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hrombopoietin cDNA sc ccr clr | crisy nt NN stststss NM 4— Erythropoietin-like domain —|—_ Carbohydrate-rich domain ———+} rhTPO N-linked! PEG-thhlG DF carbohydrate —— §-or Tlinked Q carbohydrate Qs [1 Disulfide bond i Predicted a helives Figure 1, The Structure of the Thrombopoietin Gene and Its Clinical Derivatives. A model ofthe thrombopoietin polypeptide (top) can be clerived from analysis offs com plementary DNA (eDNA) structure. Amino acids responsible for important properties of the molecule are highlighted ancl include serine (S), cysteine (C), threonine (Ti, and asparagine (N) residues. Several of the disulfide bonds and the sites at which modifications of N, T., or Sinked carbohydrates concur in the recombinant protain produced in mammalian calls (recombinant human thrombopoietin [:hTPO)) have been identified (rmicldla, The site of truncation and the addition of polyethylene glycol (PEG) are shown (bottom for PEG conjugated recombinant human megakaryooyte growth ancldevelopment factor (PEG-rhNIGDF). Thisform of thrombopoiatin is produced in Escherichia coli and is cevoid of carbohycrate Stem cell a Multipotent progenitor cell @ Committed megakaryocyte- progenitor cell oa Immature megakaryocyte Mature megakaryocyte Steel factor Thrombopoietin Steel factor Interleukin-3 Interleukin-& Interloukin-11 Leukemia inhibitory factor G-CSF Thrombopoietin Steel factor Interleukin-3 Interleukin-& Interleukin-11 Leukemia inhibitory factor Erythropoietin Thrombopoietin Interleukin-& Interleukin-11 Thrombopoietin Fige2 Theol of Cores n Neal ayceytcins Noy stpsofmegsarat dlopmertce bac by sev ool in vit, rdudrg eo tr oo tered stall nase rt te otitis 25), tek 20 eat retin pnt cow trating str (GSP. eto aia inn ete a rerbaomin 229 Teton beter seme ec mtgotrtpegerion ah inti fi tu is ned on i resets proaeduebls reppin ola harap ein ally cir Aton tase res snc evel ast of reglaneye cvlopmet in vim. genet iin of colt ctor trambopoit= (cine, re tel te ineievintrecpn,oluein nie fa fests meskraei and pb prcctonin via Liver Kidney Br & Thrombopsietin 3 ~< aa i ie re OS ete “ge oa Oe Meqakaryocyte Megakaryocyte hypoplasia: hyperplasia: Ter eipanls Thrombacytosis High plasma Low ane thro istin thrombapoietin concentrations concentrations Bone marrow. en nee) Steacly-state platelet production Figure. A Moc of Thobopisin elt, ‘The Ter ad ihys pros thombrpitn ct Iy23e and ease int the clon. Fees exp ‘ursfondwonézpitn and oe tio pis nas cfthrnbopen shan inthe pty on thf, is cftrceasedthrtoposn state ate meting ign ls trabopin enact tut he ppl rer. xii, manewstome podisthon- poi cng tnnbopen ued? Tha big pes trosbopoetin cantor ip rst mee Fenner an ptetpeducton, aes. darn thems+ cyto shun ne thy on er, eights fps enero che thoi fo faci Inn end mano stoelel prin nay se a ret te tonbopitn& ett ator te rues rmegeroe inte eo cued ar rh, ing it ebm to dps pit pct, Tis mal i tpt to one prey a and oa