Longitudinal Aspects of VITT

Abstract

In hundreds of patients worldwide, vaccination against COVID-19 with adenovirus vector vaccines (ChAdOx1 nCoV-19; Ad26.COV2.S) triggered platelet-activating anti-platelet factor 4 (PF4) antibodies inducing vaccine-induced immune thrombotic thrombocytopenia (VITT). In most VITT patients, platelet-activating anti-PF4-antibodies are transient and the disorder is discrete and non-recurring. However, in some patients platelet-activating antibodies persist, associated with recurrent thrombocytopenia and sometimes with relapse of thrombosis despite therapeutic-dose anticoagulation. Anti-PF4 IgG antibodies measured by enzyme-immunoassay (EIA) are usually detectable for longer than platelet-activating antibodies in functional assays, but duration of detectability is highly assay-dependent. As more than 1 vaccination dose against COVID-19 is required to achieve sufficient protection, at least 69 VITT patients have undergone subsequent vaccination with an mRNA vaccine, with no relevant subsequent increase in anti-PF4 antibody titers, thrombocytopenia, or thrombotic complications. Also, re-exposure to adenoviral vector-based vaccines in 5 VITT patients was not associated with adverse reactions. Although data are limited, vaccination against influenza also appears to be safe. SARS-CoV-2 infection reported in 1 patient with preceding VITT did not influence anti-PF4 antibody levels. We discuss how these temporal characteristics of VITT provide insights into pathogenesis.

Keywords: COVID-19; ChAdOx1 nCoV-19; TTS; VITT; platelet factor 4; vaccination.

Fig. 1

Dynamic of the anti-PF4-response within the German follow-up cohort. In the acute phase of VITT all 65 patients showed a positive anti-PF4/heparin IgG EIA and platelet-activating antibodies were confirmed in the platelet activation assay (PAA). Platelet activating anti-PF4 antibodies are transient. First, the PAA becomes negative, and later the anti-PF4/heparin IgG EIA. The proportion of patients with the respective assay results is shown after a follow-up period of 3 months (65 patients), 6 months (57 patients), and 9 months (14 patients). As not all patients have reached a follow-up time of 6 and 9 months, respectively, the overall number of analyzed patients declined over time. After 9 months in all observed patients (n = 14) platelet-activating antibodies had disappeared. However, further follow-up analysis will be required to re-evaluate potential antibody persistence in a small group of patients.

Fig. 2

Time in weeks until first negative platelet activation assay (PAA) in patients with VITT (platelet-activating antibodies + thrombocytopenia + thrombosis; n = 42) vs patients with pre-VITT (platelet-activating antibodies + thrombocytopenia without thrombosis; n = 7). There are no major differences in the persistence of platelet-activating antibodies between VITT and pre-VITT patients. However, we followed only a small number of pre-VITT patients and some patients have not yet attained a negative PAA (15 VITT patients, 1 pre-VITT patient).

Fig. 3

Long-term follow-up of a patient with pre-VITT (originally described in Salih et al .). Platelet count and optical density of the anti-PF4/heparin IgG EIA over time are shown together with the results of the platelet activation assay (PAA; plus = positive result, minus = negative result). In this patient VITT appeared as severe headache 8 days after vaccination with ChAdOx1 nCoV-19; cranial imaging did not reveal any thrombosis. The patient was treated with 5 mg apixaban but after 1 dose she developed a drug exanthema and anticoagulation was stopped. Platelet count slowly recovered without further treatment. Second vaccination with the COVID-19 vaccine of BioNTech/Pfizer did not show any effect on the dynamics of platelet count and anti-PF4 antibodies.