Michael D. Tarantino, MD, is Professor in the Department of Pediatrics and Professor at the Department of Medicine at the University of Illinois College of Medicine in Peoria. He is the Medical Director of the Comprehensive Bleeding Disorders Center and the Laboratory Director of the Comprehensive Hemostasis and Thrombosis Institute also in Peoria.

Please submit a question by clicking the link below. Response to questions will be answered the following Friday.

Each month, an expert in ITP will be "On Call" to answer your ITP-related questions. Check back each month for updates!

Q: I would like to incorporate a QoL measure into my management of ITP. Which tool do you recommend? Is there evidence suggesting that ITP therapy improves the QoL score in concert with the platelet count? If they do correlate, do I really need the QoL measure, and if they do not correlate, is the improved QoL coming from an unrelated activity of the therapy?

A: Patients with ITP generally have a health related quality of life (HRQoL) lower than the general population and similar to other chronic diseases such as diabetes. This is generally attributed to physical symptoms associated with the disease and/or its treatment, social limitations, and psychological effects.

Two quality of life measures have been used in the analysis of ITP patients. The Short Form 36 (SF-36) questionnaire is used in studies of a variety of different diseases. The ITP-Patient Assessment Questionnaire (ITP-PAQ) was designed specifically for patients with ITP.

Although in a recent clinical study patients who responded to romiplostim had improved QoL, platelet count should not be used as a surrogate marker for QoL. First, in this study platelet counts were often not stable over the course of treatment. Platelet count may improve, but QoL could be worse due to side effects of the therapy. QoL measures have only recently been incorporated into ITP studies, therefore the effects of specific treatments on platelet responses, side effects, and QoL remain mostly unknown.

References:

George JN, Mathias SD, Go RS, et al. Improved quality of life for romiplostim-treated patients with chronic immune thrombocytopenic purpura: results from two randomized, placebo-controlled trials. Br J Haematol. 2009;144(3):409-415.

Mathias SD, Bussel JB, George JN, et al. A disease-specific measure of health-related quality of life in adults with chronic immune thrombocytopenic purpura: psychometric testing in an open-label clinical trial. Clin Ther. 2007;29(5):950-962.

McMillan R, Bussel JB, George JN, et al. Self-reported health-related quality of life in adults with chronic immune thrombocytopenic purpura. Am J Hematol. 2008;83(2):150-154.

Snyder CF, Mathias SD, Cella D, et al. Health-related quality of life of immune thrombocytopenic purpura patients: results from a web-based survey. Curr Med Res Opin. 2008;24(10):2767-2776.

Q: I have a 6-year-old patient with ITP suffering with a painful knee. Is the joint pain likely related to the ITP? Should I treat the ITP or the knee?

A: In ITP patients, bleeding and excessive bruising are the main clinical sequelae of severe thrombocytopenia. However, more systemic symptoms such as fatigue are well described yet hard to quantify and explain. Knee pain is not a common complaint in primary ITP. If there was injury to the knee a hemarthrosis can be considered, but is uncommon in primary disorders of hemostasis such as ITP. Secondary ITP may be associated with SLE or other rheumatologic disorders and might present with joint pain. If there are symptoms to suggest SLE or other rheumatologic conditions these diagnoses should be pursued and treated accordingly.

Unless otherwise indicated, I would not treat the ITP, as childhood ITP often resolves spontaneously without any specific therapy. The joint pain should be treated symptomatically, but aspirin and other non-steroidal antagonists should be used with extreme caution as they may exacerbate the bleeding risk in thrombocytopenic patients.

References:

Arkfeld DG, Weitz IC. Immune thrombocytopenia in patients with connective tissue disorders and the antiphospholipid antibody syndrome. Hematol Oncol Clin North Am. 2009;23(6):1239-1249.

Mestanza-Peralta M, Ariza-Ariza R, Cardiel MH, Alcocer-Varela J. Thrombocytopenic purpura as initial manifestation of systemic lupus erythematosus. J Rheumatol. 1997;24(5):867-870.

Q: Please clarify the currently preferred nomenclature of ITP. Is "idiopathic" TP autoimmune in nature and is this considered an underlying cause?

A: The "I" in ITP has been variably referred to as "idiopathic" or "immune". A recent international working group of ITP experts has decided to abandon the term "idiopathic" preferring "immune" in order to emphasize the immune nature of primary ITP. As purpura is often absent from the acronym ITP, which was preserved due to its historical use, is now proposed to stand for immune thrombocytopenia. A platelet cut off < 100 x10⁹/L was used as the threshold for diagnosis. "Primary ITP" indicates cases without any obvious initiating events or underlying cause. "Secondary ITP" has been proposed to encompass all other forms of immune-mediated thrombocytopenia.

References:

Rodeghiero F, Stasi R, Gernsheimer T, et al. Standardization of terminology, definitions and outcome criteria in immune thrombocytopenic purpura of adults and children: report from an international working group. Blood. 2009;113(11):2386-2393.

Q: I have a patient who responded very well to interferon/ribavirin for treatment of hepatitis C. After 6 weeks, the viral load was practically undetectable, however, her platelets were at 27,000 and treatment was stopped. Can the IFN/ribavirin protocol be continued after her platelets recover? What is the threshold and is there a waiting period after recovery?

