Omicron / mRNA Vaccine : Increasing Incidences Of Cerebral Venous Sinus Thrombosis (CVST)

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There seems to be sudden increase of diagnosis and admissions of otherwise healthy individuals having Cerebral Venous Sinus Thrombosis (CVST).

Some had initially tested positive for COVID-19 but only had mild symptoms or were asymptomatic and a few were confirmed as having the Omicron variant (Not all medical establishments provide genomic sequencing).

Some patients admitted for Cerebral Venous Sinus Thrombosis (CVST) said that they never had a test for COVID-19 done.
 
Most of these patients however complained of headaches and some experienced mental fogginess and also pains behind the eye in the initial stages.
 
For those who are not aware, Cerebral Venous Sinus Thrombosis (CVST) occurs when a blood clot forms in the brain’s venous sinuses. This prevents blood from draining out of the brain. As a result, blood cells may break and leak blood into the brain tissues, forming a hemorrhage. The condition can often be fatal.
 
The increased in incidences were observed starting at the same time as the debut of Omicron in November 2021 and the initial incidences were observed in UK, Germany and then in the United States, Singapore and Thailand.
 
In Thailand for instance, reported cases are not even tested for COVID-19 and or even checked if they had previous COVID-19 infections as physician are ignoring any possibilities of any linkages between Cerebral Venous Sinus Thrombosis (CVST) and the SARS-CoV-2 virus!
 
There could be a possibility  that due to the increased vaccination uptakes as a result of the threat of Omicron, the increased in Cerebral Venous Sinus Thrombosis (CVST) is being observed as it is already known that COVID-19 vaccines can also induce Cerebral Venous Sinus Thrombosis (CVST) as an adverse effect in a very extremely small proportion of the population. 

https://www.ncbi.nlm.nih.gov/labs/pmc/articles/PMC8593397/
 
https://pubmed.ncbi.nlm.nih.gov/34610990/
 
https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2785610

Coronavirus disease 2019 (COVID-19) has caused a pandemic, and detailed information of adverse effects for its vaccines is to be timely needed. Adenovirus vector–based vaccines can be related to the development of venous thrombotic events including cerebral venous sinus thrombosis (CVST) associated with thrombocytopenia and platelet factor 4 (PF4)–heparin antibodies [1, 2]. Here, we report a case of CVST with prolonged mild headache after mRNA-based COVID-19 vaccination.

A man in his 50 s without remarkable medical history visited our department complaining of 1-week headache, which started 26–30 h after his second dose of tozinameran (Comirnaty® from Pfizer–BioNtech). He was evaluated by blood test, brain computed tomography (CT), and magnetic resonance imaging (MRI).

His headache was a combination of pulsative and tension types, predominantly felt around the bilateral occipital area. Nonetheless, it was mild; thus, he could still continue his office work, with over-the-counter pain reliever medication. No other common adverse events of vaccination were noted. On admission, he was alert and had no neurological deficit. His platelet count was normal (271,000/µL [reference range: 158,000–348,000]), but his D-dimer level was elevated (6.01 µg/mL [reference value: < 1.00]).

Brain CT and MRI (Fig. 1), which were both conducted 7 days after second vaccination, showed thrombosis in the superior sagittal sinus, right transverse sinus, right sigmoid sinus, and right internal jugular vein [3]. There were no remarkable abnormalities in brain parenchyma.

Nasopharyngeal swab samples were negative for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) according to the polymerase chain reaction test. Blood tests for the risk factors of venous thrombosis such as antiphospholipid antibody and protein S/C showed no remarkable abnormality, and the screening test for antibodies against PF4–heparin was negative. After heparin treatment, his headache was relieved in 2 weeks, with sinus thrombosis partially disappearing.

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Fig. 1 . a Sagittal view of the enhanced CT imaging of the brain showing CVST in superior sagittal sinus (arrow heads). b Sagittal view of the enhanced CT imaging of the brain showing partially disappearing CVST, 1 week after the admission (arrow heads). c MRV showing CVST in the superior sagittal sinus, right transverse sinus, right sigmoid sinus, and right internal jugular vein. d MRV showing partially disappearing CVST, 2 weeks after the admission. e MRI of the thrombosed right transverse sinus showing slight hyperintensity on the T1-weighted image (arrow heads). f MRI of the thrombosed right transverse sinus showing hypointensity on the T2-weighted image (arrow heads). g MRI of the right transverse sinus showing hypointensity on the T2*-weighted sequence (arrow heads). CT, computed tomography; CVST, cerebral venous sinus thrombosis; MRI, magnetic resonance imaging; MRV, magnetic resonance venography

CVST after SARS-CoV-2 vaccines are divided into a CVST in the setting of the vaccine-induced immune thrombotic thrombocytopenia syndrome (VITT), mainly related to adenovirus vector–based vaccines, and a CVST without VITT characteristics, related also to mRNA-based vaccines [4]. This case was a CVST not related to VITT.

In the UK (https://www.gov.uk/government/publications/coronavirus-covid-19-vaccine-adverse-reactions), USA (Vaccine Adverse Event Reporting System [VAERS]: https://wonder.cdc.gov/vaers.html), Europe (http://www.adrreports.eu/en/index.html), and Japan (https://www.mhlw.go.jp/stf/shingi/shingi-kousei_284075.html), the occurrence of CVST after mRNA-based COVID-19 vaccinations has been reported to the authorities. In the analysis of thrombotic events reported to the WHO VigiBase, CVST, as well as PE and DVT, occurred after the injection of mRNA-based and adenovirus vector vaccines [5], but their causal relationship was not supported in a US epidemiologic study [6].

