Thrombosis Risk Assessment in Myeloproliferative Neoplasm-Is There a Role for Viscoelastic Testing?

Philadelphia chromosome-negative myeloproliferative neoplasms include polycythemia vera, essential thrombocythemia, and myelofibrosis. They are associated with increased thrombotic events, and the primary goal of therapy, in particular those with polycythemia vera and essential thrombocythemia, is the prevention of thrombotic complications typically with antiplatelet therapy and/or cytoreduction. While several patient-, disease-, and genomic-related factors have been identified to influence thrombotic risks, there are no routine laboratory investigations to date that are sufficiently accurate to assess the underlying procoagulant state and predict the thrombotic risks. Conventional coagulation testing only measures time to clot formation and cannot reliably predict bleeding and thrombotic risks. Global coagulation assays such as thromboelastography, thrombin, and fibrin generation may provide a more thorough assessment of hemostatic function. Thromboelastography and thromboelastometry are viscoelastic tests which measure the mechanical properties of the hemostatic process, including the global dynamics of clot formation, stabilization, and dissolution. While viscoelastic testing is gaining traction in the investigations of coagulopathies and goal-directed blood product replacement in trauma and massive transfusion settings, the role of these assays in thrombosis is less well defined. Here, we provide a review of the current evidence of the role of viscoelastic testing in myeloproliferative neoplasm, particularly in the thrombotic risk assessment.

Thrombosis in Myeloproliferative Neoplasms: A Single Center Experience of Using Whole Blood Platelet Aggregation Studies for Risk Assessment and Thromboprophylaxis.

CONCLUSION: Routine use of WBPA studies enables safe and effective risk-adapted thromboprophylaxis in MPN patients, irrespective of the underlying driver mutation and their risk predicted by the IPSET- thrombosis criteria.

Momelotinib for the treatment of myelofibrosis.

Introduction: The abnormally activated JAK-STAT pathway plays a central role in the pathogenesis of BCR/ABL-negative myeloproliferative neoplasms (MPNs), simultaneously providing a theoretical and clinical basis for the development of small-molecule compounds targeting JAK. The first approved drug, ruxolitinib, demonstrated a rapid and durable improvement of symptoms and splenomegaly accompanied with better overall survival in myelofibrosis (MF) patients. However, ruxolitinib-related adverse effects and resistance are limitations, so there is an urgent need to develop new JAK inhibitors to retain the efficacy of ruxolitinib and avoid its deficiency. Areas covered: This review discusses the preclinical and clinical studies of momelotinib (MMB) aiming to gain a deeper understanding of the advantages and clinical limitations of this drug. Expert opinion: The clinical trial data available thus far indicate that MMB is not inferior to ruxolitinib in spleen response and symptoms response, with the improvement of anemia surprising. The only obstacle that may slowdown its approval is treatment-emerged peripheral neuropathy (PN). If we can minimize MMB's treatment-related PN by administration optimization, MMB promises to be a good choice of individualized treatment for MF patients mainly manifesting as anemia.

Clinical and laboratory assessment of a patient with thrombocytosis.

Elevated platelet counts are frequently encountered in hospital medicine and arise from both physiological and pathological mechanisms. Thrombocytosis may be secondary, reflecting an inflammatory state, iron deficiency, recent surgery or point towards an underlying neoplasm. Thrombocytosis may be the presenting sign of solid tumours and haematological conditions. The discovery of the activating mutations affecting thrombopoiesis led to greater understanding of the pathobiology of essential thrombocythaemia and other myeloproliferative neoplasms. The investigation of suspected primary thrombocytosis has evolved to include testing for these disease-associated mutations. Therapy for patients with essential thrombocythaemia aims to reduce their risk of thrombotic complications by addressing cardiovascular risk factors, and using antiplatelet agents and, in selected patients, cytoreductive therapy. This article provides a logical approach to distinguishing reactive or secondary thrombocytosis from thrombocytosis associated with an underlying myeloproliferative neoplasm and gives an overview of the management of essential thrombocythaemia.

The evaluation of the relevance of thrombin generation and procoagulant activity in thrombotic risk assessment in BCR-ABL-negative myeloproliferative neoplasm patients.

INTRODUCTION: It has been recently suggested that microparticles (MP) play a role in the pathogenesis of thrombotic complications. This study aimed to assess the contribution of procoagulant activity expressed by circulating MP in thrombotic events in MPN patients. METHODS: Seventy-four MPN patients were enrolled in a trans-sectional study. The MP procoagulant activity was measured using two assays: (i) the thrombin generation (TG) assay used in different conditions with the addition of both tissue factor (TF) and phospholipids (PL) and with the addition of TF or PL alone and (ii) the PROCOAG-PPL assay. RESULTS: The mean age was 62 (26 men and 48 women). The prevalence of thrombotic events was 28%. When comparing patients with thrombosis to those without, age, sex, MPN type, cardiovascular risk factors, and history of thrombosis were not significantly associated with thrombosis. The JAK2 V617F mutation was significantly associated with thrombotic events (90% vs 67%; P=.04). Results from the TG assay and the PROCOAG-PPL assays did not demonstrate a significant association between the MP procoagulant activity and thrombotic events. CONCLUSION: The MP procoagulant activity did not predict thrombosis in MPN patients. The contribution of TG assay in the assessment of the thrombotic risk is still in debate.

