key: cord-0691899-t1vo3xco
authors: Andraska, E.A.; Kulkarni, R.; Chaudhary, M.; Sachdev, U.
title: Three cases of acute venous thromboembolism in females following vaccination for COVID-19
date: 2021-08-02
journal: J Vasc Surg Venous Lymphat Disord
DOI: 10.1016/j.jvsv.2021.07.009
sha: 9bef4f0c28c04169325b64f9fd3d322d207d2cb5
doc_id: 691899
cord_uid: t1vo3xco

Since December 2020, four vaccines for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been developed and three have been approved for immediate use in the United States. Two are mRNA vaccines, while one uses a viral vector mechanism. There are reports of thrombotic complications following vaccine administration, which are primarily cerebral sinus thromboses following administration of the viral vector vaccines. Here, we are the first to report venous thrombotic complications within days of administration of the mRNA-1273 (Moderna) vaccine. We present a series of three women who developed venous thromboembolism (VTE) following mRNA-1273 vaccination at a single healthcare system.

In response to the pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-4

CoV-2; COVID-19 pandemic), four vaccinations have been rapidly developed worldwide. Two 5 of these vaccines utilize mRNA coded to the spike protein antigen of SARS-CoV-2, and two use 6 a viral vector for vaccination 1 . Three of these vaccines have been approved in the United States 7 and since December 2020, the United States has vaccinated over 60 million people. While the 8 vast majority of persons experience uncomplicated vaccinations, there has been growing 9 documentation of serious thrombotic complications after administration of COVID-19 10 vaccines 2,3 . Further, there have been recent reports of cerebral venous sinus thrombosis in 11 women after receiving the Ad26.COV2.S (Johnson & Johnson/Janssen) vaccine 4 ; which has 12 caused the US Food and Drug Association (FDA) to recommend a pause in its use in the United 13

States 5 . 14 15

The mRNA-1273 (Moderna) vaccine was first approved in December 2020. Since that time, its 16 safety profile has been excellent, with the majority of adverse events reported involving flu-like 17 symptoms and muscle pain 6 . While there are cases of thrombotic complications documented 18 following other vaccines, there are no documented cases of thrombotic complications following 19 the mRNA-1273 vaccine. Here, we present a series of three women who presented to a single 20 hospital system with acute venous thromboembolism (VTE) shortly after vaccination with the 21 mRNA-1273 vaccine. 22

Index case 3 4 An otherwise healthy 25-year-old woman presented to the emergency department two days after 5 receiving the first of the mRNA-1273 vaccine series with acute onset shortness of breath and 6 dyspnea on exertion. She took oral contraceptive pills (OCPs) for years prior to this admission. 7 8 Clinical details are outlined in Table I . On presentation, she did not require supplemental 9

oxygen. An echocardiogram was performed which noted mild/moderate right ventricular strain. 10

A computed tomography scan with dedicated pulmonary embolism (PE) protocol (CTA-PE) 11 revealed bilateral segmental PE (Figure 1) . Venous dopplers showed no deep venous thrombosis 12 (DVT). She was admitted to the intensive care unit (ICU) and monitored on a heparin drip. Her 13 symptoms improved with heparin. She was discharged on hospital day 3 after being transitioned 14 to apixaban. 15

A 77-year-old female with a history of gastrointestinal bleeds presented to the emergency 19 department with four days of shortness of breath. She had received the first of the mRNA-1273 20 vaccine series three days prior to symptom onset. She had a remote history of breast cancer, 21 which was diagnosed and treated in 2009. She was prescribed Raloxifene for osteoporosis, which 22

