Rare But Emerging Conditions Associated with COVID-19 Vaccines

Figure 1: Clinical findings included hemorrhagic bullae in the buccal region of the patient’s mouth (left) and scattered petechiae on his lower extremities (right)

Table 1: Management of COVID-19 Vaccine–Related ITP vs. VITT1,9

(click for larger image) Table 1: Management of COVID-19 Vaccine–Related ITP vs. VITT1,⁹

Putting aside the undefined risk of the vaccine-induced spike protein response, the pathogenesis of COVID-19 vaccine–induced VITT does also seem to share pathophysiology with another well-established condition, heparin-induced thrombocytopenia (HIT). In almost every case of COVID-19 vaccine–related VITT, high levels of antibodies to platelet factor 4 (PF4)–polyanion complexes were identified.^9,13 The same PF4 complexes are typically detected in patients with HIT, in which heparin binds to PF4, creating a heparin-PF4 complex, which is then recognized and bound by IgG, resulting in platelet activation, binding, and destruction.¹⁴ It is theorized that the spike protein may similarly bind PF4, resulting in the same platelet activation, binding, and destruction, but this has not been definitively proven.⁹

Practically speaking, when facing a recently vaccinated patient with thrombocytopenia, how can emergency physicians differentiate between ITP and VITT, and why does it matter?

As the name implies, the difference lies in whether the patient is also experiencing or at risk of thrombosis in the presence of their thrombocytopenia, a phenomenon not seen in classic ITP. It must be stressed, however, that clinical signs of thrombosis may be elusive. In the event of venous thromboembolism (VTE), signs include classic evidence of deep vein thrombosis (DVT) or pulmonary embolism (PE), such as unilateral extremity pain/swelling, chest pain, and dyspnea. In other less common sites of thrombosis, such as cerebral venous sinus thrombosis (CVST), signs may be subtle, including headache, vomiting, or visual changes, with or without a focal neurological deficit. Given that thrombosis can occur at any site in the body, the best initial approach includes a thorough history and physical plus full review of systems, with additional testing targeted by individual findings and clinical suspicion. In the absence of overt clinical signs of thrombosis, another promising method to screen for VITT is by checking D-dimer levels.⁹ In a patient with post-vaccination thrombocytopenia, a D-dimer of >2,000 ng/mL with strong clinical suspicion of thrombosis or a D-dimer of >4,000 ng/mL alone makes a strong case for VITT. If these criteria are met, one can reasonably begin treatment while awaiting a more definitive diagnosis in consultation with Hematology. The diagnosis of VITT can be firmly established with a PF4 ELISA assay, which is unlikely to be available on-site in many hospitals. By contrast, D-dimer levels are widely available and will not typically be grossly elevated in ITP (some studies suggest minor elevations but nowhere near the several thousand threshold for VITT diagnosis), rendering it an excellent discerning piece of evidence.^9,16,17

Determining whether a patient has COVID-19 vaccine–induced ITP versus VITT is critical when choosing a treatment algorithm. As detailed in Table 1 below, treatment pathways for each condition are distinct. It should be noted that there have not been nearly enough cases to definitively substantiate all aspects of proposed VITT treatment algorithms, but the following table represents expert consensus regarding best practice for early therapy in COVID-19 vaccine–related VITT.⁹

While the pathophysiologies of VITT and HIT are similar, the treatments do diverge slightly. Because HIT is caused by heparin, the first step is to discontinue it. The relatively short half-life of heparin renders HIT relatively reversible and treatable.^18–20 Once heparin has been discontinued, treatment with non-heparin anticoagulants (warfarin or direct oral anticoagulants) should be initiated because the HIT antibody continues to activate platelets, leading to their binding, thrombosis, and destruction. Anticoagulation should generally be continued until platelet values normalize, but there still is no clear consensus on this timing.²⁰ Interestingly, IVIg has shown positive results in select cases of HIT, but in practice. it is rarely required.²¹ Additionally, there has typically been no role of steroids or rituximab in the treatment of HIT, further differentiating it from management of VITT.^19-21

Conclusion

Despite the rare, emerging hematologic complications of both COVID-19 and the novel coronavirus vaccines, the massive benefit of the COVID-19 vaccines cannot be understated. These exceptional vaccines have prevented millions of infections and continue to save lives around the world.

In determining the risk-benefit ratio of administering the vaccine to patients with preexisting risk factors for ITP and VITT, such as prior history of ITP or HIT, the data are still emerging, and decisions must be made on a case-by-case basis. Patients with prior history of autoimmune disease or ITP would be well-advised to seek counsel from their rheumatologist or hematologist, respectively. Clinicians must carefully weigh the dangers and susceptibility of their patients with regards to COVID-19 infection against the extremely rare complications observed with the vaccines. The incidence of symptomatic thrombocytopenia post-vaccination is well below the risk of death and morbidity from COVID-19.³ When patients do present with sudden and significant thrombocytopenia post-vaccination, the emergency physician must understand the difference between ITP and VITT and actively investigate clinical signs of thrombosis. In the absence of a newly diagnosed thrombosis, the astute emergency physician may consider checking a D-dimer in order to properly diagnose the cause of thrombocytopenia before initiating therapy for ITP or VITT.

Dr. Goodwin and Dr. Latimore are PGY2 emergency medicine residents at Aventura Hospital and Medical Center in Miami. Dr. Baker is residency program director and associate professor of emergency medicine at NYU Grossman School of Medicine in New York City.