Myeloproliferative and thrombotic burden and treatment outcome of thrombocythemia and polycythemia patients

Abstract

Prospective studies indicate that the risk of microvascular and major thrombosis in untreated thrombocythemia in various myeloproliferative neoplasms (MPN-T) is not age dependent and causally related to platelet-mediated thrombosis in early, intermediate and advanced stages of thrombocythemia in MPN-T. If left untreated both microvascular and major thrombosis frequently do occur in MPN-T, but can easily be cured and prevented by low dose aspirin as platelet counts are above 350 × 10(9)/L. The thrombotic risk stratification in the retrospective Bergamo study has been performed in 100 essential thrombocythemia (ET) patients not treated with aspirin thereby overlooking the discovery in 1985 of aspirin responsive platelet-mediated arteriolar and arterial thrombotic tendency in MPN-T disease of ET and polycythemia vera (PV) patients. The Bergamo definition of high thrombotic risk and its persistence in the 2012 International Prognostic Score for ET is based on statistic mystification and not applicable for low and intermediate MPN-T disease burden in ET and PV patients on aspirin. With the advent of molecular screening of MPN patients, MPN-T disease associated with significant leukocytosis, thrombocytosis, constitutional symptoms and/or moderate splenomegaly are candidates for low dose peglyated interferon (Pegasys(R), 45 μg/mL once per week or every two weeks) as the first line myeloreductive treatment option in JAK2(V617F) mutated MPN-T disease in ET and PV patients. If non-responsive to or side effects induced by IFN, hydroxyurea is the second line myelosuppressive treatment option in JAK2(V617F) mutated ET and PV patients with increased MPN-T disease burden.

Keywords: Aspirin; Essential thrombocythemia; Hydroxyurea; Interferon; JAK2V617F mutation; Myeloproliferative neoplasms; Polycythemia vera.

Figure 1

Platelet counts in 100 case histories of hemorrhagic thrombocythemia and 99 cases of erythromelalgic thrombotic thrombocythemia subdivided in patients with essential thrombocythemia and polycythemia vera (left)[1,2]. The relationship between platelet-mediated microvascular thrombosis in ETT at platelet counts between 350 to 1000 × 10⁹/L in ETT and mucocutaneous bleedings at platelet counts between about 1000 to above 2000 x 10⁹/L in HT patients (Table 3)[1-7]. The relationship of increasing platelet counts and decreasing von Willebrand factor (VWF) levels, VWF:ristocetine cofactor activity (VWF:RCo), and VWF collagen binding activity (VWF:CB) as the cause of an acquired Von Willebrand Disease (AVWD) type 2A due to proteolysis of large VWF nultimers in patients with paradoxical occurrence of ETT and HT and in patients with HT[8]. HT: Hemorrhagic thrombocythemia; ETT: Erythromelalgic thrombotic thrombocythemia; ET: Essential thrombocythemia; PV: Polycythemia vera.

Figure 2

Retrospective study on the probability of cardiovascular thrombotic event-free survival (days up to 3600 d = 10 years) according to the JAK2^V617F mutational state in 323 polycythemia vera and 639 essential thrombocythemia patients (Vannucchi et al[20]). Only major thrombotic events were retrospectively recorded and the erythromelalgic peripheral, ocular and cerebral ischemic events were excluded from evaluation. The overall incidence of major thrombotic events in JAK2^V617F mutated PV patients during 10 years follow-up is about 25% in the Italian study[20]. A similar incidence of thrombotic events was found in our literature analysis of 1241 ET patients not on aspirin from 14 retrospective studies[22]. Source Vannucchi et al[20] Blood 2007. ET: Essential thrombocythemia; PV: Polycythemia vera.

Figure 3

Mode of treatment in the Dutch 2008 survey of 363 myeloproliferative neoplasm (123 essential thrombocythemia, 190 polycythemia vera and 50 myelofibrosis) patients: 93% of polycythemia vera, 71% of essential thrombocythemia and 37% of myelofibrosis were on aspirin; 6% of essential thrombocythemia, 78% of polycythemia vera and 9% of myelofibrosis were treated with phlebotomy[23]. Because of symptomatic MNP disease burden 31% of ET, 29% of PV and 30% of MF were on treatment with hydroxyurea and 16% of ET, 16% of PV and 4% of MF were on treatment with pegylated interferon (Pegasys^R)[23]. ET: Essential thrombocythemia; PV: Polycythemia vera; MF: Myelofibrosis; MNP: Myeloproliferative neoplasm.