she stated she had been taking for years. 23 arrival to the hospital. Echocardiogram showed mild right ventricular strain. CTA-PE was 3 notable for bilateral segmental PE (Figure 2) . Venous dopplers revealed DVT of the right 4 common femoral, femoral, and profunda veins. She was admitted to the ICU on twice daily 5 therapeutic lovenox. Overnight, her symptoms improved, and her oxygen requirement dropped to 6 3 liters. She was discharged on hospital day 5 on rivaroxaban. 7 8 An 84-year-old female presented with 8 days left leg pain and swelling. Her symptoms started 9 three days after receiving the second shot of the mRNA-1273 vaccine series. CTA-PE showed no 10 PE but did reveal thrombus in the common femoral vein (Figure 3) . Venous duplex confirmed 11 left common femoral, popliteal, and peroneal DVT. She was admitted to a monitored floor on a 12 heparin drip. Her symptoms improved on a heparin drip and was ultimately discharged hospital 13 day 3 on apixaban. 14 15 In all cases, patients were active and lived independently. They denied personal or family history 16 of VTE, recent surgery, trauma, or any recent travel. Each patient was tested for COVID and 17 were negative. Hematology performed a hypercoagulable panel in all patients which was 18 negative for a genetic predisposition to VTE (hospital days 2-4). None of the three women have 19 been seen in follow-up. All patients involved in the current series consented to be included in 20 this report. While risk of thrombosis following infection with COVID-19 is well documented 7-9 , the risk of a 6 COVID-19 vaccine is not well known. In recent weeks there has been growing recognition of a 7 potential thrombotic risks following vaccination for COVID-19. Cerebral venous sinus 8 thrombosis has been identified following both the Ad26.COV2.S and ChAdOx1 nCov-19 9 vaccines 2,4,5 . Patients with these complications have been found to develop a spontaneous 10 immune thrombotic thrombocytopenia mediated by platelet-activating antibodies against PF4, 11 similar to autoimmune heparin-induced thrombocytopenia 2,3 . In March 2021, use of the 12 ChAdOx1 nCov-19 was temporarily halted in some European countries due to these safety 13 concerns 10 . Additionally, these cases have lead the FDA to recommend a temporary pause in the 14 use of the Ad26.COV2.S vaccine in the United States 5 . It is possible that a similar mechanism is 15 occurring in the patients in this case series. 16 17 While the majority of thrombotic complications following COVID-19 vaccines are primarily 18 from the ChAdOx1 nCov-19 or Ad26.COV2.S vaccines, there is one reported case of a popliteal 19 and peroneal DVT after the second dose of the BNT162b2 (Pfizer-BioNTech) vaccine 11 . Of 20 note, this patient was found to be heterozygous for the Factor V Leiden mutation. To date, this 21 series is the first to report VTE after the mRNA-1273 vaccine in patient with no other apparent 22 risk factors. 23 J o u r n a l P r e -p r o o f 1 One of the patients in this series had a remote history of breast cancer and was also 2 concomitantly prescribed Raloxifene for osteoporosis. Raloxifene has been documented to have 3 a slightly elevated risk of venous thromboembolism compared to non-users (0.27 vs. 0.39, HR 4 1.44) 12 . However, the patient in this series endorsed chronic use of this medication without any 5 prior adverse effects. Additionally, another patient in the series was taking OCPs at the time of 6 her event. OCPs have a relative risk of venous thrombosis 3.5 compared to non-users 13 . 7

Similarly, this patient endorsed chronic use of this medication without prior adverse effects. 8

While it is impossible to determine the exact mechanism of venous thrombosis here, the timing 9 of onset is concerning for a potential connection to the COVID-19 vaccine itself. Additionally, it 10 was not documented whether these patients experienced malaise after the vaccine or mobility-11 limiting complications after vaccine administration. It is possible that these patients could have 12 had a reduction in functional mobility that could lead to venous stasis and thus VTE. 13 14 With mass vaccination campaigns and new vaccines arriving on the market, there is incentive to 15 identify and quantify the incidence of thrombotic events following COVID-19 vaccination. Li et 16 al analyzed a multi-national network of administrative claims data to characterize and estimate 17 adverse events following COVID-19 vaccines. PE was estimated to be as high as 427 events per 18 vaccination campaign and the vaccination itself is a confounding variable. However, the timing 1 of the VTE events suggest a possible relationship that is important to document. It is imperative 2 to obtain vaccination history in patients with symptoms of VTE with no other obvious 3 predisposing factors. Furthermore, given the rapid and widespread vaccination campaigns, 4 reports of adverse events following the new COVID-19 vaccines are essential to the proper care 5 and education of these patients. 6 7 Conclusions 8 9

We report three cases of VTE after the mRNA-1273 at a single healthcare system. While 10 vaccination for COVID-19 is essential in the pandemic, we should continue to be vigilant for any 11 potential adverse effects. 12 thrombosis associated with thrombocytopenia post-vaccination for COVID-19. 

for Disease Control and Prevention. COVID-19 Vaccines

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