However, mild CVST events, as seen in our patient, might be possibly excluded in these analyses because headache may be too mild to be spontaneously reported. Therefore, our case suggests that the precise relationship between CVST and COVID-19 vaccination remains unclear, and its evaluation should include mild cases.

Although excessive concern to post-vaccination headache is inappropriate, we recommend performing brain CT or MRI to evaluate CVST for patients whose headache lasts for > 1 week after vaccination, even for mild ones.


The most frequent clinical manifestations of COVID-19 infection are cough, fever, dyspnea, diarrhea, and fatigue associated with radiological lung abnormalities [7]. Moreover, the neurologic manifestations such as seizures, headache, and loss of smell are not uncommon [5], [8]. The neurotropism of covid-19 virus was confirmed by the presence of the virus in cerebrospinal fluid [9], [10] and its neuroinvasive potential could happen through the retrograde neuronal route as similar to the MERS-CoV and SARS-CoV-1 [10], [11].

A wide spectrum of neurological complications has been reported with the new version of corona virus (Covid-19) [3], which could involve the acute cerebrovascular insult [8].

COVID-19 disease shows a state of hypercoagulability with a high prevalence of venous thromboembolism associated with thrombotic complications mostly related to the pulmonary vasculature [6], [12], [13], [14]. However; these thrombotic complications may involve the brain vasculature as well in 2% of patient with confirmed COVID-19 infection [3].

The mechanism of thrombophilic state with COVID-19 infection has not been fully elucidated. However, the severe inflammatory response after COVID-19 infection leads a cytokine storm that intern can induce a pro-coagulable state [15], [16]. In addition, the virus itself has its specific pro-coagulant effect [16].

Covid 19 infection induces widespread endothelial dysfunction (endotheliopathy) and inflammation [17]. Von Willebrand factor (VWF) and factor VIII (FVIII) are known to be elevated COVID-19 patients [18], [19]. FVIII and VWF are not only related to inflammation and risk of thrombosis but also associated with endothelial damage [20]. A decrease in FVIII/VWF ratio values on COVID 19 patients’ admission could determine which patient will be at higher risk of worsening respiratory status, and subsequently shows an increase in oxygen requirements [20].

Ultra large VWF (ULVWF) has a higher adhesive ability to platelets than VWF [21]. Exocytosis of ULVWF stored at endothelial Weibel-Palade bodies (WPB) into the circulation can be triggered by hypoxia, Interleukin (IL)-1, as well as, tumor necrosis factor (TNF)-alpha. Moreover, IL-6 can inhibit the cleavage of ULVWF–platelet strings [22]. Tremblay et al showed that there is no difference in the outcome of COVID 19 patients who were receiving anti-platelet or anti- coagulants compared to those who were not [23].

So, preventing the binding of platelets to ULVWF at the glycoprotein IX-Ib receptor through agents like; caplacizumab [22] or anfibatide [22], recombinant ADAMTS13 concentrate [24], or dissolving the ULVWF multimers by using N Acetylcysteine [25] might represent an attractive way to prevent microthrombosis formation.

The most frequent cerebrovascular disease after COVID-19 infection is ischemic stroke as demonstrated in the series of Helms et al., [5] where, one sub-acute and two acute ischemic strokes out of 13 patients with confirmed covid-19 infection were reported. Moreover there are reported cases of cerebral venous sinus thrombosis among COVID-19 infected patients [6].

Cerebral venous sinus thrombosis is a rare thrombotic disease and has a relatively good outcome when treated promptly although it could be fatal if not [26]. The use of oral contraceptive pills Pregnancy & puerperium, presence of genetic predisposition, malignancy, connective tissue disease and local infections of the head & neck are considered risk factors for development of CVST [26], [27], [28].

The CVST manifestation includes symptoms and signs of intracranial hypertension, encephalopathy or focal neurological deficit and can cause cerebral infarction and/or hemorrhage [26]. Heparin anticoagulation is the initial treatment of CVST even in the presence of intracerebral hemorrhage [29]. Despite limited reports in the literature described the association between COVID-19 infection and CVST [4], [30], the current report demonstrates two patients with confirmed COVID-19 infection complicated by CVST.

In the current report both patients are young adult males and have no other risk factors of hypercoagulable state apart from being COVID-19 infection victims which could support the association between COVID-19 infection and CVST. Both patients in the current report died within one week of their initial symptoms in spite the aggressive medical and surgical treatment. Seizures attack was reported in few cases with COVID-19 infection [3]. The attacks of convulsion after COVID-19 infection may be due to blood–brain barrier breakdown with excessive release of pro-inflammatory cytokine leading to cortical irritation and seizures [31], [32]. In the current report only one seizures attack has been reported in (Case-1).

In our both cases, no antiviral protocol was administrated.

Conclusion
The devastating consequences of CVST associated with COVID-19 infection whenever diagnosis is delayed should initiate high index of suspicion among clinicians in order to start early investigations for cerebrovascular integrity by using MRA, MRV whenever there are unexplained neurological manifestations. Moreover whenever there is unexplained thrombogenicity in a neurological case presented with CVST, one showed think about associated COVID 19 infection even in the absence of classic constitutional symptoms.

This study has several limitations. It has only two cases; however it can still raise the suspicion among CVST cases presented only with neurological manifestation without clear predisposing factors being possibly COVID 19 cases in the recent pandemic era. And the possible association could be related to the known COVID 19 associated thrombogenicity that has been proven recently in many literatures. There were several missing laboratory data among our patients, because of their ambiguous initial presentation, not classic to COVID 19 patient and the rapid progressive deterioration scenarios in both of cases.

reference link:https://www.sciencedirect.com/science/article/pii/S2214751921000037?via%3Dihub

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