A: Thrombocytopenia is common in patients with hepatitis C and cirrhosis, occurring in up to 65% of patients. The etiology is multifactorial and may include decreased production of TPO in the liver, viral suppression of megakaryopoiesis, splenic sequestration, and ITP. Thrombocytopenia is also a common side effect (may be dose limiting) of IFN/ribavirin treatment of hepatitis C. The thrombocytopenia in liver disease may be exacerbated by IFN, which can itself cause immune thrombocytopenia, leading to dose reduction or discontinuation. Recent data published in the New England Journal of Medicine support using eltrombopag to maintain a safe platelet count in hepatitis C patients being treated with IFN. Eltrombopag is not FDA approved for this use. LFTs should be monitored closely as eltrombopag may be hepatotoxic in some patients. Further safety and efficacy studies of eltrombopag in patients with hepatitis C are ongoing. Since your patient showed a great virologic response, eltrombopag (initially dosed at 25 mg po daily) would be a reasonable treatment option as would be dose reduction of IFN. In patients treated with PEG-alfa 2a, dose reduction is necessary in 3 to 4% of patients; recommendations are included in the package insert. Once platelet counts recover to a safe range retreatment can be considered without a prolonged waiting period.

References:

Dusheiko G. Thrombopoietin Agonists for the Treatment of Thrombocytopenia in Liver Disease and Hepatitis C. Clin Liver Dis. 2009;13(3):487-501.

Rajan SK, Espina BM, Liebman HA. Hepatitis C virus-related thrombocytopenia: clinical and laboratory characteristics compared with chronic immune thrombocytopenic purpura. Br J Haematol. 2005;129:818-824.

McHutchison JG, Dusheiko G, Shiffman ML, et al; TPL102357 Study Group. Eltrombopag for thrombocytopenia in patients with cirrhosis associated with hepatitis C. N Engl J Med. 2007;357(22):2227-2236.

Bashour FN, J Teran C and Mullen KD. Prevalence of peripheral blood cytopenias (hypersplenism) in patients with nonalcoholic chronic liver disease. Am J Gastroenterol. 2000;95:2936-2939.

Fried MW, Shiffman ML, Reddy KR, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med. 2002;347(13):975-982.

Q: Is the MMR vaccine associated with ITP, and are there special considerations in managing such patients?

A: In a review of patients who presented with purpura and platelets < 30 x 10⁹/L within 1 month after vaccination an estimated ITP risk of approximately 1 in 30,000 MMR inoculations was noted. Symptoms were nearly always acute. Thrombocytopenia disappeared within a month in 74% of the patients and lasted longer than 6 months in only 10%. Bleeding episodes were uncommon during the follow-up period.

In a review from the United Kingdom the relative risk estimate for ITP within 6 weeks after MMR vaccination, compared to the combined group of unvaccinated children and children vaccinated with MMR more than 26 weeks previously was 6.3 (95% CI 1.3-30.1). The attributable risk of developing ITP within 6 weeks after MMR vaccination was estimated to be 1 in 25,000 vaccinations, similar to the study noted above. The authors concluded that there is an increased risk of ITP within 6 weeks after MMR vaccination, but the absolute risk was still low.

A Cochrane database review also suggested that the vaccine was likely to be associated with benign thrombocytopenic purpura.

Given the fact that the disease spontaneously remits in the majority of patients, treatment should be conservative and analogous to primary childhood ITP, unless the child has clinical bleeding or refractory disease where traditional therapies such as steroids or gammaglobulin should be considered.

References:

Rajantie J, Zeller B, Treutiger I, Rosthöj S; NOPHO ITP working group and five national study groups. Vaccination associated thrombocytopenic purpura in children. Vaccine. 2007;25(10):1838-1840.

Black C, Kaye JA, Jick H. MMR vaccine and idiopathic thrombocytopaenic purpura. Br J Clin Pharmacol. 2003;55(1):107-111.

Demicheli V, Jefferson T, Rivetti A, Price D. Vaccines for measles, mumps and rubella in children. Cochrane Database of Systematic Reviews. 2005;Issue 4. Art. No.: CD004407. DOI: 10.1002/14651858.CD004407.pub2

Q: I have a 30-year-old female ITP patient who has undergone splenectomy and is now on oral prednisone. She is getting married and wants to use oral contraceptives. What are the risks of oral contraceptives in patients with ITP, and should I recommend another method for her?

A: The role of estrogen therapy in ITP is not well studied and remains controversial. On one hand, estrogen is used in ITP patients to prevent heavy menstrual bleeding and treat or prevent steroid-induced osteoporosis. On the other hand, estrogen could conceivably play a role in disease pathogenesis, as ITP is more common in women and has been associated with pregnancy. In a small number of patients, estrogen has been associated with induction or worsening of ITP.

Recent studies have shown an increased risk of VTE in hematology patients who have undergone splenectomy. Even though this risk was greatest in patients with hemolytic disorders, a potential risk in ITP patients was noted. Estrogen therapy also increases VTE risk. Whether estrogens impart an additional thrombotic risk in splenectomized ITP patient remains uncertain.

In the presented patient, estrogen may help bone density, but whether it can be expected to adversely affect the course of ITP remains unknown. It would be reasonable to use the minimum dose of estrogen combined with a progestin if barrier methods of contraception are not feasible. Platelet count should be monitored closely in the first months after estrogen administration.

References:

Onel K, Bussel JB. Adverse effects of estrogen therapy in a subset of women with ITP. J Thromb Haemostasis. 2004;2(4):670-671.

Crary SE, Buchanan GR. Vascular complications after splenectomy for hematologic disorders. Blood. 2009;114(14):2861-2868.

Q: Is there any information on combination therapy using IVIg with a TPO agonist such as romiplostim or eltrombopag for ITP?

