Unprovoked Venous Thrombosis Following COVID-19 Vaccination: A Retrospective Analysis of the Role of mRNA Vaccines

Abstract

Background

Despite the effectiveness of COVID-19 vaccines in combating the infection through neutralizing antibodies, several side effects have been documented. Vigilant drug safety surveillance has gathered reports on vaccine-induced adverse effects, mainly mild to moderate in severity. Rarely, severe adverse effects such as anaphylaxis, thrombosis, and thrombocytopenia have been observed. Among these, thrombosis emerged as a particularly concerning issue.

Objectives

This has prompted an investigation into the potential existence of a valid link between the vaccine and the occurrence of thrombosis.

Methods

This case series is aimed to assess clinical features of venous thrombosis after injection of two anti-COVID-19 vaccines: the Pfizer-bioNTech vaccine (BNT162b2) and the Moderna (mRNA-1273) vaccine.

Results

We summarized all the salient demographic and clinical features, vaccination details, laboratory investigations, and outcomes. The individual cases are highlighted in more detail. In this case series involving seven patients, we observed rare adverse effects of venous thromboembolism (VTE) following COVID-19 vaccinations of mRNA vaccines, including Pfizer-bioNTech and Moderna.

Conclusion

While our findings addressed the rare adverse effect of VTE postvaccination, it is crucial to recognize the overall benefits of these vaccines in combating the COVID-19 pandemic. The underlying mechanism behind thromboembolism due to mRNA vaccines remains uncertain, distinguishing these cases from those related to adenovirus-based vaccines. More studies will be needed to establish if any relation exists.

Keywords

COVID-19 - management - prognosis - thrombosis - unprovoked thrombosis

Introduction

To combat the COVID-19 pandemic, Qatar has administered 7,609,178 vaccine doses.[1] The primary vaccines used are the FDA-approved Pfizer-bioNTech (BNT162b2) and Moderna (mRNA-1273).[2] The vaccines were rapidly introduced relatively quickly, necessitating continuous and thorough safety monitoring to detect and investigate potential adverse effects.[3] Despite the effectiveness of these vaccines in combating COVID-19 infection through neutralizing antibodies, numerous side effects have been documented.[4] [5] Vigilant drug safety surveillance has gathered reports on vaccine-induced adverse effects, mainly mild to moderate in severity. Rarely, severe adverse effects such as anaphylaxis, thrombosis, and thrombocytopenia have been observed.[5] Among these, thrombosis emerged as a particularly concerning issue[3] [4] [5] [6] [7] [8] [9] [10] [11] [12] as a postvaccination adverse event.

Thrombosis can arise from a range of well-known risk factors, including recent trauma to the leg, recent surgeries, family history of thrombosis, and prolonged immobility.[7] Common risk factors for vascular thrombotic events encompass age, obesity, diabetes mellitus (DM), hypertension (HTN), hypertriglyceridemia, infections (systemic and localized), inflammatory diseases, and malignancies.[8] Currently, the only recognized risk factors following mRNA vaccination are female gender and age below 60 years.[4] This has prompted an investigation into the potential existence of a valid link between the vaccine and the occurrence of thrombosis.[3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18]

There are several tertiary care hospitals in Qatar. Hamad General Hospital (HGH) in Doha is one of the largest tertiary care centers in the country. We reported seven cases from the anticoagulation clinic, part of HGH. This case series aims to assess the clinical presentation and diagnostic challenges of venous thrombosis, an adverse event following COVID-19 vaccination with the Pfizer-bioNTech (BNT162b2) and Moderna (mRNA-1273) vaccines.

Case Series

[Tables 1] and [2] summarize all the salient demographic and clinical features, vaccination details, laboratory investigations, and outcomes. The individual cases are highlighted in more detail.

