Platelet Growth Factors


After either failure to respond to first-line ITP treatments or maintenance of a very low platelet count with bleeding, platelet growth factors or thrombopoietin (TPO) receptor agonists are often considered. These agents stimulate the bone marrow to produce more platelets. TPO receptor agonists have been shown to reduce bleeding events, and the need for concomitant medications like steroids and rescue treatments by raising platelet counts. Once thought to be only a disease of platelet destruction, research advances have shown that many people with ITP also have a platelet production problem which is believed to be caused by the same antibodies and cells that attack the platelets.14  In these cases, they are thought to also attack the megakaryocytes (the cells that make platelets) in the bone marrow.15

Thrombopoietin (TPO) is a protein made in the liver. It is a natural stimulator of platelet production in the bone marrow. TPO receptor agonists (TPO-RA) bind to the same receptor on cells in the bone marrow just as when TPO is produced by the body. This prompts cells in the bone marrow to produce even more platelets, with variable responses depending upon many individual factors.

Types of platelet growth factors or TPO-RA, including: avatrombopag (Doptelet®), eltrombopag (Promacta®/Revolade®), and romiplostim (Nplate®) stimulate the bone marrow to produce more platelets. About 50-80% of people with ITP who receive treatment with platelet growth factors see an increase in their platelet count above 50,000 μL. This response is often sustained while on treatment for many.9,16

It is estimated that approximately 20% of individuals receiving a TPO-RA will be able to eventually discontinue these treatments while maintaining an elevated platelet count. The exact number of such individuals eventually able to discontinue treatment is unknown and especially it is unknown how frequently this will continue to occur as these agents are taken for more than 1-2 years.8,9  In general, the goal of these treatments is a platelet count above 50,000μL, not a normal platelet count.

The TPO receptor agonists avatrombopag (Doptelet®), eltrombopag (Promacta®/Revolade®), and romiplostim (Nplate®), are approved by the U.S. Food and Drug Administration (FDA) for adults with ITP who have either responded poorly or not had a sustained off-treatment response to at least one other ITP medical therapy. Eltrombopag and romiplostim are also approved for use in children with ITP; romiplostim is approved for a patient with ITP at any time starting at or soon after diagnosis. As of November 2019, avatrombopag is not approved for use in children with ITP. These TPO receptor agonists are available for use in many other countries with varying eligibility criteria to access them.

Another TPO receptor agonist, lusutrombopag (Mulpleta®) was approved by the FDA only for adult patients with liver disease and a platelet count less than 50,000 μL and require a short course of treatment in advance of a required surgical procedure of any kind, including advanced dental work.  Since this drug is not used on a daily basis for treatment by those with ITP, we will not include any further information about this drug on this website at this time.

The most common adverse reactions reported with all three TPO-RAs include headaches, joint and muscle pain, dizziness, gastrointestinal issues, rash, flu, upper respiratory infections, and the potential for platelet counts to drop too low. There had been concern regarding bone marrow fibrosis, but extensive testing has demonstrated that this does not appear to be a clinically significant problem. The potential for platelet counts to drop too low after response to TPO agents if discontinued abruptly is the reason that small and slow changes in dose (tapering) is recommended when attempting to discontinue all agents.9

The most important serious adverse event is venous or arterial thromboembolism (blood clot). In long-term studies, this has been seen in 6-7% of patients using TPO-Ras.13 While venous thromboembolism (TEE) does not occur related to the platelet count, arterial thromboembolism, such as heart attack and stroke, may be related to the platelet count and may be more prevalent in the elderly.

Finally, with all agents there is a risk that malignant or pre-malignant cells in the bone marrow may respond to a TPO agent with progression to a more serious state.9

The International Consensus Report (2019) and the American Society of Hematology Guidelines for ITP (2019) both provide the most up-to-date clinical recommendations for who should consider TPO-RA therapy use.


Avatrombopag (Doptelet®)

Avatrombopag is a pill taken daily. While there are no dietary restrictions, it is recommended that the pill be taken with food in order to have its absorption (and subsequent blood levels) be more consistent.  In June 2019 the FDA approved this drug for adults with ITP who had an insufficient response to a previous treatment; it had already been approved in April-May 2018 for patients who with chronic liver disease and thrombocytopenia scheduled to undergo surgery including minor procedures, regardless if the procedure is related to the liver. As of November 2019, avatrombopag is only available in the United States. There is very limited data on long term use of this drug in treating ITP or any condition, as it is still relatively new. Individuals with ITP receiving this drug will need to have their platelet counts monitored weekly until their count is above 50,000/μL, and then monthly thereafter. Platelet counts must be measured for at least four weeks following discontinuation of avatrombopag.22

Dosage:

Avatrombopag is a pill that is taken with food. Dosing ranges depend on how an individual’s platelet count responds to the drug. The recommended starting dose is 20 mg once a day (this dose is referred to as a level 4 dose). The dose, or frequency of dosing, can be adjusted to reach and maintain a safe platelet count of at least 50 000/μL. Do not exceed 40 mg per day.

