Cerebral venous sinus thrombosis after Vaccine-induced Immune Thrombotic Thrombocytopenia
Health care providers should be familiar with the clinical presentations, pathophysiology, diagnostic criteria, and management consideration of this rare but severe and potentially fatal complication of the SARS-COV2 vaccine
Cerebral venous sinus thrombosis (CVT) prior to the COVID pandemic was rare, responsible for 0.5 of all strokes, at the onset of the pandemic on the East Coast, overall cross-sectional imaging volumes declined due to maintaining ventilation, high levels of care and limiting disease spread, although COVID-19 patients have a 30-60 times greater risk of CVT compared to the general population, and vaccination is currently the best option to mitigate severe disease. In early 2021, reports of adenoviral vector COVID vaccines causing CTV and Vaccine-induced Immune Thrombotic Thrombocytopenia (VITT), led to a 39.65% increase in cross-sectional venography, however, in this study unvaccinated patients in 2021 had a higher incidence of CVT (10.1%), compared to the vaccinated patients (4.5%). Clinicians should be aware that VITT CVT may present with a headache 5-30 days post-vaccination with thrombosis best diagnosed on CTV or MRV. If thrombosis is present with thrombocytopenia, platelets <150 × 109, elevated D-Dimer >4000 FEU, and positive anti-PF4 ELISA assay, the diagnosis is definitive. VITT CVT resembles spontaneous autoimmune heparin-induced thrombocytopenia (HIT) and is postulated to occur from platelet factor 4 (PF4) binding to vaccine adenoviral vectors forming a novel antigen, anti-PF4 memory B-cells, and anti-PF4 (VITT) antibodies. 1).
Neurosurgical management involves treating intracranial hypertension however survival outcomes in a cohort were poor. In these series, decompression was performed in deteriorating patients however prophylactic decompression, in the presence of extensive venous sinus thrombosis, should be considered on a case-by-case basis. As vaccination programs accelerate across the world, neurosurgeons are likely to be increasingly involved in managing intracranial hypertension in patients with VITT-related sinus thromboses. 2).
Non-heparin anticoagulants and immunoglobulin treatment might improve outcomes of VITT-associated cerebral venous thrombosis 4)
Sixty-two studies reporting 160 cases were included from 16 countries. Patients were predominantly females with a median age of 42.50 (22) years. AZD1222 was administered to 140 patients (87·5%). TTS onset occurred in a median of 9 (4) days after vaccination. Venous thrombosis was most common (61.0%). Most patients developed cerebral venous sinus thrombosis (CVST; 66.3%). CVST was significantly more common in female vs male patients (p = 0·001) and in patients aged <45 years vs ≥45 years (p = 0·004). The mortality rate was 36.2%, and patients with suspected TTS, venous thrombosis, CVST, pulmonary embolism, or intraneural complications, patients not managed with non-heparin anticoagulants or IVIG, patients receiving platelet transfusions, and patients requiring intensive care unit admission, mechanical ventilation, or inpatient neurosurgery were more likely to expire than recover. 5)
Cerebral venous thrombosis caused by vaccine-induced immune thrombotic thrombocytopenia (VITT-CVT) is a rare adverse effect of adenovirus-based SARS-COV2 vaccines. In March 2021, after autoimmune pathogenesis of VITT was discovered, treatment recommendations were developed. This comprised immunomodulation, nonheparin anticoagulants, and avoidance of platelet transfusion. The aim of the study was to evaluate adherence to these recommendations and their association with mortality.
Scutelnic et al. used data from an international prospective registry of patients with CVT after adenovirus-based SARS-CoV-2 vaccination. They analyzed possible, probable, or definite VITT-CVT cases included until 18 January 2022. Immunomodulation entailed the administration of intravenous immunoglobulins and/or plasmapheresis.
99 VITT-CVT patients from 71 hospitals in 17 countries were analyzed. Five of 38 (13%), 11/24 (46%), and 28/37 (76%) of patients diagnosed in March, April, and from May onwards, respectively, were treated in-line with VITT recommendations (p<0.001). Overall, treatment according to recommendations had no statistically significant influence on mortality (14/44 (32%) vs 29/55 (52%), adjusted OR 0.43 (95%CI 0.16-1.19)). However, patients who received immunomodulation had lower mortality (19/65 (29%) vs 24/34 (70%), adjusted OR 0.19 (95%CI 0.06-0.58)). Treatment with non-heparin anticoagulants instead of heparins was not associated with lower mortality (17/51 (33%) vs 13/35 (37%), adjusted OR 0.70 (95%CI 0.24-2.04)). Mortality was also not significantly influenced by platelet transfusion (17/27 (63%) vs 26/72 (36%), adjusted OR 2.19 (95%CI 0.74-6.54)).
