Cerebral Venous Thrombosis Developing after COVID-19 Vaccination: VITT, VATT, TTS, and More

Young Female ◽

Enzyme Linked Immunosorbent Assay ◽

Platelet Factor ◽

Viral Spread ◽

Respiratory Coronavirus

AbstractDespite the huge efforts globally underway for preventing or limiting the spread of severe acute respiratory coronavirus disease 2 (SARS-CoV-2), the coronavirus disease 2019 (COVID-19) pandemic outbreak appears still virtually unstoppable. As for many other infectious diseases, COVID-19 vaccination has now become crucial for limiting viral spread, especially for averting hospitalizations, need for intensive care, and fatal outcome. Nonetheless, as for other vaccines, COVID-19 vaccination is not completely free from side effects. Among the adverse events that have been reported after receiving COVID-19 vaccination, special emphasis has been given to an unexpected number of thrombocytopenic episodes with or without thrombotic complications, especially in recipients of adenovirus-based COVID-19 vaccines. Along with a specific clinical presentation, encompassing “atypical” thrombosis (especially cerebral venous [sinus] thrombosis, CVT) more prevalent in young female subjects, this new syndrome called vaccine-induced thrombocytopenia and thrombosis (VITT) is characterized by, and thereby diagnosed for, the presence of three paradigmatic laboratory abnormalities, i.e., low platelet count (<150 × 109/L), elevated plasma D-dimer levels (>0.5 mg/L), accompanied by a positive test for anti-PF4 (platelet factor 4) antibodies assayed with ELISA (enzyme-linked immunosorbent assay) techniques. Timely identification of these important abnormalities by both clinicians and laboratory professional is essential for early diagnosis and management of VITT, since the outcome of this condition may be fatal in half or even more of effected patients with severe disease. Therefore, this narrative review aims to review here the epidemiology, pathogenesis, clinical, and laboratory characteristics of VITT and other COVID-19 vaccine-associated thrombocytopenias.

Case Series of Thrombosis with Thrombocytopenia Syndrome following COVID-19 vaccination--United States, December 2020-August 2021

10.1101/2021.11.10.21266063 ◽

2021 ◽

Author(s):

Isaac See ◽

Allison Lale ◽

Paige Marquez ◽

Michael B Streiff ◽

Allison P Wheeler ◽

...

Keyword(s):

United States ◽

Adverse Event ◽

Sinus Thrombosis ◽

Adverse Event Reporting System ◽

Case Series ◽

Reporting Rate ◽

Enzyme Linked Immunosorbent Assay ◽

Platelet Factor ◽

Reporting Rates

Background: Thrombosis with thrombocytopenia syndrome (TTS) is a potentially life-threatening condition associated with adenoviral-vectored COVID-19 vaccination. TTS presents similarly to autoimmune heparin-induced thrombocytopenia. Twelve cases of cerebral venous sinus thrombosis following Janssen/Johnson & Johnson (Ad26.COV2.S) COVID-19 vaccination have been described. Objective: Describe surveillance data and reporting rates of TTS cases following COVID-19 vaccination. Design: Case series. Setting: United States Patients: Case-patients reported to the Vaccine Adverse Event Reporting System (VAERS) receiving COVID-19 vaccine from December 14, 2020 through August 31, 2021, with thrombocytopenia and thrombosis (excluding isolated ischemic stroke or myocardial infarction). If thrombosis was only in an extremity vein or pulmonary embolism, a positive enzyme-linked immunosorbent assay for anti-platelet factor 4 antibody was required. Measurements: Reporting rates (cases/million vaccine doses) and descriptive epidemiology. Results: 52 TTS cases were confirmed following Ad26.COV2.S (n=50) or mRNA-based COVID-19 (n=2) vaccination. TTS reporting rates were 3.55per million (Ad26.COV2.S) and 0.0057 per million (mRNA-based COVID-19 vaccines). Median age of patients with TTS following Ad26.COV2.S vaccination was 43.5 years (range: 18-70); 70% were female. Both TTS cases following mRNA-based COVID-19 vaccination occurred in males aged >50 years. All cases following Ad26.COV2.S vaccination involved hospitalization including 32 (64%) admitted to an intensive care unit. Outcomes following Ad26.COV2.S vaccination included death (12%), discharge to post-acute care (16%), and discharge home (72%). Limitations: Under-reporting and incomplete case follow-up. Conclusion: TTS is a rare but serious adverse event associated with Ad26.COV2.S vaccination. The lower reporting rate and different demographic characteristics for the two cases following mRNA-based COVID-19 vaccines suggest a potentially different pathogenesis or background occurrence.