Table 1 Summary of the clinical features, thrombosis site details, laboratory results, and vaccine details of all presented patients

Case	1	2	3	4	5	6	7
Demographics
Age (y)	34	29	36	39	42	57	39
Sex	Female	Male	Male	Male	Female	Male	Male
Smoking	Nonsmoker	Nonsmoker	Nonsmoker	Nonsmoker	Nonsmoker	Nonsmoker	Nonsmoker
Body mass index (kg/m2)	25.38	27.2	36.63	28.41	23.12	26.14	27.72
Vaccine details
Vaccine name	Pfizer	Moderna	Pfizer	Moderna	Pfizer	Moderna	Pfizer
Number of doses	2	2	2	2	2	2	2
Presentations
Onset of symptoms postvaccination (d)	20	87	32	17	5	10	21
Presenting symptoms	Right lower leg swelling and pain with shortness of breath	Left lower leg pain	Pleuritic chest pain and shortness of breath	Left shoulder pain + swelling, discoloration and restricted movement	Left leg pain and swelling	Shortness of breath, nonproductive cough, and left leg pain	Epigastric pain
Type of thrombosis	DVT	Superficial vein thrombosis	DVT	DVT	DVT	DVT	PVT
DVT	1	0	1	1	1	1	0
DVT + PE	1	0	1	1	0	1	0
PVT	0	0	0	0	0	0	1
Site of thrombosis	Right lower leg	Left lower leg	Left lower leg	Left subclavian, axillary, and brachial veins	Left common femoral and proximal superficial veins	Left lower leg	Right and left main portal veins

Abbreviations: DVT, deep venous thrombosis; Full recovery, full recovery with no complications or recurrences; PE, pulmonary embolism; PVT, portal vein thrombosis.

Table 2 Summary of the laboratory tests and treatment outcomes of all presented patients

Case	1	2	3	4	5	6	7
Laboratory tests
White blood count (×103/µL)	15.4	7.8	5.9	7.2	11.1	8	6.1
Hemoglobin (g/dL)	7.2	19.7	12.2	14	5.8	11.3	14.7
Platelets (×103/µL)	439	250	226	255	610	168	213
Mean platelet volume (fL)	9.5	9.1	10.4	9.1	9.4	10.8	10.6
Prothrombin time (s)	11.4	12	11.7	9.6	10.8	9.9	10.7
APPT (s)	27.9	30.1	28.2	26.4	26.5	33.3	25.4
INR	1.1	1.1	1	0.9	1	1	1
D-dimer (mg/L FEU)	2.17	1.88	NA	1.21	2.32	13.36	NA
Treatment and outcome
Anticoagulation	Rivaroxaban	Rivaroxaban	Apixaban	Rivaroxaban	Rivaroxaban	Rivaroxaban	Rivaroxaban
Clinical outcome	Full recovery	Full recovery	Full recovery	Full recovery	Full recovery	Full recovery	Full recovery

Abbreviations: APPT, activated partial thromboplastin time; DVT, deep venous thrombosis; FEU, fibrinogen equivalent units; Full recovery, Full recovery with no complications or recurrences; INR, international normalized ratio; NA, not applicable; PE, pulmonary embolism; PVT, portal vein thrombosis.

Case 1

A 34-year-old woman presented with acute complaints of right lower leg swelling and pain for 1 day. She also reported experiencing shortness of breath and generalized weakness. She did not report other associated complaints. The patient had no history of smoking or alcohol consumption and denied any recent immobilization, travel history, trauma, contraceptive use, or chronic medical conditions. Notably, she had received her second dose of the COVID-19 Pfizer vaccination 20 days before symptom onset. The laboratory and radiological investigations were performed. Computed tomography pulmonary angiography (CTPA) revealed filling defects in segmental arteries of the left posterior lung, indicative of pulmonary embolism (PE).

Additionally, a Doppler ultrasound detected deep venous thrombosis (DVT) in the right lower leg. Thrombophilia workup yielded negative results, failing to identify any underlying cause for the thrombotic event. She was promptly initiated on oral anticoagulant therapy with rivaroxaban 20 mg. The prescribed medication was continued for 6 months but was subsequently discontinued due to menorrhagia. Over a follow-up period of 24 months, no further complications or recurrences were reported.

