Adjunct Immune Globulin for Vaccine-Induced Immune Thrombotic Thrombocytopenia

Abstract

The use of high-dose intravenous immune globulin (IVIG) plus anticoagulation is recommended for the treatment of vaccine-induced immune thrombotic thrombocytopenia (VITT), a rare side effect of adenoviral vector vaccines against coronavirus disease 2019 (Covid-19). We describe the response to IVIG therapy in three of the first patients in whom VITT was identified in Canada after the receipt of the ChAdOx1 nCoV-19 vaccine. The patients were between the ages of 63 and 72 years; one was female. At the time of this report, Canada had restricted the use of the ChAdOx1 nCoV-19 vaccine to persons who were 55 years of age or older on the basis of reports that VITT had occurred primarily in younger persons. Two of the patients in our study presented with limb-artery thrombosis; the third had cerebral venous and arterial thrombosis. Variable patterns of serum-induced platelet activation were observed in response to heparin and platelet factor 4 (PF4), indicating the heterogeneity of the manifestations of VITT in serum. After the initiation of IVIG, reduced antibody-induced platelet activation in serum was seen in all three patients. (Funded by the Canadian Institutes of Health Research.).

Figure 1. Clinical and Laboratory Data for the Three Study Patients with VITT.

Serial platelet counts and coagulation tests for d-dimer and fibrinogen levels are shown in relation to clinical events in the three patients. The timing of blood samples obtained before and after the administration of intravenous immune globulin (IVIG) correspond to the performance of enzyme-linked immunosorbent assays and platelet-activation assays. Panel A shows the findings in Patient 1, a 72-year-old woman in whom vaccine-induced immune thrombotic thrombocytopenia (VITT) was complicated by limb-artery thrombosis and partial celiac-artery thrombosis. The calculation of the IVIG dose was based on both weight and height, according to the “dosing weight” designation (1 g per kilogram of body weight) of the Ontario dose calculator. Thus, for a female patient weighing 59 kg with a height of 162 cm, the dose would be 55 g, which the patient received. However, the first dose was divided into portions of 15 g and 40 g, since the patient had an adverse reaction (severe chills) after the initial 15-g infusion of IVIG; the remaining 40 g was given the next day without incident. Panel B shows the findings in Patient 2, a 63-year-old man with VITT that was complicated by limb-artery thrombosis, pulmonary embolism, and deep-vein thrombosis. According to the “dosing weight” on the Ontario dose calculator, for a male patient weighing 158 kg with a height of 198 cm, the dose of IVIG would be 120 g; the patient’s actual dose was 165 g because the ordering physician opted to use a dose closer to the patient’s actual body weight. Panel C shows the findings in Patient 3, a 69-year-old man with VITT that was complicated by stroke involving the right middle cerebral artery, cerebral venous sinus thrombosis (right cerebral transverse and sigmoid sinuses), and thromboses in the right internal carotid artery, right internal jugular vein, hepatic vein (main and left branch), and distal lower-limb vein (one branch of the left trifurcation), along with a diagnosis of pulmonary embolism. According to the “dosing weight” on the Ontario dose calculator, for a male patient weighing 140 kg with a height 185 cm, the IVIG dose would be 105 g; the actual dose the patient received was 100 g. A third dose of IVIG was given on day 24 because of concern regarding a partial loss of the IVIG effect, with possible exacerbation of VITT, since the patient’s platelet count fell from 125,000 to 106,000 per cubic millimeter and the d-dimer level increased from 14.8 to more than 20 mg per liter. After the third dose of IVIG, the platelet count rose to 165,000 per cubic millimeter, and the d-dimer level fell to 13.1 mg per liter. SC denotes subcutaneous, and UFH unfractionated heparin (which is shown in units per kilogram per hour in Patient 2; details regarding heparin dosing were not available for Patient 1).

Figure 2. Results of Platelet-Activation Assays.

Panel A shows the results of a conventional platelet-activation assay for heparin-induced thrombocytopenia (a serotonin-release assay) in the three study patients. Platelet activation was inhibited in serum obtained from the three patients after treatment with IVIG. Panel B shows the results of a modified platelet-activation assay to detect VITT antibodies reactive against platelet factor 4 (PF4) in the three patients. Variable levels of inhibition of PF4-enhanced serotonin release were seen in patients’ serum obtained after treatment with IVIG. Complete inhibition was seen with the addition of FcγIIa receptor–blocking monoclonal antibody (IV.3) or the addition of IVIG at a concentration of 10 mg per milliliter.