting immunogenic complex activates the immune system, as described before. However, there is still no unequivocal evidence about the pathophysiology of the thromboembolic events observed after vaccination because a consistent number of these events are not accompanied by thrombocytopenia and PF4 antibodies.

In this report, we describe a case of cerebral venous thrombosis (CVT) following immunization with the Janssen/Johnson &Johnson COVID-19 (Ad26.COV2.S) vaccine in a woman without any prothrombotic comorbidities. The absence of anti PF4 antibodies and thrombocytopenia and the remarkable response to warfarin therapy, contraindicated in VITT, sheds new light regarding other possible mechanisms of this serious and possibly fatal adverse event.

Case report

On June 22nd, 2021, a 45-year old woman was admitted to the hospital complaining of a persistent bilateral frontal headache and retro-orbital pain started 8 days before. The patient’s past medical history included migraine without aura in prophylactic treatment with beta-blocker (propanolol 20 mg two times/day). No history of previous systemic thrombotic events or spontaneous abortions was reported. During the medical interview, the patient reported being injected with a single dose of viral vector Janssen/Johnson&Johnson COVID-19 (Ad26.COV2.S) vaccine 2 weeks before the onset of the aforementioned symptoms.

At admission, the patient neurological examination was normal. However, the fundus oculi inspection revealed bilateral papilledema. Hence, the patient underwent a brain computed tomography (CT) with venous and arterial angiography sequences of intracranial and extracranial vessels, which showed a blurred hyperdense signal alteration in the cortical-subcortical portion of the right temporal lobe. Thus, a brain magnetic resonance image (MRI) was performed which revealed a hyperintense signal in the right temporal and insular lobes in the T2-Fluid attenuated inversion recovery (FLAIR) sequences with a T1-positive contrast enhancement suggestive of cerebral venous thrombosis in association with brain oedema (Fig. 1). Considering the recent vaccination, a case of VITT was suspected and anticoagulation therapy with Fondaparinux (7.5 mg/day) was started. Then, blood examination tests were performed which included coagulation assessment, thrombophilia tests, and auto-antibodies screening, which resulted all within the normal range (Table 1). Anti-platelet factor 4 autoantibodies (anti-PF4) were absent, excluding the diagnosis of VITT. Thus, according to the AHA/ASA guidelines for cerebral venous thrombosis9, the patient was gradually shifted to warfarin. Furthermore, corticosteroids (dexamethasone ev 12 mg/day) and acetazolamide (500 mg/day) were started to reduce cerebral edema and intracranial pressure.

Fig. 1
figure 1

Cerebral MRI performed at admission with signs of cerebral venous thrombosis. Fluid attenuated inversion recovery sequence (FLAIR) (a) and T2 (b) axial MRI showing hyperintense signal in right temporal and insular subcortical white matter, with “patchy” aspect and no mass effect. Axial T1 post-gadolinium (c) showing high contrast enhancement. These findings are suggestive for venous infarction

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Table 1 Main laboratory data in patients affected by CVT
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In the following days, the clinical condition gradually improved with complete regression of the headache and the papilledema. Two follow-up brain MRI, performed at day 26 and at day 60 after the symptoms’ onset, showed a progressive reduction of the signal alterations and the disappearance of the T1 contrast enhancement and the signs of brain oedema (Fig. 2).

Fig. 2
figure 2

Cerebral MRI performed after anticoagulant therapy which shows progressive resolution of cerebral venous thrombosis. MRI images at 26 days after symptoms onset showing the clear reduction of right temporal signal alteration in FLAIR (a), involving only the right temporal gyrus, and significant reduction of contrast enhancement (b), visible in the underlying venous. At 60 days, further reduction of temporal hyperintensity (c) and complete resolution of contrast enhancement (d)

