Early diagnosis and use of intravenous immunoglobulin can be helpful for managing SARS-CoV-2 vaccine-induced clotting-related adverse events

As more and more people become vaccinated against SARS-CoV-2 worldwide, a few cases of rare adverse events, clotting-related or immune thrombocytopenia, have been reported with the adenoviral-vector based Oxford-AstraZeneca ChAdOx1 nCoV-19 (AZ) or Johnson & Johnson/Janssen (J&J) vaccines¹. CITF-funded researcher Dr. Ishac Nazy has recently published an article in The New England Journal of Medicine (NEJM) covering case reports detailing the diagnosis of three patients suffering from vaccine-induced immune thrombotic thrombocytopenia (VITT).² The paper also discusses the impact of intravenous immune globulin (IVIG) plus anticoagulation therapy for managing this condition. Dr. Nazy adds to recent literature on the subject, which is summarized here.

Key points:

• VITT can be diagnosed by an enzyme immunoassay (EIA) against PF4-polyanion complexes and a functional platelet activation test and tends to manifest as a reduction in blood platelets, elevated D-dimer and low-normal fibrinogen levels.
• Early IVIG treatment after hospitalization can lead to the restoration of platelet counts, reduced D-dimer levels and an increase in fibrinogen levels, consistent with decreased hypercoagulability.

Dr. Nazy’s report covered three patients, two male and one female, between the ages of 63 and 72. All three patients developed symptoms related to thrombocytopenia (limb pain/cramps, headache, confusion) between 1-3 weeks post-vaccination. The clinicians recorded that IVIG administration led to a dramatic restoration of platelet levels within 2-3 days without any clinical evidence of progressive thrombosis after treatment. They also recorded that patients had initially presented elevated D-dimer and low-normal fibrinogen levels (clotting-related factors in the blood), which is indicative of intravascular coagulation. Once IVIG was administered, D-dimer and fibrinogen levels were corrected, thereby resulting in restored platelet counts. Finally, the serum from these patients also tested strongly positive for antibodies against platelet factor 4 (PF4) using an enzyme immunoassay (EIA). While no consistent reduction in EIA activity was observed post-IVIG treatment, they demonstrated a dramatic reduction in platelet activation after one or two doses of IVIG. Overall, the clinicians want to use their observations to help inform testing strategies to diagnose and manage VITT.

Alongside Dr. Nazy’s report, the NEJM published multiple articles focusing on VITT. Scully M. et al, reported 23 patients who presented with thrombosis and thrombocytopenia 6-24 days after receiving the first dose of AZ vaccine. Testing in almost all patients resulted in the presence of antibodies to PF4. They suggested that the rapid identification of this condition is essential for therapeutic management. Dr. Nazy’s report is likely to complement and address this need.

A separate phase 3 clinical study examining the safety and efficacy of the single-dose from J&J vaccine demonstrated high levels of vaccine efficacy against severe/critical disease including hospitalization and death⁴. However, researchers observed venous thromboembolic events – 11 in the vaccine group vs three in the placebo group – which were attributed to underlying medical conditions or other predisposed factors. Researchers are further evaluating whether those thrombotic events were related to the VITT observed in response to the AZ vaccine.

Finally, the NEJM has also published an editorial¹ describing thrombocytopenia in people who had received the AZ vaccine. In general, individuals presenting with this severe adverse effect associated with a 40% mortality rate were generally otherwise healthy or in a medically stable condition. Most were women under 50 with some receiving estrogen-replacement therapy or consuming contraceptives. A large proportion of these patients demonstrated thrombotic events at unusual sites. Nevertheless, these patients consistently presented low platelet counts, high D-dimer levels and low fibrinogen levels, indicative of systemic activation of coagulation or clotting. In almost every patient, high levels of antibodies to PF4 were detected by an EIA and assays evaluating platelet activation. The authors also suggested that IVIG could improve patient outcomes with early detection and intervention.

Overall, the clinicians¹ suggest that the true incidence of VITT due to vaccines is estimated at 1 in 100,000 compared to the 0.22 – 1.57 cases recorded per 100,000 in the general population. At this point, further work is needed to understand and manage this serious adverse effect. The authors stress that we do not yet understand the component of the vaccine that may be responsible for eliciting a new or recall response to the PF4 protein. At this time, numerous countries have imposed limitations on the use of the AstraZeneca vaccine. Similarly, the administration of the Johnson & Johnson single-shot vaccine has also been halted in various countries until certain populations can be identified as suitable candidates or until methodologies can be developed to better manage this complication.