Guidance on diagnosis and management of cerebral venous sinus thrombosis after a COVID-19 vaccine

Reviewed by Emily Henderson, B.Sc.Apr 29 2021

Last Friday, the Centers for Disease Control and Prevention (CDC) and the U.S. Food & Drug Administration (FDA) lifted the pause in administration of the Johnson & Johnson (Janssen) COVID-19 vaccine in the U.S. The temporary pause was due to reports of a serious condition called cerebral venous sinus thrombosis (CVST), which refers to blood clots in the brain's veins - not in the arteries, as is the case for most strokes - in combination with thrombocytopenia (low blood platelet count).

CVST and thrombocytopenia together is called thrombosis-thrombocytopenia syndrome (TTS). When TTS is linked to receiving a COVID-19 vaccine, it is called vaccine-induced immune thrombotic thrombocytopenia (VITT). CVST has also been associated with cases of TTS in adults who received the AstraZeneca COVID-19 vaccine available in Europe, according to the European Medicines Agency, the agency responsible for the scientific evaluation, supervision and safety of medicines in the European Union.

The American Heart Association/American Stroke Association Stroke Council Leadership convened quickly to provide important guidance about CVST, TTS and VITT - the signs and symptoms and the best treatment options. The special report, "Diagnosis and Management of Cerebral Venous Sinus Thrombosis with Vaccine-Induced Thrombotic Thrombocytopenia," published today inStroke, a journal of the American Stroke Association, a division of the American Heart Association.

COVID-19 infection is a significant risk factor for CVST. A preliminary analysis of U.S. data during the COVID-19 pandemic, available online, preprint on April 15, 2021, found that the risk of CVST due to infection with COVID-19 is 8-10 times higher than the risk of CVST after receiving a COVID-19 vaccine. The public can be reassured by the CDC's and FDA's investigation and these statistics - the likelihood of developing CVST after a COVID-19 vaccine is extremely low. We urge all adults to receive any of the approved COVID-19 vaccines."

Karen L. Furie, M.D., M.P.H., lead author of the special report, chair of the department of neurology at The Warren Alpert Medical School of Brown University, and chief of neurology at Rhode Island Hospital, The Miriam Hospital and Bradley Hospital in Providence, Rhode Island

The analysis included data from 59 health care organizations, totaling 81 million patients, more than 98% of whom were in the U.S. Among the nearly 514,000 patients in the database who were diagnosed with COVID-19 infection from January 20, 2020 through March 25, 2021, 20 patients were diagnosed with CVST. This data was compared to the incidence of CVST in adults who received either the Pfizer or Moderna COVID-19 vaccine before March 25, 2021, excluding those who had previously been diagnosed with COVID-19. No cases of thrombocytopenia (low platelets) were diagnosed among almost 490,000 vaccinated adults.

"CVST blood clots are very rare adverse events. We recommend immediate screening of all patients who arrive in the ER with a suspected clot - did they receive a COVID-19 vaccine during the recent weeks prior to this event?" said Furie. "Patients who present with the symptoms of CVST or blood clots and who recently received the COVID-19 vaccine should be treated using non-heparin anticoagulants. No heparin products in any dose should be given for suspected CVST, TTS or VITT. With the right treatment, most patients can have a full recovery after CVST, TTS or VITT."

CVST is an extremely rare but serious type of stroke caused by a blood clot in a part of the brain known as the venous sinus, involving veins that carry blood away from the brain. CVST clot symptoms are very similar to several other neurological conditions, and the symptoms can include severe headache; blurry vision; fainting or loss of consciousness; weakness; sensory changes; confusion or trouble speaking; seizures; abdominal pain; leg pain; difficulty breathing or shortness of breath. CVST occurs in the veins of the brain; blood clots may also occur in other blood vessels, like those in the legs, lungs or abdomen. Among the cases reported in the U.S., the most common symptoms were severe headaches; vomiting; back pain; fatigue; weakness or the inability to move one side of the body (hemiparesis); inability to speak or understand speech (aphasia); loss of consciousness; and abdominal pain.

If associated with the COVID-19 vaccine, cases of TTS/VITT occurred several days up to 2-1/2 weeks after being vaccinated with the Johnson & Johnson (Janssen) COVID-19 vaccine in the U.S., or up to 3-1/2 weeks after receiving the AstraZeneca COVID-19 vaccine in Europe.

The CDC and FDA's report on April 23, 2021, confirms the agencies investigated 15 reported cases of TTS in the U.S., in women ages 18-59 years, from the nearly 7 million adults who received the Johnson & Johnson COVID-19 vaccine before the temporary pause on April 13, 2021. The European Medicines Agency's investigation, reported on April 7, 2021, lists 62 cases of CVST, among adults ages 22-60 years, mostly women, from the more than 25 million people who received the AstraZeneca COVID-19 vaccine throughout the European Union .

