Living up to its former name, idiopathic thrombocytopenic purpura, the pathophysiology of what is now currently called immune thrombocytopenic purpura (ITP) remains somewhat enigmatic. A multitude of inciting factors have been identified, from infections and drugs to vaccinations and autoimmune conditions.1 Although most any vaccine can potentially trigger ITP, the alarming, emerging condition of vaccine-induced thrombotic thrombocytopenia (VITT) appears to have a specific link to the novel coronavirus (COVID-19) vaccines.2 While both clinical entities can present with signs and symptoms of thrombocytopenia, the pathophysiology and clinical management differ in significant ways. A predisposition to thrombosis, even in the setting of critical thrombocytopenia, distinguishes VITT from ITP and poses particular diagnostic and therapeutic challenges in the emergency department. In this article, a case of COVID-19 vaccine–induced ITP will be discussed in contrast with COVID-19 vaccine–induced VITT.

The Case

A 34-year-old man with a past medical history of diabetes mellitus type II, hypertension, and hyperlipidemia presented to the emergency department for bleeding lesions in his mouth. The lesions began as painless, flat purple discolorations several days prior to his ED visit. They progressed in size and number, and when they began bleeding, he sought emergency care. He otherwise felt well. The patient reported that he had received his second dose of the Moderna COVID-19 vaccine one day prior to the lesions appearing and three days prior to presenting to the emergency department. He denied any adverse reactions to the first dose of vaccine or prior history of bleeding or easy bruising. Review of systems was negative for fevers, chills, weakness, fatigue, abdominal pain, hematemesis, dark tarry stools, or hematuria. He also denied any illicit drug abuse or history of alcoholism, cancer, and HIV. His initial vital signs were normal.

On physical exam, there were two hemorrhagic bullae in the buccal region of his mouth, approximately 2 cm in diameter, and scattered petechiae on his right shoulder and bilateral lower extremities (see Figure 1). The remainder of his exam was normal. Initial bloodwork revealed a normal comprehensive metabolic panel except for a glucose of 265 mg/dL. C-reactive protein was elevated at 3.7 mg/L. Erythrocyte sedimentation rate was normal at 14 mm/hr. Complete blood count revealed a platelet value of 1×10³/µL, teardrop cells, and ovalocytes but was otherwise unremarkable. Coagulation studies were all normal, as was fibrinogen, but his D-dimer was mildly elevated at 285 ng/ml DDU (normal <250).

Reproduced with permission from Pavord et al.⁹

Clinical Course and Resolution

The patient was presumptively diagnosed with ITP, thought to be precipitated by the vaccine. He was immediately given intravenous immunoglobulin (IVIg) 1 gm/kg and methylprednisolone 60 mg IV. A CT scan of his brain was performed. A second tube of blood was sent to confirm the initial findings. The patient was promptly admitted to the ICU and underwent further workup, including HIV testing, flow cytometry of peripheral blood, hepatitis testing, antinuclear antibody (ANA) testing, and bone marrow biopsy with interventional radiology. ANA was positive at 1.4 (normal 0–0.9), and imaging revealed splenomegaly but unremarkable flow cytometry. The patient responded well to IVIg and high-dose IV steroids. He was subsequently discharged with oral prednisone after six days, with a platelet count of 285×10³/µL.

Discussion

While ITP has long been established in the medical literature, the novel COVID-19 viral infection and its respective vaccines, treatments, and side effects are still being studied across the globe. Both the illness itself and the remarkably effective vaccines have been associated with disruptions in the coagulation cascade.³ Discoveries and developments in these arenas are occurring almost daily. Currently, there are three COVID-19 vaccines approved by the Food and Drug Administration (FDA) for use in the United States: Pfizer-BioNtech, Moderna, and Johnson & Johnson.^4–6

The Johnson & Johnson vaccine utilizes an adenovirus vector and is the only single-dose formulation.^4–6 The Pfizer and Moderna formulations, by contrast, are each delivered in a two-shot regimen and have been heavily scrutinized as the first vaccines to employ the long-studied messenger RNA (mRNA) vector technology. In these vaccines, a genetically engineered mRNA molecule coding for the immunogenic coronavirus spike protein is encapsulated in a lipid nanoparticle, which facilitates cellular uptake, transport to ribosomes in the endoplasmic reticulum, and subsequent translation to endogenously produced spike protein.⁷ The mRNA is then rapidly degraded, decomposing within the cell, while the spike protein stimulates activated T cells to mount a protective immune response without the risk of active infection. While mRNA vaccine technology is relatively new in the world of vaccines, this method of treatment has been studied for years and successfully utilized in the treatment of certain cancers and genetic diseases.^7,8 

