In March 2021, a report of a possible connection between the Johnson & Johnson COVID-19 vaccine and an uncommon blood clot known as cerebral venous sinus thrombosis (CVST) was submitted to the Vaccine Adverse Events Reporting System (VAERS), a U.S.-wide clearinghouse for vaccine-related side effects. Less than a month later, five more reports of CVST occurring within two weeks of Johnson & Johnson vaccination had been submitted.
The Centers for Disease Control and Prevention (CDC) and the Food and Drug Administration (FDA) took note of these cases. Though at the time, only 6 people—all women between the ages of 18 and 48—out of a total of 6.8 million doses of the vaccine reported the rare blood clotting condition, the two agencies recommended that use of the Johnson & Johnson vaccine be paused while scientists investigated the matter to determine whether a link truly exists between the vaccine and CVST. In late April, the FDA ended its recommended pause on the vaccine and added a warning label about an uncommon, but potentially serious, blood clotting disorder.
The type of blood clot experienced by these six women is rare. For every 100,000 people, there are only about 0.22 to 1.57 cases of cerebral venous thrombosis each year. But CVST is a dangerous and potentially lethal disorder. It can cause a range of symptoms, from headache to impaired vision to problems speaking to, in severe cases, coma. Fortunately, treatments are available for CVST, and with early diagnosis, patient outcomes tend to be good.
“Treatment for CVST may include measures to reduce intracranial pressure, treat infection, if present, and the use of anti-epileptics to prevent or treat seizures,” says Yale Medicine hematologist Robert Bona, MD, “What’s most important, however, is prompt and adequate anticoagulation with heparin. But it’s important to note that the treatment of CVST associated with the COVID-19 vaccine is a very rare event and a different approach to treatment, including avoidance of heparin, is indicated.”
What is cerebral venous sinus thrombosis?
To function properly, the brain requires a steady supply of oxygen-rich blood. This blood is provided by the heart, which pumps oxygenated blood to the brain through a system of arteries and blood vessels.
But after the brain uses up the oxygen, the blood must be returned to the heart. This is done via a network of veins and what are known as venous sinuses, or tube-like channels.
In rare cases, a blood clot can form in a venous sinus. This is a condition known as cerebral venous sinus thrombosis.
When a blood clot forms in a cerebral venous sinus, it functions like a stopper in a bottle and effectively blocks the flow of blood. The accumulation of blood causes edema, or swelling, in the area of the brain near the clot. This swelling can damage and destroy brain cells. And if enough pressure builds, veins and other blood vessels can rupture, resulting in a cerebral hemorrhage, or bleeding in the brain, triggering a number of serious symptoms.
Some venous sinuses also play a role in absorbing cerebrospinal fluid, a clear liquid found in the brain and around the spinal cord. If a blood clot develops in one of these particular venous sinuses, it can reduce the absorption of cerebrospinal fluid which, in rare cases, may result in hydrocephalus, a condition that occurs when cerebrospinal accumulates in the brain. This can increase pressure within the brain and produce a range of symptoms including headache, nausea, vision problems, and impaired cognition.
CVST is a rare type of blood clot. It can affect people of any age and sex, though it most commonly occurs in young adults and women.
What is unique about the cerebral venous sinus thrombosis cases associated with the Johnson & Johnson COVID-19 vaccine?
The form of CVST experienced by the 6 women who received the Johnson & Johnson vaccine differs from the usual case of CVST. While the women experienced blood clot(s) in the cerebral venous sinuses, they also had a condition known as thrombocytopenia, or lower than normal levels of platelets.
Platelets, known as thrombocytes, are blood cells that play an important role in the formation of blood clots in blood vessels. When people have thrombocytopenia, they are prone to excessive bleeding. Because they have low levels of platelets, they tend to have difficulty forming clots.
The blood clotting condition experienced by these women who received the Johnson & Johnson vaccine is known as thrombosis with thrombocytopenia syndrome (TTS) or vaccine-induced immune thrombotic thrombocytopenia (VITT). TTS can cause blood clotting in common sites, such as deep vein thromboses or pulmonary embolisms, but it can also lead to clotting in atypical sites, including the cerebral venous sinuses.
Between March and August 2021, a total of 54 cases of TTS had been identified out of 14.1 million Johnson & Johnson vaccine shots administered. Of these cases, 29 had CVST, which resulted in 7 deaths. TTS most commonly affects women between 30 and 49 years of age. There is about 1 case for every 100,000 doses given in this age group. In all cases, symptoms of TTS began within 18 days of receiving an initial dose of the Johnson & Johnson vaccine.
When the issue first came to light in April 2021, the FDA added a warning to the Johnson & Johnson vaccine fact sheet about the increased risk of blood clots. In mid-December 2021, the FDA revisited the matter and based on their analysis of the data, added a new warning to the fact sheet, noting that the “available evidence supports a causal relationship between TTS” and the Johnson & Johnson vaccine. Days later, the CDC evaluated the data, and announced that due to the increased risk of TTS, the agency now prefers the Pfizer or Moderna COVID-19 vaccines to the Johnson & Johnson vaccine.
