Inhibition of tissue factor expression by hydroxyurea in polymorphonuclear leukocytes from patients with myeloproliferative disorders: a new effect for an old drug?

Abstract

Summary. Background: Polymorphonuclear leukocytes (PMN) from healthy subjects can produce and store tissue factor (TF), which is expressed on PMN surface upon in vitro stimulation with P-selectin. Results: We report here that platelets and PMN from 12 patients with myeloproliferative disorders (MPD) (six with polycythemia vera, six with essential thrombocythemia) show up regulation of P-selectin and TF, respectively, in the absence of any in vitro challenge. The number of circulating mixed platelet-PMN aggregates was also increased. PMN TF expression as well as mixed platelet-PMN aggregates, but not platelet P-selectin, were significantly reduced in six MPD patients after treatment with hydroxyurea (HU). In vitro studies performed on PMN separated from healthy donors confirmed HU effects (0-1400 lM). HU prevented both P-selectin-induced TF expression and mixed cell aggregate formation. The inhibitory effect of HU was specific for P-selectin-induced PMN activation, as it did not affect formyl-methionyl-leucylphenylalanine-induced PMN TF expression. Conclusions: In MPD patients, platelet P-selectin-mediated TF expression on circulating PMN may play a role in thrombus formation and represents a novel target for the antithrombotic activity of HU.

Life expectancy and prognostic factors in the classic BCR/ABL-negative myeloproliferative disorders

“…JAK2 V617F has been associated with higher leukocyte counts 80,81,95 and neutrophil activation, whereas neutrophil/platelet complexes have been implicated in the thrombosis of the MPDs. [79][80][81]106 Older age, higher Hb level and higher leukocyte count displayed by V617F-mutated patients might represent confounding factors in the association of mutant genotype with thrombosis, particularly in homozygous ET patients with higher rate of thrombosis. In ET and PV, the independent predictive role of JAK2 mutant allele burden was maintained after elimination of potential confounders at multivariate analysis, in which wellestablished risk factors for thrombosis, such as age, previous thrombosis and leukocytosis, were included.…”

Pulmonary hypertension in patients with chronic myeloproliferative disorders

“…In the PT1 trial [77], the efficacy and safety of hydroxyurea plus aspirin were significantly higher than those of anagrelide plus aspirin with a reduced number of both thromboses and bleedings in this group. The high antithrombotic efficacy of hydroxyurea can be attributed to its effect on leukocyte count and, possibly, on leukocyte activation [78]. The effectiveness of antiplatelet agents in reducing the incidence of vascular events was investigated in several studies.…”

Thrombosis in myeloproliferative disorders: pathogenetic facts and speculation

“…In spite of comparable control of platelet count in the two arms, the efficacy and safety of HU plus aspirin were significantly higher than those of anagrelide plus aspirin because of a reduced number of both thromboses and bleedings in this group. The high antithrombotic efficacy of HU can be attributed to its effect on leukocyte count and, possibly, on leukocyte activation, 76 whereas the increased bleeding risk of anagrelide could be tentatively attributed to the weak antiaggregating effect of this agent.…”