No Evidence of Increased Rate of Thrombotic Recurrences in Patients with History of Venous Thromboembolism after Vaccination for COVID-19

We read with interest the report by Gil-Díaz and coll., published in Thrombosis Research in January 2022 [[1]Gil-Díaz A. Gil-Hernández A. Lozano-Jiménez A.I. et al.Safety of COVID-19 vaccination in patients with previous cerebral venous sinus thrombosis.Thromb. Res. 2022; 209 (Epub 2021 Dec 8): 84-85https://doi.org/10.1016/j.thromres.2021.12.004Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar]. In this study, the Authors evaluated whether patients with history of cerebral venous sinus thrombosis (CVST) were at increased risk of short-term serious adverse events after vaccination against Coronavirus Disease-19 (COVID-19). The rationale was that cases of CVST after COVID-19 vaccination have been reported and there are no data on thrombosis risk in prior CVST patients [2Rizk J.G. Gupta A. Sardar P. Henry B.M. et al.Clinical characteristics and pharmacological management of COVID-19 vaccine-induced immune thrombotic thrombocytopenia with cerebral venous sinus thrombosis: a review.JAMA Cardiol. 2021; 6: 1451-1460https://doi.org/10.1001/jamacardio.2021.3444Crossref PubMed Scopus (37) Google Scholar, 3Uaprasert N. Panrong K. Rojnuckarin P. et al.Thromboembolic and hemorrhagic risks after vaccination against SARS-CoV-2: a systematic review and meta-analysis of randomized controlled trials.Thromb. J. 2021 Nov 13; 19: 86https://doi.org/10.1186/s12959-021-00340-4. PMID: 34774069; PMCID: PMC8590131Crossref PubMed Google Scholar, 4Schultz N.H. Sørvoll I.H. Michelsen A.E. et al.Thrombosis and thrombocytopenia after ChAdOx1 nCoV-19 vaccination.N. Engl. J. Med. 2021; 384 (Epub 2021 Apr 9): 2124-2130https://doi.org/10.1056/NEJMoa2104882Crossref PubMed Scopus (675) Google Scholar]. Gil-Díaz and coll. Found that none of the 62 patients with history of CVST who received COVID-19 vaccine in their study experienced a thrombotic recurrence within 30 days of vaccination and concluded that COVID-19 vaccines are safe in patients with previous CVST. We believe that this report is both timely and useful, because it provides physicians with substantiated evidence to address the typical concern of patients who have suffered from thrombotic events in the past, i.e., whether they are at increased risk for a new thrombotic event after COVID-19 vaccination. In our Thromboembolic Disease Outpatient Clinic, we provide care specifically to subjects who are affected, or have been affected in the past, by venous thromboembolism (VTE). Some of them have just recovered from acute deep vein thrombosis (DVT) or pulmonary embolism (PE). Other have experienced VTE many years ago. Some are still on anticoagulant therapy, while other have stopped anticoagulation after completion of a treatment regimen. Nonetheless, they are all afraid that vaccines against COVID-19 might lead to a thrombotic recurrence and are hesitant to undergo vaccination. Although these concerns have little scientific foundation, it is true – as also stated by Gil-Díaz and coll. – that there are no published data on the safety of COVID-19 vaccines in specific subgroups of patients with a higher likelihood of vein thrombosis, such as those with a history of VTE. Based on this, we analyzed the records of patients with history of VTE treated at our Outpatient Clinic who were vaccinated against COVID-19 in 2021. Inclusion criteria were age ≥ 18 years and at least one episode of VTE prior to vaccine administration. To be included in the analysis, it was necessary that all the data regarding the characteristics of the previous VTE episode (including the date of thrombosis, the site of thrombosis, and the type and duration of anticoagulation treatment they received) and information about the COVID-19 vaccine (including the type of vaccine, the number of doses, and the date of each dose, and the presence of risk factors for thrombosis at the time of vaccination) were available. We identified 242 subjects with fully available data, and these were included in the analysis. Their demographic and clinical characteristics are presented in Table 1. There were 72 males and 170 females, with a mean age of 63.8 ± 14.3 years. History of VTE consisted of previous DVT of the lower limbs in 143 patients (59.1%), DVT of the upper extremities (catheter-related) in 41 patients (16.9%), splanchnic DVT in 5 patients (2.0%), and CVST in 1 patient (0.4%). History of PE, either isolated or associated with DVT, was present in 103 patients (42.6%). Regarding the presence of risk factors at the time of vaccination, 155 patients (64.0%) had previous or current cancer, 99 patients (40.9%) were on active chemotherapy. There were also 15 patients (6.2%) with thrombophilic conditions (on a total of 18 who had been offered screening for