What are the risk factors for cerebral venous sinus thrombosis?
CVST has been associated with the following risk factors:
- Oral contraceptives
- Pregnancy and the first month and a half after childbirth
- Hormone replacement therapy
- Inflammatory diseases and conditions (inflammatory bowel disease, systemic lupus erythematosus, sarcoidosis, Behçet disease, granulomatosis with polyangiitis)
- Nephrotic syndrome
- Antiphospholipid syndrome
- Genetic conditions that increase the tendency to form blood clots (factor V Leiden mutation, protein C deficiency, protein S deficiency, antithrombin deficiency, prothrombin gene mutation, hyperhomocysteinemia,)
- Certain infections of the head and neck (meningitis, sinusitis, otitis, mastoiditis)
- Head injury, previous neurosurgery
In the vast majority of cases, people who experience CVST have one or more of these risk factors. In some cases, however, doctors are unable to identify any known risk factors or causes.
What are the symptoms of cerebral venous sinus thrombosis?
CVST can cause a number of symptoms including:
- Headache (present in 90% of cases)
- Nausea, vomiting
- Weakness or impaired control of one side of the body, both sides of the body, or one leg or one arm
- Difficulty speaking
- Difficulty understanding language
- Blurred or double vision; brief periods (lasting seconds) in which vision becomes gray or black
- Decreased level of consciousness
A patient may experience one or several of these symptoms. While symptoms may appear suddenly, in general they develop over the course of a week or longer. In about a third of cases, headache (which often steadily worsens over several days and intensifies when lying down) is the only symptom.
How is cerebral venous sinus thrombosis diagnosed?
To diagnose CVST, doctors collect a medical history, perform a physical exam, and order imaging studies and bloodwork.
The doctor will gather information about the medical history, including what symptoms are present, when they began, whether symptoms have worsened in recent days, and whether there are any underlying medical conditions associated with CVST.
During the physical exam, the doctor will evaluate the patient for signs and symptoms associated with CVST.
Imaging studies are essential to diagnosis of CVST. The most commonly used imaging tests for CVST are magnetic resonance imaging (MRI) and computed tomography (CT) scans. The doctor may also order a magnetic resonance venogram or CT venogram of the brain. These are special types of scans that are used to visualize the veins and venous sinuses, which are the structures involved in CVST. In some cases, doctors may recommend another type of imaging study called an angiogram. This test produces an image of the blood vessels in the brain.
A diagnosis of CVST may also require blood tests to evaluate potential underlying causes. In some cases, the doctor will perform a lumbar puncture (a spinal tap) to collect cerebrospinal fluid for testing.
How is cerebral venous sinus thrombosis treated?
The main treatment for CVST is the anticoagulation drug heparin. Heparin and other anticoagulants—or blood thinners—are used to treat CVST because they help to prevent new blood clots from forming in blood vessels throughout the body, including the venous sinuses of the brain, and can keep existing clots from getting larger. Blood thinners, however, cannot dissolve existing clots. Heparin is delivered to the body intravenously or via injection.
If patients do not improve upon administration of heparin or another blood thinner, the doctor may administer thrombolytic enzymes, which can dissolve existing blood clots. Because they may cause hemorrhage, these medications are typically used only in severe cases. Alternatively, a surgeon may perform a procedure known as a thrombectomy to remove the blood clot(s). The goal of thrombolytic enzymes and thrombectomy is the same: to remove the blood clot and restore blood flow.
Once the acute phase of CVST has been controlled, doctors will transition the patient to an oral blood thinner, such as warfarin. Anticoagulation therapy is continued to prevent recurrence of CVST or other clotting disorders. Patients will typically stay on oral blood thinners for three or more months. Pregnant women, however, should not take warfarin because it may cause birth defects.
Treatment for people who experience CVST following Johnson & Johnson vaccination differs from the usual treatment protocols. These patients should not take heparin, as it may be unsafe for the particular type of clot associated with this vaccine. Anyone who experiences headache, stomach pain, leg pain, or shortness of breath within three weeks of receiving the Johnson & Johnson vaccine should get in touch with their health care provider.
What is the outlook for people who have cerebral venous sinus thrombosis?
CVST is a rare but potentially serious condition. Around 80% of people make a strong recovery, though some will continue to experience headache, vision problems, impaired motor control, speech problems, or other mild symptoms for weeks or months. For some, these symptoms may be permanent.
In general, the best outcomes are associated with early diagnosis and treatment. CVST recurs in about 2% to 4% of cases, and people who have experienced CVST are at increased risk for venous thromboembolism elsewhere in the body.
What makes Yale Medicine’s approach to cerebral venous sinus thrombosis unique?
“While headache is seen in most patients with CVST, it is also a very common symptom seen in many disorders. Clinicians at Yale Medicine are trained to have a high index of suspicion for CVST in the appropriate clinical circumstance [OCP use, known thrombophilia, pregnancy, presence of papilledema-swelling of the optic nerve noted on physical examination indicating high levels of intracranial pressure],” says Dr. Bona. “This training is especially important as early diagnosis with early treatment will result in better long-term outcomes.”