Thrombocytosis is a condition in which there are an increased number of platelets in the peripheral blood. Thrombotic thrombocytosis, in which the increased platelet count results in intravascular clotting, is most commonly associated with chronic myeloproliferative diseases. Examples of myeloproliferative diseases include primary thrombocythemia, polycythemia vera and chronic myelogenous leukemia. Primary thrombocythemia, also known as essential thrombocythemia, idiopathic thrombocythemia, hemorrhagic thrombocythemia and megakaryocytic leukemia, may result in spontaneous hemorrhages, both external and into the tissues. Polycythemia vera involves both an increase in red cell mass and an increase in total blood volume. An increase in circulating platelets is also often associated with reactive processes. In reactive processes to splenectomy, surgery, inflammation, iron deficiency or hemorrhage, the platelets typically exceed one million per microliter. This level of thrombocytosis is accompanied by little tendency toward thrombosis unless there are additional risk factors such as preexisting arterial disease or prolonged immobility. In chronic myeloproliferative disease, circulating platelets often approach 5 million per microliter. In addition to hemorrhage, thrombosis is often observed in association with such a high number of platelets. It has been postulated that thrombosis is due to spontaneous platelet aggregation in the circulation of patients with chronic myeloproliferative disease. Left untreated, the thrombosis may lead to ischemic lesions of the toes, pulmonary embolism, apoplexy, and even death.
Current clinical practice in these neoplastic-thrombocytosis patients is to lower the platelet count when values exceed one million per microliter. The treatment of choice is presently concomitant platelet pheresis in association with marrow suppressive therapy using radioactive phosphorus or alkylating agents. The disadvantages to this concomitant therapeutic approach is that the former therapy requires hospitalization and technical assistance and the latter treatment is well recognized to enhance leukemogenic responses.
A more desirable pharmaceutical approach to this condition would be administration of a drug with a direct, specific effect on lowering the platelet population without any side effects. Currently, at least two drugs with the desired thrombocytopenic effect are being evaluated in the treatment of thrombocytosis associated with chronic myeloproliferative disease: hydroxyurea and anagrelide. In the case of hydroxyurea, granulocytopenia is an undesired side effect and there is also a theoretical concern that this drug may have leukemogenic potential. Anagrelide, 6,7-dichloro-1,5-dihydroimidazo-[2,1-b]quinazolin-2(3H)-one monohydrochloride, which is currently being given 4 times a day with maintenance doses of 1.5 to 4.0 mg/day, has been reasonably effective in lowering platelet counts beginning about 5 days after initiation of treatment. However, in addition to transient side effects of headache and nausea, higher doses of this drug may cause potent aggregation. U.S. Pat. No. 4,743,445, indicates that alpha interferon may be used to treat thrombocythemia, but that it also reduces the white blood cell count.