Cerebral Venous Sinus Thrombosis and Papilledema in Vaccine-Induced Thrombotic Thrombocytopenia After SARS-CoV-2 Vaccination

A healthy 45-year-old woman received the first dose of AstraZeneca ChAdOx1 vaccination against SARS-CoV-2. Eight days later, she presented to the emergency department with new onset of severe bilateral flank pain where she was assessed and diagnosed with a herniated disk. She was discharged without any abdominal imaging performed. At home, she rapidly deteriorated and was brought back by her family 2 days later with severe generalized weakness and decreased level of consciousness.

Bloodwork showed thrombocytopenia with platelet count 82 × 10⁹/L. Noncontrast CT head was interpreted as normal. CT of the chest, abdomen, and pelvis although showed multiple subsegmental pulmonary emboli, left renal vein embolism, left common iliac, and renal vein thrombi (Fig. 1A, B). Bilateral hemorrhagic adrenal infarction was present, accounting for her flank pain (Fig. 1C). Heparin-induced thrombocytopenia (HIT) assay was performed and was positive confirming the diagnosis of vaccine-induced thrombotic thrombocytopenia (VITT). She was admitted to the intensive care unit and treatment with intravenous argatroban commenced at 3.6 mL/hour for 2 days, and she was then transitioned to oral rivaroxaban 15 mg twice daily. She also received intravenous immunoglobulins (IVIg) 1 g/kg for 2 days. Her severe adrenal insufficiency was treated with IV hydrocortisone 25 mg 4 times daily.

FIG. 1.

Vaccine-induced thrombotic thrombocytopenia causing extensive venous thromboembolic events. A. Left internal iliac vein thrombosis (white arrow) on coronal CT with sagittal slices showing left lower pole renal infarction (B, black arrow) and C, coronal section revealing bilateral adrenal gland hemorrhagic infarction (white arrowheads).

Four days later, she developed severe headaches, vertigo, and bilateral blurred vision. MRI of the brain with venography revealed extensive cerebral venous sinus thrombosis (CVST) involving the superior sagittal sinus, straight sinus, torcula, bilateral transverse sinuses, vein of Galen, and right internal jugular vein (Fig. 2A–C). Nonocclusive thrombus was present near the left carotid bifurcation (Fig. 2D), and there was right vertebral artery occlusion with an area of acute infarction in the right posterior inferior cerebellar artery territory (Fig. 2E–H). On ophthalmologic examination, the visual acuity was 20/20 and 20/25 and there was no relative afferent pupillary defect. Extraocular motility was full, and she was orthophoric on alignment testing. Ophthalmoscopy revealed severe bilateral optic nerve head edema with peripapillary hemorrhages. A total of 24-2 visual fields were normal in each eye, consistent a diagnosis with papilledema, secondary to her extensive CVST.

FIG. 2.

Cerebral venous sinus thrombosis in vaccine-induced thrombotic thrombocytopenia. A. Coronal and (B) sagittal 3D reconstructions of MR venography sequences show multiple intraluminal filling defects within the dural venous sinuses with the absence of cortical vein thrombosis. (C) This illustrates multiple irregular filling defects within the superior sagittal sinus (white arrows), with thread-like opacification of the straight sinus and filling defect within the torculum (white arrowheads). CT venography showed adherent, nonocclusive thrombus within the proximal left internal carotid near the bifurcation (D, white arrow) and nonfilling of the right V4 segment (E, black arrow). Right vertebral artery occlusion was confirmed on MR angiography (F, black arrow) with acute infarction present within the right cerebellar hemisphere (G, diffusion-weighted imaging; H apparent diffusion coefficient).

When her platelet count continued to decline to a nadir of 31 × 10⁹/L, treatment with plasma exchange commenced. Her headaches and overall clinical status improved, and she was discharged home 17 days after initial presentation on fondaparinux and oral prednisone.

Vaccine-induced thrombotic thrombocytopenia is a recently described clinical entity occurring after adenoviral-based vaccination against SARS-CoV-2. The observation of thrombocytopenia and thrombosis in combination immediately led to comparison with heparin-induced thrombotic thrombocytopenia (HITT); however, in these patients, assays for binding platelet factor-4 (PF4) anion complexes were positive in the absence of any exposure to heparin. It is hypothesized that vaccine-derived DNA molecules may bond to PF4 in a manner similar to heparin to provoke a strong immune response (1).

Most VITT cases occur in previously healthy patients, often younger than 55 years with female preponderance. Onset of symptoms occurs within 4–24 days postvaccine administration. A characteristic feature of VITT is thrombosis at unusual sites, including CVST and portal, splanchnic, or hepatic vein thrombosis (2). While VITT itself is rare, CVST in VITT is common, although the reason for this predilection remains unknown. Greinacher et al reported 11 cases of VITT after the AstraZeneca vaccine, 9 of which had CVST (3). A case series by Schultz et al also reported a high percentage of CVSTs in VITT patients (80%, 4/5). Headaches were the presenting complaint (2). See et al reported 12 cases of CVST after administration of Johnson & Johnson vaccine, most of which (92%, 11/12) also presented with headaches with all 12 patients hospitalized and 10 admitted to ICU (4). VITT is associated with a significant mortality rate, most commonly secondary to cerebral edema or hemorrhage from CVST (5). Mortality in CVST because of VITT approaches 50% (2,4,5).

Headache is a commonly reported symptom postvaccination along with myalgia and malaise. Fundoscopy with examination of the optic nerve head is essential in differentiating benign and potentially life-threatening causes of headache such as CVST and is seldom performed in the emergency department. Prompt ophthalmology consultation is required when any red flags are present in clinical presentation of headache including focal neurologic symptoms or decreased level of consciousness and should be obtained in any patient with a recent history of adenoviral-based SARS-CoV-2 vaccination and thrombocytopenia.

It is important for ophthalmologists to be aware of this newly described entity of VITT. In the eye clinic setting, most cases of papilledema are secondary to idiopathic intracranial hypertension; however, patients with CVST may present first ophthalmology clinics (6), and this diagnosis must particularly be considered in patients outside of the typical demographic for IIH of young women with elevated BMI. Maintaining a high index of suspicion for VITT is key as diagnosis requires urgent investigations, and mortality is high. All patients with suspected papilledema require MRI of the brain with venography to rule out CVST, and this should be performed on an urgent basis in clinically unwell patients. A noncontrast CT head as initially performed in this case is insufficient. Patients should be asked about the history of recent vaccinations, and if present, a complete blood count should also be performed immediately to rule out thrombocytopenia.

Ophthalmologists must be aware of this new entity of VITT described after the administration of adenoviral SARS-CoV-2 vaccinations, which in North America are AstraZeneca and Johnson & Johnson vaccines. CVST is very common in VITT and can produce papilledema. Early recognition is key to avoiding significant morbidity and mortality.

STATEMENT OF AUTHORSHIP

Conception and design: L. Donaldson, E. Margolin, J. Qian, L. AlShafai; Acquisition of data: L. Donaldson, E. Margolin, J. Qian, L. AlShafai; Analysis and interpretation of data: L. Donaldson, E. Margolin, J. Qian; Drafting the manuscript: L. Donaldson, E. Margolin, J. Qian, L. AlShafai; Revising the manuscript for intellectual content: L. Donaldson, E. Margolin, J. Qian; Final approval of the completed manuscript: L. Donaldson, E. Margolin, J. Qian, L. AlShafai.