The use of IV immunoglobulin in the treatment of vaccine-induced immune thrombotic thrombocytopenia

TO THE EDITOR:

The ChAdOx1 nCoV-19 is a recombinant chimpanzee adenoviral vector vaccine encoding the spike glycoprotein of severe acute respiratory syndrome coronavirus 2, which has a good efficacy rate and safety profile.¹ Over the past 2 months, concern has been raised over reported thrombotic events associated with thrombocytopenia after ChAdOx1 nCoV-19 vaccination, a complication called vaccine-induced immune thrombotic thrombocytopenia (VITT).^2-6 The pathophysiology of VITT is still unclear but seems to be similar to spontaneous autoimmune heparin-induced thrombocytopenia (aHIT).^2,7 In fact, as in aHIT, VITT patients develop platelet factor-4 (PF4) antibodies without any recent exposure to heparin. These antibodies are able to activate platelets and induce procoagulant platelet phenotype via crosslinking the Fc γ receptor IIA on platelet surface. IV immunoglobulin (IVIG) has been successfully used in the treatment of spontaneous aHIT.^8,9 We and others have recently shown that IVIG inhibits the in vitro induction of procoagulant platelet phenotype by sera from VITT patients.^2,7 Herein, we report our clinical experience on the use of IVIG in the management of VITT and present novel laboratory analysis of the effect of IVIG therapy on anti-PF4 antibody level and platelet activation in VITT patients.

The study cohort consisted of patients who were admitted to our hospitals between February 1 and May 5, 2021 with suspected VITT due to neurological or hematological symptoms after first immunization with ChAdOx1 nCoV-19 (Vaxzevria; AstraZeneca, London, United Kingdom). The diagnosis of VITT was serologically confirmed according to the recommendations of the International Society on Thrombosis and Haemostasis Scientific and Standardization Subcommittee on Platelet Immunology,¹⁰ using an immunoglobulin G (IgG)-enzyme immune assay (EIA) to detect IgG antibodies against PF4 (Hyphen Biomed, Neuville-sur-Oise, France). The ability of the sera to activate platelets was tested using a modified heparin-induced platelet aggregation assay as previously described.⁷ Sera-induced procoagulant platelets were analyzed using flow cytometer as previously described.¹¹ For more details, see the supplemental material, available on the Blood Web site. The study was conducted in accordance with the Declaration of Helsinki. The study protocol was approved by the Institutional Review Board of the University of Tuebingen (236/2021BO1). We used GraphPad Prism, version 7.0 (GraphPad, La Jolla, CA) for statistical analysis. A value of P < .05 was accepted as statistically significant.

Five patients (3 females) with a median age of 47 years (range, 20-57) were included in this study. The duration between vaccination and hospital admission was 7 to 9 days. All patients had severe thrombocytopenia (41.2 ± 9.7 × 10⁹/L; range, 10-60; Figure 1A-E) and increased D-dimer (9 µg/mL or higher; range, 9-54). At admission, several thrombotic events, including cerebral venous sinus thrombosis (CVST; 4 patients, cases 1-3 and 5), pulmonary embolism (2 patients, cases 4 and 5), and deep vein thrombosis (case 4), were detected. Detailed case descriptions and patient characteristics are given in the supplemental methods and in supplemental Table 1A. VITT diagnosis was confirmed by detecting anti-PF4 IgG antibodies in EIA (optical density [OD] 2.98 ± 0.23; range, 2.07-3.36), platelet activation in the modified heparin-induced platelet aggregation assay (median time to platelet aggregation, 5 minutes; range, 5-5 minutes ), and formation of procoagulant platelets (CD62p/PS⁺ platelets mean: 45 ± 7; range, 23-66). Laboratory investigations at admission and after IVIG therapy are presented in supplemental Table 1B.

All patients received parenteral anticoagulation with argatroban (n = 4) or danaparoid (n = 1), and 1 patient (case 5) initially received apixaban. Two patients (cases 3 and 5 on a prophylactic dose of argatroban and apixapan, respectively) developed a new thromboembolic complication at day 4 and 3 of hospitalization (before IVIG administration), respectively. Anticoagulation was continued in these patients with argatroban in a therapeutic dosage (Figure 1C,E).

