Barbui et al. Blood Cancer Journal (2021)11:21 https://doi.org/10.1038/s41408-021-00417-3 Blood Cancer Journal ARTICLE Open Access Among classic myeloproliferative neoplasms, essential thrombocythemia is associated with the greatest risk of venous thromboembolism during COVID-19 Tiziano Barbui 1, Valerio De Stefano 2, Alberto Alvarez-Larran3, Alessandra Iurlo 4, Arianna Masciulli1, Alessandra Carobbio 1, Arianna Ghirardi1, Alberto Ferrari1, Valeria Cancelli5, Elena Maria Elli6, Marcio Miguel Andrade-Campos7, Mercedes Gasior Kabat8, Jean-Jaques Kiladjian9, Francesca Palandri 10, Giulia Benevolo11, Valentin Garcia-Gutierrez 12, Maria Laura Fox13, Maria Angeles Foncillas 14, Carmen Montoya Morcillo15, Elisa Rumi 16, Santiago Osorio17, Petros Papadopoulos18, Massimiliano Bonifacio 19, Keina Susana Quiroz Cervantes 20, Miguel Sagues Serrano21, Gonzalo Carreno-Tarragona 22, Marta Anna Sobas23, Francesca Lunghi24, Andrea Patriarca25, Begoña Navas Elorza26, Anna Angona27, Elena Magro Mazo28, Steffen Koschmieder 29, Giuseppe Carli30, Beatriz Cuevas 31, Juan Carlos Hernandez-Boluda 32, Emma Lopez Abadia33, Blanca Xicoy Cirici34, Paola Guglielmelli 35, Marta Garrote3, Daniele Cattaneo4, Rosa Daffini5, Fabrizio Cavalca6, Beatriz Bellosillo7, Lina Benajiba9, Natalia Curto-Garcia36, Marta Bellini37, Silvia Betti2, Claire Harrison36, Alessandro Rambaldi 37,38 and Alessandro Maria Vannucchi35 1234567890():,; 1234567890():,; 1234567890():,; 1234567890():,; Abstract In a multicenter European retrospective study including 162 patients with COVID-19 occurring in essential thrombocythemia (ET, n = 48), polycythemia vera (PV, n = 42), myelofibrosis (MF, n = 56), and prefibrotic myelofibrosis (pre-PMF, n = 16), 15 major thromboses (3 arterial and 12 venous) were registered in 14 patients, of whom all, but one, were receiving LMW-heparin prophylaxis. After adjustment for the competing risk of death, the cumulative incidence of arterial and venous thromboembolic events (VTE) reached 8.5% after 60 days follow-up. Of note, 8 of 12 VTE were seen in ET. Interestingly, at COVID-19 diagnosis, MPN patients had significantly lower platelet count (p < 0.0001) than in the pre-COVID last follow-up.This decline was remarkably higher in ET (−23.3%, p < 0.0001) than in PV (−16.4%, p = 0.1730) and was associated with higher mortality rate (p = 0.0010) for pneumonia. The effects of possible predictors of thrombosis, selected from those clinically relevant and statistically significant in univariate analysis, were examined in a multivariate model. Independent risk factors were transfer to ICU (SHR = 3.73, p = 0.029), neutrophil/lymphocyte ratio (SHR = 1.1, p = 0.001) and ET phenotype (SHR = 4.37, p = 0.006). The enhanced susceptibility to ET-associated VTE and the associated higher mortality for pneumonia may recognize a common biological plausibility and deserve to be delved to tailor new antithrombotic regimens including antiplatelet drugs. Correspondence: Tiziano Barbui (tbarbui@fondazionefrom.it) Introduction 1 2 FROM Research Foundation, Papa Giovanni XXIII Hospital, Bergamo, Italy Coronavirus-2 (SARS-CoV-2) infection, when present- Section of Hematology, Department of Radiological and Hematological ing as coronavirus disease 2019 (COVID-19), mainly Sciences, Catholic University, Fondazione Policlinico “A. Gemelli” IRCCS, Rome, Italy affects the respiratory system. However, multiple organ Full list of author information is available at the end of the article © The Author(s) 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. Blood Cancer Journal Barbui et al. Blood Cancer Journal (2021)11:21 Page 2 of 11 damage, involving the brain, heart, kidney, and vascular hematology units in Europe, on behalf of European Leuke- system are being reported with increasing frequency, and miaNet (ELN) and with the endorsement of the European contribute to the high mortality rate. COVID-19 is Hematology Association (EHA) and GEMFIN Spanish characterized by the occurrence of venous thromboem- network. bolism (VTE) and/or arterial thrombosis, as well as The sponsor of the study is FROM—Fondazione per la occlusions in the microcirculation, leading to severe Ricerca Ospedale di Bergamo at Papa Giovanni XXIII morbidity and mortality1–3. A possible mechanism of this hospital in Bergamo (Italy), which obtained national systemic damage may be that coronavirus attacks the approval for conducting the study in Italy by the ethical human body through the angiotensin-converting enzyme committee of the Spallanzani Hospital (approval number: 2 (ACE2), which is distributed over blood vessels and in 77-2020), in Rome (Italy); all other participating centers various organs4,5. got the approval by their respective