Risk of Thrombosis in Myeloproliferative Neoplasms after Sars-Cov-2 Vaccination

Philadelphia chromosome–negative myeloproliferative neoplasms (MPNs), including polycythemia vera (PV), essential thrombocythemia (ET), myelofibrosis (MF), and prefibrotic MF (pre-MF), carry a high risk of thrombosis, which affects morbidity and mortality. The disease management, particularly in PV and ET, remains highly dependent on the patient's thrombotic risk [[1]Marchetti M. Vannucchi A.M. Griesshammer M. Harrison C. Koschmieder S. Gisslinger H. et al.Appropriate management of polycythaemia vera with cytoreductive drug therapy: European LeukemiaNet 2021 recommendations.Lancet Haematol. 2022; 9 (e301–e11)Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar]. The severe form of COVID-19 is characterized by interstitial pneumonia, multiorgan dysfunction, and a high thrombotic incidence, especially venous thromboembolism (VTE). In patients with MPN, mortality associated with COVID-19 was reported to be as high as 33% during the so-called “first wave” and 8.6% during the “second wave.” [[2]Passamonti F. Cattaneo C. Arcaini L. Bruna R. Cavo M. Merli F. et al.Clinical characteristics and risk factors associated with COVID-19 severity in patients with haematological malignancies in Italy: a retrospective, multicentre, cohort study.Lancet Haematol. 2020; 7: e737-e745Abstract Full Text Full Text PDF PubMed Scopus (376) Google Scholar,[3]Barbui T. Iurlo A. Masciulli A. Carobbio A. Ghirardi A. Carioli G. et al.Second versus first wave of COVID-19 in patients with MPN.Leukemia. 2022; 36: 897-900Crossref PubMed Scopus (5) Google Scholar] Patients with MF had the highest mortality (48%) [[4]Barbui T. Vannucchi A.M. Alvarez-Larran A. Iurlo A. Masciulli A. Carobbio A. et al.High mortality rate in COVID-19 patients with myeloproliferative neoplasms after abrupt withdrawal of ruxolitinib.Leukemia. 2021; 35: 485-493Crossref PubMed Scopus (67) Google Scholar], whereas patients with ET had the highest risk of venous thromboembolism (16.7%) [[5]Barbui T. De Stefano V. Alvarez-Larran A. Iurlo A. Masciulli A. Carobbio A. et al.Among classic myeloproliferative neoplasms, essential thrombocythemia is associated with the greatest risk of venous thromboembolism during COVID-19.Blood Cancer J. 2021; 11: 21Crossref PubMed Scopus (23) Google Scholar]. Vaccination against SARS-CoV-2 should reduce the risk of infection and the risk of severe disease. Up to now, more than 11 billion doses of vaccines against SARS-CoV-2 have been administered worldwide. Survey data collected from January 2020 to June 2021 by the GIMEMA Foundation reported that vaccination against SARS-CoV-2 was performed in approximately 80% of a whole cohort of 11,276 patients affected with MPN and that seroconversion was demonstrated in all patients with ET, in more than 80% of patients with PV and in 72.9% of patients with MF. [[6]Breccia M. Piciocchi A. Messina M. Soddu S. De Stefano V. Bellini M. et al.COVID-19 in Philadelphia-negative myeloproliferative neoplasms: a GIMEMA survey on incidence, clinical management and vaccine.Leukemia. 2022; 36: 2548-2550Crossref PubMed Scopus (3) Google Scholar] However, concerns about COVID-19 vaccine–associated thrombosis arose after the characterization of a rare prothrombotic condition, called vaccine-induced immune thrombotic thrombocytopenia (VITT), associated with adenoviral vector–based COVID-19 vaccines [[7]Pavord S. Scully M. Hunt B.J. Lester W. Bagot C. Craven B. et al.Clinical features of vaccine-induced immune thrombocytopenia and thrombosis.N Engl J Med. 2021; 385: 1680-1689Crossref PubMed Scopus (307) Google Scholar]. Moreover, a recent study demonstrated that vaccination with the adenoviral-based vaccine ChAdOx1-S is associated with some changes in hemostatic parameters (e.g. an increase in both thrombin and von Willebrand factor serum level and a consumption of coagulation factors) suggesting a shift of the hemostatic system to a more procoagulant state compared to unvaccinated individuals [[8]de Laat B. Stragier H. de Laat-Kremers R. Ninivaggi M. Mesotten D. Thiessen S. et