Case 2

A 29-year-old man presented to the hospital with a complaint of left lower calf pain persisting for 4 days. He had no medical history, surgery, recent travel, or immobilization. The patient was a nonsmoker and nonalcoholic. Notably, 3 months before the presentation, the patient received both doses of the Moderna COVID-19 vaccine. Physical examination revealed unilateral swelling and redness in the left lower calf region. The radiological investigations were performed along with blood biochemistry. Doppler ultrasound examination confirmed the presence of superficial vein thrombosis with no evidence of DVT. Initial laboratory investigations showed polycythemia with a hematocrit (HCT) level of 57%. The JAK-2 test, used to assess for underlying polycythemia vera or myeloproliferative disorders, yielded negative results. The treatment plan was initiated with rivaroxaban 20 mg. The patient was followed up at the clinic regularly for 3 months. At the 3-month follow-up visit, the clinical decision was to discontinue anticoagulation therapy since there was no underlying pathology. Further, the patient had a 24-month follow-up with no complications or recurrence of thrombotic events.

Case 3

A 36-year-old male patient with Klinefelter's syndrome complained of a sudden onset pleuritic chest pain and shortness of breath. He did not report any other systemic and associated symptoms. He had no other medical or surgical history, travel, or immobilization. The patient had been undergoing treatment for infertility for the past 4 months, receiving anastrozole and chorionic gonadotropin 50,000 units intramuscularly. Additionally, the patient received the second dose of the Pfizer COVID-19 vaccine 1 month ago. The physical examination was unremarkable. Laboratory investigations revealed normal blood biochemistry. However, CTPA detected bilateral PE among the radiological investigations. A Doppler ultrasound study confirmed the presence of deep vein thrombosis in the left lower leg. Thrombophilia workup was negative for any disease. The patient was initiated on oral anticoagulant therapy with apixaban 5 mg, and a clinical decision was made to continue for 12 months. The patient's subsequent follow-up examinations over 12 months showed no recurrence of symptoms or complications.

Case 4

A 39-year-old man with no medical history presented with chest discomfort and left shoulder pain for 4 days. The left shoulder pain was accompanied by swelling, discoloration, and restricted movement. He did not have any past medical or surgical history. The patient denied any history of trauma or strenuous physical activity involving his arm and was not taking any medications. He reported no associated symptoms such as fever, night sweats, chest pain, dyspnea, or hemoptysis. He never smoked or drank alcohol. However, the patient received the second Moderna vaccine 2 weeks back in the same left arm. On physical examination, the left upper limb was observed to have swelling and tenderness, along with superficial dilated veins over the upper part of the left chest, with no associated lymphadenopathy.

Consequently, radiological investigations of X-ray, CT, and ultrasound were performed. Ultrasound Doppler of the upper limb veins revealed thrombosis in the subclavian, axillary, and brachial veins (proximal to middle part). However, the distal brachial, radial, ulnar, and cephalic veins appeared patent. The patient was diagnosed with left upper arm DVT involving the left subclavian, axillary, and brachial veins. Chest X-ray and CT scans were negative for PE. Thrombophilia workup yielded negative results. The treatment plan involved initiating an oral anticoagulant therapy with rivaroxaban 20 mg. He followed the anticoagulation regimen for 3 months under physician supervision, after which it was discontinued. The patient underwent a 24-month follow-up, during which no complications or recurrence was reported.

Case 5

A 42-year-old woman presented with a 4-day history of progressive left leg pain and swelling. The patient denied having a fever, cough, joint swelling, skin rash, and other associated symptoms. She does not smoke or consume alcohol. She had no recent history of immobility, contraceptive use, or chronic medical conditions. Additionally, there were no reported incidents of trauma or travel within the past 2 years. She had a history of two prior cesarean sections, both uncomplicated, with the most recent one occurring 4 years ago. The patient received her second dose of the Pfizer COVID-19 vaccine 5 days before presentation. During the examination, the patient exhibited a limp due to pain in the lower leg. The affected area had notable swelling, tenderness, and firmness compared with the contralateral side. Motor and sensory function remained intact in all limbs. Upon radiological investigations, an ultrasound Doppler evaluation of the lower limb veins revealed left common femoral and proximal superficial femoral vein thrombosis. Thrombophilia workup showed negative results. The diagnosis was made as unprovoked proximal DVT. The patient was initiated on an oral anticoagulant, rivaroxaban 20 mg, and continued the medication for 12 months. However, due to severe menorrhagia, anticoagulant therapy was discontinued after a follow-up ultrasound showed partial recanalization of the femoral vein. Subsequent follow-ups over 26 months revealed no complications or recurrence of DVT.