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 ◽

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.

A case report of extensive cerebral venous sinus thrombosis: a sequela of COVID-19?

Acute Medicine Journal ◽

10.52964/amja.0866 ◽

2021 ◽

Vol 20 (3) ◽

pp. 219-222

Author(s):

S Sivalokanathan ◽

◽

MO Syed ◽

A Sharmila ◽

◽

...

Keyword(s):

Sinus Thrombosis ◽

Venous Sinus ◽

Low Molecular Weight ◽

Diagnostic Challenge ◽

Venous Sinus Thrombosis ◽

Refractory Headache ◽

Medical Intensive Care ◽

Persistent Headache

Coronavirus disease 2019 (COVID-19) is an infectious respiratory disease that is often the trigger for thrombotic complications. Cerebral venous sinus thrombosis (CVST) represents a small percentage of strokes, frequently proving to be a diagnostic challenge. We report a 31-year-old lady presenting with a persistent headache, 18 weeks after a mild COVID-19 illness. On her second visit, CT venography revealed extensive CVST. She was commenced on low-molecular-weight heparin, and was monitored closely in the neuro-medical intensive care unit. She was discharged 2 weeks later, with no residual neurological deficit, and commenced on a direct oral anticoagulant in the community. CVST should be considered in patients presenting with a refractory headache, with greater suspicion if previously infected with SARS-CoV-2.

Atypical venous thromboses in myeloproliferative neoplasias

Phlebologie ◽

10.12687/phleb2292-6-2015 ◽

2015 ◽

Vol 44 (06) ◽

pp. 324-329

Author(s):

C. Dicke ◽

A. Frölich ◽

K. Holstein ◽

C. Bokemeyer ◽

F. Langer

Keyword(s):

Platelet Count ◽

Deep Vein Thrombosis ◽

Sinus Thrombosis ◽

Jak2 V617f ◽

Venous Sinus Thrombosis ◽

Vein Thrombosis ◽

Deep Vein ◽

Venous Thromboses

SummaryWe describe two patients who developed an extensive catheter-related upper extremity deep vein thrombosis and a cerebral venous sinus thrombosis, respectively. Both thrombotic complications occurred in the presence of an elevated platelet count. Subsequent detection of the JAK2 V617F and MPL mutations led to the diagnosis of a myeloproliferative neoplasia.

Assessment of HIT Antibody Complex in Hip Fracture Patients Receiving Enoxaparin or Unfractionated Heparin

Clinical and Applied Thrombosis/Hemostasis ◽

10.1177/1076029611398121 ◽

2011 ◽

Vol 17 (6) ◽

pp. 567-571

Author(s):

Justin W. Griffin ◽

William J. Hopkinson ◽

Michael R. Lassen ◽

Indermohan Thethi ◽

Evangelos Litinas ◽

...

Keyword(s):

Hip Fracture ◽

Elderly Patients ◽

Unfractionated Heparin ◽

Standard Of Care ◽

The Elderly ◽

Enzyme Linked Immunosorbent Assay ◽

Platelet Factor ◽

Surgical Fixation ◽

Antibody Complex

Thromboembolic disease is a common complication of hip fracture in the elderly. Anticoagulants represent a standard of care in preventing postoperative thrombotic complications following surgical fixation. We asked whether levels of antibody to heparin–platelet factor 4 (PF4) complex were differentially present in unfractionated heparin (UFH) versus Enoxaparin, following hip fracture and whether one particular subtype of antibodies was more prevalent. Plasma samples from elderly patients sustaining a hip fracture treated with either enoxaparin or UFH were collected pre- and postoperatively and analyzed using enzyme-linked immunosorbent assay (ELISA) sandwich method for the prevalence of antiheparin-PF4 antibodies and later subtyped. The prevalence of antiheparin-PF4 antibodies was higher in the UFH group especially on postoperative day 7. Patients treated with UFH showed a greater prevalence of antiheparin-PF4 antibodies and a greater prevalence of immunoglobulin G (IgG) subtype. Heparin and enoxaparin are capable of generating heparin-induced thrombocytopenia (HIT) antibodies in elderly patients undergoing orthopedic surgery but perhaps not to the same extent. When comparing low-molecular-weight heparin (LMWH) with UFH, the incidence of new antiheparin-PF4 antibody production is higher in patients treated with UFH.

