Prothrombotic immune thrombocytopenia after COVID-19 vaccine

We report five cases of prothrombotic immune thrombocytopenia after exposure to the ChAdOx1 vaccine (AZD1222, Vaxzevria) against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Patients presented 5 to 11 days after first vaccination. The spectrum of clinical manifestations included cerebral venous sinus thrombosis (CVST), splanchnic vein thrombosis (SVT), arterial cerebral thromboembolism, and thrombotic microangiopathy (TMA). All patients had thrombocytopenia and markedly elevated D-Dimer. Autoantibodies against platelet factor 4 (PF4) were detected in all patients although they had never been exposed to heparin. Immunoglobulin from patient sera bound to healthy donor platelets in an AZD1222-dependant manner, suppressed by heparin. Aggregation of healthy donor platelets by patient sera was demonstrated in the presence of buffer or AZD1222 and was also suppressed by heparin. Anticoagulation alone or in combination with eculizumab or intravenous immunoglobulin (IVIG) resolved the pathology in three patients. Two patients had thromboembolic events despite anticoagulation at a time when platelets were increasing after IVIG. In summary, an unexpected autoimmune prothrombotic disorder is described after vaccination with AZD1222. It is characterized by thrombocytopenia and anti-PF4 antibodies binding to platelets in AZD1222-dependent manner. Initial clinical experience suggests a risk of unusual and severe thromboembolic events.

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Cerebral Venous Sinus Thrombosis due to Thrombosis with Thrombocytopenia Syndrome Following Ad26.COV2.S: A First Real-World Case Report of a Male Subject

The Neurohospitalist ◽

10.1177/19418744211055065 ◽

2021 ◽

pp. 194187442110550

Author(s):

Samia Asif ◽

Meghana Kesireddy ◽

Scott A. Koepsell ◽

Marco A. Gonzalez-Castellon ◽

Krishna Gundabolu ◽

...

Keyword(s):

Sinus Thrombosis ◽

Young Male ◽

Cerebral Venous Sinus Thrombosis ◽

Venous Sinus ◽

Platelet Factor ◽

Venous Sinus Thrombosis ◽

Vein Thrombosis ◽

First Case ◽

Control And Prevention ◽

Underlying Pathophysiology

Thrombosis with Thrombocytopenia Syndrome (TTS) or Vaccine-induced Immune Thrombotic Thrombocytopenia (VITT) had been reported in patients receiving the Ad26.COV2.S vaccination (Johnson & Johnson [J&J]/Janssen) vaccine. They frequently presented with cerebral venous sinus thrombosis (CVST), but venous or arterial thrombosis at other locations can be present. The majority of those affected are younger adult females. Therefore, after a brief pause from April 13–23, 2021, the Centers for Disease Control and Prevention (CDC) and the U.S. Food and Drug Administration (FDA) recommended caution in using this vaccine in females under 50 years. Based on the reported 28 cases of TTS after this vaccination (data till April 21, 2021) by CDC, 22 were females (78%), and 6 were male. None of those males had CVST but had thrombosis at other locations. We report the first case of a young male with TTS and CVST following Ad26.COV2.S vaccine presented with severe headache and diagnosed with acute right transverse and sigmoid cerebral venous sinus thrombosis, multiple right-sided pulmonary emboli, and right hepatic vein thrombosis. He was treated with parenteral anticoagulation with argatroban and intravenous immune globulin with the improvement of his symptoms. A heparin-induced thrombocytopenia with thrombosis (HITT) like syndrome caused by the genesis of a platelet-activating autoantibody against platelet factor 4 (PF4) triggered by adenoviral vector-based COVID-19 vaccinations is understood to be the underlying pathophysiology. TTS with CVST should be considered when patients present with headaches, stroke-like neurological symptoms, thrombocytopenia, and symptom onset 6–15 days after Ad26.COV2.S vaccination.

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An Update on COVID-19 Vaccine Induced Thrombotic Thrombocytopenia Syndrome and Some Management Recommendations

Molecules ◽

10.3390/molecules26165004 ◽

2021 ◽

Vol 26 (16) ◽

pp. 5004

Author(s):

Amin Islam ◽

Mohammed Sheraz Bashir ◽

Kevin Joyce ◽

Harunor Rashid ◽

Ismail Laher ◽

...