IVIG was administered at a dose of 1 g/kg body weight for 2 to 5 days. Median of total IVIG dose was 140 g (range, 95 to 600 g). Absolute platelet increment was 32.6 ± 17.1 × 10⁹/L within 48 hours (P vs baseline, .12) and 94.2 ± 23.3 × 10⁹/L within 72 hours after IVIG (P vs baseline, .01; Figure 2A). A complete platelet response (platelet count ≥100 × 10⁹/L) was achieved in 4 patients within 96 hours. One patient had a platelet response (platelet count ≥30 × 10⁹/L and at least twofold increase the baseline count) within 72 hours after IVIG therapy. From a clinical perspective, increasing the platelet count is important in thrombocytopenic patients requiring therapeutic anticoagulation. This is most critical when thrombosis occurs at unusual sites, such as CVST, because of the increased mortality risk due to hemorrhagic transformation after an arterial stroke or CVST. In our cohort, 1 patient (case 1) suffering from VITT-associated CVST had postthrombotic hemorrhage during the thrombocytopenic period, prior to receiving IVIG.

Successful use of IVIG in the treatment of aHIT has been reported.^8,9,12 Mainly because of similarities between aHIT and VITT, recent societal guidelines recommend the use of IVIG in VITT with the assumption that IVIG could mitigate the platelet activation induced by anti-PF4 antibodies and thus reduce the platelet consumption and the development of new thrombosis.^10,13,14 However, concerns of increased new thrombotic events limit its use.¹⁵ Serial D-dimer levels were available from 3 cases, and all of them showed a decrease within 72 hours after IVIG therapy (Figure 1). We observed progression of CVST in 1 patient (case 5). Other patients receiving nonheparin anticoagulation at therapeutic doses combined by IVIG did not develop new thrombosis, indicating sufficient antithrombotic efficacy. Similarly, Thaler et al successfully used IVIG (1 g/kg for 2 consecutive days) and argatroban in a patient with VITT.¹⁶ Tiede et al reported a positive platelet response in 3 VITT patients after IVIG therapy (1 g/kg for 2 consecutive days).⁵ However, 2 patients developed new thromboembolic events (extensive splanchnic vein thrombosis and popliteal artery occlusion).⁵ New thromboembolic events are common in patients with VITT.^5-7 Therefore, clinicians should pay attention to dynamic changes in clinical as well as laboratory parameters and exercise extra vigilance in VITT patients in order to detect new thromboembolic events in a timely manner.

To assess the mechanism by which high-dose IVIG downregulates hypercoagulability in VITT, we analyzed the ability of VITT patients’ sera to generate procoagulant platelets before and after IVIG therapy. The reactivity in PF4 EIA did not change significantly after IVIG administration (n = 4, 3.21 ± 0.06 OD vs 3.18 ± 0.08 OD; P: .798; supplemental Table 1B). On the other hand, the ability of the sera from VITT patients to induce procoagulant platelets reduced after IVIG therapy in 3 cases in the absence and in 2 out of 4 cases in the presence of PF4 (Figure 2B-C; supplemental Table 1B). Noteworthy, diluted sera showed specific platelet activation only in the presence of PF4 (supplemental Figure 1A-D). These data suggest that IVIG interferes with the pathogenic anti-PF4 antibodies by competing with them to bind to Fc γ receptor IIA receptors, which might be in vivo associated with reductions in platelet activation and disseminated intravascular coagulation. The later ones are confirmed in our study by the rapid response in platelet count and decrease in D-dimer levels.^7,9 However, the effect of IVIG on other cells cannot be ruled out as another explanation for the observed therapeutic benefit.

In summary, we showed that high-dose IVIG inhibits antibody-mediated procoagulant platelet generation, rapidly increases the platelet count, and finally, deescalates the hypercoagulable state in VITT. Adjunct use of IVIG can be recommended as a therapeutic option to prevent disease progression.