local ethical com- The incidence rate of thromboembolic events is variable mittees and institutional review boards. and largely depends on whether patients were specifically Eligible patients were consecutive adults (aged ≥ 18 screened for the presence of thrombosis and hospitalized years) with WHO-2016 diagnosis of MPN and SARS in the intensive care unit (ICU) rather than in regular CoV-2 infection detected between February 15 and May wards6. In hospitalized COVID-19 patients, the overall 31, 2020. The minimum follow-up time was 1 month; the incidence of these events was estimated 22.7% in patients study was closed on June 30, 2020. An amendment to the transferred to ICU and 7.9% in general wards6. On the original protocol (version no. 2, 25/06/2020) has been basis of autopsy findings, extensive thrombosis of pul- approved to extend the follow-up study period by an monary microvascular circulation has been consistently additional 6 months after the last study visit for survivors. documented7 and the concept of “in situ” pulmonary Inclusion criteria included hospitalized COVID-19 thrombosis associated with respiratory worsening and cases ascertained by a positive real-time reverse tran- eventually death, was proposed8,9. scriptase polymerase chain reaction from nasopharyngeal VTE and arterial thrombosis may be a major concern in swab; however, given the exceptional situation of emer- some categories of patients with SARS-CoV-2 infection, gency determined by pandemic crisis, also home-treated such as the ones with generic cardiovascular risk factors, patients unable to swab were included, when the presence including hypertension, obesity, diabetes, or cardiovas- of pneumonia and symptoms were highly suggestive for cular and chronic respiratory disease, and cancer. Patients SARS CoV-2 infection (i.e., fever, cough, oxygen satura- with myeloproliferative neoplasms (MPN), who are con- tion (O2 saturation) ≤ 93% at rest, dyspnea, diarrhea). For stitutively prone to develop thrombotic complications, the purposes of this analysis, only patients with non- might be amongst the most vulnerable to these events. missing information regarding assessment of thrombosis Patients with essential thrombocythemia (ET), poly- were included. cythemia vera (PV), and myelofibrosis (MF) suffer from a Written informed consent of participants was collected 2–4-fold higher incidence of arterial and venous throm- whenever possible according to each Country regulation. bosis than the general population10,11, and also the fre- Data collection was centralized at FROM and per- quency of spontaneous or drug-related bleeding is also formed through a dedicated Electronic Data Capture higher than in general population12. Therefore, knowing (EDC) system supporting electronic case report forms (e- whether the rate of thrombotic and hemorrhagic events in CRFs) set up on purpose. Data on demographic and the course of COVID-19 is higher in these patients than in clinical characteristics, laboratory parameters, and drug the general COVID-19 population and identifying asso- exposure were collected at relevant time points, namely (i) ciated risk factors, could be of great benefit in indivi- last MPN follow-up visit before COVID-19 onset; (ii) dualizing prophylaxis and antithrombotic therapy. COVID-19 diagnosis; (iii) MPN follow-up after COVID- Based on these premises and given that the prevalence 19; and (iv) last visit. of MPN is relatively low13,14, we launched an international All nasopharyngeal swabs for COVID-19 diagnosis were multicenter study collecting data in ET, PV, and MF managed according to national recommendations and patients with COVID-19, recruited in specialized hema- COVID-19 disease was assessed according to current tology European centers, during the first wave of the WHO guidance15. Respiratory disease severity at COVID- pandemic. The primary goal was to evaluate the incidence 19 diagnosis was categorized based on oxygen support of thrombosis and bleeding and to identify associated needs, as non-intensive (including low-flow oxygen, predictors. Venturi mask, non-rebreather masks, continuous positive airway pressure [CPAP], non-invasive ventilation [NIV]) Subjects and methods and intensive (whether in need of either endotracheal MPN-COVID (ClinicalTrials.gov identifier: NCT04385160) intubation, or invasive mechanical ventilation, or extra is a multicenter, retrospective, cohort study that involved 38 corporeal membrane oxygenation [ECMO]). Blood Cancer Journal Barbui et al. Blood Cancer Journal (2021)11:21 Page 3 of 11 The primary outcome was the incidence of pulmonary relevant and significantly associated in univariate analysis, embolism (PE) with or without deep vein