What Is the Price of Preventing COVID-19 Infection? Rare Thrombotic/Thrombocytopenic Events Reported After Vaccination

For hematologists, COVID-19 brought fear and uncertainty to our patients, especially those with compromised immune systems, and required early expertise to understand what infection meant for thrombotic risk and how best to safely mitigate that risk. Currently, multiple COVID-19 vaccines have demonstrated both safety and efficacy in preventing COVID-19 infection and death. Despite the widespread success of these innoculations however, rare and unusual thrombotic events were reported in patients recieving the AstraZeneca and Johnson & Johnson (JJ) vaccines.

On April 9, 2021, two case reports were simultaneously published in the New England Journal of Medicine describing a total of 16 patients who developed thrombotic events shortly after vaccination with ChAdOx1 nCov-19 (AstraZeneca). The cases were further characterized by thrombocytopenia and subsequent identification of strongly positive platelet factor 4 (PF4) -polyanion reactive antibodies in ELISA. These reactions were observed in vaccinated patients in the absence of proximate heparin exposure. Among these 16 patients, at least 13 had cerebral vein thrombosis (pathology pending in 1 case), three had splanchnic vein thrombosis, and three had pulmonary emboli, with several patients having thrombosis in multiple locations. The majority (n=13) were relatively young women with an age range of 22 to 54 years. The platelet count at presentation ranged widely from 9,000 to 107,000/mm³ , and many patients presented with disseminated intravascular coagulation with low fibrinogen and elevated D-dimer levels. Many patients did receive initial anticoagulation with heparin or low-molecular-weight heparin; nine of the 16 cases (~56%) were fatal, one from intracranial hemorrhage. The clinical circumstances of these thrombotic events strongly resemble the presentation of “spontaneous heparin-induced thrombocytopenia (HIT) syndrome,” which has been previously described in patients with thrombosis and thrombocytopenia with positive HIT serologies in the absence of proximate heparin exposure.^1,2  Many patients were treated with intravenous immunoglobulin (as in prior cases of spontaneous HIT and refractory HIT)^1–3  and steroids. A third larger report⁴  presented findings in 23 patients with this syndrome, all of whom received the same (AstraZeneca) vaccine. This report showed a less skewed sex distribution (61% female) with an age range of 21 to 77 years (median age, 46 years).

The pathogenic antibodies do not appear to be commonplace HIT antibodies. Rather many of the cases studied required the use of PF4-treated platelets instead of the standard heparin-treated platelets for detection in functional (platelet-activation–based) assays. This has led to the development of several PF4-dependent functional assays such as the PIPA (PF4-induced platelet activation test), PF4-SRA, and the previously reported PEA (PF4-dependent P-selectin expression assay). Importantly, several nontraditional ELISAs (such as automated and rapid assays) seem to provide false-negative results. The vast majority of these patient samples are strongly positive (high optical densities) in solid phase PF4-polyanion ELISAs; however, Dr. Marie Scully and colleagues' series⁴  included two patients who were not positive even in these ELISAs, which could represent a less-frequent subtype of this syndrome. To further add to the complexity, some patients may have isolated severe thrombocytopenia (and bleeding) without thrombotic manifestations.

Close on the heels of these publications, a joint statement by the Centers for Disease Control and Prevention (CDC) and the U.S. Food and Drug Administration (FDA) was released on April 13, 2021, announcing a pause in administering the JJ vaccine (Ad26.COV2.S) in order to investigate six reported cases of cerebral vein thrombosis with associated thrombocytopenia that appeared similar to reports of the AstraZeneca vaccine.⁵  This pause was ultimately lifted on April 23, 2021, with the addition of a warning to the Ad26.COV2.S label based on the FDA/CDC's conclusion that the benefits of vaccination outweighed the risk of this rare thrombotic complication.⁶ 

Initial recommendations for the recognition and treatment of this disorder, now variably called vaccine-induced immune thrombotic thrombocytopenia (VITT) or thrombosis with thrombocytopenia syndrome (TTS) have been published by the International Society on Thrombosis and Haemostasis,⁷  ASH,⁸  and other groups. Increased clinical vigilance for symptoms potentially consistent with thromboembolism/thrombocytopenia, especially signs of cerebral vein thrombosis in younger women, is recommended, with special attention paid to platelet count. Patients diagnosed with thrombosis/ thrombocytopenia within 30 days after vaccination should have solid-phase PF4-polyanion ELISA, D-dimer, and fibrinogen testing. Treatment should be initiated rapidly, similar to treatment of severe/spontaneous HIT including high-dose IVIg and nonheparin anticoagulants. Platelet transfusions should be avoided, and fibrinogen repletion may be considered for very low levels or bleeding patients. Currently available data do not allow for conclusive recommendations on the use of corticosteroids. Additional therapies such as therapeutic plasma exchange may be considered in refractory patients.