A: In the pivotal clinical trials of both romiplostim and eltrombopag, patients were required to have failed one first-line therapy and be on no other or a stable dose of another oral ITP therapy for at least a month prior to enrollment. If IVIg had been used in treatment it had to be last administered at least 2 weeks prior to enrollment. Thus IVIg was not routinely used in these trials other than for rescue therapy. Conventional ITP treatments aim to decrease platelet destruction while the TPO agonists stimulate platelet production. Combining these two therapies may seem an attractive way of treating ITP. The effects of both IVIg and the TPO agonists, however, are only temporary; when either of these drugs is stopped the platelet count will typically return to baseline, unless there was a spontaneous remission of the disease. Thus these drugs would be unlikely to be used as concomitant therapy other than in emergent situations where the response to high- dose steroids or IVIg was suboptimal. There are insufficient data to recommend IVIg and TPO agonists together for long term therapy outside of a clinical trial.

References:

Bussel JB, Cheng G, Saleh MN, et al. Eltrombopag for the treatment of chronic idiopathic thrombocytopenic purpura. N Engl J Med. 2007;357(22):2237-2247.

Kuter DJ, Bussel JB, Lyons RM, et al. Efficacy of romiplostim in patients with chronic immune thrombocytopenic purpura: a double-blind randomized controlled trial. Lancet. 2008;371(9610):395-403.

Bussel JB, Pham LC. Intravenous treatment with gammaglobulin in adults with immune thrombocytopenic purpura: review of the literature. Vox Sang. 1987;52(3):206-211.

Q: I have a patient who has had ITP since 2004. He has always been steroid refractory and has been treated with splenectomy, accessory splenectomy, and periodic IVIg. Rituximab was given for a relapse in January 2008 and the patient responded until April 2009, when he relapsed and was retreated with rituximab. He continues to do well with a platelet count of 70-80k. He is requesting maintenance rituximab (every 6 months) to prevent/delay relapse. Please advise if that is indicated.

A: In a large, systematic review of the efficacy and safety of rituximab treatment in ITP, approximately 60% of patients had a platelet response, with a complete response occurring in 46% of patients. The median duration of response is around 10.5 months with a 15-20% long-term complete response rate.

The optimal dosing regimen for rituximab in ITP has never been formally established and the standard dose of 375 mg/m² weekly for four weeks is borrowed from the literature concerning the treatment of low grade lymphoma. Doses lower than the standard one may be effective in ITP, and may have a more favorable side-effect profile in addition to a substantially lower cost.

Retreatment is successful in approximately 75% of patients who respond to rituximab but subsequently relapse. Although maintenance rituximab has been shown to be effective in the treatment of low-grade lymphoma, similar data do not exist in ITP and currently can not be recommended outside of a clinical trial.

References:

Arnold DM, Dentali F, Crowther MA, et al. Systematic review: efficacy and safety of rituximab for adults with idiopathic thrombocytopenic purpura. Ann Intern Med. 2007;146(1):25-33.

Provan D, Butler T, Evangelista ML, et al. Activity and safety profile of low-dose rituximab for the treatment of autoimmune cytopenias in adults. Haematologica. 2007;92(12):1695-1698.

Cooper N, Evangelista ML, Amadori S, et al. Should rituximab be used before or after splenectomy in patients with immune thrombocytopenic purpura? Curr Opin Hematol. 2007;14(6):642-646.

Hainsworth JD, et al. Single-agent rituximab as first-line and maintenance treatment for patients with chronic lymphocytic leukemia or small lymphocytic lymphoma: a phase II trial of the Minnie Pearl Cancer Research Network. J Clin Oncol. 2003;21:1746-1751.

Q: I have a patient in the 7th month of her first pregnancy. She has suffered from ITP since conception. What are the special considerations during prenatal and postnatal care and how does her pregnancy affect the choice of therapeutic options for ITP?

A: The American Society of Hematology and British Committee of Standards have published guidelines concerning the treatment of ITP in pregnancy, although recent approaches have evolved as additional evidence has become available. Typically, platelet counts of 50,000/µL are sufficient for vaginal delivery and 50,000-80,000/µL for c-section or epidural anesthesia. In the third trimester, IVIG is often preferred over steroids. Splenectomy is not generally recommended beyond the second trimester.

The delivery plan should be based on obstetric reasons and not necessarily on the platelet count. The maternal platelet count is a very poor predictor of the fetal platelet count. Given a rather low risk of life-threatening fetal hemorrhage which is even lower than the risk of periumbilical sampling (PUBS), monitoring of the fetal platelet count is not recommended antepartum.

Postpartum determination of the newborn platelet count by way of cord sampling is recommended with follow-up platelet counts for several days. It is generally recommended that infants with platelet counts less than 20,000/µL or with clinical bleeding receive treatment with IVIG and/or steroids. Routine brain imaging can be considered for platelet counts less than 50,000/µL.

References:

Gernsheimer T, McCrae KR. Immune thrombocytopenic purpura in pregnancy. Curr Opin Hematol. 2007;14:574-580.

George JN, Woolf SH, Raskob GE, et al. Idiopathic thrombocytopenic purpura: a practice guideline developed by explicit methods for the American Society of Hematology. Blood. 1996;88(1):3-40.

British Committee for Standards in Haematology General Haematology Task Force. Guidelines for the investigation and management of idiopathic thrombocytopenic purpura in adults, children and in pregnancy. Br J Haematol. 2003;120(4):574-596.

Gill KK, Kelton JG. Management of idiopathic thrombocytopenic purpura in pregnancy. Semin Hematol. 2000;37(3):275-289.

Q: I have a 40-year-old female patient with a history of SLE and ITP. She did not respond to steroids and requires gamma globulin every 2 weeks to keep her platelet count greater than 10k. She has been on mycophenolate mofetil for about a month with no response. We tried rituximab a few months ago with a brief response and are trying it again. The patient is hesitant to try romiplostim due to the chance of bone marrow fibrosis. Do you have any suggestions?

