Comparative mechanisms of action between TM mutations in familial ET and Elt proposed in this issue of Blood by Levy and colleagues. In the monomeric state, (1) a possible break in the secondary helical structure of the TM domain may result in W491 associating on the extracellular side of the plasma membrane. TM mutations seen in familial ET (2) may lead to the rotation on W491 inward, stabilizing interactions between other TM residues leading to activation. The authors also propose that Elt may use a similar mechanism (3) via interactions with H499 and W491, breaking the TpoR-membrane interactions and permitting receptor activation.