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Arterial and venous thrombosis/thromboembolism significantly contributes to morbidity and mortality of MPN patients [18, 31]. We here describe the frequency and risk factors for thrombotic/thromboembolic and major bleeding events in a cross section of patients with classical MPN and MPN-U in Germany, using clinical data from the SAL-MPN registry. In contrast to many clinical trials, our “real-world” analyses include a largely unselected group of MPN patients, ranging from newly diagnosed patients to those with a long disease history and covering different health care service settings (university hospitals, non-university hospitals, and office-based physicians) mirroring organization of hematological patient care in the German health care system.

Approximately 50 % of analyzed patients were male which is in accordance with recently published data [32], whereas the median age at first diagnosis was considerably lower (57 years) in our study. This difference may be caused by a selection bias (selected MPN centers documentation vs population-wide cancer registry) and the time period of inclusion (2012–2015 vs 1980–2009). Alternatively, the difference may be due to an earlier diagnosis in today’s patients.

About one third of the evaluated patients suffered from arterial or venous thromboembolism. DVT was the most common event followed by cardiac events, which is in accordance with previous findings [31, 33]. Regarding the subtype analysis, especially in PV and ET, the occurrence of thromboembolic complications was similar to previous findings [31, 34]. Interestingly, only in approximately one quarter of patients developing a thrombosis/thromboembolism subsequent events were registered, suggesting a lower frequency than in the published literature (33.6 % [26]) and, possibly, a more effective cytoreduction, anticoagulation, or antiplatelet therapy after the initial event.

Atypical venous thrombosis occurs more frequently in MPN patients, when compared to patients without MPN [35, 36]. We also report splanchnic vein thrombosis (SVT) accounting for 15 % of all thromboembolic events. However, in our series, the proportion of SVT in PV and ET was lower (2–5 % in all patients) than previously reported in the literature (10–13 %) [34], and PV patients had less SVT events compared to other MPN subtypes, which also reached statistical significance in our cohort. Others support our observation that SVT is less common in PV compared to ET [31], whereas other studies did not find significant differences in the different MPN subgroups. Differences among the studies, including our own, may be caused by a reporting bias or the small numbers of events per group (e.g., only three events in the PV group).

Patients from our cohort were less likely to develop a recurrent thrombosis, with only one fifth of patients in our cohort suffering from two or more thromboembolic events, and this proportion was clearly lower than in other studies (about 30 %) [26]. This may be due to a lower MPN-dependent and MPN-independent risk of thrombosis/thromboembolism, as evidenced by the younger age of the patients in our cohort and/or the high fraction of patients that were followed by watchful waiting.

Our univariate analyses revealed that only post-PV-MF diagnosis and splenomegaly were significant risk factors for the development of a thrombotic/thromboembolic event. In contrast to reports from the literature, a high white blood count (WBC) and JAK2V617F positivity were no identifiable risk factors for such events in our study [9, 16, 21, 24, 26].

Thrombotic/thromboembolic events are crucial factors of morbidity and mortality in PV and ET [10, 14, 37]. The particular time point of the events is meaningful, notably to detect vulnerable phases in the clinical course. In our cohort, most patients’ thrombotic/thromboembolic events peaked around the time of diagnosis, with an almost normal distribution around this time point. This suggests that thrombotic/thromboembolic events constitute a major indicator of an MPN and often triggers MPN diagnosis. However, it also suggests that some patients may have thrombotic/thromboembolic events already long before the diagnosis of MPN. This should be taken into account when strategies of enhancing public awareness of MPN and prevention of thrombotic/thromboembolic complications are concerned. Furthermore, the distribution of events may be an indicator for successful strategies in preventing recurrent thrombotic/thromboembolic events and suggest that a rigorous work-up regarding a potential underlying MPN should be initiated, particularly in patients with SVT.

Strikingly, the distribution of major bleedings followed a different pattern, without a peak around diagnosis but rather with most events occurring after the diagnosis of an MPN. This suggests that major bleeding occurs as a consequence of an MPN itself (i.e., ET-associated AVWS), portal hypertension with esophageal varices due to MPN-associated SVT, or primary prophylactic MPN therapy (e.g., ASS in PV) or anticoagulation in patients with previous thrombosis [27–29].

In our cohort, the overall major bleeding rate was 8 % which is close to the rates described in other studies [26, 38, 39]. However, while nearly 10 % of PV patients had a major hemorrhage, which is significantly higher than in the published literature [38], major bleeding rated in our ET patients were slightly below the published data [38]. The reduced frequency of bleedings in ET patients could be due to a higher proportion of patients receiving cytoreduction as well as the restrictive use of antiplatelet therapy with regard to an acquired von Willebrand Syndrome (AVWS), similar to what has been described for the ANAHYDRET trial [39]. Furthermore, the OR of 0.34 as a protective effect of bleeding events corroborates a careful and optimized therapy of ET patients documented in the SAL-MPN registry. Though the ET diagnosis also leads to a protective effect for thrombotic/thromboembolic events, an insufficient treatment with antiplatelet or anticoagulative substances cannot be assumed.

