TNF and Rare hereditary thrombophilia: ,6 Numerous studies have noted the superior safety profile of transdermal estrogen compared with oral,2,4, 5, 6, 7 likely due to upregulation of proinflammatory cytokines IL-1, IL-6, IL-8, and TNF-alpha,3,4,7 which lead to increased thrombophilia when taken orally.