thrombosis treating death as competing event. (DVT) of the legs, which had to be confirmed by imaging Two-sided P-values of 0.05 or less were considered to (ultrasounds and computed tomography [CT] angio- indicate statistical significance. All analyses were per- graphy). Presumed PEs were cases unable to be confirmed formed using Stata (StataCorp, College Station, TX) sta- by imaging due to the practical limitations imposed by the tistical software, release 16.1. severity of infection and were also registered if they were defined by sudden increase of either D-Dimer in patients Results with rapid worsening of respiration and/or increase of Description of thrombotic and major bleeding events oxygen need. In Table 1, we report the frequency and types of Secondary outcomes were the occurrence of any other thrombosis and bleeding observed over a median of major thrombosis, major bleeding and death. All out- 50.5 days of follow-up (IQR: 16.0–69.0) in 162 patients comes were measured during hospitalization for COVID- with MPN fulfilling eligibility criteria defined for this 19 or assessed by the family doctor for patients managed analysis. During the acute phase of infection, 19 patients at home. Myocardial infarction, stroke, and peripheral experienced 22 thrombo-hemorrhagic events at home arterial thrombosis were diagnosed by objective tests (n = 1/40, 2.5%), or during hospitalization in regular including electrocardiographic changes, cerebral CT scan, wards (n = 13/105, 12.4%) or in ICU (n = 5/17, 29.4%) and angiography, respectively. For the definition and (p = 0.016). Overall, only three arterial thrombosis were assessment of thrombotic and hemorrhagic events, the documented (1.9%), whereas the majority were VTE (n = International Statistical Classification of Diseases and 12, 7.4%), detected with a significantly higher frequency in Related Health Problems 10th Revision (ICD-10)-WHO ET patients (n = 8/48, 16.7%) than in PV (n = 2/42, 4.8%) current version16 were used. or MF (n = 2/56, 3.6%) (p = 0.031). In ET, 7 of 8 VTE The use of low molecular weight heparin (LMWH) as (87.5%) were PE, of which one concomitant with DVT of antithrombotic prophylaxis was recorded, defining the the legs. Two additional PE were seen in patients with PV dose as prophylactic low-dose (4000–6000 IU sc fixed- and MF each. All but two patients with VTE were dose q 24 h) or therapeutic dose (100 IU/kg bw sc q 12 h). receiving anticoagulation with low or intermediate doses LMWH doses higher than the prophylactic ones but not (n = 5/10, 50%) or therapeutic doses (n = 5/10, 50%) of reaching those of therapeutic level were defined as LMWH. Mortality was recorded in 7 of 14 (50%) patients intermediate dose. with thrombosis, of which one was attributed to acute Potential risk factors for primary and secondary end- myocardial infarction, while the other 6 were not con- points were investigated, including patient comorbidities, sidered to be related to the previous vascular event; causes MPN type and status, MPN-directed therapies, laboratory of death were indistinguishable from other concomitant parameters at COVID-19 diagnosis, COVID-19 severity, conditions, such as multi-organ failure (MOF) (n = 4), and treatments. Results concerning mortality rate in this pneumonia (n = 1), or unknown reason (n = 1). series were previously reported17. Seven patients of 162 (4.3%) developed major bleeding, in particular in MF, where all the four hemorrhagic epi- Statistical analysis sodes required blood transfusions. These events were An initial sample size of at least 80 patients was esti- diagnosed starting from the second week after the onset of mated to detect a proportion of PE of 0.35 vs. 0.20, as the SARS-CoV-2 infection and occurred mainly in reported in non-MPN COVID-19 cases (alpha = 0.05; patients admitted to regular ward (n = 6/7, 85.7%) and in beta = 0.20). one case in ICU (14.3%). Details of bleeding in the seven Continuous variables are expressed as median (IQR) patients are illustrated in Table 2. We note that most of and the Kruskal–Wallis test was used to compare MPN the bleeding events occurred in patients over the age of 70 phenotypes. Categorical variables are presented as fre- years with MF and affected the gastrointestinal tract in quencies and percentages, and were analyzed using the three cases. All but two patients were receiving antic- χ² test or Fisher’s exact test, as appropriate. oagulant treatment: four were on LMWH (low-dose n = Cumulative incidence function (CIF) for death, throm- 3, therapeutic dose n = 1) and one was on apixaban. Only bosis, and bleeding were estimated considering death as patient #1 with MF (Table 2) had an activated partial competing