al.Population-wide persistent hemostatic changes after vaccination with ChAdOx1-S.Front Cardiovasc Med. 2022; 9966028Crossref Scopus (9) Google Scholar]. Although mRNA COVID-19 vaccines have not been linked to VITT [[9]Barda N. Dagan N. Ben-Shlomo Y. Kepten E. Waxman J. Ohana R. et al.Safety of the BNT162b2 mRNA Covid-19 vaccine in a nationwide setting.N Engl J Med. 2021; 385: 1078-1090Crossref PubMed Scopus (573) Google Scholar,[10]Klein N.P. Lewis N. Goddard K. Fireman B. Zerbo O. Hanson K.E. et al.Surveillance for adverse events after COVID-19 mRNA vaccination.JAMA. 2021; 326: 1390-1399Crossref PubMed Scopus (335) Google Scholar], or with relevant modifications of hemostatic parameters [[11]Peyvandi F. Scalambrino E. Clerici M. Lecchi A. Revelli N. Palla R. et al.No changes of parameters nor coagulation activation in healthy subjects vaccinated for SARS-Cov-2.Thrombosis Update. 2021; 4100059Crossref Scopus (8) Google Scholar], concerns about thrombotic events after vaccination persist. [[12]Houghton D.E. Wysokinski W. Casanegra A.I. Padrnos L.J. Shah S. Wysokinska E. et al.Risk of venous thromboembolism after COVID-19 vaccination.J Thromb Haemost. 2022; 20: 1638-1644Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar] With widespread vaccination some thrombotic events will occur shortly after vaccination by chance alone because VTE is a common condition that affects 1 to 2 cases every 1000 persons each year. Due to the well-known vascular risk associated with MPN, patients with MPN frequently had vaccine hesitancy because of fears of adverse effects such as VTE and some of them even refused to be vaccinated. To estimate the potential risk of vascular events associated with SARS-CoV-2 vaccination in the population with MPN, we evaluated all patients followed at our department affected with MPN and vaccinated against SARS-CoV-2 with at least 1 dose. Vascular complications included major thrombosis and major bleedings, as previously defined; [[13]Landolfi R. Marchioli R. Kutti J. Gisslinger H. Tognoni G. Patrono C. et al.Efficacy and safety of low-dose aspirin in polycythemia vera.N Engl J Med. 2004; 350: 114-124Crossref PubMed Scopus (808) Google Scholar,[14]Finazzi G. Barbui T. The treatment of polycythaemia vera: an update in the JAK2 era.Intern Emerg Med. 2007; 2: 13-18Crossref PubMed Scopus (15) Google Scholar] minor mucocutaneous bleedings were excluded from the analysis. Qualitative variables have been described as counts and percentages of each category; quantitative variables were summarized as median and interquartile range (IQR). The proportional hazard Cox model for multiple failures was used to compare the risk of vascular complications according to vaccine exposure (treated as time-dependent covariate), and results of these models were reported in terms of hazard ratio (HR) for vaccine exposure vs nonexposure periods, together with its 95% CI. The exposure period was defined for each patient from the date of any SARS-CoV-2 vaccine dose till 30 days after (according to the diagnostic criteria for VITT [[7]Pavord S. Scully M. Hunt B.J. Lester W. Bagot C. Craven B. et al.Clinical features of vaccine-induced immune thrombocytopenia and thrombosis.N Engl J Med. 2021; 385: 1680-1689Crossref PubMed Scopus (307) Google Scholar]); the nonexposure period included for each patient the 6 months before the first dose and the period beyond 30 days after each dose till last follow-up (Figure 1). Thus, using the same patient as control of himself eliminated the risk of bias of an observational study comparing 2 groups; namely, the patient had the same risk category and the same cardiovascular risk factors both in the exposure period and in the nonexposure period, besides vaccination status. To take into account the time between diagnosis and enter date, left truncation was applied. Type I error alpha was set at 0.05. All statistical analyses have been performed using Stata 17 (StataCorp LLC. 2021. Stata Statistical Software: Release 17). Starting from January 2021 we included 335 patients with MPN, of which 99 affected with PV, 176 affected