Farzan Poonawala

 Introduction. The COVID-19 virus is a positive-sense single-stranded RNA virus in which viral pathogenesis is initiated by the interaction between the ACE2 receptor and the virus.¹ An increase in public health concerns has accelerated the production of different vaccines such as mRNA based or viral vector vaccines. In recent months, there has been a great degree of attention placed on the AstraZeneca and J&J vaccine candidates in terms of thrombosis of unknown cause that appears 5-16 days after vaccination. There has been a wide array of clinical manifestations such as cerebral venous thrombosis and pulmonary embolism that prompt the need for evaluation to ensure long-term vaccine safety.² Methods. Platelets were purified from whole blood from healthy volunteers, none of who were taking antiplatelet drugs or had been previously vaccinated in the past 10 days. Enzyme-linked immunosorbent assays were used to detect platelet factor 4-heparin antibodies. The platelets were placed into either low molecular weight heparin or PF4 with FcgIIa receptor–blocking antibody IV.3 either present or absent.² Results. Patients’ serum from the heparin-induced groups exhibited moderate to severe thrombotic events and tested positive on the screenings for PF4-heparin immunoassay. Vaccinated individual blood samples had no previous COVID-19 infections due to negative testing for SARS-CoV-2 nucleocapsid protein antibodies yet showed similar IgG antibodies to PF4-anion complex and enhanced reactivity with PF4 addition. PF4 significantly enhanced reactivity in all samples and none of the controls sera showed platelet activation. Platelet activation was inhibited by high levels of heparin, immunoglobulin, and a monoclonal antibody blocking Fc receptors.² Patients who had heparin-induced thrombocytopenia were not activated into the clotting cascade unless low levels of heparin were added and, in contrast, aggregation was highly reduced with high heparin levels.³ Conclusions. The patients in contention for vaccine-induced immune thrombotic thrombocytopenia did not require additional heparin to induce clotting and had immune complexes with antibody specificity that is similar to patients with autoimmune heparin-induced thrombocytopenia. Inhibition of Fcg receptors and subsequently the clotting cascade suggests platelet activation potentially occurred through these receptors in vaccine-induced thrombotic patients. Should these events continue to occur after administrating these vaccines to large, diverse populations, low molecular weight heparin in addition to immune globulin may lead to common responses of increased platelet numbers.³ It is important to continue to monitor the specific adenoviral platform and its components as possible causes since the precise mechanism is yet to be determined.⁴

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2. Greinacher A, Thiele T, Warkentin TE, Weisser K, Kyrle PA, Eichinger S. Thrombotic thrombocytopenia after ChAdOx1 nCov-19 vaccination. N Engl J Med. 2021. https://doi.org/10.1056/NEJMoa2104840. doi: 10.1056/NEJMoa2104840.
3. Schultz NH, Sørvoll IH, Michelsen AE, et al. Thrombosis and thrombocytopenia after ChAdOx1 nCoV-19 vaccination. N Engl J Med. 2021. https://doi.org/10.1056/NEJMoa2104882. doi: 10.1056/NEJMoa2104882.
4. See I, Su JR, Lale A, et al. US Case Reports of Cerebral Venous Sinus Thrombosis With Thrombocytopenia After Ad26.COV2.S Vaccination, March 2 to April 21, 2021 [published online ahead of print, 2021 Apr 30]. JAMA. 2021;10.1001/jama.2021.7517. doi:10.1001/jama.2021.7517