thrombophilia). In particular, there were 5 patients with Factor V Leiden heterozygous mutation, 2 patients with Factor V Leiden homozygous mutation, 1 patient with protein S deficiency, and 2 patients with both Factor V Leiden heterozygous mutation and G20210A prothrombin mutation. There were also 5 patients with antiphospholipid syndrome (APS), one of whom also had protein S deficiency. Regarding anticoagulation at the time of vaccination, 35 patients (15.5%) were on full anticoagulant treatment because of a recent thrombotic event, 163 patients (67.4%) were on a low-dose anticoagulant treatment for the prevention of VTE recurrence, and 5 patients (2.1%) were on full anticoagulant treatment because they had APS. Finally, there were 39 patients (16.1%) who were not on anticoagulant treatment at the time of vaccination. Of these, 36 had no indications to extended anticoagulation after completion of therapeutic regimen for acute VTE, 1 had suspended treatment after the removal of a central venous catheter (CVC), and 2 had suspended treatment for chemotherapy-induced thrombocytopenia. In the course of 2021, this cohort of patients received a total of 550 doses of COVID-19 vaccine, distributed as follows: Comirnaty 463 doses (84.2%), Moderna 72 doses (13.1%), Vaxzevria 12 doses (2.2%), Janssen 3 doses (0.5%). The number of first, second, and third (booster) doses were 242 (44.0%), 231 (42.0%), and 77 (14.0%), respectively. We found 1 early (within 30 days after vaccination) and 4 late (beyond 30 days after vaccination) thrombotic recurrences on a total of 550 doses of vaccine (recurrence rate was 0.2% and 0.7%, respectively).Table 1Demographic and clinical characteristics of the population.Mean age (years ± SD)63.8 ± 14.3Gender (male/female ratio)72/170Site of previous VTE-Lower limb, n (%)143 (59.1)-Upper limb (catheter-related), (%)41 (16.9)-Splanchnic, n (%)5 (2.0)-Cerebral venous site, n (%)1 (0.4)-Pulmonary embolism, n (%)103 (42.6)Risk factors at the time of vaccination-Cancer, n (%)155 (64.0)-Chemotherapy, n (%)99 (40.9)-Thrombophilic condition, n (%)15 (6.2)Anticoagulation at the time of vaccination-Full anticoagulation for treatment of a recent event, n (%)35 (15.5)-Low-dose anticoagulant for prevention of VTE recurrence, n (%)163 (67.4)-No anticoagulation, n (%)39 (16.1)-Full anticoagulation for prevention of VTE recurrence in APS, n (%)5 (2.1)Doses of vaccine, n550-Comirnaty, n (%)463 (84.2)-Moderna, n (%)72 (13.1)-Vaxzevria, n (%)12 (2.2)-Janssen, n (%)3 (0.5)Days elapsed between previous VTE and vaccination-Mean, n-Minimum, n-Maximum, n562.441439Early thrombotic recurrences, n (%)1 (0.2)Late thrombotic recurrence, n (%)4 (0.7%) Open table in a new tab The early recurrence occurred in an 80-years-old woman, who was on chemotherapy for colon cancer, and was on treatment with rivaroxaban 10 mg once daily for prevention of thrombotic recurrences (her index VTE event was a DVT of the lower limbs in 2019). The thrombotic recurrence that this patient experienced was a symptomatic CVC-related DVT of the upper extremities. The diagnosis was made 2 days after receiving the second dose of the Comirnaty vaccine, when the patient presented edema and pain of the upper limb. The 4 late recurrences also occurred in patients with active cancer. The mean time elapsed between the last dose of vaccine and the thrombotic recurrence was 105.5 days. The clinical characteristics of these patients are presented in detail in Table 2.Table 2Thrombotic recurrences after vaccination.Characteristics of the patient with early recurrence-Age80-GenderFemale-Type of previous VTE (year)Lower limbs DVT (2019)-Risk factors for thrombosis at the time of vaccinationColon cancer, chemotherapy, CVC-Type of anticoagulation at the time of vaccinationRivaroxaban 10 mg od-Type of vaccineComirnaty, 2nd dose-Time elapsed between vaccination and recurrence2 days-Type of thrombotic recurrenceSymptomatic CVC-related upper limb DVTCharacteristics of the patients with late recurrencesPatient #1-Age49-GenderFemale-Type of previous VTE (year)CVC-related upper limb DVT (2020)-Risk factors for thrombosis at the time of vaccinationbreast cancer, hormonal therapy-Type of anticoagulation at the time of vaccinationRivaroxaban 10 mg od-Type of vaccineComirnaty, 2nd dose-Time elapsed between vaccination and recurrence157 days-Type of thrombotic recurrenceSymptomatic upper limb DVTPatient #2-Age77-Genderfemale-Type of previous VTE (year)PE and lower limbs DVT (2020)-Risk factors for thrombosis at the time of vaccinationovarian cancer, chemotherapy-Type of anticoagulation at the time of vaccinationRivaroxaban 10 mg od-Type of vaccineComirnaty, 2nd dose-Time elapsed between vaccination and recurrence75 days-Type of thrombotic recurrenceSymptomatic lower limb DVTPatient #3-Age55-Gendermale-Type of previous VTE (year)Lower limbs DVT (2020)-Risk