Arterial Embolic Infarction After COVID-19 Vaccination Associated With Antiplatelet Factor 4 Antibody

Dear Editor,

Coronavirus disease 2019 (COVID-19) vaccinations are actively being performed worldwide. Four vaccines are currently administered in South Korea: Ad26.COV2.S (Janssen), mRNA-1273 (Moderna), ChAdOx1 nCoV-19 (AstraZeneca, University of Oxford, and Serum Institute of India), and BNT162b2 (Pfizer-BioNTech). Among them, ChAdOx1 nCoV-19 and Ad26.COV2.S vaccines are based on adenoviral vectors.

Vaccine-induced prothrombotic immune thrombocytopenia (VIPIT) is one of the significant adverse events of COVID-19 vaccines. Clinical features of VIPIT include thrombocytopenia, thromboses, and coagulation abnormalities, and they typically appear at 4 to 28 days after vaccination. The clinical presentation and course are similar to heparin-induced thrombocytopenia (HIT), forming part of the spectrum of platelet-activating antiplatelet factor 4 (PF4)/heparin disorders.1 Venous thrombosis is one of the most common presentations of VIPIT. Cerebral venous thrombosis was found in 13 of 23 patients who were diagnosed as VIPIT after ChAdOx1 nCoV-19 vaccination, while arterial ischemic stroke was only diagnosed in 2 of these patients.1 Here we describe a case of arterial ischemic stroke in a VIPIT patient after ChAdOx1 nCoV-19 vaccination in South Korea.

A 69-year-old female visited the emergency department with dysarthria that occurred 13 days after ChAdOx1 nCoV-19 vaccination. She had a previous history of coronary artery disease and dyslipidemia, and was receiving aspirin and rosuvastatin, but she had no history of previous heparin exposure. At 1 day after the vaccination the patient reported experiencing myalgia and mild fever. No other focal neurological deficits were observed, and there was no sign of thromboembolism. Brain magnetic resonance imaging showed small scattered cortical infarctions in both middle cerebral arterial territories without steno-occlusive lesions (Fig. 1). Embolic workups including transthoracic echocardiography and Holter monitoring produced negative results. Chest computed tomography and lower extremity sonography yielded no evidence of pulmonary thromboembolism or deep vein thrombosis, respectively. Serological testing at admission showed marked thrombocytopenia (69,000/µL). The D-dimer level was elevated at 5.06 µg/mL, and the fibrinogen level was 446 mg/dL. A peripheral blood smear showed no blast cells. After admission, the vaccination history prompted the antiheparin/PF4 immunoglobulin G antibody to be checked using an enzyme-linked immunosorbent assay, which showed positivity with an optical density of 0.89 (cutoff criterion <0.4). The patient was finally diagnosed as VIPIT. Rivaroxaban was started at 15 mg per day, while intravenous immunoglobulin was not considered since the patient was stable and showed only mild severity. Serological testing in the outpatient clinic showed normalization of both the platelet (168,000/µL) and D-dimer (0.48 µg/mL) levels.

Fig. 1
Brain magnetic resonance imaging performed at 14 days after ChAdOx1 nCoV-19 vaccination. A and B: Diffusion-weighted images show multiple small infarctions in bilateral hemispheres (arrows). Time-of-flight magnetic resonance angiography (MRA) (C) and contrast-enhanced MRA show no steno-occlusive lesion (D).

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Based on the relevance of VIPIT to HIT, a recently proposed hypothesis for the pathomechanism of VIPIT is as follows: after injection into the muscle, negatively charged adenoviral DNA (which plays a role similar to that of heparin in HIT) forms the viral nucleic acid/PF4 complex. The complex is internalized in antigen-presenting cells, which then results in the massive production of anti-PF4 antibodies. The venous drainage system, and especially splanchnic and cavernous sinus drainage, provides an environment that facilitates a strong interplay with microbiota due to its vicinity with the gut and respiratory barrier tissue. A physiologically adequate level of immunity toward microbes can be maintained by PF4 immunity within the venous system.2 In the presence of a high titer of anti-PF4 antibodies, these reactions may result in pathological immunothrombosis, which is mediated by platelet activation and the release of alpha granules including thrombin, leading to thrombosis.3 However, arterial infarctions including in our case have also been reported despite their rarity. One study suggested that the PF4/Von Willebrand factor complexes bind with HIT antibody, leading to injury of the arterial endothelium, thrombus formation, and propagation that is associated with arterial thrombosis.1, 4

There have been no comprehensive reports on the lesion pattern or severity of stroke following COVID-19 vaccination.2 Several cases of malignant infarction with large-vessel occlusion have been reported in patients with high titers of anti-PF4 antibody. It was particularly interesting that our patient showed a lower titer of anti-PF4 antibody with multiple small embolic infarctions. This might reflect a spectrum of VIPIT-related stroke, and so further data are needed to confirm the factors affecting the severity of VIPIT-related stroke.

The incidence of VIPIT is unknown. For the ChAdOx1 nCoV-19 vaccine, the highest reported incidence was 5 cases from among approximately 130,000 individuals (Norwegian data).5 Despite this rarity, screening for VIPIT is important for stroke management. Although the most frequent form of cerebral involvement of VIPIT is venous thrombosis, rare cases of arterial infarctions have been reported.1 The main stroke mechanism in these cases has been large-artery occlusions.4 Because of its pathophysiological background, treatments for VIPIT-related strokes are nonheparin anticoagulation and intravenous immunoglobulin. Considering its pathophysiology, the application of heparin and platelet transfusion are contraindicated.6 Therefore, checking the vaccination history is important in suspected stroke patients.