A rare complication in a child undergoing chemotherapy for Hodgkin lymphoma - multiple cerebral venous sinus thrombosis

Srpski arhiv za celokupno lekarstvo ◽

10.2298/sarh201207102k ◽

2021 ◽

pp. 102-102

Author(s):

Aleksandar Kostic ◽

Danijela Jovancic-Petkovic ◽

Aleksandra Aracki-Trenkic ◽

Nebojsa Stojanovic ◽

Vesna Nikolov

Keyword(s):

Venous Thrombosis ◽

Intracranial Hypertension ◽

Hodgkin Lymphoma ◽

Sinus Thrombosis ◽

Rare Complication ◽

Fatal Outcome ◽

Posterior Part ◽

Venous Catheter ◽

Sagittal Sinus

Introduction. Risk factors for thrombotic events in patients receiving treatment for Hodgkin lymphoma are not well known. Administration of some cytostatic medication, especially via central venous catheter, corticosteroids and hyperlipidemia can present some of them. Case outline. A case of a 15-year-old boy that had been newly diagnosed with Hodgkin lymphoma is presented here. Chemotherapy according to vincristine, etoposide, prednisone, and doxorubicin (OEPA) protocol was introduced a month before headache and vomiting occurred, so subsequently, brain- computer tomography (CT) was performed, and reviled laminar subdural pseudo hemorrhage in the right occipital region. After performing magnet resonance imaging (MRI) venous thrombosis of the posterior part of superior sagittal sinus, right transverses and sigmoid sinus were presented. Low-molecular-weight heparin (LMWH) and anti-edematous therapy was immediately initiated. Two weeks later the patient resumed the second cycle of chemotherapy combined with LMWH, as the previous symptoms of intracranial hypertension resolved. Two years after MRI showed almost complete resolution of finding. The boy was in good clinical condition. Conclusion. Although administration of oral corticosteroids, could be rarely a risk factor per se for cerebral sinus venous thrombosis in HL patients, it remains important treatment option. Adequate and prompt diagnostics and therapy are mandatory in cases of wide intracranial venous thrombosis as prevention of possible intracranial hypertension and even fatal outcome.

Prothrombotic immune thrombocytopenia after COVID-19 vaccine

Blood ◽

10.1182/blood.2021011958 ◽

2021 ◽

Author(s):

Andreas Tiede ◽

Ulrich J Sachs ◽

Andreas Czwalinna ◽

Sonja Werwitzke ◽

Rolf Bikker ◽

...

Keyword(s):

Healthy Donor ◽

Immune Thrombocytopenia ◽

Sinus Thrombosis ◽

Clinical Manifestations ◽

Dependent Manner ◽

Thromboembolic Events ◽

Platelet Factor ◽

Vein Thrombosis ◽

Heparin Anticoagulation

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.

Extensive cerebral venous sinus thrombosis: a potential complication in a patient with COVID-19 disease

BMJ Case Reports ◽

10.1136/bcr-2020-236820 ◽

2020 ◽

Vol 13 (8) ◽

pp. e236820 ◽

Cited By ~ 3

Author(s):

Paul Bolaji ◽

Babatunde Kukoyi ◽

Nasar Ahmad ◽

Chris Wharton

Keyword(s):

Sinus Thrombosis ◽

Inpatient Rehabilitation ◽

Venous Sinus ◽

Pulmonary Vasculature ◽

Venous Sinus Thrombosis ◽

Ventilation Imaging ◽

Potential Association ◽

Recent Diagnosis

A 63-year-old man was admitted with left-sided weakness and subsequent focal seizures following a recent diagnosis of Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pneumonia in a nearby hospital. He developed status epilepticus and became comatose, requiring intensive care unit admission for invasive ventilation. Imaging done at admission confirmed extensive cerebral venous sinus thrombosis (CVST) with bilateral venous cortical infarcts and acute cortical haemorrhage. No known risk factor for CVST could be identified. He improved with anticoagulation and antiepileptic therapy. He was subsequently transferred to an inpatient rehabilitation facility. Although Coronavirus disease 19 (COVID-19) infection has been previously associated with thrombotic complications, these mostly relate to the pulmonary vasculature. We present this case as a potential association between CVST and COVID-19 infection.

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 ◽

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.

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 ◽

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.