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Review

Cerebral Venous Sinus Thrombosis Associated with Vaccine-Induced Thrombotic Thrombocytopenia—A Narrative Review

by
Adrian Scutelnic
1,
Justine Brodard
2,
Johanna A. Kremer Hovinga
2,
Marcel Arnold
1 and
Mirjam R. Heldner
1,*
1
Department of Neurology, Inselspital, Bern University Hospital, University of Bern, 3010 Bern, Switzerland
2
Department of Hematology, Inselspital, Bern University Hospital, University of Bern, 3010 Bern, Switzerland
*
Author to whom correspondence should be addressed.
Clin. Transl. Neurosci. 2022, 6(2), 11; https://doi.org/10.3390/ctn6020011
Submission received: 14 February 2022 / Revised: 22 March 2022 / Accepted: 31 March 2022 / Published: 11 April 2022
(This article belongs to the Special Issue Neurological Manifestation of COVID-19: Current Knowledge on Pathophysiology, Clinical Manifestation and Management)
Browse Figure
Review Reports Versions Notes

Abstract

:
In March 2021, cerebral venous sinus thrombosis and thrombocytopenia after vaccination with adenovirus-based vaccine against SARS-CoV-2 were first reported. The underlining condition has been termed vaccine-induced immune thrombocytopenia (VITT). Anti-platelet factor 4 antibodies have been proposed as a central component of the pathomechanism. Treatment recommendations entailed immunomodulation with intravenous immunoglobulins, avoidance of heparins and avoidance of platelet transfusions. Although mortality from VITT-associated cerebral venous sinus thrombosis has decreased over time, it remains high. The aim of this narrative review is to describe different aspects of this disease according to the current state of knowledge.

1. Introduction

Blood clots in the brain’s cerebral venous system cause cerebral venous sinus thrombosis (CVST) (Figure 1). Cerebral venous oedema, infarction and haemorrhage may result after CVST [1]. CVST is a rare disease [2].
CVST has been reported in relation with vaccine-induced thrombotic thrombocytopenia (VITT). VITT was first well-described by Greinacher A et al. in March 2021. He published a case series (n = 11) of patients with thrombosis and thrombocytopenia 5–16 days after administration of the adenovirus-based SARS-CoV-2 vaccine ChAdOx1 nCoV-1 (AstraZeneca/Oxford, Oxford, UK) [3]. The authors proposed a pathomechanism similar to autoimmune heparin-induced thrombocytopenia (aHIT), as all VITT patients tested positive for anti-platelet factor (PF) 4/heparin antibodies and for platelet activation assays, although they had no recent exposure to heparin. The condition was named vaccine-induced immune thrombotic thrombocytopenia (VITT). As of March 2021, several reports have been published stating that VITT occurs within a few weeks of administration of the adenovirus-based SARS-CoV-2 vaccines ChAdOx1 nCoV-1 (AstraZeneca/Oxford) and Ad26.COV2.S (Janssen/Johnson & Johnson, New York, NY, USA) [3,4,5,6,7,8,9,10,11,12,13,14,15,16,17].
The aim of this narrative review was to describe different aspects of CVST-VITT according to the current state of knowledge.

2. Methods

Pubmed was searched until March 2022 for original articles, reviews and editorials using the following keywords: ‘vaccine’, ‘cerebral’, ‘thrombosis’, ‘vaccine’ and ‘thrombocytopenia’.

