Treatment of Essential Thrombocythemia with Anagrelide: A Novel Antiangiogenic Agent?.

Essential thrombocythemia is a myeloproliferative disorder complicated by thrombotic phenomena as a result of the platelet-clotting hyperactivation linked to increased angiogenesis. It is reported that vascular endothelial growth factor (VEGF) generates thrombin and promotes platelet activation and that activated megakaryocytes and platelets release VEGF. Anagrelide (ANA) is a newer cytoreductive agent which decreases megakaryocyte mass and inhibits the platelet activation. Therefore, we studied platelet factor 4 (PF4), as indicator of platelet activation, VEGF and prothrombin fragment 1+2 (F1+2) and d-dimer (DD), as indicators of thrombin generation, in 22 patients (12 males and 10 females, mean age 50 years) affected by ET diagnosed according to PVSG criteria. Their mean duration of disease was 4.8 years. All patients were on either HU (6 patients) or IFN-α (4 patients) and ANA (12 patients). HU was used at doses ranging between 1 and 1.5g/day. The dosage of IFN-α was 3 MIU, 3 days/week. ANA was initially administered in dose of 0.5 mg/day, with increases of 0.5 mg/day every 7 days until the platelets decreased below 500×109/L and with a average maintenance dosage of 2.2 mg/day. All patients recieved antiplatelets either aspirin (ASA) (15 patients) or indobufen (IND) (6 patients) and dipirydamole (DYP) (1 patient). Platelets, PF4, VEGF, F1+2 and DD were measured before cytoreduction and to complete response defined as platelets≤ 500×109/L. Platelets were determined by automated analyser. PF4, VEGF and F1+2 were assayed by ELISA and DD by immunoturbimetric latex agglutination. Before treatment all patients had marked platelets (1060±356×10⁹/L) and high PF4 and VEGF^PLT (157±83 IU/ml vs 1.6±0.9 IU/ml and 1.2±1 pg/ml vs 0.3±0.2 pg/ml, respectively) (p<0.0001 and p= 0.002, respectively). F1+2 and DD were elevated 3.6±3.7nml/L and 205±83 μg/L, respectively) than controls (0.6±0.3nmol/L and 75±21 μg/L, respectively) (p<0.0001 and p<0.0001, respectively). After a median time of 4.5 months from cytoreduction all patients had platelets ≤ 500 × 10⁹/L (430±70 × 10⁹/L). PF4 and VEGF^PLT remained high (121±72 IU/ml and 3.5±4.6 pg/ml, respectively) such as F1+2 and DD (3.5±3.8 nmol/L and 197±55 μg/L, respectively) in the HU- and IFN-α-treated patients. PF4 and VEGF^PLT normalised (7.4±3 IU/ml and 0.9±0.5 pg/ml, respectively) in the ANA-treated patients such as F1+2 and DD (1.1±0.4 nmol/L and 98±62 μg/L, respectively). These measurements were repeated in another sample collected after 1 o 2 months and showed concordance for PF4, VEGF^PLT, F1+2 and DD concentrations. A positive correlation we found between PF4 and F1+2 and DD (p=0.023 and p=0.019, respectively) and between VEGF and F1+2 (p=0.020, respectively). Interestingly, these data might suggest that ANA has antiangiogenic property and hence antiplatelet and anticoagulant effects.