If an individual using avatrombopag cannot reach a platelet count of at least 50,000/μL after four weeks at the maximum dose of 40mg per day (level 6) (or if the platelet count is higher than 400,000/μL) the drug should be tapered and discontinued. In some cases, an individual who achieves a platelet count of 20-40,000/μL on 40mg daily and even this level cannot be achieved by another acceptable treatment, then treatment may be continued following discussion between the patient and the health care provider.22

Individuals taking other medications may need to follow a different dosing regimen. (Complete prescribing information)

Side Effects:

As of November 2019, there are no specific side effects unique to avatrombopag.11 Issues such as the exact risk for thrombosis and marrow fibrosis in particular have not yet been established.9 Unique to avatrombopag is the potential for side effects such as bleeding that can mimic ITP including petechiae, bruising, nosebleeds and bleeding from the gums.4,11


Eltrombopag (Promacta®/Revolade®)

Eltrombopag is a pill taken daily with important dietary restrictions. The drug gained FDA approval in November 2008 for use in adults with ITP who have not shown a significant response to at least one other ITP treatment. For example, a non-significant response could include patients who achieve a high platelet count only for a very short period following IVIG or patients receiving high dose daily steroids but with very low platelet levels. Eltrombopag received FDA approval in June 2015 for treatment of ITP in children between the ages of 1-18 years. 

This drug should not be used by those with a pre-existing liver disease (or risk of worsening liver disease or clotting too much); liver tests should be monitored throughout treatment. This drug should also not be used by individuals with myelodysplastic syndrome (MDS) as there could be a risk of progression to leukemia.

Individuals with ITP receiving eltrombopag will need to have their platelet counts monitored weekly until their count is above 50,000/μL, and then monthly thereafter. Platelet counts must be measured for at least four weeks following discontinuation.21

Dosage:

The pill is given as a 25, 50 or 75 mg (milligram) daily dose. The recommended starting dose for adults and children over 6 years is 50 mg. It must be taken on an empty stomach as food affects the absorption and the presence of calcium or iron will inactivate the drug. The ideal recommendation therefore is to not eat at all for 2 hours before AND for 2 hours after taking eltrombopag. In particular, however, dairy and broccoli and other calcium or iron rich foods should be avoided even longer before and after eltrombopag. Individuals with ITP who are of Japanese heritage may require a lower starting dose.9 Children between the ages of 1-6 years should begin with a lower dose of 25mg per day dose.9,18

After two weeks, if a platelet count of at least 50,000 μL has not been reached and the time and way of taking eltrombopag reviewed with the hematologist, the dose can be increased (not more often than every 2 weeks) by 25mg per day up to a maximum daily dose of 75mg per day.

If after two weeks from starting eltrombopag the platelet count is between 200,000μL - 400,000μL it is recommended to reduce the dose by half or by 25mg/day. If platelet counts do not increase to at least 50,000 μL at the maximum dose after one month, eltrombopag should be tapered and discontinued.

If an individual achieves a platelet count of 20-40,000μL on 40mg daily and this level cannot be achieved by another acceptable treatment, then treatment might continue following discussion with an appropriate health care provider.

If the platelet count reaches above 400,000μL, eltrombopag should either be temporarily discontinued for one week, or the dose can be reduced by 25mg daily. Once a dose change has been made further change should not be instituted for at least 2 weeks until a new equilibrium has been reached.21 (Complete prescribing information)

Side Effects: 

Eltrombopag is well-tolerated with minimal adverse effects reported. Side effects include the low potential risk for hepatic toxicity (liver damage) and transaminitis (high levels of certain liver enzymes).2,3,5,6,10 The risk of cataracts has not been clarified yet.7,9 Less than 2% of patients have reported the development of skin rashes and troublesome diarrhea.19


Romiplostim (Nplate®)

Romiplostim is a manufactured so-called peptibody (part small protein and part antibody) liquid that is given through weekly subcutaneous (under the skin) injections. In August 2008 the FDA approved romiplostim for adults with ITP who have failed at least one other treatment for the disease at any time starting from diagnosis.3 It received FDA approval in December 2018 for children over a year old with ITP who haven’t had success with corticosteroids, IVIG, or splenectomy.