2.1. Pathophysiological Aspects

VITT, in which anti-platelet factor (PF) 4 antibodies are produced after adenovirus-based SARS-CoV-2 vaccination as part of the inflammatory response and immune stimulation, is a condition very similar to HIT, and even more similar to autoimmune HIT (aHIT). Venous thrombosis and/or arterial vessel occlusions and thrombocytopenia are hallmarks of both VITT and aHIT. Heparin-induced thrombocytopenia (HIT) is a systemic hypercoagulable state that occurs when heparin-dependent IgG antibodies bind to PF4/heparin complexes. aHIT is a condition in which anti-PF4 antibodies are produced without recent exposure to heparin [18].
Anti-PF4 antibodies were discovered in VITT, as in aHIT, by an enzyme-linked immunosorbent assay (ELISA) [3,9]. In addition to the similarities in clinical presentation, the thrombus structure in VITT is also similar to aHIT, with platelet-rich ‘white’ venous thrombi as opposed to ‘red’ stasis thrombi seen in classical CVST [4].
It remains to be determined which components of the adenovirus-based SARS-CoV2 vaccines trigger the production of anti-PF4 antibodies [3,19,20]. PF4 is a naturally occurring, positively charged chemokine that binds to negatively charged molecules, such as heparin, bacterial cell walls and polyanionic compounds used in prosthetic surgery [19]. PF4–anionic complexes trigger the production of anti-PF4 antibodies. Greinacher et al. 2021 demonstrated the formation of PF4–vaccine complexes, which stimulated a pro-inflammatory response of B-lymphocytes, a phenomenon that was induced by the addition of DNA [20]. Other mechanisms possibly involved in the pathophysiology of VITT are suspected, such as the downregulation of ACE-receptors, molecular mimicry between the SARS-CoV-2 spike protein and PF4 molecules, RNAemia, and the involvement of vaccine constituents, such as ethylenediaminetetraacetic acid (EDTA) [20].
The occurrence of CVST and other venous thromboses and arterial vessel occlusions after mRNA-based SARS-CoV-2 vaccines have also been described [7,21,22,23,24,25]. However, so far, there is no report on VITT in these patients. The mechanism of venous thrombosis and arterial vessel occlusion after mRNA-based SARS-CoV-2 vaccination is, so far, less understood than after adenovirus-based SARS-CoV-2 vaccination [26]. In the following sections, we focus exclusively on VITT after adenovirus-based SARS-CoV-2 vaccination.

2.2. Epidemiology

The phase 3 trial of ChAdOx1 nCoV-1 (AstraZeneca) randomized 23,848 participants [27], and the trial of Ad26.COV2.S (Janssen) vaccine 39,321 participants [28]. However, these clinical trials, which led to the clinical approval of the adenovirus-based SARS-CoV-2 vaccines, were underpowered to detect rare adverse events such as VITT.
So far, more than 11 billion SARS-CoV-2 vaccinations have been administered worldwide [29]. The largest vaccination campaign in history is still ongoing.
An analysis of patients vaccinated in Europe using the Eudravigilance database from 1 January to 30 July 2021 showed that 38,664,988 people had been vaccinated with ChAdOx1 nCoV-1 (AstraZeneca/Oxford) and 10,972,234 with Ad26.COV2.S (Janssen/Johnson & Johnson) [30]. In this analysis, the rate of CVST with thrombocytopenia during the study period of 6 months was 21.6 (95%CI 20.16-23.11) per 1 million vaccination days for ChAdOx1 nCoV-1 and 11.48 (95%CI 9.57–13.67) per 1 million vaccination days for Ad26.COV2.S vaccination [30]. Another study by the UK Medicines and Healthcare Products Regulatory Agency and the US Centers of Disease Control and Prevention came to very similar conclusions [31].
An analysis of hospitalization or death associated with thrombocytopenia, venous thromboses and arterial vessel occlusions within 28 days after vaccination with ChAdOx1 nCoV-1 (AstraZeneca/Oxford) using a case-control design that analysed the data of 30 million vaccinated people in England between 1 December 2020 and 24 April 2021 found a higher risk of thrombocytopenia and venous thromboses after COVID-19 infection than after vaccination with ChAdOx1 nCoV-1 (AstraZeneca/Oxford) (after 1–7 days OR 4.91, 95%CI 3.5–6.89; after 8–14 days 1.91, 95%CI 1.2–3.06) [21].
Overall, VITT and CVST-VITT are rare after SARS-CoV-2 vaccination; CVST after COVID-19 is more common, and ischaemic strokes or disabling or deadly events show even higher incidence rates [32].
CVST-VITT was observed mainly after the application of the first dose of adenovirus-based SARS-CoV-2 vaccines, and in young-to-middle-aged, predominantly white and female individuals [3,8,9,10,11,12,13,14,21]. Based on the observed age distribution, many national medical agencies in various countries around the world currently recommend avoiding the administration of adenovirus-based SARS-CoV-2 vaccines in young-to-middle-aged people [32,33].
Several conventional CVST risk factors are known, but they seem to be less present in patients with CVST-VITT. Conventional CVST risk factors may be temporary (prothrombogenic drugs, pregnancy and puerperium, infections) or permanent (common prothrombotic disorders such as thrombophilia, antiphospholipid syndrome, myeloproliferative disorders and malignancies) [8,10,11,17,34].
The occurrence of thrombosis with thrombocytopenia caused by idiopathic thrombocytopenic purpura (ITP) has been described after the administration of the measles–mumps–rubella vaccine [35]. Given the rarity (1 case for every 40,000 doses) and the lower total number of doses administered compared with COVID-19 vaccines, the evidence on ITP following measles–mumps–rubella vaccination in the context of post SARS-CoV-2 VITT is of limited relevance.

