Acquired thrombocytopenia develops secondary to inadequate platelet production in the setting of primary or secondary marrow disorders, as well as secondary to platelet sequestration in the spleen and to destruction in the periphery. The latter is typically a result of autoimmune or drug-induced immune-mediated processes. Two of the more common clinical settings requiring platelet transfusion therapy include patients with hematologic disorders receiving high-dose chemotherapy or undergoing bone marrow transplantation, and patients with severe liver disease. While splenomegaly contributes to thrombocytopenia in the setting of severe liver disease, inadequate thrombopoietin (TPO) production by the failing liver also contributes significantly.
The 1994 cloning of human TPO (5
), the primary cytokine required for normal numbers of bone marrow megakaryocytes and circulating platelets, engendered great excitement for the treatment of thrombocytopenia. Two products underwent clinical trials, a full-length recombinant molecule administered intravenously and a pegylated, amino-terminal fragment administered subcutaneously (8
). These molecules successfully minimized the extent and duration of thrombocytopenia during chemotherapy for non-hematologic malignancies, including high-dose platinum-based treatment for gynecologic tumors, where the treatment reduced the need for platelet transfusions from 77% of patients to 24% (9
). However, neither agent meaningfully attenuated the extent or duration of thrombocytopenia when given to patients either receiving high-dose chemotherapy for leukemia or undergoing bone marrow transplantation. Interestingly, TPO treatment of donor mice prior to stem cell collection accelerated platelet reconstitution (10
), and TPO stimulation of stem cell donors reduced platelet transfusion requirements in a human trial (11
), suggesting that treatment of the cellular transplant product, as opposed to the transplant recipient, could have clinical value.
A single dose of TPO administered to platelet donors was shown to double the platelet count 14 days after injection and increase apheresis platelet yield by nearly 3-fold (12
), a promising finding for improving platelet availability to treat thrombocytopenia. However, excitement for TPO abruptly diminished when 4 clinical trial patients and 13 of 334 healthy subjects in a large safety trial developed antibodies against the administered TPO therapeutic that cross-reacted with native TPO, producing profound and prolonged thrombocytopenia (8
). While this complication developed only in patients receiving the subcutaneously administered pegylated, amino-terminal TPO fragment formulation, clinical development was halted for both products.
IL-11 is the only FDA-approved agent to treat thrombocytopenia. However, it does not alter platelet transfusion needs in the setting of high-dose chemotherapy and autologous bone marrow transplantation (13
), and its narrow therapeutic window and side-effect profile limit its use. New TPO mimetics (14
), some FDA approved to treat immune thrombocytopenic purpura, have rekindled hope that imaginative use of TPO receptor agonists will provide meaningful new approaches to treat a broad range of thrombocytopenic conditions, but this remains to be proven.
Beyond biomolecules, others have focused on developing novel cellular therapies for thrombocytopenia. New methods to generate megakaryocytes (15
) and platelets (16
) from human embryonic stem cells raise the possibility of a potentially endless platelet supply, but this approach has tremendous technical and safety hurdles before it could reach the clinic. More realistically, TPO is being explored ex vivo as a way to expand megakaryocyte progenitors in cord blood samples to hasten time to platelet independence (17