Introduction
Vascular malformations, caused by either inherited or sporadic mutations, are present at birth1 but may not become clinically obvious until later. Slow-flow vascular malformations (SFVM)—both lymphatic and venous malformations—are associated with enlargement in the setting of infection, trauma, or hormonal changes (pregnancy or puberty).1-3 To date, the role of vaccination in the exacerbation and clinical emergence of SFVMs has been underdiscussed in the literature. We present a case series of three consecutive patients who presented to an outpatient vascular anomalies clinic with new clinical presentation or exacerbations of venous malformation after COVID-19 vaccination.
Case series
The case series received IRB approval with a waiver of informed consent. Three adult patients who presented to our outpatient vascular anomalies clinic with a new complaint of possible vascular anomaly were observed after our patient clinic had fully resumed regular clinical volume between September 2021 and November 2021.
Case 1
A 72-year-old female with no past medical history of vascular malformation or history of COVID-19 infection received 2 doses of the Moderna (mRNA-1273) COVID-19 vaccine in her left upper arm with the 2 doses given 4 weeks apart. The patient reported noticing a left forearm mass 6 weeks after her second dose, as well as significant lateral arm pain that lasted 10 days. She later presented to our vascular anomalies clinic with the primary complaint of a mass on her left, proximal, ventral forearm. Magnetic resonance imaging (MRI) demonstrated venous malformation in her left forearm (Fig. 1). The patient was ultimately recommended for 6-month follow up with repeat ultrasound.
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Figure 1.: (A) B-mode ultrasound image (EPIQ 5G, Philips Medical Systems, Milwaukee, WI) demonstrating the hypoechoic venous malformation (circle) with an internal echogenic phlebolith (arrow) and posterior acoustic shadowing. (B) T2-weighted magnetic resonance (Magnetom, 1.5 Tesla; Siemens Healthineers, Germany) coronal image (TE, 90 ms; TR, 4480 ms; FA, 160°) with fat saturation demonstrating a 4.1 × 1.4 × 6.8 cm heterogenous hyperintense venous malformation (circle) at the ventral aspect of the left elbow with an internal phlebolith (asterisk). (C) Enhanced T1-weighted coronal image (TE, 4.42 ms; TR, 263 ms; FA, 70°) demonstrating delayed venous filling of the venous malformation (circle) with enhancement of the nearby median cubital vein.
Case 2
A 25-year-old female who was born with slight skin discoloration at her left clavicle and shoulder region reported that, 3 years prior, she noted a non-painful small lump in her left, supra-clavicular region that would intermittently appear. At the time, she attributed this to a reactive lymph node and did not seek further work up. She reported that she was in an otherwise normal state of health and reported no history of COVID-19 infection when she received the Pfizer (BNT162b2) COVID-19 vaccine series in her left upper arm with the 2 doses given 4 weeks apart. Four weeks after her second dose, she noticed pain in her left supraclavicular region and a palpable mass at the same site of her previously palpable mass. She presented to an outside facility where she had a CTA and a surgical biopsy which demonstrated a benign vascular lesion. An MRI performed at the time of presentation to our institution demonstrated an intramuscular venous malformation at the left deltoid (Fig. 2). As the patient did not report significant symptoms or functional impairment, she was recommended to follow up if her symptoms worsened.
Figure 2.: (A,B) T2-weighted magnetic resonance (Skyra, 3 Tesla; Siemens Healthineers, Germany) axial images (TE, 93 ms; TR, 3010 ms; FA, 150°) with fat saturation demonstrating a 4.1 × 1.8 × 5.1 cm venous malformation (circle) at the left deltoid (A) with an internal phlebolith (arrow) as well as (B) smaller intramuscular malformations seen at the anterior and posterior muscles of the shoulder (asterisks). (C) Enhanced T1-weighted axial image (TE, 4.42 ms; TR, 290 ms; FA, 70°) demonstrating delayed venous filling of the left deltoid venous malformation with internal fluid-fluid level, likely hematocrit deposition (arrow).
Case 3
A 52-year-old female with no prior history of vascular malformation or COVID-19 infection presented to our outpatient vascular anomalies clinic with the chief complaint of a large lump superior to her right clavicle that she noticed two weeks after receiving the Johnson & Johnson’s Janssen (Ad.26.COV2.S) COVID-19 vaccination in her right arm and has since grown in size. According to her, the mass fluctuates in size and is associated with localized, dull achy, 4/10 pain. Stress and lifting heavy objects aggravate her pain, while a hot bath alleviates it. Phleboliths were palpable within the mass during the physical examination. Magnetic resonance imaging (MRI) revealed a venous malformation in the supraclavicular region (Fig. 3). Elective percutaneous sclerotherapy was recommended for the patient.
Figure 3.: (A) T2-weighted magnetic resonance (Skyra, 3 Tesla; Siemens Healthineers, Germany) axial image (TE, 93 ms; TR, 4730 ms; FA, 150°) with fat saturation demonstrating a 2.8 × 2.1 × 1.8 cm hyperintense venous malformation (circle) at the right ventral supraclavicular space showing an internal phlebolith (arrow) and fluid-fluid level suggestive of hematocrit deposition (asterisks). (B) Magnetic resonance angiography image (TWIST sequence) demonstrating partial delayed venous filling of the venous malformation (arrow).
Discussion
To date, few studies have discussed the association between vaccinations and vascular malformation exacerbation. The COVID-19 vaccinations have been associated with a systemic inflammatory response, with recent studies demonstrating vaccine related axillary adenopathy4.
COVID-19 vaccinations may induce a greater inflammatory response when compared to other vaccines. Interestingly, while inflammation is a well-recognized trigger for SFVM exacerbation, the genetic and molecular impact of inflammation on the exacerbation and clinical emergence of SFVMs is incompletely understood. Early research suggests that inflammation may lead to the recruitment of macrophages expressing vascular endothelial growth factor A (VEGFA)—a mitogen involved in vasculogenesis—and monocytes to the site of venous malformations where VEGFA receptors are expressed on endothelial cells5.
In this case series, subclinical venous malformations in these patients may have been uncovered by the systemic inflammation associated with COVID-19 vaccination. This series also suggests that clinical enlargement of vascular malformations after SARS-CoV-2 vaccination does not result in adverse clinical course.
Conclusions
While data emerging since Spring 2020 suggest that COVID-19 vaccination is safe and effective, especially when compared to the clinical sequala of COVID-19 itself, systemic inflammation associated with COVID-19 vaccination may play a role in the uncovering of previously existing but clinically silent venous malformations.
Conflict of interest statement
The authors declare that they have no financial conflict of interest with regard to the content of this report.
References
1. Mulliken JB, Burrows PE, Fishman SJ, eds. Mulliken and Young’s Vascular Anomalies: Hemangiomas and Malformations. Oxford University Press; 2013.
2. Markovic JN, Shortell CK. Venous malformations. J Cardiovasc Surg (Torino). 2021;62:456–466.
3. Kumar S, Lanzino G, Brinjikji W, Hocquard KW, Flemming KD. Infratentorial developmental venous abnormalities and inflammation increase odds of sporadic cavernous malformation. J Stroke Cerebrovasc Dis. 2019;28:1662–1667.
4. Mortazavi S. COVID-19 Vaccination–associated axillary adenopathy: imaging findings and follow-up recommendations in 23 women. Am J Roentgenol. 2021;217:857–858.
5. Li Y, Yang J, Huang Y, et al. Cellular heterogeneity and immune microenvironment revealed by single-cell transcriptome in
venous malformation and cavernous
venous malformation. J Mol Cell Cardiol. 2022;162:130–143.