2.3. Definition and Laboratory Features of VITT

Different societies and research groups have proposed criteria for VITT (Table 1) [8,36,37,38,39,40,41]. Some criteria require only the detection of thrombosis and thrombocytopenia, while others require additional laboratory parameters, such as D-dimer and fibrinogen levels and positive anti-PF4 antibodies, for the diagnosis of VITT. In addition, the time window after vaccination varies considerably depending on the definition (Table 1) [8,36,37,38,39,40,41].
The symptoms at the time of onset of VITT have been described as varying [42,43]. For example, headache has been suggested as an early symptom of CVST-VITT without radiologic evidence of early stage CVST [43,44,45]. Furthermore, anti-PF4 antibodies are potentially negative at the beginning of the clinical course and only become positive later [42]. In some patients, D-dimer and fibrinogen levels were described to be within the normal range throughout the clinical course [46].
In summary, some patients diagnosed with VITT may not fully meet the proposed VITT definition criteria.
Thrombocytopenia and positive anti-PF4 antibodies have been repeatedly described in CVST-VITT. A descriptive analysis of baseline thrombocytopenia in patients with CVST from the pre-COVID-19 era, conducted by the International Cerebral Venous Thrombosis Consortium (ICVST), found baseline thrombocytopenia—vastly non-severe—in 8% of patients, with obvious explanations for the thrombocytopenia in the majority of cases, such as cancer, inflammation, alcohol dependence or intake of drugs. HIT with anti-PF4/heparin antibodies was diagnosed in one single patient. In the pre-COVID-19 era, baseline thrombocytopenia was uncommon in patients with CVST, and HIT and anti-PF4/heparin antibodies were rare. The results suggest a causal association between adenovirus-based SARS-CoV-2 vaccination and CVST with thrombocytopenia [47].
Around 7% of healthy individuals develop antibodies to PF4/polyanion complexes at lower titres than in VITT. This urges caution when screening healthy individuals for VITT, as in a significant proportion of individuals, antibodies against PF4/polyanion complexes have no clinical significance and do not require treatment [48].
Other laboratory features that have been described as typical for VITT include increased D-dimer levels, a shortened pro-thrombin time and an activated partial thromboplastin time (aPTT) (Table 1).

2.4. Location of VITT

Thromboses in VITT have been shown to occur in the cerebral venous system, but also in other, sometimes unusual, locations. According to an analysis of 220 patients with definite or probable VITT, about half of all patients suffered from CVST, one third from pulmonary and deep venous thrombosis, one fifth from splanchnic venous thrombosis, one fifth from arterial vessel occlusion, and 29% had more than two affected vascular beds [8]. Moreover, according to a meta-analysis, about half of the patients with VITT suffered from CVST [19].
A role of PF4 in the interaction of the drainage of the splanchnic and cerebral venous systems with bacteria and viruses from the intestinal and nasal tissues has been proposed as an explanation for the unusual location of thrombosis in VITT. Endothelial activation facilitates the activation of the innate immune system through an interaction between the pathogens and PF4. A higher titre of tissue factor and PF4 in these environments may lead to a higher titre of immunogenic complexes at these sites with stronger local immune responses and consecutive thrombosis [49].

2.5. Clinical Features of VITT

One notable clinical aspect of CVST-VITT is the occurrence of headache. Headache occurs in 40–60% of cases after vaccination with an adenovirus-based SARS-CoV-2 vaccine [27,28,50,51], but it can also be a symptom of CVST [44,45,52]. However, the timing of the onset of headache could be different for CVST-VITT (after 5 days) than for vaccination (within 48 h) [27,28,44,45,50,51,52,53].
Other symptoms depend on the extent and location of the thromboses and arterial vessel occlusions. It is noteworthy that a considerable number of CVST-VITT patients have severe disease with coma and intracerebral haemorrhage [9,10,35].