factors for thrombosis at the time of vaccinationInguinal pleomorphic sarcoma-Type of anticoagulation at the time of vaccinationApixaban 2.5 mg bid-Type of vaccineComirnaty, 2nd dose-Time elapsed between vaccination and recurrence120 days-Type of thrombotic recurrenceSymptomatic lower limb DVTPatient #4-Age63-Genderfemale-Type of previous VTE (year)CVC-related upper limb DVT (2019)-Risk factors for thrombosis at the time of vaccinationMetastatic ovarian cancer-Type of anticoagulation at the time of vaccinationNo anticoagulation-Type of vaccineComirnaty, 2nd dose-Time elapsed between vaccination and recurrence63 days-Type of thrombotic recurrenceSymptomatic thrombosis of jugular, subclavian, and axillary veins Open table in a new tab The results of our analysis indicate that the rate of thrombotic recurrence is low among subjects with history of VTE who have received vaccination against COVID-19. It is 0.2% when considering only early events (within 30 days from vaccination), which are those with a higher likelihood of being associated with vaccine administration. Nonetheless, in our cohort, the only early recurrence occurred in a patient at very high risk of thrombosis, regardless of a potential effect of vaccination. Indeed, she was an elderly woman with active cancer who developed a DVT at the level of the upper limb where a CVC was present and used for chemotherapy. In this type of patients, it is estimated that rate of thrombotic recurrence is greater than 5% per year, and more than 30% over 5 years [5Heit J.A. Mohr D.N. Silverstein M.D. et al.Predictors of recurrence after deep vein thrombosis and pulmonary embolism: a population-based cohort study.Arch. Intern. Med. 2000; 160: 761-768https://doi.org/10.1001/archinte.160.6.761Crossref PubMed Scopus (759) Google Scholar, 6Albertsen I.E. Nielsen P.B. Søgaard M. et al.Risk of recurrent venous thromboembolism: a Danish nationwide cohort study.Am. J. Med. 2018; 131 (e4): 1067-1074https://doi.org/10.1016/j.amjmed.2018.04.042Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar]. Therefore, it is more likely that this thrombotic event is due to the intrinsic thrombotic risk of the patient, rather than to the vaccine. The same considerations can be made for the late recurrent events observed in our cohort, which always occurred in subjects affected by active cancer and many days after vaccination. In this context, it should be pointed out that, in our cohort, the percentage of patients with active cancer was higher than usually reported in VTE epidemiological studies [8Heit J.A. Epidemiology of venous thromboembolism.Nat. Rev. Cardiol. 2015; 12: 464-474Crossref PubMed Scopus (517) Google Scholar, 9Heit J.A. Spencer F.A. White R.H. The epidemiology of venous thromboembolism.J. Thromb. Thrombolysis. 2016; 41: 3-14Crossref PubMed Scopus (507) Google Scholar]. This is due to the fact that our Thrombosis Clinic receives a considerable number of patients from the various Oncology Divisions of our University Hospital. However, regarding the objective of the current study, this cannot be considered a limitation, but instead a factor that strengthens the concept that COVID-19 vaccination does not increase the risk of recurrence, even in subjects at high risk of thrombosis, as cancer patients are. This is true also for the patients with thrombophilic conditions that were included in our cohort. Importantly, none of them experienced thrombotic complications after vaccination. On the other hand, it is also worth mentioning that in our cohort there were 84 doses of COVID-19 vaccine that were administered to patients who were not on anticoagulant treatment, because they had completed a therapeutic regimen for acute VTE and had no indication to extended anticoagulation, as they were considered at low risk of recurrence [[7]Konstantinides Stavros V. Meyer Guy Becattini Cecilia et al.ESC scientific document group, 2019 ESC guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS): the task force for the diagnosis and management of acute pulmonary embolism of the European Society of Cardiology (ESC).Eur. Heart J. 2020; 41: 543-603Crossref PubMed Scopus (1145) Google Scholar]. Interestingly, none of them experienced a new thrombotic event after receiving the COVID-19 vaccine. This strengthens the concept that the risk of recurrence depends on the presence or the absence of persistent risk factors for thrombosis, such as cancer, and not on the administration of the vaccine. In conclusion, our analysis – although limited by the small sample size – shows that patients with history of VTE do not have increased rate of thrombotic recurrence after COVID-19 vaccination. These data may support physicians in dealing with patients who have vaccine hesitancy because of a previous history of VTE. The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.