Current clinical guidelines recommend the administration of ASS for all PV patients to prevent thrombotic/thromboembolic events [31]. However, only about two third of PV patients in our series received ASS. Contraindications such as gastric ulcers and esophageal varices were detected in 16 patients. Other reasons for the lack of ASS administration could be the administration of anticoagulant therapy (e.g., VKA), as the combination of VKA and antiplatelet therapy should be only used with caution [31]. Our data further illustrate that so far, only a minority of patients with MPN received NOAC. And the risk of bleeding cannot currently be adequately assessed. However, with the development of the dabigatran antidote idarucizumab, there are new therapeutic options in case of major bleeding occurring in dagibatran-treated patients [40].

In the analysis of potential risk factors for major bleeding events, a previous history of vascular events, splenomegaly, and the administration of heparin were identified. Interestingly, neither ASS nor VKA were identified as risk factors. This lacking association, especially for patients receiving VKA, may be due to an intense surveillance of this cohort. P2Y12 antagonists as well as double-agent antiplatelet therapy narrowly missed the significance level, possibly due to small sample size (27 and 20 patients). These findings, especially the elevated odds of developing a major bleeding with heparin, need to be evaluated in future prospective studies. Although bleeding events are not the main cause for mortality in MPN patients [41], the prevention of such incidents is crucial, especially in case of long-term antiplatelet and anticoagulative treatment [42]. Clinical recommendations frequently discuss this topic and develop strategies to prevent bleeding caused by the antithrombotic medication [12, 17, 18, 31, 38].

In the past years, survival of MPN patients, especially for PV and ET subtypes has improved [13], yet the relative 5-year survival for MPN patients in Germany decreases from 92.3 % at ages 14–49 years to 63 % at 70+ years of age [43]. Reasons for the higher mortality rates in elderly patients were, in particular, thrombotic/thromboembolic events [10, 14, 44]. Our cohort showed a low proportion of recurrent thrombosis but a high frequency of thrombosis after the date of diagnosis. Intriguingly, 10 PV patients and 6 ET patients from our cohort had a thrombotic/thromboembolic event but did not receive cytoreductive therapy. Besides cytoreductive therapy for high-risk PV and ET, control of cardiovascular risk factors (smoking, dyslipidemia, hypertension) is crucial and should not be neglected [10, 18, 21, 37, 45, 46].

We would like to discuss our findings with regard to the already existing European LeukemiaNet (ELN) guidelines [47] and guidelines of the German and Austrian Society of Hematology and Oncology (DGHO/ÖGHO) and the Society of Thrombosis and Haemostasis Research (GTH) [31]. According to ELN guidelines, antiplatelet therapy with ASS in PV patients is recommended for all patients unless there is a contraindication. ASS was not shown to increase the bleeding risk in this patient cohort. For ET patients, ASS is recommended in case of microvascular disturbances according to ELN guidelines. In all patients “aspirin should be withdrawn in the event of major bleeding, most frequently GI, or in the rare cases of allergy or intolerance” [47]. Our own results, presented in this study, confirm the safety of aspirin in this patient cohort. But we suggest to restrict the use of aspirin in patients without a clear indication. Furthermore, the ELN consortium gave a detailed recommendation on SVT management. “Treatment of splanchnic vein thrombosis includes low molecular weight heparin followed by [life-long] oral anticoagulation […]” [47]. However, the ELN recommendations did not contain further detailed recommendations on the management of other thrombotic/thromboembolic.

In our study, the administration of vitamin K antagonists (VKA) did not result in an increased major bleeding risk, which is in accordance to the findings of the DGHO/ÖGHO/GTH recommendations paper [31]. Conversely, our study suggests that the administration of P2Y12 antagonists might be associated with major bleeding events. However, further evaluations are needed, in light of the DGHO/ÖGHO/GTH guidelines currently recommending the administration of P2Y12 antagonists in case of ASS allergy or intolerance [31].

Interestingly, in the RESPONSE trial, which assessed the JAK inhibitor ruxolitinib vs standard therapy for the treatment of polycythemia vera, a significant reduction of thromboembolic events was seen in the ruxolitinib group [48]. Since ruxolitinib is known to reduce spleen size, we investigated whether enlargement of the spleen is a risk factor for thrombotic/thromboembolic events. Indeed, our study showed that splenomegaly was a risk factor for thrombotic/thromboembolic events in our cohort. Potentially, a reduction of the spleen size in MPN patients may be an attractive future goal to reduce the incidence of thromboembolic events.

Several limitations of our study should be acknowledged. As mentioned above, patients’ data were obtained from MPN centers in Germany and not from a country-wide cancer registry, which may be an explanation for the lower median age of first diagnosis. Therefore, we cannot exclude a selection bias, since the centers that participate in our registry have a special interest in MPN pathogenesis and treatment, rendering generalization of the results difficult. Additionally, no data regarding length, intensity, and combination of any specific or general treatments was gathered. Furthermore, our cohort was very broad regarding the time of data collection. Some patients entered the registry at the time of diagnosis and others after a long latency period. It is imaginable that, in particular for patients with longstanding MPN history, thrombotic/thromboembolic, or bleeding events may have been underreported if they occurred before referral to the participating centers. The number of patients and the low incidence of these diseases (1–3 per 100 000 inhabitants) is also a limiting factor of this study and might affect our results.

On the other hand, the strength of our registry is the inclusion of patient data from academic centers, community hospitals, or office-based environments, providing a representative picture of MPN-care in Germany. Thus, the reported patients much more reflect the “real-world” population without the plethora or restrictings generated by stringent in-/exclusion criteria of patients treated in controlled clinical trials.