Classic Cardiovascular Risk Factors and Certain Comorbidities May Contribute to the Risk of Thrombembolic and Bleeding Events in Patients with Classical Myeloproliferative Neoplasms
Authors: Isfort Susanne , Kaifie Andrea , Schmitt Karla , Jost Edgar , Bruemmendorf Tim H. , Koschmieder Steffen 
Published: October 2019

Abstract
Background. Thrombembolic (TE) and bleeding (B) events pose a severe risk for patients (pts) with myeloproliferative neoplasms (MPN). Multiple disease-related factors have been identified that contribute to these events, such as the interaction between platelets, leucocytes, and endothelial cells. However, not all pts develop thrombosis or severe bleeding, suggesting that further contributing factors may play a role, including specific comorbidities and cardiovascular risk factors.
Aims. The aim of our analysis was to evaluate the association between thromboembolic events, specific comorbidities, and cardiovascular risk factors in MPN pts.
Methods. We analyzed clinical data frompts treated at the MPN Center at RWTH Aachen University hospital. All pts were aged ≥18 years and carried a diagnosis of classical BCR-ABL negative MPN (polycythemia vera [PV], essential thrombocythemia [ET], primary and secondary myelofibrosis [MF]), as defined by WHO criteria (2008). In addition, data about MPN disease complications, age, cardiovascular risk factors (smoking habits, arterial hypertension, diabetes mellitus, obesity, and hyperlipoproteinemia) and MPN subtype were included. Comorbidities were scored using three different comorbidity scales (CIRS, Charlson comorbidity index, and ACE-27).
Results. 75 MPN pts were included in this analysis, 25 with PV, 19 ET pts and 31 pts with MF (19 pts with PMF, 9 Post-PV-MF pts and 3 pts with Post-ET-MF). Characterization of pts regarding age, sex, thrombembolic/bleeding events as well as median scores in comorbidity scales are shown in Table 1. In addition, pts were divided into a group with (Group TE+B) or without (Group no TE+B) thromboembolic or severe bleeding events. 40 patients (53.3%) had previously experienced a thrombembolic or bleeding event. These pts showed significantly higher median comorbidity scores (CIRS of 6.5 vs. 2.0, p< 0,001, Charlson score of 1 vs. 0, p<0,001, and median ACE-27 of 2 vs. 0, p<0,001). Presence of classic cardiovascular risk factors among groups TE+B vs. no TE+B was heterogeneous (10 vs. 11 (ex-)smokers; 18 vs. 9 pts with arterial hypertension; 9 vs. 14 pts with a BMI > 25; 4 vs. 1 pts with diabetes mellitus; 4 vs. 0 pts with hyperlipoproteinemia). TE+B pts had high scores in certain CIRS categories (each category includes a scale of 0-4) especially in categories regarding cardiac diseases, hypertension, vascular disease & endocrinological disease (see Table 2). Furthermore, more than one third of the TE+B pts had also neurological (16/40 pts. (40%) vs. 3/35 (8.6%) in the no TE+B group) and upper-GI-disease (13/40 pts (32.5%) vs. 8/35 (22.9%) in the no TE+B group).
Summary and Conclusions. Given the obvious limitations of this analysis due to small sample numbers, this analysis provides an indication that classic cardiovascular risk factors (especially diabetes mellitus, arterial hypertension, and hyperlipoproteinemia) and additional comorbidities contribute to the risk of thromboembolic and bleeding events in pts with classical MPN. Clinical trials should address whether the improvement of such risk factors in addition to anti-MPN treatment can minimize the risk of such events.
Table 1. Characterization of pts Subtype of MPN Number of patients Median age at diagnosis (range) Number of patients that developed thromboembolic events (TE) or bleeding (B)* Number of patients without thromboembolic/bleeding events Median CIRS score(Range 0-56) Median Charlson comorbidity index(Range 0-37) Median ACE-27 score(Range 0-3) Polycythemia vera 25(11m/14f) 58 (31-77) 15 (15 TE, 2 B) 10 6 1 1 Essential Thrombo-cythemia 19(10m/9f) 54 (23-64) 6 (5 TE, 1 B) 13 4 0 1 All Myelofibrosis 31(22m/9f) 63 (29-77) 19 (16 TE, 7 B) 12 5 0 1 Myelofibrosis PMF 19(16m/3f) 61 (29-77) 11 (9 TE, 4 B) 8 4 0 1 Post-PV-MF 9(3m/6f) 63 (42-73) 7 (6 TE, 3 B) 2 8 1 1 Post-ET-MF 3(3m/no f) 68 (68-73) 1 (1 TE) 2 13 2 2
· Few Pts had suffered from both thromboembolic and bleeding events
Table 2. Number of pts in the TE+B group in comparison to the no TE+B group in certain CIRS categories subdivided according to score CIRS category (TE+B pts vs. no TE+B pts) Score of 0 per category Score of 1 per category Score of 2 per category Score of 3 per category Score of 4 per category Cardiac disease 20 vs. 30 6 vs. 2 5 vs. 3 9 vs. 0 0 vs. 0 Hypertension 22 vs. 26 2 vs. 0 4 vs. 6 12 vs. 3 0 vs. 0 Vascular disease 21 vs. 32 3 vs. 1 12 vs. 0 3 vs. 1 1 vs. 1 Endocrinological disease 21 vs. 26 0 vs.1 19 vs.7 0 vs.1 0 vs.0

Disclosures
Isfort: Pfizer: Honoraria; BMS: Honoraria; Mundipharma: Other: Travel & Accomodation; Roche: Other: Travel & Accomodation; Novartis: Other: Travel & Accomodation; Amgen: Other: Travel & Accomodation; Hexal: Other: Travel & Accomodation. Bruemmendorf:Ariad: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Patent on the use of imatinib and hypusination inhibitors: Patents & Royalties. Koschmieder:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel reimbursement for scientific conferences, Research Funding; Novartis Foundation: Research Funding; Baxalta/CTI: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel reimbursement for scientific conferences; Janssen Cilag: Other: Travel reimbursement for scientific conferences.