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Pathologic Antibodies to Platelet Factor 4 after ChAdOx1 nCoV-19 Vaccination

Our take —

A rare and serious adverse event involving abnormal blood clotting (vaccine-induced thrombosis and thrombocytopenia, or VITT) has been associated with the ChAdOx1 nCoV-19 (AstraZeneca) vaccine. This study reported on the clinical features and laboratory features of 23 patients who had received the AstraZeneca vaccine and who subsequently developed thrombosis and thrombocytopenia 6-24 days later, despite being mostly young and healthy. As seen in other studies, the clinical presentation of patients strongly resembled heparin-induced thrombocytopenia (HIT), even though patients had not been treated with heparin before symptom onset. All but two of the patients tested positive for anti-platelet factor 4 (anti-PF4) antibodies, which strongly supports the hypothesis that platelet activation induced by anti-PF4 antibodies leads to VITT. The results have implications for clinical guidance; the authors recommend avoidance of platelet transfusions, and suggest intravenous immunoglobulin and direct thrombin inhibitors as the first line of treatment. The study is limited by a relatively small sample size, which is a consequence of the rarity of this serious adverse event. It is still unknown how the vaccine might induce production of anti-PF4 antibodies, and what might predispose individuals to this reaction.

Study design

Case Series

Study population and setting

This study from the UK evaluated blood samples of 22 patients with venous thrombosis and thrombocytopenia and one patient with isolated thrombocytopenia and markedly elevated D-dimer after vaccination with the ChAdOx1 nCoV-19 vaccine (AstraZeneca). Because the clinical presentation in 22 patients highly resembled heparin induced thrombocytopenia (HIT), the investigators used enzyme-linked immunosorbent assays (ELISA) to test for antibodies against platelet factor 4 (PF4), which are the primary cause of HIT. A functional assay that tests platelet activation was used to confirm ELISA results for 7 of the 23 patients. The authors also described clinical characteristics and outcomes of the patients who provided samples.

Summary of Main Findings

All patients presented 6-24 days after receiving the first dose of ChAdOx1 nCoV-19, with a median time of 12 days. The median age was 46 years (range 21-77 years). Sixteen patients (70%) were younger than 50 years, and 14 (61%) were female. One patient had a history of deep vein thrombosis, and one patient was taking oral contraceptive pills at the time she sought medical attention. Clinically, 13 patients (56%) presented with cerebral venous thrombosis (one had deep vein thrombosis and pulmonary embolism along with cerebral venous thrombosis). One patient had deep vein thrombosis and bilateral adrenal hemorrhage, two patients had acute stroke due to thrombosis at the middle cerebral artery, and two patients had portal vein thrombosis: one with concurrent myocardial infarction and the other one had concurrent aortic thrombosis. Seven patients (30%) died. One patient had available data on post-mortem evaluation, which showed thrombosis at small arteries in the intestine, brain, lung, venous sinuses and intracerebral hemorrhage. Of note, additional thrombotic events occurred among patients who received platelet transfusion for thrombocytopenia and/or heparin for thrombosis. Only 10 patients (34%) had their sera available for antibody testing against coronavirus. All of these patients had negative antibodies against SARS-CoV-2 nucleocapsid protein, which ruled out recent COVID-19 infection. The levels of anti-SARS-CoV-2 receptor binding domain (RBD) and anti-spike antibodies were consistent with the level expected after ChAdOx1 nCoV-19 vaccination. The level of antibodies against non-SARS-CoV-2 coronavirus antibodies were similar to those in the general population. Thirteen patients (56%) had low fibrinogen levels, and all patients had markedly elevated D-dimer levels. Twenty-one patients (91%) had positive anti-PF4 antibodies via ELISA. One patient whose sample was collected five days after clinical presentation (and who had multiple platelet transfusions) tested  negative for anti-PF4 antibodies, and another had equivocal results. Of the 7 patients tested with the functional HIT assay, 5 had significant platelet activation in the absence of heparin. Adding heparin in excess of physiological doses fully suppressed platelet activation.

Study Strengths

In addition to ELISA, the authors used a functional platelet assay in a subset of patients to identify the presence of platelet activation. The clinical presentation of patients was reported in detail.

Limitations

The study had a small sample size (n=23). Only 10 patients were investigated for the possibility of previous SARS-CoV-2 infection, and only one-third of patients with detectable anti-PF4 antibodies were tested with the functional HIT assay. The course of treatments provided to the patients was not reported in detail, limiting inference about the benefits or harms associated with VITT treatment. Patient characteristics were also not reported in detail, and key demographic details were not available (e.g., ethnicity, country of origin, comorbidities); since it is not yet known what characteristics might predispose individuals to VITT, these data would have been particularly useful.

Value added

The study adds significant data pertaining to the mechanism of a rare adverse event known as vaccine-induced thrombosis and thrombocytopenia (VITT), which appears to be causally related to ChAdOx1 nCoV-19 (AstraZeneca) vaccine.

This review was posted on: 7 May 2021