Cerebral Vein Thrombosis With Vaccine-Induced Immune Thrombotic Thrombocytopenia

Abstract

In the spring of 2021, reports of rare and unusual venous thrombosis in association with the ChAdOx1 and Ad26.COV2.S adenovirus-based coronavirus vaccines led to a brief suspension of their use by several countries. Thromboses in the cerebral and splanchnic veins among patients vaccinated in the preceding 4 weeks were described in 17 patients out of 7.98 million recipients of the Ad26.COV2.S vaccine (with 3 fatalities related to cerebral vein thrombosis) and 169 cases of cerebral vein thrombosis among 35 million ChAdOx1 recipients. Events were associated with thrombocytopenia and anti-PF4 (antibodies directed against platelet factor 4), leading to the designation vaccine-induced immune thrombotic thrombocytopenia. Unlike the related heparin-induced thrombotic thrombocytopenia, with an estimated incidence of <1:1000 patients treated with heparin, and a mortality rate of 25%, vaccine-induced immune thrombotic thrombocytopenia has been reported in 1:150 000 ChAdOx1 recipients and 1:470 000 Ad26.COV.2 recipients, with a reported mortality rate of 20% to 30%. Early recognition of this complication should prompt testing for anti-PF4 antibodies and acute treatment targeting the autoimmune and prothrombotic processes. Intravenous immunoglobulin (1 g/kg for 2 days), consideration of plasma exchange, and nonheparin anticoagulation (argatroban, fondaparinux) are recommended. In cases of cerebral vein thrombosis, one should monitor for and treat the known complications of venous congestion as they would in patients without vaccine-induced immune thrombotic thrombocytopenia. Now that the Ad26.COV2.S has been reapproved for use in several countries, it remains a critical component of our pharmacological armamentarium in stopping the spread of the human coronavirus and should be strongly recommended to patients. At this time, the patient and community-level benefits of these two adenoviral vaccines vastly outweigh the rare but serious risks of vaccination. Due to the relatively low risk of severe coronavirus disease 2019 (COVID-19) in young women (<50 years), it is reasonable to recommend an alternative vaccine if one is available. Ongoing postmarketing observational studies are important for tracking new vaccine-induced immune thrombotic thrombocytopenia cases and other rare side effects of these emergent interventions.

Keywords: COVID-19; cerebral venous thrombosis; platelet factor 4; thrombocytopenia; vaccine.

Figure 1.

Timeline of events related to coronavirus disease 2019 (COVID-19) vaccine approval and cerebral vein thrombosis (CVT) events. CDC indicates United States Centers for Disease Control and Prevention; CMA, Conditional Marketing Authorization; EMA, European Medicines Agency; EUA, Emergency Use Authorization; FDA, Food and Drug Administration; and VITT, vaccine-induced thrombotic thrombocytopenia. Image generated using Biorender.com.

Figure 2.

Mechanism of PF4 immune-mediated thrombotic thrombocytopenia. PF4 indicates platelet factor 4.

Figure 3.

Annualized incidence rates for cerebral vein thrombosis (CVT). COVID-19 indicates coronavirus disease 2019.

Figure 4.

Management of vaccine-induced immune thrombotic thrombocytopenia (VITT). Note that the 1 in 40 000 risk of cerebral vein thrombosis (CVT) following ChAdOx1 vaccination is derived from the estimate by Pottegård et al regarding excess event rates rather than laboratory confirmed VITT in CVT. For these excess events, VITT should be suspected. Image generated using Biorender.com. COVID-19 indicates coronavirus disease 2019; CTV, computed tomography venogram; HITT heparin-induced thrombotic thrombocytopenia; MRV magnetic resonance venogram; PF4 platelet factor 4, IVIg intravenous immunoglobulin; and VTE, venous thromboembolism.