A: Secondary ITP can be rather difficult to treat and initial treatment is often aimed at controlling the underlying disease. In SLE many causes of thrombocytopenia may exist, but with platelet counts < 10,000/µL immune-related causes, such as ITP, are more likely. There are no large studies or evidence-based guidelines to suggest optimal therapy in patients with SLE. Steroids and IVIG are very reasonable initial therapies. Rituximab has been effective in the treatment of both isolated ITP and isolated SLE and seems like a logical choice in this setting. The Phase II and Phase III studies of the TPO agonists romiplostim and eltrombopag excluded patients with secondary ITP so efficacy in these settings remains uncertain. Splenectomy remains a viable option, but whether to perform this prior to or after a trial of a TPO analogue remains a matter of opinion. Given that SLE may be responsive to oral immunosuppressants, mycophenolate seems like a reasonable option as well. Many of these oral immunosuppressants can have a delayed response in ITP and should be continued for several months before deeming them a failure. Response rates of oral immunosuppressants and oral chemotherapeutic agents typically are no greater than 30% in primary ITP.

References:

Bussel JB. Therapeutic approaches to secondary immune thrombocytopenic purpura. Semin Hematol. 2009;46(1 Suppl 2):S44-58.

Bussel JB, Cheng G, Saleh MN, et al. Eltrombopag for the treatment of chronic idiopathic thrombocytopenic purpura. N Engl J Med. 2007;357(22):2237-2247.

Kuter DJ, Bussel JB, Lyons RM, et al. Efficacy of romiplostim in patients with chronic immune thrombocytopenic purpura: a double-blind randomized controlled trial. Lancet. 2008;371(9610):395-403.

Arnold DM, Dentali F, Crowther MA, et al. Systematic review: efficacy and safety of rituximab for adults with idiopathic thrombocytopenic purpura. Ann Intern Med. 2007;146(1):25-33.

Q: I have a 24-year-old patient with a stable platelet count of 100K who is thinking of having a baby. How frequently should she be monitored and what are the best steps if her platelet count starts to drop? What are the risks for mother and baby?

A: The first question to ask is what is the etiology of her thrombocytopenia. If any prior counts are available they should be reviewed. In addition, a good family history should be taken to evaluate for a hereditary thrombocytopenia as a cause of her low platelet counts. The blood smear should be reviewed to rule out clumped platelets suggesting pseudothrombocytopneia and very large platelets which would suggest a macrothrombocytopenia. Medications and herbal remedies should be reviewed. HIV testing could be considered. If the patient has a bleeding history then testing for Type II-B vWD can be considered which may be associated with mild thrombocytopenia.

If your patient is presumed to have ITP after this evaluation, the disease could either remain quiescent or worsen during the pregnancy. Women with pre-existing ITP are less likely to require therapy than those with newly diagnosed ITP.

I would initially check the platelet counts biweekly when she first becomes pregnant and then monthly if stable. If her counts remain stable you could likely check even less frequently until delivery approaches.

If the platelet counts drop below 10,000-20,000/µL early in the pregnancy or if bleeding occurs, IVIG or steroids could be considered. A platelet count greater than 50,000/µL should be targeted for vaginal delivery and greater than 50,000-80,000/µL for c-section. The maternal platelet count does not predict the fetal platelet count. Although mild fetal thrombocytopenia is not uncommon (up to 25% of patients), severe thrombocytopenia is less common and life-threatening neonatal bleeding relatively rare.

References:

Gernsheimer T, McCrae KR. Immune thrombocytopenic purpura in pregnancy. Curr Opin Hematol. 2007;14:574-580.

Webert KE, Mittal R, Sigouin C, Heddle NM, Kelton JG. A retrospective 11-year analysis of obstetric patients with idiopathic thrombocytopenic purpura. Blood. 2003;102(13):4306-4311.

George JN, Woolf SH, Raskob GE, et al. Idiopathic thrombocytopenic purpura: a practice guideline developed by explicit methods for the American Society of Hematology. Blood. 1996;88(1):3-40.

Gill KK, Kelton JG. Management of idiopathic thrombocytopenic purpura in pregnancy. Semin Hematol. 2000;37(3):275-289.

Q: I have a 60-year-old female patient who was treated with antibiotics for H pylori several months ago. She is on steroids for polymyalgia rheumatica. She was admitted to the hospital for coughing up blood and now has intracranial hemorrhage. The admitting physician diagnosed ITP. Tomorrow's CT scan should show if she responds to IVIG. What is the best course of action at this time?

A: High dose corticosteroids such as methylprednisolone 1.0 g/kg/d x3 days or pulse dexamethasone 40 mg daily x4 days in conjunction with IVIG or anti-D therapy give the best chance for an early response and are indicated in the early emergency treatment of ITP. In the patient with intracranial hemorrhage platelet transfusion should be administered as well and may be more effective after IVIG administration. Aminocaproic acid and Factor VIIa can also be considered as adjuvant therapy in patients with life-threatening bleeding to help minimize bleeding and obtain hemostasis, but will not raise the platelet count. Other options such as rituximab, splenectomy, and TPO agonists such as eltrombopag and romiplostim can be considered if the patient fails the above therapy. Responses to TPO agonists are usually seen within the first two weeks while the response to splenectomy can be immediate. Both early and delayed responses have been seen with rituximab. It may also be reasonable to confirm by the urea breath test or stool antigen test that H pylori has been eradicated, although ITP responses to such therapy in the United States remain controversial.

References:

Cines DB, Bussel JB. How I treat idiopathic thrombocytopenic purpura (ITP). Blood. 2005;106(7):2244-2251.

Cines DB, McMillan R. Management of adult idiopathic thrombocytopenic purpura. Annu Rev Med. 2005;56:425-442.

