Thrombosis in essential thrombocytemia and early/prefibrotic primary myelofibrosis: the role of the WHO histological diagnosis

Many literature data, mainly arising from the Cologne Group, showed that approximately 40% to 50% of patients with clinical “ET” have an initial stage of PMF presenting with thrombocytosis and characterized by prominent granulocytic and megakaryocytic proliferation and significant anomalies of megakaryocytes [10]. In our study the review of initial bone marrow specimens, confirmed ET diagnosis in only 43% and changed to early PMF in 50% and is in line with these data. The relevance of a sharp distinction of ET and early PMF is stressed by clinical results of Barbui et al. in an international-based data collection of 1104 patients with a clinical phenotype of ET [2]: WHO-defined ET patients showed a lower risk of overt myelofibrosis, AML evolution, and, finally, a better survival compared with PMF. The discussion on the reproducibility of the WHO-subjective morphological criteria is still ongoing, as for many authors these criteria are not simple to apply [8,9,11], whereas for others an agreement among pathologists can be achieved in 88% to 93% of cases [10,12,13]. In our study the issue of the inter-observer histologic reproducibility was beyond our aims, although it may be considered a potential bias. In reality, as the original diagnoses were made by a group of general pathologists with different degree of expertise in the field and were reviewed in approximately 60% of cases by a single expert hemopathologist from the same department, we believe that it offers the perspective of the diagnostic work in the daily-practice by general practitioners and referral pathologists, pointing out the importance of careful clinico-pathological correlation in patient with MPNs [16].

In our series, at diagnosis, early PMF patients showed greater leukocyte count, history of thrombosis and thrombosis at the onset of disease, than ET patients. Statistical analysis of morphological features (semiquantitative scoring system) and clinical data showed a significant correlation between medullary leukocytosis and thrombosis. Multivariate analysis undoubtedly states that histology (early/prefibrotic PMF) is a predictor of reduced survival as well as age over 60 years. It is well known that Thiele and co-workers [10] first stated that BM fibrosis is not an intrinsic and necessary marker of PMF, and proposed a new category of patients with dual megakaryocytic and granulocytic myeloproliferation associated with characteristic megakaryocyte dysplasia and absence of relevant reticulin fibrosis in BM. This variant with BM fibrosis grade 0 was called prefibrotic myelofibrosis whereas the variant with the BM morphological features of early PMF but having at least grade 1 fibrosis was categorized into the fibrotic type category of PMF. In the present study progression (to overt myelofibrosis and leukemia) and death rates were similar between the fibrotic and prefibrotic early PMF, while WHO-ET patients showed a significantly superior OS than fibrotic PMF. Furthermore, statistical analysis allowed us to recognize that prefibrotic PMF patients, although younger, presented with a higher probability of thrombotic events (48%) compared with WHO-ET (16%) or fibrotic PMF patients (17%). Some characteristics of our prefibrotic PMF show striking similiarities with those that were well-outlined in the series of Barosi [17,18]. The mobilization of endothelial progenitors (ECFCs) cells is consistently higher in patients who received a diagnosis of prefibrotic myelofibrosis, thus giving rise to the hypothesis that endothelial progenitor cell-mediated neoangiogenesis, could intervene in determining the distinctive phenotypic profile of prefibrotic PMF [19]. As for thrombotic risk, until now, the incidence of thrombosis in prefibrotic PMF have been rarely assessed. Barbui et al. [20] showed that the rate of major cardiovascular events in PMF was comparable with that reported in ET, and it was increased in aged patients and those with JAK2V617F mutation and leukocytosis. Unfortunately in that study, the so-called “prefibrotic” form of PMF was not considered. In the same year, Brousseau et al. [9] applied WHO criteria to bone marrow specimens of patients previously diagnosed as having ET and observed no clinical (including thrombosis) or biologically differences between “true ET”, prefibrotic and fibrotic PMF. The clinical course of 264 patients with early/prefibrotic PMF was subsequently studied by Buxhofer-Ausch and co-warkers [21]; the authors suggested the importance of early/prefibrotic PMF as a distinct sub-entity of MPNs and indicated that leukocytosis at diagnosis was the preminent risk of total and arterial thrombosis in particular. Initial bone marrow reticulin fibrosis also exerts an impact on clinical outcome in polycythemia vera [22]. Barbui found a significantly higher occurrence of major thrombotic events during follow-up, in PV patients without reticulin fibrosis; on the contrary PV patients with increases in reticulin fibrosis displayed a higher prevalence of palpable splenomegaly and were more prone to develop overt myelofibrosis. The authors speculated that the variant without reticulin fibrosis might be characterized by a different biology or that the higher rate of thrombotic events might be related to a longer disease duration [22]. The major consequence of these findings is that the prefibrotic forms of PV and PMF could be considered acquired thrombophilic conditions, potentially requiring a new way of therapeutic intervention. Current thrombosis risk factors in ET are age and previous vascular events [23-26] and mutational status for JAK2, MPL, and Calreticulin [27]. Our study provides evidence that a morphologic discrimination of prefibrotic PMF from true ET has a significant impact on the risk of thrombosis. At multivariate analysis, among the potential predictors, only age and histopathology remained independent risk factors for thrombosis during follow-up. Patients older than 60 or with prefibrotic PMF are high-risk patients whereas those younger and with fibrotic PMF or true ET should be considered low-risk. Whether our new risk classification may optimize the management of patients presenting clinically with “ET” needs to be validated in association with mutational analysis. If prefibrotic PMF is strongly affected by thrombosis, its recognition might favor an early intervention at the time of diagnosis, to reduce MPN clone-derived prothrombotic features. Probably it is time to better understand the characteristics of prefibrotic PMF, change our “wait and watch strategy” [28] and start an upfront therapy (e.g. IFN-α [29] as monotherapy or in addition to JAK₂-inhibitors) combined with the treatment of all modifiable factors that increase the vascular risk [30]. Moreover, the antithrombotic effectiveness of aspirin, demonstrated in PV and to a lesser extent in ET [31,32], might be tested in prefibrotic PMF after a careful evaluation of the individual hemorrhagic risk.