with ET, 49 affected with primary or secondary myelofibrosis, and 11 were affected with MPN unclassifiable. The median age was 55 years (IQR: 43-68, range 15-88); 153 (46%) were men and 182 (54%) were women. Considering the mutational status, 252 patients (75.2%) were JAK2 V617F-mutated, 55 patients (16.4%) were CALR-mutated, 6 patients (1.8%) were MPL-mutated and 22 patients (6.6%) were triple negative. Seventy of 335 patients (20.9%) were not receiving cytoreduction at the time of vaccination; the remaining 265 (79.1%) were under cytoreductive treatment (226 with hydroxyurea, 22 with ruxolitinib, 13 with interferon, 4 with busulfan). Almost all patients received at least 2 doses of vaccination against SARS-CoV-2 (331/335, 98.8%); 75% of patients (224 of 335) received also the third dose. In most patients (320/335, 95.5%) the first 2 doses consisted of mRNA-based vaccines (i.e. BNT162b2 or mRNA-1273); in only 15 of 335 (4.5 %), the first 2 doses consisted of adenovirus-vectored vaccines (i.e. ChAdOx1-S). In all cases, the third vaccination was performed with mRNA-based vaccines (i.e. BNT162b2 or mRNA-1273). The risk of thrombosis in the exposure period did not significantly differ from the risk of thrombosis in the nonexposure period (HR = 0.8; 95% CI, 0.04-15.4; P = .866), as shown in Figure 2. No case of cerebral venous thrombosis was reported in the post-vaccine period, thus reassuring regarding the risk of VITT [[7]Pavord S. Scully M. Hunt B.J. Lester W. Bagot C. Craven B. et al.Clinical features of vaccine-induced immune thrombocytopenia and thrombosis.N Engl J Med. 2021; 385: 1680-1689Crossref PubMed Scopus (307) Google Scholar] When considering the risk of major bleedings, we observed an increased risk in the exposure period although not statistically significant (HR = 5.5; 95% CI, 0.5-59.2; P = .158). To explore the reason for such HR we analyzed the cases of major bleedings that occurred after vaccination. As a matter of fact, there was a single case of major bleeding occurring after vaccination: a young girl, affected with ET and a previous history of portal thrombosis complicated by esophageal varices, experienced a high fever (40 °C) on the day of vaccination; the day after she was admitted to the hospital due to hematemesis related to esophageal bleeding. We assume that the high fever and not the vaccine per se was responsible for this complication. Although these results need to be confirmed in larger studies, these data deliver an important message to the clinical community: COVID-19 vaccines do not increase the risk of thrombosis in patients with MPN; as the humoral response of patients with myeloid malignancies to the mRNA-based vaccines appears to be satisfactory [[15]Mori A. Onozawa M. Tsukamoto S. Ishio T. Yokoyama E. Izumiyama K. et al.Humoral response to mRNA-based COVID-19 vaccine in patients with myeloid malignancies.Br J Haematol. 2022; 197: 691-696Crossref PubMed Scopus (19) Google Scholar] it is pivotal to vaccinate the highest number of patients with MPN, reassuring them regarding vascular complications. O.B. and E.R. conceived this study, collected and analyzed data, and wrote the manuscript. V.V.F. and A.D.S. conducted statistical analyses. I.C C., D.V., and C.T. collected clinical data. D.P. performed the molecular analysis. L.A. revised the manuscript. The manuscript has been read and approved for submission to JTH by all authors. O.B. reported support for attending meetings and travel from Novartis. D.V. reported support for attending meetings and travel from Novartis. C.T. reported support for attending meetings and travel from Novartis. L.A. reported research funding from Gilead Science and payment or honoraria for speakers bureaus from Novartis. E.R. reported payment for lectures, presentations, and speakers bureaus from Bristol-Myers Squibb and support for attending meetings and travel from Novartis. Other authors have no competing interests to disclose. This study was supported by the AIRC award number 21267, AIRC IG 2021 ID 25703, and Italian Ministry of Health for young researchers grant (GR-2016-02361272).