During a 2-week period, we encountered five cases presenting with a combination of cerebral venous thrombosis (CVT), intracerebral hemorrhage, and thrombocytopenia. A clinical hallmark was the rapid and severe progression of disease in spite of maximum treatment efforts, resulting in fatal outcomes for 4 out of 5 patients. All cases had received the ChAdOx1 nCov-19 vaccine 1-2 weeks earlier and developed a characteristic syndrome thereafter. The rapid progressive clinical course and high fatality rate of CVT in combination with thrombocytopenia in such a cluster and in otherwise healthy adults is a recent phenomenon. Cerebral autopsy findings were those of venous hemorrhagic infarctions and thrombi in dural venous sinuses, including thrombus material apparently rich in thrombocytes, leukocytes, and fibrin. Vessel walls were free of inflammation. Extra-cerebral manifestations included leech-like thrombi in large veins, fibrin clots in small venules, and scattered hemorrhages on skin and membranes. CVT with thrombocytopenia after adenovirus vectored COVID-19 vaccination is a new clinical syndrome that needs to be recognized by clinicians is challenging to treat and seems associated with a high mortality rate 7)
A patient was rapidly treated with steroids, immunoglobulin, and fondaparinux. She underwent within 6 h after hospital admission a mechanical thrombectomy in order to allow flow restoration in cerebral venous systems. Neuroendovascular treatment in cerebral venous thrombosis related to VITT has never been described before. It can represent a complementary tool along with the other therapies and a multidisciplinary approach 8).
Two cases of ChAdOx1 nCov-19 (AstraZeneca)-are associated with thrombotic thrombocytopenia syndrome (TTS) and cerebral venous sinus thrombosis (CVST). At the time of emergency room presentation due to persistent headache, blood serum levels revealed reduced platelet counts. Yet, 1 or 4 days after the onset of the symptom, the first MR-angiography provided no evidence of CVST. Follow-up imaging, performed upon headache refractory to nonsteroidal pain medication verified CVST 2-10 days after initial negative MRI. Both the patients received combined treatment with intravenous immunoglobulins and parenteral anticoagulation leading to an increase in platelet concentration in both individuals and resolution of the occluded cerebral sinus in one patient 9).
Rodriguez et al. reported the first described post Ad26.COV2.S (Janssen, Johnson & Johnson) vaccine-induced immune thrombocytopenia (VITT) case outside US. CASE DESCRIPTION: CA young woman without any medical history presented an association of deep vein thrombosis and thrombocytopenia at day 10 after vaccine injection. The patient was treated with low-molecular-weight heparin at a first medical institution. Twelve days post Ad26.COV2.S vaccination, the patient was admitted to the hospital for neurological deterioration and right hemiplegia. Medical imaging using MRI showed thrombosis of the major anterior part of the sagittal superior sinus with bilateral intraparenchymal hemorrhagic complications. Screening tests for antibodies against platelet factor 4 (PF4)-heparin by rapid lateral flow immunoassay and chemiluminescence techniques were negative. Platelet activation test using heparin-induced multiple electrode aggregometry confirmed the initial clinical hypothesis. Despite immediate treatment with intravenous immunoglobulin, dexamethasone, danaparoid, and attempted neurosurgery the patient evolved toward brain death.
Even though it is an extremely rare complication of vaccination physicians should maintain a high index of suspicion of VITT in patients who received an adenovirus-vector-based SARS-CoV-2 vaccine within the last 30 days with persistent complaints compatible with VITT or thromboembolic event associated with thrombocytopenia. The diagnosis should not be excluded if the rapid anti-PF4 immunological or chemiluminescence techniques yield negative results. An adapted functional assay should be performed to confirm the diagnosis. Early treatment with intravenous immunoglobulin and non-heparin anticoagulants is essential as delayed diagnosis and administration of appropriate treatment are associated with poor prognosis 10).
A case of VITT in a young female who presented 11 days after receiving the first dose of the Covishield vaccine, with severe headache and hemiparesis. She was diagnosed with CSVT with a large intraparenchymal bleed, requiring decompressive craniectomy and an extended period of mechanical ventilation.
The patient was successfully treated with intravenous immunoglobulin and discharged after 19 days in ICU. Although she was left with long-term neurological deficits, an early presentation and a multidisciplinary approach to management contributed to a relatively short stay in the hospital and avoided mortality 11).