The pathogenesis of COVID-19 is complex and not fully understood. Thrombotic complications of the illness have been widely reported in patients with COVID-19, and early data suggest that the endogenous spike protein created by the vaccine response (whether by mRNA or adenovirus vector) could confer some risk of thrombotic and/or bleeding complications as well.^9–13 One theory posits that the spike protein binds to the angiotensin-converting enzyme 2 receptors on endothelial cells, resulting in a pro-thrombotic cascade.^9,10 It must be emphasized, however, that the data are conflicting and still emerging. Additionally, these effects were seen most compellingly with the AstraZeneca vaccine, which is not currently approved for use in the United States.^8,9

(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.

References

1. Silverman MA. Immune thrombocytopenia (ITP) in emergency medicine. Medscape website. Accessed Sept. 10, 2021.
2. Sangli S, Virani A, Cheronis N, et al. Thrombosis with thrombocytopenia after the messenger RNA-1273 vaccine [published online ahead of print June 29, 2021]. Ann Intern Med. 2021;174(10):1480-1482.
3. Cines DB, Bussel JB. SARS-CoV-2 vaccine-induced immune thrombotic thrombocytopenia. N Engl J Med. 2021;384(23):2254-2256.
4. Johnson & Johnson’s Janssen. Centers for Disease Control and Prevention website. Accessed Sept. 10, 2021.
5. Pfizer-BioNTech. Centers for Disease Control and Prevention website. Accessed Sept. 10, 2021.
6. Moderna. Centers for Disease Control and Prevention website. Sept. 10, 2021.
7. Schoenmaker L, Witzigmann D, Kulkarni JA, et al. mRNA-lipid nanoparticle COVID-19 vaccines: structure and stability. Int J Pharm. 2021;601:120586.
8. Heublein M, Gandhi M, Chiu C, et al.  COVID-19 Vaccines with Dr. Monica Gandhi. The Curbsiders website. Accessed Sept. 10, 2021.
9. Pavord S, Lester W, Makris M, et al. Guidance from the expert haematology panel (EHP) on Covid-19 vaccine-induced immune thrombocytopenia and thrombosis (VITT). British Society for Haematology website. Accessed Sept. 10, 2021.
10. Kowarz E, Krutzke L, Reis J, et al. “Vaccine-induced Covid-19 mimicry” syndrome: splice reactions within the SARS-CoV-2 spike open reading frame result in spike protein variants that may cause thromboembolic events in patients immunized with vector-based vaccines. Research Square website. Accessed Sept. 10, 2021.
11. Lu L, Xiong W, Mu J, et al. The potential neurological effect of the COVID-19 vaccines: a review. Acta Neurol Scand. 2021;144(1):3-12.
12. Greinacher A, Thiele T, Warkentin TE, et al. A prothrombotic thrombocytopenic disorder resembling heparin-induced thrombocytopenia following coronavirus-19 vaccination. Research Square website. Accessed Sept. 10, 2021.
13. Greinacher A, Selleng K, Mayerle J, et al. Anti-SARS-CoV-2 spike protein and anti-platelet factor 4 antibody responses induced by COVID-19 disease and ChAdOx1 nCov-19 vaccination. Research Square website. Accessed Sept. 10, 2021.
14. Arepally GM, Padmanabhan A. Heparin-induced thrombocytopenia: a focus on thrombosis. Arterioscler Thromb Vasc Biol. 2021;41(1):141-152. doi:10.1161/ATVBAHA.120.315445.
15. Immune thrombocytopenia. National Organization for Rare Disorders website. Accessed Sept. 10, 2021.
16. Zeller B, Helgestad J, Hellebostad M, et al. Immune thrombocytopenic purpura in childhood in Norway: a prospective, population-based registration. Pediatr Hematol Oncol. 2000;17(7):551-558.
17. Dominguez M. Immune thrombocytopenia (ITP). Medbullets website. Accessed Sept. 10, 2021.
18. Patriarcheas V, Pikoulas A, Kostis M, et al. Heparin-induced thrombocytopenia: pathophysiology, diagnosis and management. Cureus. 2020;12(3):e7385.
19. Linkins LA. Heparin induced thrombocytopenia. BMJ. 2015;350:g7566.
20. Warkentin TE, Pai M, Linkins LA. Direct oral anticoagulants for treatment of HIT: update of Hamilton experience and literature review. Blood. 2017;130(9):1104-1113.
21. Padmanabhan A, Jones CG, Pechauer SM, et al. IVIg for treatment of severe refractory heparin-induced thrombocytopenia. Chest. 2017;152(3):478-485.