event. Univariate analysis testing the associa- thromboplastin time (aPTT) prolongation and a moderate tion of each explanatory variables and thrombosis were thrombocytopenia despite the absence of heparin pro- performed using the Mann–Whitney U test, or χ² test, or phylaxis. Severe thrombocytopenia < 30 × 109/L was noted Fisher’s exact test, as appropriate. Multivariable Fine and in three patients (#5, #6, and #7), two of them receiving Gray regression model was finally applied to find inde- low-dose LMWH. All bleeding episodes but one occurred pendent predictors of thrombosis among those clinically in patients admitted to regular wards. Blood Cancer Journal Barbui et al. Blood Cancer Journal (2021)11:21 Page 4 of 11 Table 1 Types of thrombosis and bleeding, by MPN phenotypes. Total ET PV MF Pre-PMF p-value N = 162 N = 48 N = 42 N = 56 N = 16 Thrombosis Pts with thrombosis, n (%) 14 (8.6%) 8 (16.7%) 2 (4.8%) 3 (5.4%) 1 (6.3%) 0.13 N thrombosis, n (%) 15 (10.0%) 9 (18.8%) 2 (4.8%) 3 (5.4%) 1 (6.3%) 0.35 Arterial, n (%) 3 (1.9%) 1 (2.1%) 0 (0.0%) 1 (1.8%) 1 (6.3%) 0.47 AMI 1 0 1 0 Stroke 1 1 0 0 PAT 1 0 0 1 Venous, n (%) 12 (7.4%) 8 (16.7%) 2 (4.8%) 2 (3.6%) 0 (0.0%) 0.031 a PE 10 6 2 2 a DVT+PE 1 1 0 0 SVT 1 1 0 0 Time to any thrombosis, days, median (IQR) 11.5 (4.0–25.0) 7.0 (2.5–11.5) 8.0 (1.0–15.0) 25.0 (16.0–32.0) 28.0 (28.0–28.0) 0.27 Time to PE, days, median (IQR) 8.0 (0.0–14.0) 4.0 (0.0–8.0) 7.0 (0.0–14.0) 27.5 (24.0–31.0) 0.097 Bleeding Pts with bleeding, n (%) 7 (4.3%) 1 (2.1%) 2 (4.9%) 4 (7.1%) 0 (0.0%) 0.51 Sites 0.20 Gastrointestinal 3 0 0 3 Muscle 2 1 1 0 Hemoptysis 2 0 1 1 Trasfusion need, n (%) 5 (3.1%) 1 (2.1%) 0 (0.0%) 4 (7.1%) 0.030 Time to bleeding, days, median (IQR) 16.0 (13.0–24.0) 14.0 (14.0–14.0) 23.0 (16.0–30.0) 17.5 (6.5–23.0) 0.50 ET essential thrombocythemia, PV polycythemia vera, MF myelofibrosis, pre-PMF prefibrotic myelofibrosis, Pts patients, AMI acute myocardial infarction, PAT pheripheral arterial thrombosis, PE pulmonary embolism, DVT deep vein thrombosis of the legs, SVT superficial vein thrombosis, IQR interquartile range. a PE diagnosis confirmed by imaging n = 8, not confirmed n = 3. Cumulative incidence of thrombosis and bleeding accounted for a cumulative incidence rate of 0.6%, 2.4% Figure 1a reports CIF curves for the competing risks of and 3.6% at 10, 20, 30 days, respectively (Fig. 1b). death and thrombosis. At 60 days, mortality reached Fatal events were reported in 41 of 162 patients (25.3%), 26.6% (95% CI: 4.9–13.4%). Most of the fatal events and the two most frequently reported were pneumonia occurred within the first 15 days (20%); of these, 7 in (n = 15, 37%) and MOF (n = 17, 41%), being the patients experiencing major thrombosis (see above) and remaining unknown or unspecified causes (n = 9, 22%). subsequently the curve grew more slowly until 30 days, Note that among the 11 deaths that occurred in ET becoming almost stable afterwards. Adjusting for the patients, pneumonia was more frequent (n = 6, 55%) than competing risk of dying before the event, probability of in PV (n = 2/6, 33%) and MF (n = 6/21, 29%) while there total thrombosis progressively increased in the first was no difference between fatalities from MOF in ET month and reached 8.5% after 60 days follow. The (n = 5/11, 45%) and PV (n = 3/6, 50%). Remarkably, ET cumulative incidence rate at 10, 20, 30 days was 4.1%, patients with thromboses vs. the ones without these 5.9% and 7.1%, respectively. In COVID-19 patients fol- events had a survival probability of 53.6% (95% CI: lowed at home or in regular ward (n = 40, 25% and n = 23.3–76.6%) and 75.6% (95% CI: 67.5–82.0%), respectively 105, 65%, respectively), the rate was 1.0% and 2.8%, (p = 0.052) (supplementary Fig. 1S). respectively, whereas it reached 18.4% in the 17 (10% of the entire cohort) ICU patients. Univariate and multivariate analysis for thrombosis The overall major bleeding rate was 4.3% (95% CI: MPN patients’ characteristics stratified by thrombosis 1.9–8.2%) and the 7 events occurring in 7 patients are presented in Table 3. Gender, age and MPN type Blood Cancer Journal Barbui et al. Blood Cancer Journal (2021)11:21 Page 5 of 11 Transfusion need Plt (×109/L)a aPTT (s)a Fibrinogen (mg/dL)a distribution were comparable in the two groups, with the Pt patient, y year, Plt platelets count, aPTT activated partial thromboplastin time, M male, F female, ET essential thrombocythemia, PV polycythemia vera, MF myelofibrosis, ICU intensive care unit, NA not available. exception of a significantly higher proportion of throm- bosis in ET patients (p = 0.018). We did not find any correlation between driver mutations and the incidence of thrombosis. In particular, no difference was found in 