Keyword(s):

Sinus Thrombosis ◽

Cerebral Venous Sinus Thrombosis ◽

Thromboembolic Events ◽

Patient Exposure ◽

Platelet Factor ◽

Heparin Induced Thrombocytopenia ◽

Younger Patients ◽

Venous Thromboembolic Events ◽

Venous Thromboembolic ◽

Management Recommendations

The thrombotic thrombocytopenia syndrome (TTS), a complication of COVID-19 vaccines, involves thrombosis (often cerebral venous sinus thrombosis) and thrombocytopenia with occasional pulmonary embolism and arterial ischemia. TTS appears to mostly affect females aged between 20 and 50 years old, with no predisposing risk factors conclusively identified so far. Cases are characterized by thrombocytopenia, higher levels of D-dimers than commonly observed in venous thromboembolic events, inexplicably low fibrinogen levels and worsening thrombosis. Hyper fibrinolysis associated with bleeding can also occur. Antibodies that bind platelet factor 4, similar to those associated with heparin-induced thrombocytopenia, have also been identified but in the absence of patient exposure to heparin treatment. A number of countries have now suspended the use of adenovirus-vectored vaccines for younger individuals. The prevailing opinion of most experts is that the risk of developing COVID-19 disease, including thrombosis, far exceeds the extremely low risk of TTS associated with highly efficacious vaccines. Mass vaccination should continue but with caution. Vaccines that are more likely to cause TTS (e.g., Vaxzevria manufactured by AstraZeneca) should be avoided in younger patients for whom an alternative vaccine is available.

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A case of thrombocytopenia and multiple thromboses after vaccination with ChAdOx1 nCoV-19 against SARS-CoV-2

Blood Advances ◽

10.1182/bloodadvances.2021004904 ◽

2021 ◽

Vol 5 (12) ◽

pp. 2569-2574

Author(s):

Anne Louise Tølbøll Sørensen ◽

Magalie Rolland ◽

Jacob Hartmann ◽

Zitta Barrella Harboe ◽

Casper Roed ◽

...

Keyword(s):

Sinus Thrombosis ◽

Cerebral Venous Sinus Thrombosis ◽

Cerebral Vein ◽

Platelet Factor ◽

Oral Contraceptive Pills ◽

Vein Thrombosis ◽

Contraceptive Pills ◽

Prothrombin Mutation ◽

Vectored Vaccine ◽

Clinical Awareness

Recently, reports of severe thromboses, thrombocytopenia, and hemorrhage in persons vaccinated with the chimpanzee adenovirus-vectored vaccine (ChAdOx1 nCoV-19, AZD1222, Vaxzevria; Oxford/AstraZeneca) against severe acute respiratory syndrome coronavirus 2 have emerged. We describe an otherwise healthy 30-year-old woman who developed thrombocytopenia, ecchymosis, portal vein thrombosis, and cerebral venous sinus thrombosis the second week after she received the ChAdOx1 nCoV-19 vaccine. Extensive diagnostic workup for thrombosis predispositions showed heterozygosity for the prothrombin mutation, but no evidence of myeloproliferative neoplasia or infectious or autoimmune diseases. Her only temporary risk factor was long-term use of oral contraceptive pills (OCPs). Although both the prothrombin mutation and use of OCPs predispose to portal and cerebral vein thrombosis, the occurrence of multiple thromboses within a short time and the associated pattern of thrombocytopenia and consumption coagulopathy are highly unusual. A maximum 4T heparin-induced thrombocytopenia (HIT) score and a positive immunoassay for anti-platelet factor 4/heparin antibodies identified autoimmune HIT as a potential pathogenic mechanism. Although causality has not been established, our case emphasizes the importance of clinical awareness. Further studies of this potentially new clinical entity have suggested that it should be regarded as a vaccine-induced immune thrombotic thrombocytopenia.

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Platelet Activation by Vaccine-Induced Immune Thrombotic Thrombocytopenia (VITT) Patient Serum is Blocked by COX, P2Y12 and Kinase Inhibitors

10.1101/2021.04.24.21255655 ◽

2021 ◽

Author(s):

Christopher W. Smith ◽

Caroline Kardeby ◽

Ying Di ◽

Gillian C. Lowe ◽

William A. Lester ◽

...

