Upregulation of Tissue Factor in Polymorphonuclear Leukocytes from Patients with Myeloproliferative Disorders and Inhibition by Hydroxyurea Treatment.

Abstract

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. We report here that platelets and PMN from 12 patients with myeloproliferative disorders (MPD) (6 Polycytemia Vera, 6 Essential Thrombocythemia) show up regulation of P-selectin and TF, respectively, in the absence of any in vitro challenge, in comparison to healthy subjects (31±5 vs. 2.8±0.4 percent of P-selectin-positive platelets and 6.4±1.3 vs. 0.8±0.3 percent of TF-positive PMN, both differences P<0.05). The number of circulating mixed platelet-PMN aggregates was also increased (15.1±4.4 percent of platelet-PMN aggregates in MPD vs 2.6±0.5 in healthy, P<0.05). PMN TF expression as well as mixed platelet-PMN aggregates, but not platelet P-selectin, were significantly reduced in six MPD patients after three weeks treatment with hydroxyurea (HU) (6.3±1.7 vs. 1.4±0.2 percent of TF-positive PMN and 25.1±6.3 vs. 4.7±1.1 percent of platelet-PMN aggregates, before and after HU, respectively; both differences P<0.05). In vitro studies performed on PMN separated from healthy donors confirmed HU effects (0–1,400 microM). 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 fMLP-induced PMN TF expression. Thus, 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.