469 220 355 670 NA NA 96 patients with or without thrombosis according to the presence of JAK2V617F, even if stratified by MPN phe- notypes. Of note, ET, compared to the other phenotypes 31.9 28.6 34.3 NA NA 76 24 (Supplementary Table 1S), showed no difference in terms of COVID-19 severity, as defined by age, patient managed at home, admitted to regular ward or ICU, and inflam- matory markers, with the exception of higher platelet 461 244 counts at COVID-19 diagnosis (p = 0.012). NA 97 16 28 29 Figure 1c illustrates the remarkable difference in the CIF of thrombosis in patients with ET compared with the other MPN phenotypes. Of note is the rapid steepness of the curve starting from the first hours after hospitalization and reaching the peak after 30 days. Yes Enoxaparin, terapeutic dose Yes Yes Yes Yes No No Such variables as history of thrombosis or bleeding, splenomegaly, duration of MPN disease, or proportion of patients treated with cytoreductive therapy were similar in Enoxaparin, low dose Enoxaparin, low dose Parnaparin, low dose the two groups (Table 3). Likewise, COVID-19-related Site of bleeding Days from COVID-19 diagnosis Anticoagulation symptoms were registered with comparable frequency and severity in the two groups, and no significant differ- Apixaban ence was detected in the frequency of comorbidities. The two groups did not differ for blood hemoglobin No No values, leukocyte, and platelet counts at COVID-19 diagnosis. However, at COVID-19 diagnosis, patients had significantly lower (p < 0.0001) platelet number (median 250.5 × 109/L, IQR: 151–398) than at the time of last follow-up visit performed at median of 47 days (IQR: 28–67) before diagnosis of SARS CoV-2 infection (median 326 × 109/L, IQR: 218–477). This decline was remarkable in ET (−23.3%; p = <0.0001) and less pronounced in PV (−16.4%; p = 0.1730) (Fig. 2a) and was associated with higher mortality rate (p = 0.0010), mainly due to pneu- 30 13 14 16 24 22 0 monia (p = 0.0051), which was reported in higher pro- Regular ward Gastrointestinal Regular ward Gastrointestinal Regular ward Gastrointestinal portion of ET than in PV and MF. Conversely, the platelet Regular ward Hemoptsysis Hemoptsysis drop was not linked to a significant difference of death for MOF (p = 0.06) (Fig. 2b). Regular ward Muscle Regular ward Muscle Levels of inflammation markers (neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR) and C- Pt. no. Sex Age, yr MPN Disposition reactive protein (CRP)) were significantly higher in patients with thrombosis (p = 0.004, 0.02, 0.019, respec- tively). Concerning blood coagulation tests, aPTT, pro- ICU Bleeding events. thrombin time (PT), and fibrinogen values were within the normal values, while a non-significant trend for D-Dimer MF MF MF MF PV PV Measured at bleeding event. ET increase was seen in cases with thrombosis (p = 0.10). However, in patients with ET and thrombosis, the levels 89.6 60.0 70.6 80.6 78.9 65.2 75.4 were significantly higher (median 4675.0 ng/mL, IQR: 2590.0–10,000.0) compared to cases without thrombosis M M M F F F F (median: 367.0 ng/mL, IQR: 200.0–884.0; p < 0.0001). Table 2 The effects of COVID-19 severity in patients with #1 #2 #3 #4 #5 #6 #7 thrombosis were remarkable in the univariate analysis as a Blood Cancer Journal Barbui et al. Blood Cancer Journal (2021)11:21 Page 6 of 11 Fig. 1 Cumulative incidence of thrombosis and bleeding. Cumulative Incidence Function (CIF) of thrombosis overall (A) and by MPN phenotypes (C), and bleeding (B), considering death as competing event. evidenced by the significant association with the need for events are more commonly represented by arterial hospitalization in the ICU, the elevated systemic inflam- thrombosis10–12. These complications occurred in all matory status (NLR) and the more frequent prescription patients but one, despite LMWH prophylaxis. In this of corticosteroids. The final multivariate Fine and Gray’s regard, it is relevant to note that prescription of antith- regression model showed that risk factors independently rombotic prophylaxis in COVID-19 patients, either associated with thrombosis were transfered to ICU (sub- managed at home or in regular wards during the first distribution hazard ratio [SHR] = 3.73, 95% CI = months of pandemic, was not considered a standard 1.14–12.23, p = 0.029), NLR (SHR = 1.16, 95% CI = therapy, and this may explain why only 57% of MPN cases 1.06–1.27, p = 0.001) and ET phenotype (SHR = 4.37, received antithrombotic prophylaxis which, in almost all 95% CI = 1.51–12.64, p = 0.006), the latter being the patients, was LMWH. The dosage of this drug was het- factor with the highest SHR. erogeneous (in 80% of patients was low-intermediate and in 