2.6. Treatment

The first reports on VITT also included treatment recommendations largely based on the similarities with aHIT and the in vitro inhibition of platelet activation by the VITT antibodies after the addition of intravenous immunoglobulin (IVIG) [3,8,9]. Treatment recommendations consist of IVIG and immunosuppression, administration of non-heparin anticoagulants (anti-thrombin and anti-Xa) and strict avoidance of heparin and platelet transfusions.
There is limited evidence on the efficacy and safety of these recommendations [35,54]. Their scientific validity is also changing due to new insights into the pathophysiology of this disease.
The effectiveness of IVIG is limited to case reports only [55]. Platelet transfusions are not recommended, as they can trigger immune reactions. However, no study has yet investigated how platelet transfusions affect outcome.
Other treatment options include steroids, fibrinogen transfusions, plasma exchange, rituximab and eculizimab [55,56].

2.7. Prognosis

CVST-VITT has been shown to be associated with high mortality, higher than in CVST patients from the pre-pandemic era [3,4,5,6,7,8,9,10,11,12,13,14,15,16,17]. However, a retrospective study by the ICVST consortium using EMA (European Medicine Agency) data (n = 270 CVST with thrombocytopenia) showed a decrease in mortality in patients diagnosed and treated after 28 March 2021 compared to those treated before this date (22% vs. 47%, p < 0.001) [12]. This probably reflects the recognition of less severe cases and the implementation and effectiveness of current treatment recommendations over time. Another study, conducted as part of the ICVST consortium and analysing data from a prospective registry (n = 116), found a lower mortality in patients treated after vs. before March 2021 (42% vs. 61%) [11]. Although mortality has decreased in both analyses, it is still considerable. In comparison, mortality in the pre-COVID-19 era was 3.9% [11].

3. Conclusions

CVST-VITT is rare and differs from CVST in the pre-pandemic era. The benefits of SARS-CoV-2 vaccination far outweigh the small risk of VITT. The risk of CVST after COVID-19 is higher than the risk of CVST-VITT.
CVST-VITT has a heterogeneous and severe clinical picture, and although mortality has decreased over time, it remains considerable.
Due to its heterogeneous presentation, the diagnosis of VITT is challenging. The currently proposed case definitions for VITT are heterogeneous, and the diagnosis of VITT should be made on a case-by-case basis.
The type of SARS-CoV-2 vaccine could be adjusted according to patient characteristics, such as age. For example, adenovirus-based SARS-CoV-2 vaccines may be safer in middle-aged and elderly people than in younger people.
Currently, there is limited evidence to support treatment recommendations for VITT, and data on the long-term prognosis, including mortality, disability and risk of recurrence, and long-term secondary prevention are lacking. Further research is needed.

Author Contributions

Conceptualization and methodology, A.S. and M.R.H.; resources, A.S., J.B., J.A.K.H., M.A. and M.R.H.; data curation, A.S.; writing—original draft preparation, A.S. and M.R.H.; writing—review and editing, A.S., J.B., J.A.K.H., M.A. and M.R.H.; visualization, A.S.; supervision, M.R.H. 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