Case 6

A 57-year-old man presented with progressive shortness of breath and a nonproductive cough for 2 weeks. He also reported having left leg pain. He is known to have HTN and DM. The patient denied any hemoptysis, chest pain, shoulder pain, abdominal pain, neck pain, headache, or any other associated symptom. There was no history of asthma, recent travel, or immobility history. He is a nonsmoker and nonalcoholic. He received his second dose of the Moderna COVID-19 vaccine 10 days before his presentation. Upon examination, the patient's oxygen saturation was 91% on room air, indicating hemodynamic instability. Initial laboratory investigations revealed elevated troponin T- and D-dimer levels.

Further radiological investigation with a CTPA confirmed the presence of a massive bilateral PE. Echocardiography also demonstrated severely elevated pulmonary artery pressure. Furthermore, a lower limb Doppler ultrasound revealed the presence of DVT in the left leg. Thrombophilia workup yielded negative results. Immediate treatment was initiated, and the patient was started on therapeutic anticoagulation with rivaroxaban 20 mg. Regular follow-up appointments were scheduled for 24 months to monitor the patient's progress and response to treatment. During this period, pulmonary HTN resolved, and there were no complications or recurrence of DVT. The clinical decision was made to continue lifelong anticoagulation with rivaroxaban.

Case 7

A 39-year-old man presented with a 4-day history of epigastric pain with radiation to the back. The pain was exacerbated postprandial and was accompanied by a loss of appetite. Additionally, the patient reported experiencing bloating over the past 5 days. He did not report having symptoms of nausea, vomiting, diarrhea, constipation, or melena. Furthermore, there were no complaints of chest pain, back pain, fever, dyspnea, or weight loss. The past medical history was significant for dyslipidemia. He did not have any surgical history or family history. He was a nonsmoker and nonalcoholic. He had received his second dose of the Pfizer Covid-19 vaccine 3 weeks ago. He was vitally stable with a standard laboratory baseline. The radiological investigations were performed. An ultrasound showed an echogenic structure in the portal vein with no color flow, indicating portal vein thrombosis (PVT).

Further confirmation was obtained through a contrast-enhanced CT scan of the abdomen and pelvis, which revealed thrombosis in the right and left main portal veins and extension into the superior mesenteric vein. The patient's thrombophilia workup was negative. The diagnosis was made as acute unprovoked PVT. The patient was admitted, and treatment with the oral anticoagulant rivaroxaban 20 mg was initiated, with a clinical decision for an extended duration of treatment. The patient was followed up for 26 months with no complications or recurrent episodes of thrombosis.

Discussion

The development of COVID-19 vaccines has significantly reduced the burden of COVID-19 morbidity and mortality.[5] While these vaccines have been crucial in reducing the impact of the pandemic, their effectiveness and widespread availability are undeniable. However, despite their numerous advantages, it is essential to acknowledge that these vaccines also have some side effects. Thrombosis is a rare side effect reported postvaccination.[2] [6] [7] [8] [9] [10] [11] [14] [15] [16] [17] [18] Thrombotic events triggered by anti-SARS-CoV-2 vaccines exhibit clinical characteristics resembling thromboses associated with de novo SARS-CoV-2 infection. Incidents of DVT and pulmonary artery thrombosis have been documented after vaccination. Moreover, it tends to affect the blood vessels of atypical sites, including splanchnic veins (mesenteric, hepatic, or portal), cerebral veins, and upper limb extremities.[6] It is vital to mention that venous involvement is more commonly seen than arterial thrombosis.[13]

In our discussion, it is essential to note that of the seven patients presented, none had any past medical history or prescription of medications that could lead to thrombosis, thus categorizing venous thromboembolic events as unprovoked. This observation is particularly striking given that these venous thromboembolism (VTE) events occurred in individuals within the middle-age range of 30 to 45 years without diagnosed thrombophilia. Case reports have primarily involved acute DVTs of the lower extremities.

