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Platelet Growth Factors

(TPO Receptor Agonists)

Platelet Growth Factors or thrombopoietin (TPO) receptor agonists are a class of treatments that stimulate the bone marrow to produce more platelets. TPO, a protein made in the liver, naturally stimulates platelet production in the bone marrow. TPO receptor agonists bind to the same receptor in the bone marrow as the TPO produced in the body. This prompts the megakaryocytes in the bone marrow to produce more platelets, sufficient to increase the platelet count in most people.

About 80% of people who receive these treatments respond as long as the treatments are given.2 However, it is possible that a small percent of people may be able to discontinue these treatments and maintain a safe platelet count.1 Note: the goal of these treatments is a platelet count of about 50,000/ml, not a normal platelet count.

There are two TPO receptor agonists approved by the FDA in the US for adults and by the regulatory agencies in some other countries: romiplostim (Nplate®) and eltrombopag (Promacta®/Revolade®). Both of these treatments are being tested in children.4,5 Clinical trials are ongoing for other TPO receptor agonists.

romiplostim (Nplate®)

Romiplostim is a manufactured peptibody (part peptide and part antibody) liquid that is given by weekly subcutaneous (under the skin) injection. On September 4, 2008, the US FDA approved romiplostim for adults with ITP (either splenectomized or not) who have failed at least one other treatment for the disease3. Since then other countries have approved its use, sometimes adding other criteria.

eltrombopag (Promacta®/Revolade®)

Eltrobopag is a small molecule (pill) taken daily.  The drug was given final approval in February, 2011 with the same approval criteria as romiplostim.3 Other countries have also approved its use, again, sometimes adding other criteria.

Dosage

romiplostim: The dose of romiplostim, from 1ug/kg to 10 ug/kg, depends on the patient's weight and response to previous doses. The dose is reduced or discontinued if the platelet count rises too high or if the patient doesn't respond.2

eltrombopag: The pill is given as a 25, 50, or 75 mg daily dose. It must be taken on an empty stomach as other medications and food affect its absorption2. People of Japanese heritage require a lower starting dose.7

When discontinuing these treatments, some doctors reduce the dose gradually to avoid a sharp drop in the platelet count.

Side Effects

romiplostim: The most common adverse reactions are joint and muscle pain, dizziness, insomnia, indigestion, and ‘pins and needles’ sensation. There is a slight potential for patients to develop reticulum (fibrous growths) in the bone marrow and also for the platelet count to drop below the pre-treatment count when the treatment is discontinued.6

eltrombopag: The most common adverse reaction is a mild to moderate headache. Other side effects include nausea, diarrhea, upper respiratory tract infection, vomiting, rash, flu, sore throat, back pain, and tingling or numbness in the skin.8 A small percent of people develop elevated liver functions which usually resolves when the treatment is discontinued.9

Assistance Programs

Because these treatments are expensive the manufacturers have established several programs to assist those people in the US who are not insured, underinsured or who cannot meet the insurance co-payments.

romiplostim (Amgen): financial support section of the Amgen Web site.

eltrombopag (GlaxoSmithKline): financial assistance portion of the GSK Web site

Predicting Success

Measure thrombopoietin (TPO) Levels: Since these treatments stimulate TPO production, patients who produce a lot of TPO on their own may not benefit. In one study patients with TPO levels greater than 95pg/mL did not respond well to the TPO agents.11 Quest Diagnostics has a test to measure TPO levels (test no. 16336)

Analyze platelet lifespan: In one study, the platelets of people who were able to sustain a remission had a normal lifespan and were removed from the body in the same way as those without the disease.10

References

1. Ghadaki B et al. "Sustained remissions of immune thrombocytopenia associated with the use of thrombopoietin receptor agonists." Transfusion. 2013 Mar 3.
http://www.ncbi.nlm.nih.gov/pubmed/23451917"

2. Provan, D, “International consensus report on the investigation and management of primary immune thrombocytopenia,” Blood. 2010 Jan 14; 115(2):168-86. http://bloodjournal.hematologylibrary.org/cgi/content/full/115/2/168

3. FDA Drug Safety Communication: Modified Risk Evaluation and Mitigation Strategies (REMS) for Nplate (romiplostim) and Promacta (eltrombopag) Dec. 6, 2011. http://www.fda.gov/Drugs/DrugSafety/ucm280165.htm

4. Bussel JB et al. “A randomized, double-blind study of romiplostim to determine its safety and efficacy in children with immune thrombocytopenia.” Blood. 2011 Jul 7;118(1):28-36. http://www.ncbi.nlm.nih.gov/pubmed/21502541

5. Blanchette VS et al. "Health-Related Quality of Life in Children with Chronic Immune Thrombocytopenia Treated with Eltrombopag in the PETIT Study." 2012 American Society of Hematology meeting. Abstract 2197.

6. Medline http://www.nlm.nih.gov/medlineplus/druginfo/meds/a609008.html#side-effects

7. Tomiyama Y, et al. "A lower starting dose of eltrombopag is efficacious in Japanese patients with previously treated chronic immune thrombocytopenia (ITP)." J Thromb Haemost. 2012 Mar 12. http://www.ncbi.nlm.nih.gov/pubmed/22409309

8. FDA News Release http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm282502.htm

9. Saleh MN et al. “Safety and efficacy of eltrombopag for treatment of chronic immune thrombocytopenia: results of the long-term, open-label EXTEND study.” Blood. 2013 Jan 17;121(3):537-45. http://www.ncbi.nlm.nih.gov/pubmed/23169778

10. Iuliano F. “Platelet Kinetic Study (PKS) May Early Identify a Subset of Patients with Immune Thrombocytopenia (ITP) Probably Cured by Romiplostim. Two Years Follow-up.” 2012 American Society of Hematology meeting. Abstract 2197.

11. Makar RS et al. “Thrombopoietin (TPO) levels in patients with disorders of platelet production: Diagnostic potential and utility in predicting response to TPO Receptor agonists.” Am J Hematol. 2013 Aug 1. http://www.ncbi.nlm.nih.gov/pubmed/23913253