This drug should not be used in individuals with myelodysplastic syndrome (MDS) in patients with a low platelet count due to a secondary condition.

Individuals with ITP receiving these injections will need to have their platelet counts monitored weekly, and then monthly once a stable platelet count of 50,000/μL has been reached. Platelet counts must be measured for at least two weeks following discontinuation.20

Dosage:

Romiplostim is given as a weekly injection. The recommended initial injection dose each week for both adults and children is 1mcg/kg (microgram/kilogram), however this may be too low for many individuals. In some clinical settings, a starting dose of 3 mcg/kg is used instead.

From there, dose increases depend on platelet count response and weight. Children need to be weighed before each dose, however adults only need to be weighed before the first injection unless a change in weight has occurred. If after two weeks a platelet count of at least 50,000/μL has not been reached, the dose can be increased by a minimum of 1mcg/kg per week up to a maximum weekly dose of 10mcg/kg.

If after two weeks from starting eltrombopag the platelet count is between 200,000/μL - 400,000/μL for at least two weeks, it is recommended to reduce the dose by 1mcg/kg. If platelet counts do not increase to at least 50,000/μL at the maximum dose after a few weeks (or the platelet count reaches above 400,000/μL) the drug is discontinued.

If an individual achieves a platelet count of 20-40,000/μL on romiplostim and this level cannot be achieved by another acceptable treatment, then treatment might continue following discussion with an appropriate health care provider.

If the platelet count falls below 200,000/μL romiplostim injections can resume at a 1mcg/kg reduced dose. It is important not to change the dose too much too quickly as this can lead to the platelet count cycling. When discontinuing these treatments, experienced health care providers reduce the dose gradually to avoid a sharp drop in the platelet count.20 (Complete prescribing information)

Side Effects:

Romiplostim is well-tolerated with minimal adverse effects reported. Side effects include the low potential risk of developing neutralizing antibodies to the treatment, reducing an individual’s response to the drug, thus affecting the platelet count.1,12,13,16,17 These antibodies are more frequent in children with chronic ITP.9


Assistance Programs

Since these treatments can be expensive for patients depending on insurance, the manufacturers of avatrombopag (Doptelet®), eltrombopag (Promacta®/Revolade®), and romiplostim (Nplate®) have established programs to assist those in the United States who are uninsured or who cannot afford the insurance co-payments. All of these programs endeavor to make each of the treatments accessible to all patients, but each is different and require each individual patient to contact and work with each group to make this happen.

See PDSA’s educational booklet Health Insurance and Assistance Programs for ITP Patients for more helpful information.


Predicting Success

Since these treatments stimulate thrombopoietin (TPO) production, individuals with ITP who have high TPO levels on their own may not benefit. In one study, patients with TPO levels greater than 95pg/mL (picogram per milliliter) did not respond well to the TPO agents. Some laboratories offer a test to measure TPO levels, however this approach is not standard practice as of November 2019. Patients with higher levels of reticulated platelet (newly made platelets) responded better to TPO agents.14

About 50-80 percent of people with ITP who receive treatment with platelet growth factors respond with an increase in platelet count (depending upon the definition of such an increase, usually 50,000/uL) often sustained for as long as the treatments are given. Furthermore, it is estimated that approximately 20% of individuals receiving a TPO are able to eventually discontinue these treatments while maintaining a safe platelet count; the true number of such people eventually able to discontinue treatment is unknown, especially as TPO agents are becoming more frequently used past one or two years. In general, the goal of these (or any) treatments is a platelet count over 50,000/uL, not a normal platelet count.2,9,11,13-16 This stable platelet count is more than enough to achieve all of the benefits desired by patients, allowing them to live a more normal life and minimizing worry over a low platelet count and ITP’s accompanying side effects.16


