Platelets are a major cell type found in the blood and are critical to maintaining normal hemostasis. Platelets are derived from marrow stem cells and are usually found either in the circulation or sequestered in the spleen. A normal number of platelets in human blood is around 150,000 to 400,000 per mL, the condition in which the number of platelets falls substantially below this level is referred to as a thrombocytopenic state, conversely an overabundance of platelets is referred to as a condition of thrombcytosis or thrombocythemia.
A major function of the platelet is to control bleeding and to plug any due to rupture of the vasculature via clot formation. The platelet functions not only as an integral and structural element of a clot, but also is responsive to the surrounding conditions and reacts by releasing a wide variety of mediators which effect surrounding cells and tissues. Upon encountering a aberrant situation, e.g., exposed collagen or basement membrane, platelets adhere, aggregate, and release granules containing mediators, such as ADP, smooth muscle mitogens, prostaglandins, thromboxanes, catecholamines, clotting factors, and the like. These mediators not only promote further platelet aggregation and clot formation, but also effect the behavior of smooth muscle cells causing constriction and proliferation. Additionally, these mediators effect other circulating cells, such as lymphocytes and inflammatory cells, which may initiate biological sequelae quite different from clot formation. Many of these other sequelae often have pathological consequence.
It is essential for hemostasis that an adequate number of platelets are available for the clotting reaction. Failure of the clotting system is usually considered a very serious and life-threatening condition. In cases, where the number of platelets drops below 100,000 per mL, there is cause for concern and may result in therapeutic intervention. Platelet counts less than 40,000 are on the threshold of spontaneous bleeding and must be aggressively treated, usually with platelet infusions. Such drops in platelet count may occur in cancer patients treated with cytotoxic agents or radiation, in trauma patients especially burn injuries, or in patients with immune abnormalities. (For further information, e.g., see: "Harrison's Principles of Internal Medicine", Eds. Isselbacher, K. J., et al., 9th Ed., McGraw-Hill Book Co., NYC, 1980, Chap. 54, pp. 273-276, Chap. 361, pp. 1555-1557, and references cited therein.)
However, paradoxically, as important and necessary as platelets are, they can often contribute to many detrimental conditions. For example, they are participatory and perhaps causative elements in inappropriate thrombotic events such as occlusion of arteries and vessels which precipitate ischemic events and tissue damage. Inappropriate activation of platelets can be life-threatening and there are many medical conditions which increase the risk of such activations, such as patients suffering from atherosclerosis, patients recovering surgery or trauma, patients recovering from angioplasty, and the like. One envisioned method of lowering the risk of such inappropriate activations is to lower the total number of normal platelets in the circulation. In a recent clinical report, it was shown that there was a direct correlation between platelet count and function and fatal coronary heart disease, i.e., patients with the highest platelet count and aggregability were most likely to succumb. Thus, it would seem reasonable that an agent which reduces the platelet count should demonstrate a beneficial effect in preventing coronary disease. (See: "Blood Platelet Count and Function Are Related to Total and Cardiovascular Death in Apparently Healthy Men", Thaulow, E., et al., Circulation, 84(2), pp.631-617, 1991 and "Thrombocytes and Coronary Heart Disease", Wilhelmsen, L., Circulation, 84(2), pp. 936-937., 1991).
Although a beneficial effect seems reasonable with a reduction of platelet count, it is critical that reduction does not produce thrombocytopenia. An ideal agent would have to reduce the platelet count without compromising appropriate clotting activity, i.e., the platelet count would need to remain in the normal range.
Recently, a clinical study was reported which demonstrated a lowering of the platelet count in women taking the compound tamoxifen. However, tamoxifen is known to have substantial estrogen-agonist properties, especially in the uterus, and would thus be a less than ideal agent. (See: "Effect of Tamoxifen on Measurements of Hemostasis in Healthy Women", Mannucci, P. M., et al., Arch. Internal Med., 156, Sep. 9, 1996. pp. 1806-1810.)
USPTO Backgrounds
USPTO Backgrounds