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

Abstract

Background The mainstay of control of the coronavirus disease 2019 (Covid-19) pandemic is vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Within a year, several vaccines have been developed and millions of doses delivered. Reporting of adverse events is a critical postmarketing activity. Methods We report findings in 23 patients who presented with thrombosis and thrombocytopenia 6 to 24 days after receiving the first dose of the ChAdOx1 nCoV-19 vaccine (AstraZeneca). On the basis of their clinical and laboratory features, we identify a novel underlying mechanism and address the therapeutic implications. Results In the absence of previous prothrombotic medical conditions, 22 patients presented with acute thrombocytopenia and thrombosis, primarily cerebral venous thrombosis, and 1 patient presented with isolated thrombocytopenia and a hemorrhagic phenotype. All the patients had low or normal fibrinogen levels and elevated d -dimer levels at presentation. No evidence of thrombophilia or causative precipitants was identified. Testing for antibodies to platelet factor 4 (PF4) was positive in 22 patients (with 1 equivocal result) and negative in 1 patient. On the basis of the pathophysiological features observed in these patients, we recommend that treatment with platelet transfusions be avoided because of the risk of progression in thrombotic symptoms and that the administration of a nonheparin anticoagulant agent and intravenous immune globulin be considered for the first occurrence of these symptoms. Conclusions Vaccination against SARS-CoV-2 remains critical for control of the Covid-19 pandemic. A pathogenic PF4-dependent syndrome, unrelated to the use of heparin therapy, can occur after the administration of the ChAdOx1 nCoV-19 vaccine. Rapid identification of this rare syndrome is important because of the therapeutic implications.

Towards Understanding ChAdOx1 nCov-19 Vaccine-induced Immune Thrombotic Thrombocytopenia (VITT)

“…Ultimately, ChAdOx1 nCov-19 vaccine-triggered VITT culminates in marked activation of the coagulation system. 4,5,32 Broadened reactivity of antibodies in a boosted immune response is a hallmark of certain disorders besides VITT. For example, autoimmune heparin-induced thrombocytopenia features heparin-dependent reactivity that extends to include heparin-independent reactivity.…”

Limb ischemia and pulmonary artery thrombosis after the ChAdOx1 nCoV-19 (Oxford–AstraZeneca) vaccine: a case of vaccine-induced immune thrombotic thrombocytopenia

“…It identified VITT in a much broader group of people aged 21-77 years, 60% of whom were female. 7 Our patient was a middle-aged man whose symptoms started 20 days afer he received his first dose of vaccine, and he presented with thrombosis in multiple vascular beds. Recent publications from Thrombosis Canada and the International Society on Thrombosis and Hemostasis provide diagnostic criteria and treatment information for VITT.…”

“…Vaccine-induced immune thrombotic thrombocytopenia is a syndrome that was first reported in April 2021 among patients who had recently received the ChAdOx1 nCoV-19 vaccine. [2][3][4][5][6][7] It closely resembles HIT, in which antibodies, typically immunoglobulin G (IgG), are produced against circulating complexes of PF4 and endogenous heparin. [8][9][10] and regulate hemostasis by releasing PF4, a 70-amino acid protein that binds heparin.…”

“…10 In VITT, the vaccine is believed to lead to development of an IgG that targets PF4 (as opposed to the PF4-heparin complex), also binding platelet Fcγ receptors and activating platelets. 7 Although IgG does not require heparin to activate platelets in VITT, heparin may aggravate VITT because circulating PF4-heparin complexes may also bind IgG from VITT as from HIT.…”

“…This was likely because of the ability of VITT-associated IgG to bind PF4 without requiring a PF4-heparin complex. 7 However, clinicians should withdraw heparin (or not use it at all) in patients with VITT, as reduced levels of PF4-heparin complexes can lead to less circulating PF4 antigen.…”