Stimulation of Thrombocytosis and Thrombosis

In none of the closely followed animal or human studies with TPO has there been any evidence for increased thrombotic events, but three potentially prothrombotic attributes of TPO deserve attention. These molecules are extremely potent growth factors and can markedly increase the platelet count in a short period. The deposition of platelets in an extravascular shunt in baboons is directly related to the platelet count after PEG-rHuMGDF administration (50,51). Since the extravascular shunt mimics an ulcerated atheroma in humans, these results show that except for its ability to increase the platelet count, PEG-rHuMGDF does not synergize with or exacerbate platelet deposition. Nonetheless, increasing the platelet count in individuals with active arterial thrombotic disease may exacerbate the cardiovascular disease.

When PEG-rHuMGDF or rHuTPO are added directly to platelets, they decrease by approximately 50% the threshold for activation by various agonists (ADP, collagen) in platelet aggregometry experiments (50,51). This finding may not be clinically relevant since other HGFs do the same and have not been associated with thrombosis.

The production of young platelets is stimulated ("platelet tide"), and these peak in the circulation 4-5 d after administration of PEG-rHuMGDF to normal baboons or humans (50,51). These younger platelets have a lower threshold for agonists and are more active in platelet aggregation experiments, but clinically these effects have not resulted in increased thrombosis in either animals or humans.

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