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Discussion

CVST has an annual incidence of 3 to 4 cases per million, with a significant female predominance in young adults (aged 31–50) who have inherited or acquired prothrombotic risk factors [7]. Post-marketing safety monitoring data for COVID-19 vaccines have reported several cases of CVST [8] with a median time of 8 days between vaccination and symptom onset. In these cases, the association of CVST with thrombocytopenia has been frequently observed, even though several reports of vaccine-induced CVST without thrombocytopenia have been also described [9]. Updated observed-to-expected analysis for CVST after ChAdOx1 nCoV-19 (Vaxzevria) and Janssen/Johnson &Johnson COVID-19 (Ad26.COV2.S) immunization has shown greater mortality in patients with thrombocytopenia when compared to patients without thrombocytopenia. Thus, low platelet count could be an important risk factor for a worse outcome.

In our report, we describe a case of Janssen/Johnson&Johnson COVID-19 (Ad26.COV2.S)–induced CVST without thrombocytopenia. Even though several cases of CVST without thrombocytopenia have been described in patients immunized with ChAdOx1 nCoV-19 (Vaxzevria), no reports are available so far on this possible SAE from Janssen/Johnson&Johnson COVID-19 (Ad26.COV2.S) vaccination. The mechanism through which COVID-19 vaccine might exert a prothrombotic effect without inducing thrombocytopenia is largely unknown, but there is strong evidence for the interaction between Sars-Cov2 virus and angiotensin-converting enzyme 2 (ACE2) receptor as a possible cause of platelet aggregation. Considering the mechanism through which viral vector vaccines induced immunization (simulation of S glycoprotein synthesis by the organism), binding of the S glycoprotein to ACE2 may lead to ACE2 downregulation, which in turn results in a higher formation of Angiotensin II (Ang II) by ACE, and less conversion of ACE2 to Ang-(1–7). The overactivation of ACE/AngII/AT1R pathway, with its pro-thrombotic, pro-inflammatory, and vasoconstrictor effect, could be responsible of stroke and thrombosis, also in the venous circulation [10]. Thus, it can be speculated that in a selected group of subjects, this vaccination may elicit a strong inflammatory response leading to platelet aggregation and clot formation. However, in our report, no evidence of pro-inflammatory response to vaccination has been evidenced according to blood examination, hence rejecting the possible role of an inflammatory-mediated mechanism. Undoubtfully, in about 35–40% of CVST a predisposing factor is not always identified [11] and vaccines can be considered themselves a pro-thrombotic trigger. On the other hand, it has to be reminded that CVST may happen in general population independently of vaccination, where it is often characterized by a normal platelet count. In our case, the lack of any previous prothrombotic state and the temporal association between vaccine administration and the onset of the clinical picture support the hypothesis of a causal role of the Janssen/Johnson&Johnson COVID-19 (Ad26.COV2.S) vaccine in the genesis of CVST, although not unequivocally proven.

Therapeutic management of vaccine-induced CVST without thrombocytopenia is different from the treatment of VITT. In fact, in VITT, anticoagulation therapy with low molecular weight heparin (LMWH) and vitamin K-antagonists is contraindicated due to the risk of worsening of thrombosis. Novel oral anticoagulants (NOACs) instead (dabigatran, apixaban, edoxaban, and rivaroxaban) and fondaparinux can be safely used. Urgent administration of high-dose intravenous immunoglobulin (0.5–1 g/kg for 2 days) is also recommended [12]. On the contrary, in the management of CVST without thrombocytopenia, heparins can be used and are associated with a more favorable outcome [13].

Conclusion

Thrombotic events following COVID-19 vaccination have a higher incidence in those patients who receive a viral vector vaccine, such as Vaxzevria and Jannsen, especially when associated to thrombocytopenia. However, vaccine-related CVST without thrombocytopenia has also been described. According to our experience and in line with the current guidelines, normal platelet count and the absence of anti-PF4 antibodies ruled out the diagnosis of VITT and authorized us to treat vaccine-related CVT likewise as sporadic CVST. Further studies are needed to clarify the specific etiologies of this condition, to identify subgroups of patients with an increased risk of developing CVST and avoid this complication.