Covid-19: Clotting Disorders Pause Roll-Out of Adenovirus Vaccines

Several setbacks hampered vaccination efforts in the battle against Covid-19. Among these were concerns about clotting disorders, including cerebral venous sinus thrombosis (CVST) and thrombocytopenia, which are detailed in this article, originally published April 13, 2021. Click here to read the original article and obtain CME/CE credit for the activity.

A series of reports linking a rare blood clotting disorder to two Covid-19 vaccines, both of which use adenoviral-vector technology, may disrupt efforts to vaccinate a majority of Americans by mid-summer.

Moreover, the concerns raised with the AstraZeneca vaccine and the Johnson & Johnson (J&J) vaccine call to mind the hypercoagulopathy reported in some SARS-CoV-2 infections flagged by cardiologists earlier in the pandemic.

Only one of the vaccines—J & J’s Ad26.COV2.S—has received an Emergency Use Authorization (EUA) from the FDA, and on April 13 that agency joined the CDC in recommending that its distribution be paused in response to six reported cases of cerebral venous sinus thrombosis (CVST) and thrombocytopenia. Anne Schuchat, MD, Principal Deputy Director of the CDC, said the six U.S. cases all occurred in women ages 18-48, with symptom onset a median of nine days post vaccination. As of April 12, 6.8 million individuals received the Ad26.COV2.S vaccine.

During a press briefing, officials from the CDC and FDA cautioned clinicians that vaccine recipients whose symptoms include headache, abdominal pain, or leg pain, but not fever, should not be treated with heparin, which “may be dangerous, and alternative treatments need to be given.” The officials did not, however, recommend specific alternatives, nor did they offer guidance for patients who were receiving anticoagulation therapy prior to vaccination.

Current NIH Covid-19 treatment guidelines recommend that hematologic and coagulation parameters (D-dimers, prothrombin time, platelet count, and fibrogen) be assessed in hospitalized Covid-19 patients. The guidelines do recommend that patients who were on anticoagulation or antiplatelet therapy prior to infection should continue prescribed therapies.

Of note, although coagulopathy concerns surfaced early in the pandemic, a review of data from 27,676 Covid-19 patients, published in Stroke, found that “[A]cute ischemic stroke was infrequent in patients with Covid-19 and usually occurs in the presence of other cardiovascular risk factors.”

ChAdOx1 nCov-19

Earlier in April, case reports from Europe detailed similar instances of a rare blood clotting disorder believed to be linked to AstraZeneca’s Covid-19 vaccine, ChAdOx1 nCov-19. Those reports suggested a clinical similarity to autoimmune heparin-induced thrombocytopenia (HIT).

A report from Germany and Austria outlined 11 cases of thrombosis or thrombocytopenia following immunization with the ChAdOx1 nCov-19 vaccine among 28 patients, whose blood samples were referred for investigation due to suspicion of vaccine-associated blood clots.

Nine of the 11 patients were women, with a median age of 36 years, and they presented with one or more thrombotic events 5-16 days following vaccination. Six of the patients died.

Another report detailed 5 cases — all healthcare workers — presenting with venous thrombosis and thrombocytopenia within 7-10 days of receiving a first dose of the vaccine. Four of the patients experienced severe cerebral venous thrombosis with intracranial hemorrhage, and three of these patients died. As in the othe analysis, the majority (four out of five) were women.

Both cohorts reported high levels of the HIT-related antibodies platelet factor 4-polyanion complexes despite the fact that none of the patients had received heparin prior to symptom onset.

The two case reports were published Friday, April 9 in The New England Journal of Medicine.

On April 7, the European Union’s medical regulatory group issued a statement warning that blood clotting should be considered a “very rare” side effect of the ChAdOx1 nCov-19 vaccine following a review of 62 cases of cerebral venous sinus thrombosis and 24 cases of splanchnic vein thrombosis reported in the EU drug safety database that included 18 cases that resulted in death.

Around 25 million people have received the ChAdOx1 nCov-19 vaccine outside the United States, where it is not approved, and the European Medicines Agency safety committee concluded that, at present, the benefits appear to outweigh the risks.

“Covid-19 is associated with a risk of hospitalization and death. The reported combination of blood clots and low blood platelets is very rare, and the overall benefits of the vaccine in preventing Covid-19 outweigh the risks of side effects,” the group wrote.

Also on April 7, health officials in Britain announced that the ChAdOx1 nCov-19 Covid-19 vaccine would no longer be given to anyone under the age of 30 due to mounting evidence that younger people, especially women, have an increased risk of developing blood clots from the vaccine. Health officials in Italy also recommended against giving the shot to people under the age of 60.

Several other countries where the vaccine is approved, including Germany, France, Canada, and the Netherlands, had previously stopped using the vaccine in younger adults as a result of blood clotting concerns.

In the study from Germany and Austria, patients presented within 5 to 16 days of vaccination with one or more thrombotic events, with the exception of one patient, who presented with fatal intracranial hemorrhage, Andreas Greinacher, MD, of the Institut für Immunologie und Trans­fusionsmedizin, Universitätsmedizin Greifs­wald, Greifswald, Germany, and colleagues explained.

Nine patients had cerebral venous thrombosis, three had splanchnic-vein thrombosis, three had pulmonary embolism, and four had other thromboses, the report authors wrote. Six of the patients died.

Five patients had disseminated intravascular coagulation, and none had received heparin before symptom onset. All 28 patients who tested positive for antibodies against PF4-heparin tested positive on the platelet-activation assay in the presence of PF4 independent of heparin.

Platelet activation was inhibited by high levels of heparin, Fc receptor–blocking monoclonal antibody, and immune globulin (10 mg per milliliter). Additional studies with PF4 or PF4–heparin affinity purified antibodies in two patients confirmed PF4-dependent platelet activation.

The researchers noted that triggers other than heparin exposure are now understood to cause pro-thrombotic disorders that strongly resemble HIT, including exposure to certain polyanionic drugs.

“Given the parallels with autoimmune heparin-induced thrombocytopenia, anticoagulant options should include nonheparin anticoagulants used for the management of heparin-induced thrombocytopenia, unless a functional test has excluded heparin-dependent enhancement of platelet activation,” they wrote.

They suggested that these thrombotic events be named “novel entity vaccine-induced immune thrombotic thrombocytopenia (VITT) to avoid confusion with heparin-induced thrombocytopenia.”

The five cases detailed in the separate report involved four women and one man between the ages of 37 and 54 years of age, with the five cases occurring in a population of more than 130,000 vaccinated people.

Researcher Nina Schultz, MD, PhD, of Oslo University Hospital, Oslo, and colleagues wrote that their findings “indicate a shared pathophysiological basis of the condition in these five patients and should raise awareness that a syndrome similar to autoimmune heparin-induced thrombocytopenia may occur in some persons after vaccination with ChAdOx1 nCoV-19.”

“By providing a link between thrombosis and the immune system, these results strengthen the view that vaccination may have triggered the syndrome,” they wrote, adding that while it is rare, “VITT is a new phenomenon with devastating effects for otherwise healthy young adults and requires a thorough risk-benefit analysis.”

Salynn Boyles, Contributing Writer, BreakingMED™

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