Use of the Functional Assessment of Cancer Therapy--anemia in persons with myeloproliferative neoplasm-associated myelofibrosis and anemia.

BACKGROUND: Anemia is common in myeloproliferative neoplasm (MPN)-associated myelofibrosis. The Functional Assessment of Cancer Therapy (FACT) measurement system is a patient-reported outcomes instrument that documents symptoms of the diverse aspects of cancer treatment. One FACT version, FACT-Anemia (FACT-An), documents symptoms of anemia related to cancer. The FACT-An has been validated in diverse cancer populations, but not in MPN-associated myelofibrosis. OBJECTIVE: Our aim was to evaluate the relationship between anemia response to therapy with pomalidomide with or without corticosteroids and patient-reported outcomes using the FACT-An instrument. METHODS: Data were obtained from a Phase II, randomized, double-blind Bayesian pick-the-winner trial of prednisone and pomalidomide in patients with MPN-associated myelofibrosis and anemia (red blood cell-transfusion dependence). Details of the study, including definitions of anemia, anemia response, red blood cell-transfusion, red blood cell-transfusion dependence, and red blood cell-transfusion independence, are reported. Change in quality of life from randomization to the last cycle of therapy was evaluated using the FACT-An Physical Well Being, Functional Well Being, Trial Outcome Index, and Anemia domains. Clinically important differences were used to determine the smallest difference in scores that patients perceived as beneficial in the FACT-An domains of interest. Patients were classified as meeting clinically important differences for responsiveness if their change score from baseline was >1 SEM, indicating improvement. RESULTS: Eighty-five patients were studied. Thirty-one patients (37%) were classified as anemia responders by prospectively defined criteria. Across all FACT-An domains, anemia responders showed greater improvement in Physical Well Being, Functional Well Being, and Trial Outcome Index scores than did nonresponders. This improvement began at the second 28-day cycle of therapy and was sustained. CONCLUSIONS: We show a correlation between anemia response and improved quality of life measured by the FACT-An instrument in patients with MPN-associated myelofibrosis and anemia.

Distinct clustering of symptomatic burden among myeloproliferative neoplasm patients: retrospective assessment in 1470 patients.

Symptom burden in myeloproliferative neoplasms (MPNs) is heterogeneous even among patients within the same MPN diagnosis. Using cluster analysis from prospectively gathered symptom burden data in 1470 international patients with essential thrombocythemia (ET), polycythemia vera (PV), or myelofibrosis (MF), we assessed for the presence of clusters and relationship to disease features and prognosis. In MF (4 clusters identified), clusters significantly differed by Dynamic International Prognostic Scoring System (DIPSS) risk (P < .001), leukopenia (P = .009), thrombocytopenia (P < .001), and spleen size (P = .02). Although an association existed between clusters and DIPSS risk, high symptom burden was noted in some low and intermediate-1-risk MF patients. In PV (5 clusters identified), total symptom score increased across clusters (P < .001), but clusters did not significantly differ by PV risk or the risk assessment variable of age. Among ET patients (5 clusters identified), clusters differed by gender (P = .04), anemia (P = .01), and prior hemorrhage (P = .047). Total symptom score increased across clusters (P < .001), but clusters did not significantly differ by International Prognostic Score for ET risk including the risk assessment variables. Significant symptom heterogeneity exists within each MPN subtype, sometimes independent of disease features or prognosis.

Myeloproliferative disorder therapy: assessment and management of adverse events--a dermatologist's perspective.

Development of cutaneous manifestations in patients with myeloproliferative disorders can be either due to the course of the disease itself or induced by some of the treatments given. The cutaneous manifestations may reveal an unknown haemopathy and/or indicate a poor prognosis. Some of these alter quality of life. Hydroxyurea has been shown to induce a variety of cutaneous adverse reactions ranging from benign effects such as hyperpigmentation to more severe leg ulcers and squamous cell carcinomas. Herein, we discuss the importance of undertaking regular physical examinations in order to identify and treat cutaneous manifestations early in their course.

Myeloproliferative disorder therapy: assessment and management of adverse events--a cardiologist's perspective.

Although some cardiac effects, such as palpitations and tachycardia, occur commonly in healthy people, they have also been shown to be associated with agents used to treat the myeloproliferative disorders. Various strategies exist to prevent and manage cardiac effects and minimise their impact on treatment compliance and persistence. These include pre-therapy cardiac assessment, pharmacological intervention and referral to a cardiologist. Ultimately, treating physicians must use their discretion when deciding which management strategy to use and which cardiac side effects require referral to a cardiologist, but the value of continuous dialogue between specialists should not be ignored.