20% therapeutic), mirroring the clinical practice in Discussion non-MPN patients with COVID-1920. The Scientific and The primary goal of this retrospective observational Standardization Committee of the International Society study was to evaluate the rate and risk factors for on Thrombosis and Hemostasis (ISTH) has suggested a thrombosis and bleeding in patients with MPN and universal strategy of routine thromboprophylaxis with COVID-19, collected in Europe during the first wave of LMWH after a careful assessment of the bleeding risk21. pandemic, from 15 February to 30 June 2020. However, there is a lack of studies documenting which dose of LMWH has a most favorable risk/efficacy profile; Rate of thrombosis and bleeding therefore, in the current clinical practice, the dose is Overall, the cumulative rate of arterial and VTE events chosen on an empirical basis, evaluating the underlying was 8.6%, occurring in 14 out of 162 MPN patients during pathology concomitant with COVID19 and the presence 60 days of observation for COVID-19. Most of the events of generic vascular risk factors21. during SARS-CoV-2 infection were VTE, as already In patients with PV and MF, the rate of VTE was 4.8% reported18,19, indicating that their occurrence was more and 5.4%, respectively, overall similar to that reported in closely linked to infection rather than MPN, in which non-MPN acutely ill medical patients with COVID-19 Blood Cancer Journal Barbui et al. Blood Cancer Journal (2021)11:21 Page 7 of 11 Table 3 Univariate analysis for thrombosis. Total No thrombosis Thrombosis p-value N = 162 N = 148 N = 14 Sex, n (%) 1.00 Female 66 (40.7%) 60 (40.5%) 6 (42.9%) Male 96 (59.3%) 88 (59.5%) 8 (57.1%) Age (years), median (IQR) 70.6 (60.0–79.9) 70.6 (60.0–79.9) 70.6 (60.0–80.0) 0.91 <60 years, n (%) 40 (24.8%) 37 (25.2%) 3 (21.4%) 1.00 60–70 years, n (%) 36 (22.4%) 33 (22.4%) 3 (21.4%) >70 years, n (%) 85 (52.8%) 77 (52.4%) 8 (57.1%) MPN diagnosis, n (%) 0.17 ET 48 (29.6%) 40 (27.0%) 8 (57.1%) 0.018 PV 42 (25.9%) 40 (27.0%) 2 (14.3%) 0.30 MF 56 (34.6%) 53 (35.8%) 3 (21.4%) 0.28 Pre-PMF 16 (9.9%) 15 (10.1%) 1 (7.1%) 0.72 JAK2V617F, n (%) 112 (70.9%) 103 (71.5%) 9 (64.3%) 0.57 CALR, n (%) 26 (29.5%) 23 (28.7%) 3 (37.5%) 0.61 MPL, n (%) 5 (6.0%) 4 (5.2%) 1 (16.7%) 0.26 Previous thrombosis, n (%) 23 (14.4%) 20 (13.7%) 3 (21.4%) 0.43 Previous bleeding, n (%) 12 (7.5%) 12 (8.2%) 0 (0.0%) 0.26 MPN duration before COVID-19 onset (years), median (IQR) 5.9 (2.9–10.8) 5.9 (2.6–10.4) 5.9 (4.1–10.9) 0.60 Blood values before COVID-19 diagnosisa, median (IQR) Hemoglobin, g/dL 13.0 (11.4–14.2) 12.9 (11.3–14.3) 13.1 (12.2–14.0) 0.77 9 White blood cells, ×10 /L 7.2 (5.4–10.3) 7.2 (5.5–10.1) 6.5 (5.2–12.5) 0.66 9 Platelets, ×10 /L 326.0 (218.0–477.0) 320.0 (214.5–466.0) 369.5 (288.0–550.0) 0.29 MPN-directed therapy before COVID-19 diagnosisa, n (%) Hydroxyurea 73 (45.1%) 66 (44.6%) 7 (50.0%) 0.70 b Discontinued after COVID-19 9/46 (20%) 7/39 (18%) 2/7 (28%) 0.61 Ruxolitinib 40 (24.7%) 37 (25.0%) 3 (21.4%) 0.77 Discontinued after COVID-19 9/40 (23%) 8/37 (22%) 1/3 (33%) 0.55 Anagrelide 8 (4.9%) 6 (4.1%) 2 (14.3%) 0.091 Interferon 4 (2.5%) 4 (2.7%) 0 (0.0%) 0.53 Other cytoreductive drugs 5 (3.1%) 5 (3.4%) 0 (0.0%) 0.48 ASA 94 (58.0%) 83 (56.1%) 11 (78.6%) 0.10 Patient disposition, n (%) 0.010 Home 40 (24.8%) 39 (26.5%) 1 (7.1%) Regular ward 104 (64.6%) 96 (65.3%) 8 (57.1%) ICU 17 (10.6%) 12 (8.2%) 5 (35.7%) Main symptoms, n (%) Fever 130 (80.2%) 118 (79.7%) 12 (85.7%) 0.59 Dispnea 89 (54.9%) 79 (53.4%) 10 (71.4%) 0.19 Blood Cancer Journal Barbui et al. Blood Cancer Journal (2021)11:21 Page 8 of 11 Table 3 continued Total No thrombosis Thrombosis p-value N = 162 N = 148 N = 14 Gastrointestinal 19 (11.7%) 19 (12.8%) 0 (0.0%) 0.15 Comorbidities, n (%) Cerebrovascular disease 21 (13.0%) 19 (12.9%) 2 (14.3%) 0.89 Chronic dialysis/Kidney disease 15 (9.3%) 14 (9.5%) 1 (7.1%) 0.77 Chronic heart failure 22 (13.8%) 20 (13.6%) 2 (15.4%) 0.86 COPD 22 (13.7%) 20 (13.6%) 2 (14.3%) 0.94 Current/former tobacco smoker 33 (23.2%) 31 (24.2%) 2 (14.3%) 0.40 Hyperlipidemia 45 (29.0%) 41 (28.9%) 4 (30.8%) 0.89 Hypertension 97 (61.4%) 91 (63.2%) 6 (42.9%) 0.14 Antihypertensives use 93 (60.8%) 89 (64.0%) 4 (28.6%) 0.010 ACE inhibitors/ARBs 54 (36.7%) 53 (39.6%) 1 (7.7%) 0.023 Other 33 (21.6%) 31 (22.3%) 2 (14.3%) 0.49 Diabetes mellitus 19 (11.9%) 18 (12.3%) 1 (7.7%) 0.62 O2 saturation (%), median (IQR) 93.0 (88.0–96.0) 93.0 (88.0–96.0) 94.0 (90.0–96.0) 0.81 COVID-19-directed drugs, n (%) Steroid 41 (27.2%) 34 (24.8%) 7 (50.0%) 0.044 Antibiotic 104 (68.9%) 91 (66.4%) 13 (92.9%) 0.042 Hydroxychloroquine 93 (59.6%) 84 (59.2%) 9 (64.3%) 0.71 Antiviral 54 (35.1%) 48 (34.3%) 6 (42.9%) 0.52 Lopinavir/Ritonavir 44 (88.0%) 38 (86.4%) 