Keyword(s):

Platelet Activation ◽

Healthy Donor ◽

Kinase Inhibitors ◽

Sinus Thrombosis ◽

Cerebral Venous Sinus Thrombosis ◽

Therapeutic Interventions ◽

Ivig Treatment ◽

List Type ◽

Platelet Factor

AbstractBackgroundThe novel coronavirus SARS-CoV-2 has caused a global pandemic. Vaccines are an important part of the response. Although rare, unusual thrombotic events and thrombocytopenia in recipients 4–16 days after vaccination with the AstraZeneca AZD1222 have been reported. This syndrome of vaccine-induced immune thrombotic thrombocytopenia (VITT) clinically resembles heparin induced thrombocytopenia (HIT), which is caused by platelet activating antibodies against platelet factor 4 (PF4). Here, we investigate the effect of serum from patients with VITT on platelet activation, and assess the ability of clinically available therapeutics to prevent platelet activation.MethodsAggregation responses of healthy donor washed platelets were assessed in response to serum from patients with VITT pre- and post-intravenous immunoglobulin (IVIg) treatment and in the presence of anti-FcγRIIA blocking IV.3 F(ab), anti-platelet drugs and kinase inhibitors.FindingsFour patients (21 - 48 years old) presented with thrombosis (three patients: cerebral venous sinus thrombosis, one patient: ischemic stroke) and thrombocytopenia 10-14 days after AZD1222 vaccination. All patients tested positive for anti-PF4 antibody despite no prior heparin exposure. Serum from patients with VITT, but not healthy donor controls, induced platelet aggregation, which was abrogated following IVIg treatment. Aggregation to patient sera was blocked by IV.3 F(ab) which targets FcγRIIA, and inhibitors of Src, Syk and Btk kinases downstream of the receptor. Anti-platelet therapies indomethacin and ticagrelor also blocked aggregation.InterpretationIn conclusion, serum from patients with VITT activates platelets via the FcγRIIA, which can be blocked in vitro by anti-platelet therapies suggesting possible new therapeutic interventions for this rare syndrome.FundingThis work was supported by an Accelerator Grant (AA/18/2/34218) from the British Heart Foundation (BHF).Key pointsSerum from patients with VITT activates platelets via the FcγRIIA.Platelet activation by serum from patients with VITT can be blocked by COX, P2Y12, Src, Syk and Btk inhibition.

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Cerebral venous sinus thrombosis secondary to ChAdOx-1 nCov-19 vaccine

BMJ Case Reports ◽

10.1136/bcr-2021-246200 ◽

2021 ◽

Vol 14 (12) ◽

pp. e246200

Author(s):

Syed Noman Atta ◽

Nariman Othman ◽

Munir Babar

Keyword(s):

Sinus Thrombosis ◽

Rare Condition ◽

Cerebral Venous Sinus Thrombosis ◽

Platelet Factor 4 ◽

Prior History ◽

Cerebral Veins ◽

Thromboembolic Events ◽

Platelet Factor ◽

Venous Sinus Thrombosis ◽

History Of

Thrombosis and thrombocytopaenia secondary to ChAdOx-1 nCov-19 vaccine is a new phenomenon that usually occurs after the first dose of vaccine. Most of these patients are healthy without any prior history of thromboembolic events or heparin use. Hall marks of this condition include detectable antibodies to platelet factor 4 and thrombosis at atypical sites particularly cerebral veins and sinuses mimicking atypical heparin induced thrombocytopaenia. We describe a case of a patient who was diagnosed with this rare condition and treated successfully.

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Thrombocytopenia and Intracranial Venous Sinus Thrombosis after “COVID-19 Vaccine AstraZeneca” Exposure

Journal of Clinical Medicine ◽

10.3390/jcm10081599 ◽

2021 ◽

Vol 10 (8) ◽

pp. 1599

Author(s):

Marc E. Wolf ◽

Beate Luz ◽

Ludwig Niehaus ◽

Pervinder Bhogal ◽

Hansjörg Bäzner ◽

...

Keyword(s):

