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Hospitalist Sarah Stone, MD, arrived for her dayshift at Sharp Chula Vista one day in late December. The ICU and hospital wards were still overflowing with COVID-19 patients. But over the last couple months, she'd also seen more and more recovered patients presenting with a myriad of symptoms: pulmonary emboli, cardiomyopathy, a shocking case of aspergillosis, and those rare cases of "long COVID," the patients who just can't get better.
This morning it was a woman in her 30s. She felt fine, but 2 weeks after recovering from COVID-19, she had unexplained bruising on her arm, a petechiae rash on her legs, and her gums were bleeding. Once admitted to the emergency department, her platelet count of 5000/mm3 was a dead giveaway of immune thrombocytopenic purpura (ITP).
In Stone's experience, new and otherwise unexplained symptoms so soon post-COVID can't be written off as a coincidence without some additional consideration. But a quick preliminary search of the literature during her rounds came up almost empty. She found one report with three cases of post-COVID ITP. But other online resources made no mention of it. Kenneth Johnson, MD, the hematologist/oncologist consulting on the new case, told Stone he'd seen one other case of post-COVID ITP only earlier that month. Stone called a sister hospital. They'd seen one other case just weeks before.
"I was surprised to find just three cases in the literature when we had seen three among us in a matter of weeks," Stone told Medscape Medical News. Something was missing.
A Missing Link
ITP is caused by an immune reaction against a patient's own platelets. Platelet numbers drop causing easy bruising, bleeding gums, and internal bleeding. Acute cases can usually be resolved within 3 months, but for some patients the condition can be extended or even chronic.
"We know that infections like influenza can cause ITP, so in this light, [COVID-associated ITP] might not be surprising," Gerard Jansen, MD, PhD, an internist and hematologist in Rotterdam, Netherlands, told Medscape Medical News.
Jansen and his colleagues recorded three cases of post-COVID ITP in May 2020 — the report Stone had found during her shift. Two patients developed ITP several weeks after COVID-19 and responded to treatment with corticosteroids and intravenous immunoglobulin G (IVIG). The third patient, however, died of an intracerebral bleeding while still battling COVID-19. He was retrospectively diagnosed with COVID-associated ITP.
A deeper dive into the literature uncovers additional case reports from India, France, the United Kingdom, Turkey, and one from China as early as January 2020. A September 2020 review of ITP secondary to COVID included 23 papers and a total of 45 patients. The review authors note that more than 70% of cases occurred in patients who were over 50 years and 75% had had moderate-to-severe COVID infections. However, the sample size of 45 is too small to definitively describe what's happening in the overall population.
ITP's link to COVID gained a media spotlight earlier this month after the Miami obstetrician, Gregory Michael, MD, developed ITP days after getting the Pfizer COVID vaccine. In early January, after 2 weeks in the ICU, Michael died of a hemorrhagic stroke caused by the low platelet count.
Pfizer said in a statement that they are "actively investigating" the case, "but we don't believe at this time that there is any direct connection to the vaccine." Other experts have said the timing, particularly in a relatively young and healthy man, means a link to the vaccine is possible or even likely, but final results won't be known until the US Centers for Disease Control and Prevention finishes its investigation.
But "it is quite unusual to die from ITP," San Diego hematologist Johnson told Medscape Medical News. In his more than 20 years of practice, he has never had a patient die from the condition.
For his part, Jansen, the hematologist in Rotterdam, said that at this point we just don't know if there's a link between the vaccine and ITP. Both infection and drugs are well established causes of ITP, so with that general mechanism or pathology in mind it makes sense that COVID and the vaccine could instigate ITP. But it would be very difficult to prove in just one instance, he said. And considering the millions who have thus far received the vaccine without incident, and the known risks and dangers of COVID-19, "we still advise to vaccinate," he said.
The Number of Cases Is Underestimated
Since his original case report in May, Jansen has seen five or so additional cases. But the causal link between the coronavirus and the hematologic symptoms is still undefined. "We don't know much about platelet counts in COVID-19 at all," he said. It could be that COVID somehow inhibits platelet production or that it kills existing platelets. Whatever the exact relationship to the virus, Jansen expects that the true number of COVID-related ITP cases is higher than current estimates suggest.
One reason it isn't coming up more often, Jansen said, may be because the cause of ITP in COVID patients is hard to pin down. In his case report from May, Jansen and colleagues wrote: "And there are numerous other factors that can cause thrombocytopenia where COVID is concerned. For instance the coagulation activation by COVID‐19 infection leading to disseminated intravascular coagulation (DIC) and subsequent thrombocytopenia. Also, treatments for COVID‐19, including heparin, azithromycin and hydroxychloroquine, may lead to thrombocytopenia."
Tracking and understanding COVID-associated ITP first requires the extensive process of elimination needed to diagnose it.
In addition, drugs used to treat COVID could be masking COVID-related ITP. "Dexamethasone is a mainstay of COVID treatment. And it's how we treat ITP," Johnson said, which means physicians may be treating ITP without even registering it. And that's one hypothesis for why Stone and Johnson didn't see a case until 9 months into the pandemic.
Treating COVID-associated ITP also has its challenges, particularly in patients who develop it during an acute COVID infection and are at risk for both internal bleeding and thrombosis. This was the case for the third patient in Jansen's case report. The patient developed a pulmonary embolism and had a falling platelet count. He was given a platelet infusion and then an anticoagulant for the thrombosis. But a retrospective look at the case revealed the transfusion "did not increase numbers at all — which suggests ITP," Jansen said. Intracerebral bleeding was the cause of death.
That's why "it's important to be aware of this phenomenon," Jansen said of COVID-associated ITP. If a transfusion is unsuccessful, consider that the patient may have ITP and adjust. Johnson, in San Diego, hasn't had to treat a patient battling both complications simultaneously but says the ideal course of action would be to raise platelets with steroids and IVIG and then give the anticoagulant once the platelet count is higher. But reality is rarely ideal. Often these two treatments will have to be given concurrently since the patient faces two life-threatening risks, he said. "It's a very challenging situation," he said.
The good news is that standard treatments for ITP seem to work for COVID-associated ITP. Stone and Johnson's 30-year-old patient responded so well to intravenous steroids that IVIG was unnecessary. She's now on a slow prednisone taper and maintains platelet counts at 114,000/mm3 at her weekly follow-up appointments with Johnson.
Meanwhile, Jansen's two other patients, now nearly a year out of treatment, require no additional medication. One of the patients is fully recovered and, though the other still has lower than normal platelet counts, she has no bleeding symptoms and her platelet counts remain stable. Still, Jansen is anxious for more data looking at the platelet counts in every COVID-19 patient and to combine findings from existing COVID-associated ITP patients.
For Stone, she says she's added one COVID-19–associated complication to her belt. One less aftereffect will catch her off guard. And she wants others to have the same information.
"It's just a little bit daunting. We don't know how bad post-COVID will be," she said. "There's so many levels to this disease. Some people deal with it for so long and some people just get better and move on — we think...so far."
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