Frequency of thrombocytopenia and platelet factor 4/heparin antibodies in cerebral venous thrombosis in the pre-COVID-19 era

Background and Aims: Cases of cerebral venous thrombosis (CVT) in combination with thrombocytopenia have been reported within 4-28 days of vaccination with the ChAdOx1 nCov-19 vaccine (COVID-19 vaccine manufactured by AstraZeneca). An immune-mediated response associated with anti-platelet factor 4-IgG antibodies (PF4/heparin antibodies), which promotes platelet activation and subsequent thrombosis, has been proposed as the underlying pathomechanism. Methods: We analyzed data from the pre-COVID-19 era of seven hospital-based registries participating in the International CVT Consortium. We determined the frequency of admission thrombocytopenia and heparin induced thrombocytopenia (HIT), and examined the association between thrombocytopenia and mortality, adjusted for age, sex, and active cancer. We additionally analyzed previously collected plasma samples from a subset of CVT patients for the presence of PF4/ heparin antibodies. Results: Of 865 CVT patients, 73 (8.4%, 95%CI 6.8-10.5%) had thrombocytopenia, which was mild (100-150 ∗103/mL) in 52 (6.0%), moderate (50-100 ∗103/μL) in 17 (2.0%), and severe (<50 ∗103/μL) in four (0.5%). HIT was diagnosed in only one patient (0.1% [95%CI<0.1-0.7%] of all CVT patients). Thrombocytopenia was associated with an increased risk of death at last follow-up (16% vs. 6%, adjusted OR 2.2, 95%CI 1.1-4.6), especially moderate or severe thrombocytopenia (adjusted OR 9.5, 95% CI 3.4-26.3). Of the subset of 94 patients with CVT included in the laboratory analysis, none (95%CI 0-3.9%) had PF4/heparin antibodies. Conclusions: Thrombocytopenia is infrequent and HIT is very rare in non-COVID-19 related CVT. This finding increases the plausibility that the cases of CVT with HIT-like disease reported following ChAdOx1 nCov-19 vaccination are associated with the vaccine.