Sinus Thrombosis ◽

Clinical Manifestations ◽

Venous Sinus ◽

European Medicines Agency ◽

Coagulation Disorder ◽

Platelet Factor ◽

Venous Sinus Thrombosis ◽

Antiplatelet Antibodies ◽

Imaging Results ◽

Venous Thromboembolic Events

Background: As of 8 April 2021, a total of 2.9 million people have died with or from the coronavirus infection causing COVID-19 (Corona Virus Disease 2019). On 29 January 2021, the European Medicines Agency (EMA) approved a COVID-19 vaccine developed by Oxford University and AstraZeneca (AZD1222, ChAdOx1 nCoV-19, COVID-19 vaccine AstraZeneca, Vaxzevria, Covishield). While the vaccine prevents severe course of and death from COVID-19, the observation of pulmonary, abdominal, and intracranial venous thromboembolic events has raised concerns. Objective: To describe the clinical manifestations and the concerning management of patients with cranial venous sinus thrombosis following first exposure to the “COVID-19 vaccine AstraZeneca”. Methods: Patient files, laboratory findings, and diagnostic imaging results, and endovascular interventions of three concerning patients were evaluated in retrospect. Results: Three women with intracranial venous sinus thrombosis after their first vaccination with “COVID-19 vaccine AstraZeneca” were encountered. Patient #1 was 22 years old and developed headaches four days after the vaccination. On day 7, she experienced a generalized epileptic seizure. Patient #2 was 46 years old. She presented with severe headaches, hemianopia to the right, and mild aphasia 13 days after the vaccination. MRI showed a left occipital intracerebral hemorrhage. Patient #3 was 36 years old and presented 17 days after the vaccination with acute somnolence and right-hand hemiparesis. The three patients were diagnosed with extensive venous sinus thrombosis. They were managed by heparinization and endovascular recanalization of their venous sinuses. They shared similar findings: elevated levels of D-dimers, platelet factor 4 antiplatelet antibodies, corona spike protein antibodies, combined with thrombocytopenia. Under treatment with low-molecular-weight heparin, platelet counts normalized within several days. Conclusion: Early observations insinuate that the exposure to the “COVID-19 vaccine AstraZeneca” might trigger the expression of antiplatelet antibodies, resulting in a condition with thrombocytopenia and venous thrombotic events (e.g., intracranial venous sinus thrombosis). These patients’ treatment should address the thrombo-embolic manifestations, the coagulation disorder, and the underlying immunological phenomena.

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Cerebral venous sinus thrombosis after ChAdOx1 nCov-19 vaccination with a misleading first cerebral MRI scan

Stroke and Vascular Neurology ◽

10.1136/svn-2021-001095 ◽

2021 ◽

pp. svn-2021-001095

Author(s):

Benno Ikenberg ◽

Antonia Franziska Demleitner ◽

Thomas Thiele ◽

Benedikt Wiestler ◽

Katharina Götze ◽

...

Keyword(s):

Sinus Thrombosis ◽

Intravenous Immunoglobulins ◽

Cerebral Venous Sinus Thrombosis ◽

Venous Sinus ◽

Pathological Findings ◽

Mri Scan ◽

Platelet Factor ◽

Venous Sinus Thrombosis ◽

Activation Assay ◽

Cerebral Mri

Vaccine-induced immune thrombotic thrombocytopenia (VITT) and cerebral venous sinus thrombosis (CVST) have been recently described as rare complications following vaccination against SARS-CoV-2 with vector vaccines. We report a case of a young woman who presented with VITT and cerebral CVST 7 days following vaccination with ChAdOx1 nCov-19 (AstraZeneca). While the initial MRI was considered void of pathological findings, MRI 3 days later revealed extensive CVST of the transversal and sigmoidal sinus with intracerebral haemorrhage. Diagnostic tests including a platelet-factor-4-induced platelet activation assay confirmed the diagnosis of VITT. Treatment with intravenous immunoglobulins and argatroban resulted in a normalisation of platelet counts and remission of CVST.

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Pulmonary involvements in systemic juvenile arthritis

10.21203/rs.3.rs-33776/v1 ◽

2020 ◽

Author(s):

Tingyan He ◽

Jiayun Ling ◽

Jun Yang

Keyword(s):

Sinus Thrombosis ◽

Drug Hypersensitivity ◽

Systemic Juvenile Idiopathic Arthritis ◽

Clinical Manifestations ◽

Cerebral Venous Sinus Thrombosis ◽

Chronic Inflammatory Disease ◽

Serum Cytokine ◽

Radiological Features ◽

Cytokine Levels ◽

To Receive

Abstract Background Systemic juvenile idiopathic arthritis (sJIA) is a chronic inflammatory disease of childhood. Pulmonary involvements in sJIA have been recently described. Herein, we assess unusual clinical and radiological features of patients with sJIA, and possible risk factors for pulmonary involvements in sJIA. Methods A total of thirty-nine patients with sJIA were retrospectively enrolled. Data extracted included demographics, medical history, clinical manifestations, laboratory results, serum cytokine levels, radiological findings, management, and prognosis. Results Macrophage activation syndrome (MAS) had been observed at the initial diagnosis or during disease flares in eleven patients (11/39, 28%). Cerebral venous sinus thrombosis was observed in one patient with paroxysmal headache during the MAS phase. Twenty-three patients demonstrated abnormal radiological features on chest Computed Tomography (CT). Only eleven patients had subtle respiratory symptoms with normal oxygen saturation. Eight patients had lung disease (LD) before biologic exposure. sJIA-LD occurred in another six patients after the introduction of tocilizumab. All these patients continued to receive tocilizumab therapy, and sJIA-LD was improved in twelve patients with complete resolution of pulmonary presentations, and partially relieved in two patients. Only one of the two patients with possible anaphylaxis to tocilizumab presented with LD. Severe sJIA-LD was found in two patients with trisomy 21 and Kabuki syndrome, respectively. Conclusions Pulmonary involvements are increasingly observed in children with sJIA. Possible high risks for sJIA-LD include the occurrence of MAS, some inherited diseases, and evidence of drug hypersensitivity. It is still a question of whether IL-1/IL-6 inhibitor exposure increases the risk of sJIA-LD. Vasculitis and thrombosis should be considered in sJIA during the MAS phase, particularly in patients with pulmonary involvements. Trial registration: Not applicable; this was a retrospective study.