One study using the VigiBase data reported that between December 13, 2020, and March 16, 2021 (94 days), people who received COVID-19 vaccinations were found to have spontaneous reports of thrombotic events. The reported cases were 1,197 for Pfizer/BioNTech's COVID-19 vaccine, 325 for Moderna's COVID-19 vaccine, and 639 for AstraZeneca's COVID-19 vaccine.[13]

The incidence and pathogenesis of VTE after mRNA COVID-19 vaccines remain rare. Bhan et al reported a case of deep vein thrombosis in the upper arm 3 days after the second dose of Moderna vaccination.[14] Dias et al reported two cerebrovascular vein thrombosis cases in patients who received the Pfizer vaccine.[17] Bekal et al reported four cases of unprovoked thromboembolism after mRNA vaccine administration.[18] However, we documented five instances of DVT, with four of these cases progressing to the concerning complication of PE.

PVT is a rarely experienced clinical entity involving thrombosis within the portal vein trunks and intrahepatic portal branches. It is commonly seen with liver pathologies, coagulation, neoplastic, and autoimmune disorders. With the emergence of the COVID-19 vaccine, there have been reported cases of PVT after adenovirus vector COVID-19 vaccine administration due to vaccine-induced immune thrombotic thrombocytopenia (VITT).[10] However, we reported a case of PVT after mRNA vaccine administration in a 39-year-old with no significant medical history.

Our cases of VTE post-COVID-19 vaccine should not be confused with reported instances of VITT.[12] [14] [15] The latter condition has been associated with PF4 antibodies induced by adenoviral vector COVID-19 vaccines (ChAdOx1 nCoV-19). In contrast, we reported all the cases after mRNA (Pfizer/Moderna) vaccine administration without thrombocytopenia. VITT is an autoimmune phenomenon typically occurring 5 to 42 days after the vaccination and is characterized by thrombocytopenia, elevated D-dimer, increased antiplatelet factor 4 (PF4) antibodies, and thrombosis.[10] This leads to thrombocytopenia and platelet activation with venous and arterial thromboses at multiple, unusual sites.[7] [10] [12] [14] [15]

The available data[2] [5] [11] [12] primarily associate the use of adenovirus-based vaccines with the occurrence of VTE, often attributed to PT4 antibodies, referred to as VITT. The literature contains several reports of thromboembolism after mRNA vaccines.[7] [8] [9] [10] [14] [15] [16] [17] [18] The precise mechanism underlying mRNA vaccine–associated thrombosis remains unclear, with some researchers suggesting that this phenomenon may be completely distinct from thrombotic thrombocytopenic syndrome or VITT.[18] Observations in a few studies have linked elevated factor V activity with VTE. Additionally, the spike proteins produced by mRNA vaccines may trigger a cascade of events leading to endothelial dysfunction, which could contribute to developing venous thrombosis.[7]

Comprehensive assessments, suitable anticoagulant treatment, and vigilant monitoring are crucial for effectively managing these patients. Thrombophilia workup and malignancy risk factors should be ruled out.

This study is limited by its retrospective design, small sample size, and potential underreporting of asymptomatic cases. Further prospective and multicenter studies are needed. Also, the findings underscore the need for more rigorous postvaccination surveillance, particularly for high-risk populations, to assess better the potential association between mRNA vaccines and thrombotic events. Future prospective or multicenter trials could provide stronger epidemiological evidence and help establish causality.

Conclusion

In this case series involving seven patients, we observed rare adverse effects of VTE following COVID-19 vaccinations of mRNA vaccines, including Pfizer-bioNTech and Moderna. While our findings addressed the rare adverse effect of VTE postvaccination, it is crucial to recognize the overall benefits of these vaccines in combating the COVID-19 pandemic. The underlying mechanism behind thromboembolism due to mRNA vaccines remains uncertain, distinguishing these cases from those related to adenovirus-based vaccines. More studies will be needed to establish if any relation exists.

Conflict of Interest

None declared.

Authors' Contributions

A.M.M. and A.F. contributed to data collection and analysis, literature search, and writing the manuscript. M.A.A. contributed to data collection and analysis, and literature search. V.H. contributed to data collection and analysis, literature search, and writing. N.K.B. and M.S.A. contributed to data collection. A.A-K. and A-N.E. were involved in reviewing of the manuscript and mentoring.

Compliance with Ethical Principles

The Medical Research Committee approved the study (MRC approval and consent to participate), with reference number MRC-04–24–301.

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Publication History

Article published online:
12 March 2025