Bussel JB, Cheng G, Saleh MN, et al. Eltrombopag for the treatment of chronic idiopathic thrombocytopenic purpura. N Engl J Med. 2007;357(22):2237-2247.

Kuter DJ, Bussel JB, Lyons RM, et al. Efficacy of romiplostim in patients with chronic immune thrombocytopenic purpura: a double-blind randomized controlled trial. Lancet. 2008;371(9610):395-403.

Q: I have a 63-year-old patient with chronic ITP whose platelet counts typically run between 25,000-35,000/µL. She has not responded at all to steroids, splenectomy, TPO agonists, or rituximab. What therapy would you recommend next?

A: The first thing I would do is to consider whether your patient truly has ITP. The majority of patients respond at least transiently to corticosteroids, IVIG, and splenectomy. If a bone marrow biopsy has not been performed I would recommend it, to evaluate for a primary bone marrow disorder such as myelodysplasia. I would also review prior platelet counts and the family's platelet counts to rule out a hereditary thrombocytopenia.

The next question I would consider, assuming your patient is still thought to have ITP, is whether any treatment at all is needed. If your patient has not had significant bleeding and does not have other risk factors for bleeding then no treatment is a reasonable option at this point. The majority of patients with platelet counts in the 20,000-30,000/µL range do not have spontaneous life-threatening bleeding. The likelihood of responding to additional therapies becomes significantly less and the risk-benefit ratio of any therapy needs to be considered.

If your patient is thought to need additional therapy, drugs such as danazol, immunosuppressants such as immuran or cyclosporine, and cytotoxic agents such as cytoxan have all been used. All data are based on small case reports or case series and response rates are typically less than 30-40%. Most responses are delayed and side effects are considerable. In patients with bleeding or marked thrombocytopenia combination therapies, higher dose chemotherapy, and even autologous bone marrow transplant have been tried.

References:

George JN. Management of patients with refractory immune thrombocytopenic purpura. J Thromb Haemost. 2006;4(8):1664-1672.

Godeau B, Provan D, Bussel J. Immune thrombocytopenic purpura in adults. Curr Opin Hematol. 2007;14(5):535-556.

Q: I have a patient with hepatitis C, early cirrhosis, and moderate thrombocytopenia (40,000-50,000/µL). I am not sure if the thrombocytopenia is due to ITP or hepatitis. My patient's hepatologist would like to treat her with interferon, but is reluctant due to the thrombocytopenia. Do you have any recommendations on how best to treat my patient?

A: Thrombocytopenia is common in patients with hepatitis C and cirrhosis, occurring in up to 65% of patients. The etiology is multifactorial and may include decreased production of TPO from the liver, viral suppression of megakaryopoiesis, splenic sequestration, and ITP. Interferon, although it may cause thrombocytopenia and potentially ITP, has proven to be effective therapy for hepatitis C-related ITP in some patients. As most patients (such as yours) are already thrombocytopenic, many hepatologists are reluctant to treat these patients with IFN. Recent data published in the New England Journal of Medicine supports using eltrombopag to maintain a safe platelet count in hepatitis C patients being treated with IFN. Eltrombopag is not FDA approved for this use. LFTs should be monitored closely as eltrombopag itself may be hepatotoxic. Whatever the mechanism for the moderate thrombocytopenia in your patient, eltrombopag seems to be a reasonable supportive therapy during treatment with IFN.

References:

Rajan SK, Espina BM, Liebman HA. Hepatitis C virus-related thrombocytopenia: clinical and laboratory characteristics compared with chronic immune thrombocytopenic purpura. Br J Haematol. 2005;129:818-824.

McHutchison JG, Dusheiko G, Shiffman ML, et al. Eltrombopag for thrombocytopenia in patients with cirrhosis associated with hepatitis C. N Engl J Med. 2007;357(22):2227-2236.

Bashour FN, J Teran C, Mullen KD. Prevalence of peripheral blood cytopenias (hypersplenism) in patients with nonalcoholic chronic liver disease. Am J Gastroenterol. 2000;95:2936-2939.

Q: My ITP patients have had good responses to rituximab when used as a second- or third- line therapy. Are there data to support using rituximab as a first line treatment of ITP?

A: Response rates to rituximab in refractory ITP range between 30-60% with sustained responses in the 20-30% range. There are little data which support using rituximab as a first-line treatment for ITP. However, an abstract presented at the plenary session at 2008 ASH investigated combining rituximab with dexamethasone as first-line therapy in patients with newly diagnosed ITP. Response rates were higher in patients treated with the combination of rituximab and dexamethasone compared to those treated with dexamethasone alone. This study has not been fully published and at this time there are insufficient data to recommend routine use of rituximab in the first-line therapy of ITP. It should be noted that rituximab has not been approved by the FDA for the treatment of ITP and although effective in certain settings, its use is off-label.

References:

Godeau B, Porcher R, Fain O, et al. Rituximab efficacy and safety in adult splenectomy candidates with chronic immune thrombocytopenic purpura: results of a prospective multicenter phase 2 study. Blood. 2008;112(4):999-1004.

Arnold DM, Dentali F, Crowther MA, et al. Systematic review: efficacy and safety of rituximab for adults with idiopathic thrombocytopenic purpura. Ann Intern Med. 2007;146(1):25-33.

Zaja F, Baccarani M, Mazza P, et al. A Prospective Randomized Study Comparing Rituximab and Dexamethasone vs Dexamethasone Alone in ITP: Results of Final Analysis and Long Term Follow up. Blood (ASH Annual Meeting Abstracts). 2008;112:1.