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Diagnosis and Management of Lemierre’s Syndrome Presented with Multifocal Pneumonia and Cerebral Venous Sinus Thrombosis

Case Reports in Infectious Diseases ◽

10.1155/2020/6396274 ◽

2020 ◽

Vol 2020 ◽

pp. 1-5

Author(s):

Yasar Sattar ◽

Ammu Thampi Susheela ◽

Bibek Karki ◽

Adnan Liaqat ◽

Waqas Ullah ◽

...

Keyword(s):

Sinus Thrombosis ◽

Fusobacterium Nucleatum ◽

Cerebral Venous Sinus Thrombosis ◽

Venous Sinus ◽

Jugular Vein Thrombosis ◽

Lemierre Syndrome ◽

Venous Sinus Thrombosis ◽

Vein Thrombosis ◽

Cerebral Sinus Venous Thrombosis ◽

Magnetic Resonance Imaging Mri

A 27-year-old female patient initially presented with fever, myalgia, sore throat that progressed to multifocal pneumonia, and cerebral sinus venous thrombosis. A combination of upper respiratory symptoms with tooth infection, positive blood culture for Fusobacterium nucleatum, computed tomography (CT) chest finding of multifocal pneumonia, and magnetic resonance imaging (MRI) finding of internal jugular vein thrombosis (IJVT) and cerebral venous sinus thrombosis (CVST) suggested Lemierre syndrome. The patient was managed with fluids, antibiotics, and anticoagulants. The patient survived and discharged from the hospital. The patient’s symptoms improved at 2 months of follow-up.

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COVID-19 and cerebrovascular diseases: a comprehensive overview

Therapeutic Advances in Neurological Disorders ◽

10.1177/1756286420978004 ◽

2020 ◽

Vol 13 ◽

pp. 175628642097800

Author(s):

Georgios Tsivgoulis ◽

Lina Palaiodimou ◽

Ramin Zand ◽

Vasileios Arsenios Lioutas ◽

Christos Krogias ◽

...

Keyword(s):

Cerebrovascular Disease ◽

Clinical Laboratory ◽

Sinus Thrombosis ◽

Case Reports ◽

Cardiac Injury ◽

Clinical Manifestations ◽

Relevant Information ◽

Cerebral Venous Sinus Thrombosis ◽

Stroke Patients ◽

Comprehensive Overview

Neurological manifestations are not uncommon during infection with the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A clear association has been reported between cerebrovascular disease and coronavirus disease 2019 (COVID-19). However, whether this association is causal or incidental is still unknown. In this narrative review, we sought to present the possible pathophysiological mechanisms linking COVID-19 and cerebrovascular disease, describe the stroke syndromes and their prognosis and discuss several clinical, radiological, and laboratory characteristics that may aid in the prompt recognition of cerebrovascular disease during COVID-19. A systematic literature search was conducted, and relevant information was abstracted. Angiotensin-converting enzyme-2 receptor dysregulation, uncontrollable immune reaction and inflammation, coagulopathy, COVID-19-associated cardiac injury with subsequent cardio-embolism, complications due to critical illness and prolonged hospitalization can all contribute as potential etiopathogenic mechanisms leading to diverse cerebrovascular clinical manifestations. Acute ischemic stroke, intracerebral hemorrhage, and cerebral venous sinus thrombosis have been described in case reports and cohorts of COVID-19 patients with a prevalence ranging between 0.5% and 5%. SARS-CoV-2-positive stroke patients have higher mortality rates, worse functional outcomes at discharge and longer duration of hospitalization as compared with SARS-CoV-2-negative stroke patients in different cohort studies. Specific demographic, clinical, laboratory and radiological characteristics may be used as ‘red flags’ to alarm clinicians in recognizing COVID-19-related stroke.

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