Heterogeneity among different myeloproliferative neoplasms associated with splanchnic vein thrombosis

Background: In BCR-ABL1-negative myeloproliferative neoplasms (MPNs) incidence of major thrombotic events ranges from 1.75 to 5.5% events patient-years according to the specific MPN subtype. Venous thrombosis account for about 30-40% of these complications and can occur also at unusual sites, including the splanchnic circulation (SVT) with a prevalence ranging between 1 and 23%. Aims: To evaluate differences in MPNs associated with SVT. Methods: We reported a consecutive monocentric series of 38 patients with a diagnosis of BCR-ABL1-negative MPN, who developed a SVT at diagnosis or during the follow-up between 1979 and 2016. Results: We identified 18.4% of PV, 26.3% of ET, 34.2% of MF and 21.1% of MPN-U. The latter were all diagnosed at the time of SVT onset, and characterized most frequently by a PV- or PMF-like bone marrow morphology but lacked the clinical phenotype required for a complete diagnosis. The majority of the cases (81.5%) bear JAK2V617F mutation; however, five patients were characterized by other molecular markers, i.e. MPL mutations in three patients, and CALR type 1 mutation in the remaining two cases. Among patients with a previous diagnosis of MPN who developed SVT during the follow-up, a cytoreductive treatment was already on-going in 53.8% of the cases, whereas it was then started in all but four of the remaining cases, due to young age and a blood cell count in the normal range or even below. After thrombotic index event, anticoagulants were started in 29 patients (76.3%), including six cases (15.8%) with direct oral anticoagulants (DOACs). At a median follow-up from MPN diagnosis of 12.3 years, six deaths were recorded: it was due to leukemic transformation in four patients, intracranial bleeding and infectious complication in one patient each. According to the literature, 44.7% of the patients in our series suffered from recurrent vascular events, either involving the arterial (21.1%), or the venous district (23.7%): in particular, five patients experienced a recurrent SVT. Summary/Conclusion: In this report patients with a diagnosis of MPN-U seem to represent a distinct clinical entity when compared to the other MPN subtypes. In particular, in all MPN-U cases, SVT was the initial manifestation which led to the diagnosis of the underlying MPN. They were all characterized by the presence of JAK2V617F mutation, except one case which bear an MPLW515L mutation, and showed a normal karyotype. In addition, any of these patients neither developed clinical features which could enable physicians to re-classify them among one of the so-called classical MPN subtype even according to the WHO 2017 classification, nor experienced a leukemic evolution. Being aware of the limits of the present study, we can speculate that SVT associated with MPN-U represents a disease with a more indolent course as compared with other cases associated with full-diagnosed MPNs which more frequently developed during the follow-up. Notably, all the cases of leukemic transformation were reported among patients with a previous MF diagnosis after a median follow-up of 17.9 years. Furthermore, about half of our patients developed recurrent vascular events, confirming the limited efficacy of conventional therapeutic approach in these particular patients. However, it is interesting to underline that none of the six patients treated with DOACs developed another thrombotic complication, so probably representing a more valid strategy in this setting.