6 (100.0%) 1.00 Other 6 (12.0%) 6 (13.6%) 0 (0.0%) Experimental 17 (10.7%) 14 (9.7%) 3 (21.4%) 0.17 Tocilizumab 13 (76.5%) 10 (71.4%) 3 (100.0%) 1.00 Ruxolitinib 2 (11.8%) 2 (14.3%) 0 (0.0%) Other 2 (11.8%) 2 (14.3%) 0 (0.0%) Antithrombotic 88 (56.8%) 76 (53.9%) 12 (85.7%) 0.022 LMWH 84 (54.2%) 72 (51.1%) 12 (85.7%) 0.013 Low-intermediate dose 62 (79.5%) 56 (74.8%) 6 (50.0%) 0.34 Therapeutic dose 16 (20.5%) 10 (15.2%) 6 (50.0%) Laboratory parameters at COVID-19 diagnosis, median (IQR) Hemoglobin, g/dL 12.4 (10.0–13.5) 12.3 (9.9–13.5) 12.9 (11.4–13.8) 0.37 9 White blood cells, ×10 /L 6.6 (4.7–10.3) 6.5 (4.6–10.3) 7.4 (5.4–11.3) 0.35 9 Lymphocytes, ×10 /L 0.9 (0.6–1.6) 0.9 (0.6–1.6) 0.6 (0.4–0.9) 0.049 9 Neutrophils, ×10 /L 4.8 (3.2–7.8) 4.7 (3.1–7.6) 4.9 (4.3–7.8) 0.61 Monocytes, ×109/L 0.4 (0.3–0.7) 0.4 (0.3–0.7) 0.4 (0.2–0.6) 0.45 Eosinophils, ×109/L 0.0 (0.0–0.1) 0.0 (0.0–0.1) 0.0 (0.0–0.1) 0.24 9 Basophils, ×10 /L 0.0 (0.0–0.1) 0.0 (0.0–0.1) 0.0 (0.0–0.0) 0.58 Platelets, ×109/L 250.5 (151.0–397.5) 248.5 (152.0–375.0) 347.0 (74.0–408.0) 0.93 Blood Cancer Journal Barbui et al. Blood Cancer Journal (2021)11:21 Page 9 of 11 Table 3 continued Total No thrombosis Thrombosis p-value N = 162 N = 148 N = 14 Neutrophils/lymphocytes ratio 5.2 (3.4–9.0) 4.9 (3.4–8.1) 10.5 (6.9–13.4) 0.004 Platelets/lymphocytes ratio 292.1 (172.3–450.0) 284.5 (157.6–395.2) 485.5 (286.1–678.2) 0.027 C-reactive protein, mg/dL 73.8 (23.0–156.8) 72.5 (18.8–134.1) 168.7 (81.4–219.0) 0.019 Fibrinogen, mg/dL 473.0 (276.5–598.5) 469.0 (270.0–597.0) 500.0 (400.0–689.0) 0.62 D-Dimer, ng/mL 660.0 (282.0–1655.0) 622.0 (280.5–1477.0) 2000.0 (642.0–4675.0) 0.100 INR 1.2 (1.0–1.3) 1.2 (1.0–1.3) 1.2 (1.1–1.2) 0.46 MPN myeloproliferative neoplasms, ET essential thrombocythemia, PV polycythemia vera, MF myelofibrosis, pre-PMF prefibrotic myelofibrosis, ASA acetylsalicylic acid, ICU intensive care unit, COPD chronic obstructive pulmonary disease, ACE angiotensin-converting-enzyme, ARBs angiotensin II receptor blockers, O2 oxygen, LMWH low molecular weight heparin, INR international normalized ratio, IQR interquartile range. a Data refer to the last follow-up of MPN control before COVID-19 diagnosis, performed at a median of 47 days earlier (IQR: 28–67). b Data available for 46 of 73 patients treated with Hydroxyurea. Fig. 2 Platelet changes at COVID-19. Median platelet counts before and at COVID-19 diagnosis, by MPN phenotype (A) and by causes of death (B). Blood Cancer Journal Barbui et al. Blood Cancer Journal (2021)11:21 Page 10 of 11 admitted in regular wards6. Conversely, the rate of indicating a platelet consumption due to low grade dis- thrombosis was higher in ET, even though the indicators seminated coagulation24. This process might be related to of COVID-19 severity did not show differences compared the systemic endothelial vascular cell damage associated with the other MPNs. In these patients, vascular events with viral infection4,5 and involve the interaction of pla- happened shortly after admission to hospital as docu- telets, leukocytes, neutrophil extracellular trap (NET) mented by the steepness of the cumulative incidence formation25, and vascular endothelium, leading to classic curve that reached 16.7% after 30 days of observation. arterial and venous thrombosis, but also to lung and other This incidence is higher than that reported in most series tissues vessel occlusion and hypoxia1,2. We can speculate of non-MPN patients with COVID-19 admitted in regular that in at least some of the MPN patients who died for ward6. We point out that the higher frequency of VTE, in sudden respiratory deterioration, the decline of platelet comparison with arterial thrombosis, is a finding strictly number associated with the initial diagnosis of pneumonia linked to the infection and contrasts with the experience might be due to pulmonary thrombosis, in the context of outside COVID-19 settings, in which the opposite is the a “local” intravascular coagulation and complement26. rule10–12. Remarkably, these events had a notable impact on survival of these patients that was around 25% inferior Limitations and conclusion than in ET patients without thrombosis. The main limitations of this observational study are As expected, patients transferred to ICU (n = 17/162; related to its retrospective design and to the limited 10.6%) experienced a significantly higher incidence of number of patients. However, this constrain can hardly be thrombosis than those requiring non-invasive respiratory avoided when dealing with both a rare condition, such as support and admitted in regular wards (p = 0.004). MPNs, and an exceptional situation of emergency, such as Unfortunately, we could not confirm the relationship