Q: I am considering starting one of the thrombopoietin (TPO) receptor agonists in my patient with refractory ITP who has failed steroids, splenectomy, and rituximab. What is the average time to response with these agents?

A: The TPO agonists work by stimulating megakaryopoiesis, unlike historical therapies that inhibit peripheral platelet destruction. Despite this lack of inhibition of antibody mediated platelet destruction, early platelet responses are seen with these agents. In the Phase III studies of eltrombopag, increases in platelet counts to 50,000/µL or greater had occurred in more than half of the patients treated with eltrombopag within two weeks. If there was no response by two weeks the dose was increased to 75 mg. If no responses were seen within a few weeks, patients were unlikely to respond. In the romiplostim trials 25% of patients achieved a platelet count of 50,000/µL after week 1, with 50% of responders reaching this target by weeks 2-3. The dose of romiplostim should be increased by 1 mcg/kg each week in nonresponders until a maximum dose of 10 mcg/kg is reached. If patients fail to respond after four weeks at this dose, the drug should be discontinued.

References:

Bussel JB, Provan D, Shamsi T, et al. Effect of eltrombopag on platelet counts and bleeding during treatment of chronic idiopathic thrombocytopenic purpura: a randomized, double-blind, placebo-controlled trial. Lancet. 2009;373(9664):641-648.

Bussel JB, Cheng G, Saleh MN, et al. Eltrombopag for the treatment of chronic idiopathic thrombocytopenic purpura. N Engl J Med. 2007;357(22):2237-2247.

Kuter DJ, Bussel JB, Lyons RM, et al. Efficacy of romiplostim in patients with chronic immune thrombocytopenic purpura: a double-blind randomized controlled trial. Lancet. 2008;371(9610):395-403.

Q: I have been considering using romiplostim or eltrombopag in several patients, but remain uncertain if the response rates are less after splenectomy. Should I use these drugs before or reserve them until after splenectomy?

A: In the randomized clinical trials of both romiplostim and eltrombopag these drugs were used both prior to and after splenectomy. In the eltrombopag trials, randomization was stratified by various variables, including splenectomy status. Response rates were not correlated with splenectomy status. In the romiplostim trials, two parallel studies were conducted: one of patients who had not undergone splenectomy and the other of patients who had undergone splenectomy. Response rates were higher in the non-splenectomized group, but the splenectomized group had previously received more treatment and had a longer duration of disease. Thus, any therapy would be predicted to be less effective in this group. Despite this, responses to romiplostim were significantly higher compared to placebo and the drug is thought to be effective either pre or post-splenectomy.

Whether to use the thrombopoietin receptor agonists before or after splencectomy is a matter of much debate. The decision should be based on patient comorbidities, age, and patient preference. Splenectomy, rituximab, and the thrombopoietin receptor agonists are all reasonable second-line treatment options and choices should be individualized.

References:

Godeau B, Porcher R, Fain O, et al. Rituximab efficacy and safety in adult splenectomy candidates with chronic immune thrombocytopenic purpura: results of a prospective multicenter phase 2 study. Blood. 2008;112(4):999-1004.

Bussel JB, Provan D, Shamsi T, et al. Effect of eltrombopag on platelet counts and bleeding during treatment of chronic idiopathic thrombocytopenic purpura: a randomised, double-blind, placebo-controlled trial. Lancet. 2009;373(9664):641-648.

Kuter DJ, Bussel JB, Lyons RM, et al. Efficacy of romiplostim in patients with chronic immune thrombocytopenic purpura: a double-blind randomised controlled trial. Lancet. 2008;371(9610):395-403.

Q: My patient has chronic refractory ITP. She had transient responses to pulse dexamethasone and rituximab. Her platelets typically run around 30,000/μL and only transiently increased to 80,000/μL for less than 4 months with each of these therapies. She is reluctant to consider splenectomy. Is checking for H pylori useful and how should I do this?

A: The data on the efficacy of H pylori eradication in the treatment of chronic ITP are very controversial even among expert hematologists. It was noted that in patients with chronic ITP who were treated for concomitant H pylori-positive gastrointestinal diseases that platelet responses occurred in some patients. Based on this, H pylori eradication therapy has been studied in patients with chronic ITP. Results are encouraging in Japan and Europe, but much less so in the United States. This may be attributable to different strains of H pylori in different areas of the world. A meta-analysis has suggested efficacy, but results in the USA have been disappointing. Patients with a shorter duration of ITP and lesser degrees of thrombocytopenia appear more likely to respond.

If one were to check for H pylori this should be done through the 13C urea breath test, a stool antigen test, or by histologic examination of a biopsy if endoscopy is to be performed. The diagnosis should not be based solely on serology. If the diagnosis is confirmed it would be reasonable to treat with a course of "triple therapy" consisting of two antibiotics and a proton pump inhibitor. Patients who respond usually do so within several weeks.

References:

Stasi R, Rossi Z, Stipa E, Amadori S, Newland AC, Provan D. Helicobacter pylori eradication in the management of patients with idiopathic thrombocytopenic purpura. Am J Med. 2005;118:414-419.

Kandulski A, Selgrad M, Malfertheiner P. Helicobacter pylori infection: a clinical overview. Dig Liver Dis. 2008;40(8):619-626.

Q: I have a 27-year-old patient who has chronic ITP. She responds well to steroids, but her platelets drop below 10,000/μL with mucocutaneous bleeding when the drug is tapered. She wants to consider splenectomy as she does not want long-term therapy. Is this appropriate? If so, should this be done open or laparoscopically?

A: Splenectomy is very appropriate as a second-line therapy in patients with chronic ITP. The patient has severe thrombocytopenia with bleeding so treatment is indicated. Splenectomy has been the traditional second-line treatment in adult ITP. Splenectomy still offers the best long term chance for cure without the need for ongoing therapy.