References

  1. Bussel, JB et al. “AMG 531, a thrombopoiesis-stimulating protein, for chronic ITP.” New England Journal of Medicine. 2006 Oct 19; 355(16): 1672-1681. https://www.nejm.org/doi/full/10.1056/NEJMoa054626
  2. Bussel, JB et al. “Eltrombopag for the treatment of chronic idiopathic thrombocytopenia purpura.” New England Journal of Medicine. 2007 Nov 29; 357(22): 2237-2247. https://www.nejm.org/doi/full/10.1056/NEJMoa073275
  3. Bussel, JB et al. “Effect of eltrombopag on platelet counts and bleeding during treatment of chronic idiopathic thrombocytopenia purpura: a randomised, double-blind, placebo-controlled trial.” Lancet. 2009 Feb 21; 373(9664): 641-648. https://pdfs.semanticscholar.org/1499/1c5c6072ef156162650a3087bf4aad1933e3.pdf
  4. Bussel, JB et al. “A randomized trial of avatrombopag, an investigational thrombopoietin-receptor agonist, in persistent and chronic immune thrombocytopenia.” Blood. 2014 Jun 19; 125(25): 3887-3894. https://ashpublications.org/blood/article-lookup/doi/10.1182/blood-2013-07-514398
  5. Bussel, JB et al. “Eltrombopag for the treatment of children with persistent and chronic immune thrombocytopenia (PETIT): a randomized, multicentre, placebo-controlled study.” Lancet Haematology. 2015 Aug; 2(8): e315-325. https://www.thelancet.com/journals/lanhae/article/PIIS2352-3026%2815%2900114-3/fulltext
  6. Cheng, G et al. “Eltrombopag for management of chronic immune thrombocytopenia (RAISE): a 6 month, randomised, phase 3 study.” Lancet. 2011 Jan 29; 377(9763): 393-402. https://www.ncbi.nlm.nih.gov/pubmed/20739054
  7. Cooper, et al. “Rate of cataracts across the eltrombopag studies in patients with chronic immune thrombocytopenia.” Blood. 2011; 118(21): 1164. https://ashpublications.org/blood/article/118/21/1164/78798/Rate-of-Cataracts-Across-the-Eltrombopag-Clinical
  8. 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
  9. Ghanima, W et al. “Thrombopoietin receptor agonists: ten years later.” Haematologica. 2019 Jun; 104(6): 1112-1123. http://www.haematologica.org/content/haematol/104/6/1112.full.pdf
  10. Grainger, JD et al. “Eltrombopag for children with chronic immune thrombocytopenia (PETIT2): a randomized, multicentre, placebo-controlled trial.” Lancet. 2015 Oct 24; 386(10004): 1649-1658. https://www.ncbi.nlm.nih.gov/pubmed/26231455
  11. Jurczak, W et al. “Phase 3 randomized study of avatrombopag, a novel thrombopoietin receptor agonist for the treatment of chronic immune thrombocytopenia.” British Journal of Haematology. 2018 Nov; 183(3): 479-490. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6282556/
  12. Kuter, DJ et al. “Efficiency of romiplostim in patients with chronic immune thrombocytopenia purpura: a double-blind randomized controlled trial.” Lancet. 2008 Feb 2; 371(9610): 395-403. https://www.ncbi.nlm.nih.gov/pubmed/18242413
  13. Kuter, DJ et al. “Long-term treatment with romiplostim in patients with chronic immune thrombocytopenia: safety and efficacy.” British Journal of Hematology. 2013 May; 161(3): 411-423.https://www.ncbi.nlm.nih.gov/pubmed/23432528
  14. 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 http://www.ncbi.nlm.nih.gov/pubmed/23913253
  15. McCrae, K. Immune Thrombocytopenia: No longer idiopathic. Cleveland Clinical Journal of Medicine. 2011. June; 78(6): 358-373.
  16. Provan, D, “International consensus report on the investigation and management of primary immune thrombocytopenia.” Blood. 2010 Jan 14; 115(2): 168-86. https://ashpublications.org/bloodadvances/article/3/22/3780/428877/Updated-international-consensus-report-on-the
  17. Tarantino, MD et al. “Romiplostim in children with immune thrombocytopenia: a phase 3 randomized, double-blind, placebo-controlled study.” Lancet. 2016 Jul 2; 388(10039): 45-54. https://www.ncbi.nlm.nih.gov/pubmed/27103127
  18. 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
  19. Wong, R et al. “Safety and efficacy of long-term treatment of chronic/persistent ITP with eltrombopag: final results of the EXTEND study.” Blood. 2017; 130(23): 2527-2536.
  20. Romiplostim (Nplate®) prescribing information https://www.nplatehcp.com/dosing/
  21. Eltrombopag (Promacta®/Revolade®) prescribing information https://www.pharma.us.novartis.com/sites/www.pharma.us.novartis.com/files/promacta.pdf
  22. Avatrombopag (Doptelet®) prescribing information https://dova.com/wp-content/uploads/2019/06/doptelet-prescribing-information.pdf

 

 

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