The effects of JAK inhibitor therapy upon novel markers of thrombosis In myeloproliferative neoplasms.
Thrombosis is a relatively common and potentially life-threatening complication of myeloproliferative neoplasms (MPN). The introduction of JAK inhibitors (JAKi) has had a profound effect upon the therapeutic landscape for MPN, however, potential effects of these drugs upon thrombotic risk is largely unknown. Our objective was to study, in a MPN patient cohort, the in vivo effects of these agents on novel markers of thrombosis including platelet-neutrophil aggregates, platelet-monocytes aggregates, monocyte tissue factor expression and platelet activation as compared with conventional therapy. The therapeutic management of both polycythaemia vera (PV) and essential thrombocythaemia (ET) is directed by perceived thrombotic risk. In the largest epidemiologic study in PV, the European Collaboration on Lowdose Aspirin (ECLAP), the cumulative rate of nonfatal thrombosis was shown to be 3.8 events per 100 persons per year, with no difference between arterial and venous thrombosis. In prospective studies in ET, the rate of fatal and nonfatal thrombotic events ranged from 2% to 4% patient-years. Moreover, in primary myelofibrosis (PMF), the prevalence of major thrombosis was assessed in 707 patients sequentially followed in four large European institutions where the overall cumulative rate of cardiovascular death and nonfatal thrombotic complications was 2.23 events per 100 persons per year. Collectively, these studies highlight that MPN-associated thrombosis is a significant clinical problem. As regards conventional risk factors, age at presentation, elevated haematocrit and a previous history of thrombosis are consistent prognostic factors for recurrent thrombosis in MPN. More recently, leucocyte count and JAK2 V617F allele burden have also been described as contributing to this thrombotic risk profile. Previous studies have identified that more platelets from MPN patients circulate in an activated form as determined by the surface expression of P-selectin and tissue factor. Accordingly, in ET and PV patients, thrombin generation induced by platelets is enhanced and associated with platelet activation, particularly in carriers of the JAK2 V617F mutation. Furthermore, both platelet activation status and tissue factor expression have been shown to be elevated in MPN patients compared to controls, and postulated to predict for thrombosis. Cytoreduction with hydroxycarbamide has been shown to decrease thrombotic risk in the high risk ET population, whereas the effects of more novel agents on thrombotic risk in the MPN population are as yet unclear. We note with interest the recently published article concerning the safety and efficacy of the JAK1/2 inhibitor ruxolitinib (Novartis Pharmaceuticals, Switzerland) in polycythaemia vera compared to standard therapy for patients who were intolerant or resistant to hydroxycarbamide. In addition to demonstrating superiority as regards haematocrit control, reduced spleen size and decreased symptom burden, it was also noted that thromboembolic events occurred in only one patient receiving ruxolitinib whereas six patients receiving standard therapy had a thromboembolic event. We postulated that treatment with the JAK inhibitors ruxolitinib or SAR302503 (Fedratinib, Sanofi Pharmaceuticals, Paris (now withdrawn)) may affect key surrogate markers for thrombosis in patients with MPN and hence studied the in vivo effects of these agents on the presence of platelet-neutrophil aggregates, platelet-monocytes aggregates, monocyte tissue factor expression and platelet activation . A total of 29 adult patients with myeloproliferative neoplasms were recruited into this study; 15 were receiving JAKi therapy (13 patients with MF and 2 patients with PV) and 14 (9 patients with MF and 5 patients with PV) were receiving conventional treatments or an observant approach (10 patients on hydroxycarbamide, 1 on interferon-α and 3 observation only). Among the 15 MPN patients receiving JAKi, the median age was 64 years with a median disease duration of just over 6 years. A total of 9 out of 15 (60%) patients were JAK2 V617F positive, 1 patient out of 15 (7%) had the MPL W515L mutation, 2 out of 15 (14%) patients had a mutation in CALR and 3 out of 15 (20%) patients had a prior history of thrombosis (2 deep venous thromboses, 1 arterial thrombosis). Regarding JAKi agents, four patients received SAR302503 and 11 patients received ruxolitinib. At the time of sample collection, 8 patients were receiving aspirin and 1 was receiving warfarin. No statistical difference between the two cohorts in terms of