In the last decades, many patients and providers have considered splenectomy-sparing approaches, such as intermittent IVIG or anti-D, rituximab, and the thrombopoietin receptor agonists romiplostim and eltrombopag. Each of these therapies is reasonable and could be considered as well. Each choice has its own unique risks and benefits. Many of these options, however, entail long term treatment that your patient does not prefer.

If splenectomy is chosen, immunizations should be given prior to surgery and updated when needed. Laparoscopic techniques are being used increasingly in place of traditional open splenectomy. Although OR time may be greater for laparoscopy, complications and length of hospitalization are less. No difference in efficacy has been shown between these techniques. A surgeon skilled in laparoscopic splenectomy should be chosen.

So, yes, splenectomy is one of many reasonable second-line choices and it certainly can be done laparoscopically, preferably by a surgeon experienced with this technique.

Reference:

Kojouri K, Vesely SK, Terrell DR, George JN. Splenectomy for adult patients with idiopathic thrombocytopenic purpura: a systematic review to assess long-term platelet count responses, prediction of response, and surgical complications. Blood. 2004;104(9):2623-2634.

Q: One of my ITP patients is developing hemolytic anemia and I suspect Evans' syndrome. Would romiplostim or eltrombopag be appropriate?

A: Romiplostim and eltrombopag were recently approved by the FDA for use in chronic ITP. The randomized trials leading to approval for both drugs enrolled adult patients with primary chronic ITP who had failed at least one first-line therapy. Patients with moderate (or greater) anemia were excluded from these trials. There is no mention in the published literature whether patients with Evans' syndrome were treated. A brief review of ASH abstracts from 2008 and 2009 did not identify any reports of use of these agents in Evans' syndrome.

The blood smear should be reviewed in this case and TTP ruled out. A direct Coombs' test should be ordered and if positive and if other laboratory data suggest hemolysis (reticulocyte count, indirect bilirubin, LDH, etc) then Evans' syndrome becomes a more likely diagnosis. If there is uncertainty, a bone marrow aspirate and biopsy can be done to rule out a primary bone marrow or lymphoproliferative disorder.

Romiplostim and eltrombopag as thrombopoietin receptor agonists may stimulate megakaryopoiesis, but are unlikely to be effective in the treatment of anemia. Small case series are available describing splenectomy and rituximab in the treatment of Evans' syndrome. Before any treatment is chosen the diagnosis should be confirmed, then consider whether any treatment at all is needed.

Q: What is the evidence on the use of thrombopoietic agents in patients with CLD?

A: There are limited data on using thrombopoietic agents in patients with liver disease. The results of a recent study by McHutchison et al showed that the small molecule thrombopoietin receptor (TPO-R) agonist eltrombopag was effective in increasing platelet counts in patients with hepatitis C.

Whether to use the thrombopoietin receptor agonists before or after splencectomy is a matter of much debate. The decision should be based on patient comorbidities, age, and patient preference. Splenectomy, rituximab, and the thrombopoietin receptor agonists are all reasonable second-line treatment options and choices should be individualized.

References:

McHutchison J, et al. N Engl J Med. 2007;357:2227-2236.

Q: What is the role of anti-platelet antibodies in thrombocytopenia associated with CLD?

A: The role of anti-platelet antibodies in thrombocytopenia in patients with chronic liver disease is controversial. The antigens recognized by the antibodies are believed to be in platelet glycoprotein complexes such as IIb/IIIa or Ib/IX. It is suspected that anti-platelet antibodies may enhance platelet removal in the spleen and hepatic reticuloendothelial systems by facilitating platelet binding to macrophages. The mechanism for the elevated anti-platelet antibodies is not well understood though the macrophages can act as antigen presenting cells and stimulate T cells. However, some causes of liver disease such as hepatitis C are associated with immunological disarray. Other autoimmune antibodies are not uncommon.

References:

Pereira J, et al. Am J Hematol. 1995.
Nagamine T, et al. J Hepatol. 1996;24:135-140.
McMurray RW, Elbourne K. Semin Arthritis Rheum. 1997;26(4):689-701.

Q: Are there special considerations for managing thrombocytopenia with different types of chronic liver disease?

A: A number of factors contribute to the development of thrombocytopenia with chronic liver disease, including the liver disease etiology such as hepatitis C. Some of the reasons why patients infected with hepatitis C may have a greater degree of thrombocytopenia may be direct bone marrow suppression by the viral infection and the production of anti-platelet antibodies which may enhance platelet clearance. Patients with hepatitis C may have thrombocytopenia without overt liver disease.

Not only can hepatitis C lead to cirrhosis and portal hypertension which causes thrombocytopenia, but the treatment for the viral infection can also lower the platelet count.

Between 3–4% of patients treated with pegylated interferon in pivotal trials required dose reduction for thrombocytopenia. In patients treated with pegylated interferon alfa-2a and ribavirin, the dose should be reduced to 90 mcg and discontinued when the platelet count is below 50,000 per cubic millimeter and 25,000 per cubic millimeter, respectively. In patients treated with pegylated interferon alfa-2b and ribavirin, the dose should be reduced to one half of the initial dose and discontinued when the platelet count is below 80,000 per cubic millimeter and 50,000 per cubic millimeter, respectively. Usually, patients with this degree of thrombocytopenia from antiviral therapy have advanced liver disease.

