Cerebral Venous Sinus Thrombosis and Thrombotic Events After Vector-Based COVID-19 Vaccines

Abstract

Background and Objectives:There is accumulating evidence supporting an association between the “thrombosis and thrombocytopenia syndrome” (TTS) and adenovirus vector-based vaccines against SARS-CoV-2. Yet, TTS and TTS-associated cerebral venous sinus thrombosis (CVST) remain poorly characterized. We aim to systematically evaluate the proportion of CVST among TTS cases and assess its characteristics and outcomes.Methods:We performed a systematic review and meta-analysis of clinical trials, cohorts, case series and registry-based studies with the aim to assess (1) the pooled mortality rate of CVST, TTS-associated CVST, and TTS and (2) the pooled proportion of patients with CVST among patients with any thrombotic event and TTS. Secondary outcomes comprised clinical characteristics of patients with post-vaccination thrombotic event. This meta-analysis is reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and was written according to the Meta-analysis of Observational Studies in Epidemiology proposal.Results:Sixty-nine studies were included in the qualitative analysis comprising 370 patients with CVST out of 4182 patients with any thrombotic event associated with SARS-CoV-2 vector-based vaccine administration. Twenty-three studies were further included in quantitative meta-analysis. Among TTS cases, the pooled proportion of CVST was 51% (95%CI:36-66%; I2=61%). TTS was independently associated with a higher likelihood of CVST, when compared to non-TTS patients with thrombotic events after vaccination (OR:13.8; 95%CI:2.0-97.3; I2=78%). The pooled mortality rates of TTS and TTS-associated CVST were 28% (95%CI:21-36%) and 38% (95%CI:27-49%), respectively. Thrombotic complications developed within 2 weeks of exposure to vector-based SARS-CoV-2 vaccines (mean interval:10 days; 95%CI:8-12) and affected predominantly women (69%, 95%CI:60-77%), under the age of 45, even in the absence of pro-thrombotic risk factors.Discussion:Approximately one half of TTS cases present with CVST, while almost one third of TTS patients do not survive. Further research is required to identify independent predictors of TTS following adenovirus vector-based vaccination.Registration:The pre-specified study protocol has been registered in the International Prospective Register of Ongoing Systematic Reviews PROSPERO (CRD42021250709).

SARS-CoV-2 vaccine-induced immune thrombotic thrombocytopenia

“…The majority of VITT patients are younger than 50 years old with potential predominance of women [9] , [16] . The potential risk factors of VITT patients were analyzed, including obesity, hypothyroidism, oral contraceptives, hormone therapy among women, and infections [8] , [10] .…”

“…Patients with VITT mainly present one or multiple thrombosis at unusual sites, including CVST, splanchnic venous thrombosis, arterial thromboembolism, and thrombotic microangiopathy (TMA) [2] . CVST is the most common site, occurring in more than 40% of the reported patients [3] , [4] , [5] , [6] , [9] , [16] , followed by splanchnic venous thrombosis. The most common symptom is severe headache, which worsens and is insensitive to analgesics, possibly with visual changes, nausea, and vomiting, and other symptoms include persistent abdominal pain, shortness of breath, chest pain, back pain, leg pain or swelling, petechiae, unexplained bruising or bleeding.…”

“…Patients may also develop disseminated intravascular coagulation and diffuse bleeding. Intracranial hemorrhage occurs in approximately 20%–70% of CVST cases [3] , [4] , [5] , [6] , [9] , [16] , which progresses rapidly and is often fatal [4] . Some patients may manifest as microangiopathic hemolysis, but this is not a common feature.…”

“…This complication is characterized by thrombosis at unusual sites, such as severe cerebral venous sinus thrombosis (CVST), splanchnic venous thrombosis or arterial thrombosis, increased D-dimer levels, decreased or normal fibrinogen levels, and the presence of antibodies against platelet factor 4 (PF4). It progresses rapidly, and the mortality rate can reach 20%–50%, which requires great attention [3] , [8] , [9] , [10] . Its pathogenesis is similar to that of heparin-induced thrombocytopenia (HIT).…”

Risk–benefit analysis of COVID-19 vaccines — a neurological perspective

“…TTS is frequently associated with cerebral venous sinus thrombosis (CVST); in fact, a new systematic review and meta-analysis published in Neurology by Palaiodimou et al 2 found that half of individuals who developed TTS after receiving a vector-based vaccine (ChAdOx1 nCoV-19 or Ad26.COV2.S) presented with CVST, and TTS-associated CVST had a pooled mortality of 38%. When considered in isolation, these statistics are worrying and could easily be misconstrued.…”