The special report from the Stroke Council leaders details treatment for suspected CVST, TTS or VITT:

• All patients with suspected CVST due to a COVID-19 vaccine should be treated with non-heparin anticoagulants such as argatroban, bivalirudin, danaparoid, fondaparinux or a direct oral anti-coagulant (DOAC). No heparin products in any dose should be given.
• Magnetic Resonance Imaging with a venogram (MRI/MRV) or computed tomography with venogram (CT/CTV) is recommended to accurately detect and diagnose CVST.
• Blood tests should include a CBC (Complete Blood Count) plus:
• platelet count - to determine the number of platelets per liter of blood;
• a peripheral smear - examination under a microscope to count the number of various types of blood cells and if they appear normal;
• a prothrombin time - to measure how long it takes the blood to clot;
• a partial thromboplastin time - a measurement of how long it takes the blood to clot, specifically measuring for these clotting factors: factor VIII, factor IX, factor 1V and factor XII;
• a fibrinogen test - to measure for the presence of fibrin, a protein found in the blood that indicates that blood clotting has been activated;
• a D-dimer test - to measure for the presence of D-dimer, a small protein that's made when blood clots are dissolving in the body; and
• a PF4 antibody ELISA test - to test for PF4 antibodies, which the body sometimes creates in the blood to fight against the anticoagulant heparin.
• Anticoagulation treatment doses may need to be tailored if platelet counts are extremely low (<20,000/mm³) or if there is low fibrinogen.
• Anticoagulants should be used to treat CVST even if there is a secondary hemorrhage in the brain in order to prevent progressive thrombosis and to control bleeding.
• Platelet transfusion should be avoided.
• Once platelet counts return to normal (150,000 to 450,000/mm³), most patients can be transitioned to an oral anticoagulant if there are no contraindications.
• The authors note that based on their evaluation of the American Society of Hematology's recommendations and two recently published studies, individual patient factors should be considered regarding the use of a direct oral anticoagulant (DOAC) or a vitamin K agonist (VKA) after there is full platelet count recovery.
• The authors recommend all cases of thrombosis after a COVID-19 vaccine be reported to the U.S. Department of Health and Human Services Vaccine Adverse Event Reporting System: https://vaers.hhs.gov/reportevent.html. This data will be important to understanding the incidence of CVST, TTS and VITT.
• There is still much to be investigated:
• Are there any preexisting conditions that may predispose someone to CVST or VITT?
• What is the true prevalence and risk of PF4 antibodies, low platelet count and CVST after the COVID-19 vaccine?
• Since there is currently no data about people who did not develop CVST, TTS or VITT after a COVID-19 vaccine for comparison, it is not possible to definitively state that the vaccine is the cause of the PF4 antibodies, low platelet count (thrombocytopenia) or blood clots (thrombosis).

"We are learning the various intricacies of COVID-19 live, in real-time with the patients we see in our hospitals every day. CVST is extremely rare, however, further research and investigation are necessary as the pandemic continues. We will need data and robust research on the people who did not develop blood clots after the vaccine, too, so that we can fully understand the molecular and cellular mechanisms underlying CVST related to COVID-19 infection or after vaccination," concluded Furie.

The following statement reflects the views of the American Heart Association/American Stroke Association and its science leaders:

• President Mitchell S.V. Elkind, M.D., M.S., FAHA, FAAN,
• Immediate Past President Robert A. Harrington, M.D., FAHA,
• President-Elect Donald M. Lloyd-Jones, M.D., Sc.M., FAHA,
• Chief Science and Medical Officer Mariell Jessup, M.D., FAHA, and
• Chief Medical Officer for Prevention Eduardo Sanchez, M.D, M.P.H., FAAFP.

"The American Heart Association continues to urge everyone to receive a COVID-19 vaccine as soon as they can. We concur with the CDC's and FDA's recommendations for people who receive the Johnson & Johnson (Janssen) vaccine - if they develop severe headache, abdominal pain, leg pain or shortness of breath within 3 weeks of receiving the vaccine, they should quickly contact their health care professional.

COVID-19 has disproportionately negative effects on older adults; people with underlying medical conditions; and Black, LatinX and American Indian/Alaska Native people. The American Heart Association strongly encourages everyone to get vaccinated with an approved COVID-19 vaccine. In particular, people with cardiovascular risk factors such as high blood pressure, obesity and type 2 diabetes, those with heart disease, and heart attack and stroke survivors should get vaccinated as soon as possible because they are at much greater risk of a negative outcome from the virus than they are from the vaccine.

We are confident the benefits of vaccination far exceed the very small, rare risks. The risks of vaccination are also far smaller than the risks of COVID-19 and its potentially fatal consequences.

We recommend people who have medical conditions, especially those with the propensity for blood clotting, consult with a health care professional before seeking vaccination to discuss the very rare potential increased risks.

In addition, the Association reiterates the importance of handwashing, social distancing and wearing masks as vaccinations continue, particularly for people at high risk of infection and/or severe COVID-19. These simple precautions remain crucial to protecting people from the virus that causes COVID-19. They also are crucial to getting us all back to normal activities.

Individuals should refer to their local and state health departments for specific information about when and where they can get vaccinated. We urge everyone to get vaccinated."