Recombinant human thrombopoietin: basic biology and evaluation of clinical studies

Kuter, David J.; Begley, C. Glenn

doi:10.1182/blood.v100.10.3457

Cited by 338 publications

(257 citation statements)

References 122 publications

Supporting

Mentioning

241

Contrasting

Order By: Relevance

“…This conclusion-together with the observation that thrombin generation is normal in the plasma of individuals with cirrhosis 8 (Table 3)-might justify platelet transfusion or treatment with recombinant human thrombopoietin 24 in those patients with severe trombocytopenia when they bleed spontaneously or before undergoing surgery or liver biopsy. Platelets would provide suitable phospholipid surfaces to complement the normal thrombin generation elicited by plasma.…”

Section: Discussionmentioning

confidence: 95%

Thrombin generation in patients with cirrhosis: The role of platelets

et al. 2006

View full text Add to dashboard Cite

Coagulation factor defects, thrombocytopenia, and thrombocytopathy are associated with cirrhosis. However, bleeding in patients who have cirrhosis does not entirely correlate with abnormal coagulation tests. Recently, it was shown that because of the concomitant abnormalities of the procoagulant and anticoagulant drives, thrombin generation in plasma patients with cirrhosis is normal when assessed with assays that include thrombomodulin (the main protein C activator). However, thrombin is also generated in vivo as a function of platelets, suggesting that thrombocytopenia and thrombocytopathy might affect thrombin generation in patients with cirrhosis. We addressed this issue using an assay that accounts for the contribution of plasma and platelets. The study showed that platelet-rich plasma with platelets adjusted by dilution of autologous platelet-rich into autologous platelet-poor plasma to a standard count (100 ؋ 10 9 /L) generates as much thrombin in patients with cirrhosis as in controls (1,063 nmol/L vs. 1,167 nmol/L; P value not significant). When platelets were adjusted to correspond to whole-blood counts, patients with cirrhosis generated significantly less thrombin than controls (949 nmol/L vs. 1,239 nmol/L; P < .001). Furthermore, thrombin generation correlated with platelet numbers ( ‫؍‬ 0.50; P < .001). In addition, the amount of thrombin generated as a function of the whole-blood patients' platelet counts increased significantly when the numbers were adjusted to 100 ؋ 10 9 /L (953 nmol/L vs.1,063 nmol/L; P < .001). In conclusion, severe thrombocytopenia may limit thrombin generation in patients with cirrhosis. These findings might justify platelet transfusion in patients with low platelet counts when they bleed spontaneously or before undergoing surgery or liver biopsy. Controlled clinical trials supporting this indication are warranted. (HEPATOLOGY 2006;44:440-445.)

show abstract

Section: Discussionmentioning

confidence: 95%

Thrombin generation in patients with cirrhosis: The role of platelets

et al. 2006

View full text Add to dashboard Cite

show abstract

“…rhTPO was a glycosylated recombinant protein expressed in CHO cells that had an amino acid sequence identical to that of endogenous thrombopoietin although with a slightly different glycosylation pattern. In contrast, PEG-rhMGDF was a truncated non-glycosylated protein containing all of the first 153 amino acids of TPO, the receptor-binding domain, coupled to polyethylene glycol to improve stability [7].…”

Section: Lessons Learned From Clinical Studies With Recombinant Thrommentioning

confidence: 99%

“…In 1994 two recombinant thrombopoietins, recombinant human thrombopoietin (rhTPO) and pegylated, recombinant, human megakaryocyte growth and development factor (PEG-rhMGDF), began clinical development [7]. Both were potent stimulators of megakaryocyte growth and platelet production in both animal models and human subjects.…”

Section: Introductionmentioning

confidence: 99%

The biology of thrombopoietin and thrombopoietin receptor agonists

2013

Self Cite

View full text Add to dashboard Cite

Thrombopoietin (TPO) is the major physiological regulator of platelet production. TPO binds the TPO receptor, activates JAK and STAT pathways, thus stimulating megakaryocyte growth and platelet production. There is no ''sensor'' of the platelet count; rather TPO is produced in the liver at a constant rate and cleared by TPO receptors on platelets. TPO levels are inversely proportional to the rate of platelet production. Early recombinant TPO molecules were potent stimulators of platelet production and increased platelets in patients with immune thrombocytopenia, chemotherapy-induced thrombocytopenia, myelodysplastic syndromes and platelet apheresis donors. Neutralizing antibodies formed against one recombinant protein and ended their development. A second generation of TPO receptor agonists, romiplostim and eltrombopag, has been developed. Romiplostim is an IgG heavy chain into which four TPO agonist peptides have been inserted. Eltrombopag is an oral small molecule. These activate the TPO receptor by different mechanisms to increase megakaryocyte growth and platelet production. After administration of either to healthy volunteers, there is a delay of 5 days before the platelet count rises and subsequently reaches a peak after 12-14 days. Both have been highly effective in treating ITP and hepatitis C thrombocytopenia. Studies in a wide variety of other thrombocytopenic conditions are underway.

show abstract

“…analog 14b was as potency as XDE (2). These results suggested that the configuration of (Z,Z)-diene is essential for activity and that hydrophilic substituents on the benzene rings augment the biological activity.…”

Section: Methodsmentioning

confidence: 84%

“…Thrombocytopenia, or low platelet count, is one of the serious adverse events that occur as a result of intensive cancer chemotherapy or other treatments [2]. Although recombinant human (rh)TPO has been proven to be effective for such thrombocytopenia, some difficulties, such as development of neutralizing antibodies against TPO, have been reported [3].…”

mentioning

confidence: 99%