the COVID-19 crisis. between D-Dimer elevation and VTE6,22, likely due to the In conclusion, our study should be considered as an limited number of tests carried out in most of these exploratory analysis whose results pave the way for larger patients; only a trend for this association was shown (p = follow-up studies hopefully not having the same limita- 0.10). However, in ET patients with VTE, the D-Dimer tions. In particular, the enhanced susceptibility to ET- values were significantly higher than in the ones without associated thrombosis is a finding that needs to be delved, thrombosis (p < 0.0001). especially for the possibility to tailor antiplatelet and/or While the peak of thrombotic events occurred in the antithrombotic drugs in SARS CoV-2-infected patients first days after COVID-19 diagnosis, bleeding episodes who develop COVID-19. were reported later, starting 2 weeks afterwards, and Acknowledgements accounted for a cumulative rate of 5%, a figure higher than The study was supported by a research grant by the COVID “3×1 project”, 2.3% reported in the non-ICU general population with BREMBO S.p.A., Bergamo, Italy (T.B.) and by AIRC 5×1000 call “Metastatic COVID-1923. We underscore the severity of these events, disease: the key unmet need in oncology” to MYNERVA project, #21267 (MYeloid NEoplasms Research Venture AIRC). A detailed description of the requiring blood transfusion particularly in MF. In 4 of our MYNERVA project is available at https://progettomynerva.it (A.M.V., P.G.). The cases, a coagulopathy or severe thrombocytopenia were study was also supported by HARMONY PLUS, which is funded through the associated with severe bleeding suggesting caution on the Innovative Medicines Initiative (IMI), Europe’s largest public–private initiative aiming to speed up the development of better and safer medicines for empiric intensification of LMWH particularly in MF. patients. The HARMONY Alliance has received funding from IMI 2 Joint Undertaking and is listed under grant agreement No. 945406. This Joint Risk factors Undertaking receives support from the European Union’s Horizon 2020 Research and Innovation Program and the European Federation of The low number of bleeding events precluded an analysis Pharmaceutical Industries and Associations (EFPIA). IMI supports collaborative of risk factors and also in multivariate models for throm- research projects and builds networks of industrial and academic experts in bosis, few confounders could be included given that only order to boost pharmaceutical innovation in Europe. 14 events were ascertained. As expected, patient transfer to Author details ICU and NLR inflammatory marker were confirmed sig- 1 FROM Research Foundation, Papa Giovanni XXIII Hospital, Bergamo, Italy. nificant factors associated with total thrombosis. 2 Section of Hematology, Department of Radiological and Hematological Of great interest is the association between ET and Sciences, Catholic University, Fondazione Policlinico “A. Gemelli” IRCCS, Rome, Italy. 3Hospital Clinic de Barcelona, Barcelona, Spain. 4Hematology Division, thrombosis, regardless of inflammation indicators and the Foundation IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy. severity of COVID-19. This finding requires further 5 Spedali Civili, Brescia, Italy. 6Hematology Division and Bone Marrow confirmation in a larger series of patients; however, it Transplant, San Gerardo Hospital, ASST Monza, Monza, Italy. 7Hospital del Mar – IMIM, Barcelona, Spain. 8Hospital Universitario la Paz, Madrid, Spain. 9Hospital highlights the role of platelets in the thrombogenesis of Saint-Louis, Paris, France. 10Azienda Ospedaliero-Universitaria di Bologna, Via MPN patients with COVID-19. During the acute phase of Albertoni 15, Bologna, Italia. 11AOU Città della Salute e della Scienza di Torino, infection, our patients had platelet count higher than the Torino, Italy. 12Hospital Ramon y Cajal, IRYCIS, Madrid, Spain. 13Department of Hematology, Vall d’Hebron Institute of Oncology (VHIO), Vall d’Hebron Hospital other MPN but significantly lower than the value col- Universitari, Vall d’Hebron Barcelona Hospital Campus, C/ Natzaret, 115-117, lected in the last follow-up before the infection, possibly 08035 Barcelona, Spain. 14Hospital Universitario Infanta Leonor, Madrid, Spain. Blood Cancer Journal Barbui et al. Blood Cancer Journal (2021)11:21 Page 11 of 11 15 Hospital General Universitario de Albacete, Albacete, Spain. 16Department of 5. Varga, Z. et al. Endothelial cell infection and endotheliitis in COVID-19. Lancet molecular medicine, University of Pavia, Pavia, Italy. 17Hospital Gregorio 395, 1417–1418 (2020). 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