Cooling down VITT with IVIG.

In this issue of Blood, Uzun et al report additional clinical experience using IV immunoglobulin (IVIG) for the treatment of COVID-19 vaccine–induced immune thrombotic thrombocytopenia (VITT).

The COVID-19 pandemic is keeping hematologists busy. From COVID-19 coagulopathy to prevention of COVID-19–associated thrombosis to treatment of hematological complications of COVID-19 vaccines, the pandemic has presented a series of mechanistic, clinical, and therapeutic challenges. The latest hematological COVID-19 conundrum is VITT, a rare prothrombotic complication of certain COVID-19 vaccines. VITT has been reported in patients who received the ChAdOx1 nCOV-19 (AstraZeneca/University of Oxford) or Ad26.COV2.S (Johnson & Johnson/Janssen) vaccines. Alternative names proposed for VITT include vaccine-induced prothrombotic immune thrombocytopenia and thrombosis with thrombocytopenia syndrome. VITT should not be confused with immune thrombocytopenic purpura, an uncommon but well-recognized complication of many vaccines, including the COVID-19 vaccines.

The clinical presentation of VITT resembles that of heparin-induced thrombocytopenia (HIT), particularly the spontaneous or autoimmune form of HIT that can occur in the absence of heparin administration and is associated with disseminated intravascular coagulation. In both HIT and VITT, patients present with arterial or venous thrombosis in the setting of thrombocytopenia, elevated D-dimer, and high-titer immunoglobulin G (IgG) antibodies that recognize platelet factor 4 (PF4). Some but not all clinical immunoassays designed to detect antiheparin/anti-PF4 antibodies also detect anti-PF4 antibodies in patients with VITT. In many of the cases reported so far, VITT has been associated with thrombosis in unusual sites, such as the cerebral venous sinuses or splanchnic veins.

The mechanism of thrombosis in VITT is incompletely understood, but several groups have demonstrated that serum or IgG from patients with VITT causes platelet activation in the presence of PF4, likely by crosslinking Fcγ receptor IIA (FcγRIIA; CD32A) on the platelet surface. A similar mechanism of platelet activation via FcγRIIA occurs in HIT. IVIG can block platelet activation by anti-PF4 antibodies, presumably by competing for binding to FcγRIIA. Because high-dose IVIG has been used successfully to treat autoimmune HIT, preliminary guidance for the treatment of VITT has included the use of IVIG in addition to a nonheparin anticoagulant.

Uzun et al report their clinical and laboratory experience with the use of IVIG in the management of 5 patients who presented with VITT 7 to 9 days after immunization with the ChAdOx1 nCOV-19 vaccine. In addition to high-dose IVIG (1 g/kg body weight daily for 2-3 days), the patients also received a nonheparin anticoagulant (argatroban, dabigatran, or apixaban). An increase in platelet count within 3 days of IVIG administration was observed in all patients, and 4 of 5 patients remained free of new thrombotic events (1 patient experienced progression of cerebral venous sinus thrombosis 6 days after receiving IVIG). In laboratory platelet activation assays, the ability of patient sera to generate procoagulant platelets decreased after treatment with IVIG in 3 of 4 patients tested. Interestingly, the sample without improvement after IVIG administration was from the patient who experienced progression of thrombosis. This observation raises the question of whether specific inhibitors of FcγRIIA might be more effective than IVIG in preventing thrombosis.

The observations of Uzun et al add to a small but growing body of experience supporting the use of IVIG in the clinical management of VITT. Limitations of this study include its small size and retrospective design, the lack of a control group of VITT patients who did not receive IVIG, and the relatively short follow-up period. The duration of prothrombotic risk with VITT is not known, but some patients (including 1 patient reported by Uzun et al) have experienced recurrent thrombosis after an initial improvement in platelet count. Anti-PF4 antibodies are likely to persist for weeks to months, and it is not known whether repeated dosing with IVIG or prolonged treatment with corticosteroids or other immunosuppressive drugs might decrease the risk of recurrent thrombosis. IVIG may also have beneficial effects unrelated to platelet FcγRIIA blockade, possibly via anti-idiotype effects, blocking the neonatal FcR or cooling down inflammation through its interactions with other FcγRs.

Given the low incidence of VITT, it is unlikely that large randomized controlled trials will be conducted to prospectively define its optimal treatment. It seems more likely that hematologists will learn to diagnose and manage these patients by sharing careful clinical and laboratory observations, much the same way we learned to manage HIT from the astute and pioneering observations of Kelton, Warkentin, and Greinacher, among others.

Several other questions about VITT remain unanswered. How does vaccination trigger the formation of anti-PF4 antibodies? Why does it occur after vaccination with adenoviral vector–based COVID-19 vaccines and not messenger RNA vaccines? Why is it more prevalent in women than men? Is thrombosis caused by FcγRIIA-driven platelet activation and/or other mechanisms? What explains the unusual predilection for cerebral venous sinus thrombosis? These questions will continue to keep hematologists busy for some time.