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

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Ctn 06 00011 g001 550
Figure 1. Thrombosis of the right sinus transverse and sigmoid sinus in a 29-year-old woman who presented with headache, nausea and left-sided hemiparesis. Risk factors for cerebral venous sinus thrombosis were obesity (BMI 30.5 kg/m2) and oral contraception. She was diagnosed with non-VITT CVST.
Figure 1. Thrombosis of the right sinus transverse and sigmoid sinus in a 29-year-old woman who presented with headache, nausea and left-sided hemiparesis. Risk factors for cerebral venous sinus thrombosis were obesity (BMI 30.5 kg/m2) and oral contraception. She was diagnosed with non-VITT CVST.
Ctn 06 00011 g001
Table
Table 1. Case-definition criteria according to different specialized societies.
Table 1. Case-definition criteria according to different specialized societies.
Authors/SocietyCriteriaAdditional Considerations
Brighton Collaboration CriteriaDefinite TTS: Platelets < 150,000/uL without heparin exposure within last 100 days AND imaging, surgical and/or pathology evidence of venous and/or arterial thrombosis
Probable TTS: Platelets < 150,000/uL without heparin exposure within last 100 days AND specific clinical syndromes of venous and/or arterial thrombosis AND supporting imaging or laboratory findings suggestive but not definitive of thrombosis/thromboembolism (chest X-ray, echocardiogram, CT without contrast) OR elevated D-dimer levels
Possible TTS: Platelets < 150,000/uL without heparin exposure within last 100 days AND specific clinical syndromes of venous and/or arterial thrombosis		For definite TTS: when present, laboratory findings can be supportive of the diagnosis, including: D-dimer levels elevated above the upper limit of normal for age, shortened PT, PTT below the lower limit of normal for age
Expert Hematology Panel, UKDefinite VITT: Onset of symptoms 5–30 days after vaccination against SARS-CoV-2 (or ≤42 days in patients with isolated deep-vein thrombosis or pulmonary embolism)
Presence of thrombosis
Thrombocytopenia (platelet count < 150,000 per cubic millimeter)
D-dimer levels > 4000 FEU
Positive anti-PF4 antibodies on ELISA
Probable VITT: D-dimer levels > 4000 FEU but one criterion not met (timing, thrombosis, thrombocytopenia or anti-PF4 antibodies), or D-dimer levels unknown or 2000–4000 FEU and all other criteria met
Possible VITT: D-dimer levels unknown or 2000–4000 FEU with one other criterion not met, or two other criteria not met (timing, thrombosis, thrombocytopenia or anti-PF4 antibodies)
Unlikely VITT: Platelet count < 150,000 per cubic millimeter without thrombosis with D-dimer levels <2000 FEU, or thrombosis with platelet count > 150,000 per cubic millimeter and D-dimer levels < 2000 FEU, regardless of anti-PF4 antibody result, and alternative diagnosis more likely		n/a
German Society of Thrombosis and HaemostasisDefinite VITT: Vaccination with AstraZeneca 4-16 days prior AND confirmed thrombosis and/or thrombocytopenia; positive anti-PF4 antibodies (ELISA), positive modified HIPA assay
Suspected VITT: Vaccination with AstraZeneca 4–16 days prior AND confirmed thrombosis and/or thrombocytopenia		n/a
International Society of Thrombosis and HemostasisDefinite VITT: SARS-CoV-2 vaccination 4 to 28 days ago; acute signs/symptoms of thromboembolism AND platelet count <150,000/uL AND positive anti-PF4 antibodies (ELISA) OR (when ELISA not available) D-dimer levels > 4x threshold for VTE exclusion
Suspected VITT: COVID-19-vaccination 4 to 28 days ago; acute signs/symptoms of thromboembolism AND platelet < 150,000/uL		n/a
Thrombosis CanadaSuspected VITT: Clinical signs of thrombosis AND SARS-CoV-2 vaccination within past 4–20 days AND platelet count <150,000/uL Negative imaging does not rule out CVST
TTS: thrombosis with thrombocytopenia syndrome; VITT: vaccine-induced immune thrombotic thrombocytopenia; anti-PF4: anti-platelet factor 4; PT: prothrombin time; PTT: partial thromboplastin time; ELISA: enzyme-linked immunosorbent assay; CT: computer tomography; FEU: fibrinogen equivalent unit; HIPA: heparin-induced platelet activation; VTE: venous thromboembolism.
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Scutelnic, A.; Brodard, J.; Kremer Hovinga, J.A.; Arnold, M.; Heldner, M.R. Cerebral Venous Sinus Thrombosis Associated with Vaccine-Induced Thrombotic Thrombocytopenia—A Narrative Review. Clin. Transl. Neurosci. 2022, 6, 11. https://doi.org/10.3390/ctn6020011

AMA Style

Scutelnic A, Brodard J, Kremer Hovinga JA, Arnold M, Heldner MR. Cerebral Venous Sinus Thrombosis Associated with Vaccine-Induced Thrombotic Thrombocytopenia—A Narrative Review. Clinical and Translational Neuroscience. 2022; 6(2):11. https://doi.org/10.3390/ctn6020011

Chicago/Turabian Style

Scutelnic, Adrian, Justine Brodard, Johanna A. Kremer Hovinga, Marcel Arnold, and Mirjam R. Heldner. 2022. "Cerebral Venous Sinus Thrombosis Associated with Vaccine-Induced Thrombotic Thrombocytopenia—A Narrative Review" Clinical and Translational Neuroscience 6, no. 2: 11. https://doi.org/10.3390/ctn6020011

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