Thrombocytes, or platelets, are anucleate and an important class of circulating blood cells that maintain haemostasis. A normal platelet count for an adult human is in the range of 150,000 to 450,000 per uL of blood. When the platelet count drops below 150,000 per μL of blood, it is defined as thrombocytopenia. A common pathophysiologic mechanism leading to thrombocytopenia is a disproportionate amount of consumption or destruction and loss of platelets from circulation compared to their rate of production. This most often occurs when autologous antibodies that recognize the endogenous platelets are produced in response to unknown stimuli, and these autoantibodies bind to, or opsonize the autologous platelets and are involved in their destruction, usually in the spleen or liver by tissue macrophages. This leads to the clinical disease known as immune thrombocytopenia (ITP).
Monocyte-macrophages recognize these opsonised platelets via a receptor on their outer surface called the Fc receptor (FcR) and clear them from circulation by a process called phagocytosis. ITP can be treated by reducing platelet destruction or by increasing platelet production. Current treatments for ITP include corticosteroids, rituximab, intravenous immunoglobulins (IVIG and anti-D), administration of thrombopoietin (TPO) receptor agonists, and surgical measures such as splenectomy. There are no treatments that have been proven to directly interfere with the opsonized platelet recognition by FcRs on monocyte-macrophages. Existing therapies have inherent limitations and challenges, such as the toxicities associated with immunosuppressant rituximab, relapse of ITP following discontinuation of the TPO receptor agonist treatment, and possible severe anemia and/or exposure to blood-borne infections from human plasma-derived IVIG.
Foo et al (Transfusion. 2007, 47 (2), 290-298) and Rampersad et al (Transfusion. 2005, 45 (3), 384-393) screened several small molecules carrying sulfhydryl and disulfide groups on aromatic and aliphatic compounds for their ability to inhibit the FcR-mediated phagocytosis of opsonized platelets by macrophages. It was hypothesized that these molecules would interact with the sulfhydryl or disulfide groups on the cell surface of human mononuclear phagocytes and inhibit the phagocytosis of opsonized red blood cells (RBC). This is based on the premise that cell surface proteins of monocyte-macrophages carry sulfhydryl and disulfide groups that play an important role in endocytic-phagocytic function, and small molecules carrying such groups would function as antagonists to the phagocytosis process (see Carpenter, R. R. et al J. Immunol. 1967, 98 (4), 844-853 and Sahaf, B. et al. Proc. Natl. Acad. Sci. 2003, 100 (7), 4001-4005).