REVIEWS Drug Discovery Today  Volume 13, Numbers 17/18  September 2008 Emerging treatments for thrombocytopenia: Increasing platelet production Karen Peeters 1 , Jean-Marie Stassen 2 , De ´ sire ´ Collen 1,2 , Chris Van Geet 1,3 and Kathleen Freson 1 1 Center for Molecular and Vascular Biology, University of Leuven, Herestraat 49, B-3000 Leuven, Belgium 2 ThromboGenics NV, Herestraat 49, B-3000 Leuven, Belgium 3 Department of Pediatrics, University of Leuven, Herestraat 49, B-3000 Leuven, Belgium Thrombocytopenia is a common medical problem. The first generation thrombopoietic agents, recombinant THPO and ‘megakaryocyte growth and development factor’ (PEG-rHuMGDF) entered clinical trials, but their development was discontinued owing to neutralizing auto-antibodies cross- reacting with endogenous THPO, causing thrombocytopenia in healthy volunteers. Although an approved drug for prevention of severe thrombocytopenia following myelosuppressive chemotherapy (human Interleukin-11) exists, the search for new thrombopoietic agents continued because its use is limited by side effects. Several second generation thrombopoietic factors have entered clinical trials and some new negative regulators of megakaryopoiesis have been found, such as platelet factor 4 (PF4) and the pituitary adenylate cyclase activating polypeptide (PACAP). Their inhibition may be useful in the treatment of thrombocytopenia. This article reviews second generation thrombopoietic factors and those recently discovered regulators of megakaryopoiesis. Introduction Thrombocytopenia, defined as a subnormal number of platelets (usually below 150  10 9 /L) in the circulating blood, is a common problem in the management of patients with cancer and other conditions that affect hematopoietic cells. Mild thrombocytope- nia is defined as a platelet count between 50 and 150  10 9 /L and is generally asymptomatic. Moderate thrombocytopenia (platelet count between 20 and 50  10 9 /L) is associated with an increased bleeding tendency in surgery; severe thrombocytopenia (platelet count <20  10 9 /L) can even cause severe spontaneous bleeding. While thrombocytopenia occasionally occurs with conventional chemotherapy for solid tumors, it becomes a major clinical pro- blem when dose-intensive myelosuppressive therapies are used [1]. Additionally, thrombocytopenia is a defining characteristic of idiopathic thrombocytopenia purpura (ITP) and a major problem associated with myelodysplastic syndrome (MDS), acquired immunodeficiency syndrome (AIDS) and chronic liver disease [2–5]. The chronic thrombocytopenia observed in these patients is caused by defective or diminished platelet production or enhanced immunologic or non-immunologic platelet destruction and may be associated with abnormal platelet function [2–5]. The main treatment for thrombocytopenia owing to decreased or defective platelet production is platelet transfusion, although this remains an expensive and time-consuming strategy that has limited efficacy (allo-immunization) and is still associated with several risks. In the United States, platelet utilization doubled from 4 million units transfused in 1982 to more than 8 million units transfused in 1992 [6]. This trend continued in the 1990s, as the number of platelet units transfused increased by 40% annually [7]. Thus, the search for novel thrombopoietic growth factors, to improve primary hemostasis and, eventually, reduce the need for platelet transfusion is still warranted. A broad spectrum of novel thrombopoietic agents are currently being tested; with most of them working via the cytokine thrombopoietin (THPO) path- way, however, other molecules have been identified that influence megakaryopoiesis by a different, THPO-independent manner. This review will discuss the current status of new drugs for the treat- ment of thrombocytopenia, based upon different THPO receptor Reviews  POST SCREEN Corresponding author: Freson, K. (Kathleen.freson@med.kuleuven.be) 798 www.drugdiscoverytoday.com 1359-6446/06/$ - see front matter ß 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.drudis.2008.06.002