Reference:

Nagamine T, et al. J Hepatol. 1996;24:135-140.
Afdhal N, et al. J Hepatol. 2008;48:1000-1007.
Pivetti S, et al. Br J Haematol. 1996;95(1):204-211.
Pawlotsky JM, et al. J Hepatol. 1995;23(6):635-639.
Sakuraya M, et al. Eur J Haematol. 2002;68(1):49-53.
Garcia-Suarez J, et al. Br J Haematol. 2000;110(1):98-103.
Rajan S, et al. Br J Haematol. 2005.
Manns MP, et al. Lancet. 2001;358(9286):958-965
Fried MW, et al. N Eng J Med. 2002;347:975-982.
PEGASYS®. Nutley, NJ: Hoffman-La Roche Inc; 2009.
PegIntron®. Kenilworth, NJ: Schering Corporation; 2009.

Q: What is the liver's role in platelet homeostasis and how is it affected by chronic liver disease?

A: The liver plays a critical role in the production of platelets. The hormone thrombopoietin regulates platelet production and is produced in the liver. There is a correlation between platelet number and severity of fibrosis. In fact, thrombopoietin production normalizes after liver transplantation in patients with advanced liver disease.

In patients with cirrhosis, thrombocytopenia arises from the presence of cirrhosis (decrease thrombopoietin production), portal hypertension/hypersplenism (platelet sequestration and destruction), and from medical treatment. Medical treatment can include interferon for hepatitis C and chemotherapy for hepatocellular carcinoma.

In patients with thrombocytopenia from cirrhosis, treatment for thrombocytopenia is seldom required unless the patient undergoes an invasive procedure and the platelet count is below than 50–60,000 per cubic millimeter. In patients undergoing interferon therapy for hepatitis C or chemotherapy for hepatocellular carcinoma, dose modification may be required. Between 3–4% of patients treated with pegylated interferon in pivotal trials required dose reduction for thrombocytopenia. In patients treated with pegylated interferon alfa-2a and ribavirin, the dose should be reduced to 90 mcg and discontinued when the platelet count is below 50,000 per cubic millimeter and 25,000 per cubic millimeter, respectively. In patients treated with pegylated interferon alfa-2b and ribavirin, the dose should be reduced to one half of the initial dose and discontinued when the platelet count is below 80,000 per cubic millimeter and 50,000 per cubic millimeter, respectively.

References:

Peck-Radosavljevic M, et al. Hepatology. 1998;28(5):1424-1429.
Peck-Radosavljevic M, et al. J Hepatol. 1997;27(1):127-131.
Adinolfi LE, et al. Br J Haematol. 2001;113(3):590-595.
Weksler BB. Aliment Pharmacol Ther. 2007;26(suppl 1):13-19.
Nagasako Y. Liver Transplantation. 2006.
Peck-Radosavijevic M, et al. Blood. 2000.
Manns MP, et al. Lancet. 2001;358(9286):958-965
Fried MW, et al. N Eng J Med. 2002;347:975-982.
PEGASYS®. Nutley, NJ: Hoffman-La Roche Inc; 2009.
PegIntron®. Kenilworth, NJ: Schering Corporation; 2009.

Q: Are patients with allergies more or less prone to ITP, and should they be managed differently?

A: Allergic patients do not appear to have a greater likelihood of developing ITP than persons without allergies. There have been rare or no allergic reactions to TPO agents and, in particular, eltrombopag. In contrast, patients with penicillin allergy are more likely to develop autoimmune diseases.

Q: What are the critical factors that distinguish eltrombopag and romiplostim and are some patients more appropriately treated with one or the other?

A: Eltrombopag and romiplostim are new drugs that induce platelet-producing cells in the bone marrow to produce platelets. Eltrombopag is given orally, and romiplostim is given by subcutaneous injection. They both have low toxicity and have similar ability to raise platelet counts in patients with ITP over short and long periods. Some patients who either lack or lose response to one agent may respond to the other.

http://www.promactacares.com/prescribing_information.pdf

http://www.nplate.com/patient/pdf/nplate_pi.pdf

Stasi R, Evangelista ML, Stipa E, Buccisano F, Venditti A, Amadori S. Idiopathic thrombocytopenic purpura:current concepts in pathophysiology and management. Thromb Haemost. 2008;99(1):4-13.

Q: What is the role of H pylori in ITP?

A: In Europe a strong association with H pylori infection and ITP was described. In addition, treatment for H pylori was associated with frequent remission of ITP. The high rate of infection in patients with ITP does exist in the United States but eradication of H pylori is not associated with a very high likelihood of ITP remission. Infection with H pylori is detected by antibody testing, gastric lavage, or a breath test. Many health care providers test for it and treat the infection to achieve ITP remission.

Stasi R,Rossi Z, Stipa E, Amadori S, Newland AC, Provan D. Helicobacter pylori eradication in the management of patients with idiopathic thrombocytopenic purpura. Am J Med. 2005;118:414-419.

Kandulski A, Selgrad M, Malfertheiner P. Helicobacter pylori infection: a clinical overview. Dig Liver Dis. 2008;40(8):619-626.

Q: What is ITP and does it have a genetic component?

A: ITP is an autoimmune disease which is diagnosed by exclusion. There is not a unique marker or finding, since many autoimmune disorders have a component of thrombocytopenia. Although many other autoimmune diseases are inherited and despite a rare instance of familial ITP, there is no evidence that ITP is genetic in origin. Classically, it was believed that the low platelet count in ITP was solely due to antibody-mediated platelet destruction. We now know that the majority of patients also have a deficiency in bone marrow production of platelets.

Stasi R, Evangelista ML, Stipa E, Buccisano F, Venditti A, Amadori S. Idiopathic thrombocytopenic purpura:current concepts in pathophysiology and management. Thromb Haemost. 2008;99(1):4-13.

Psaila B, Bussel JB. Immunethrombocytopenic purpura. Hematol Oncol Clin North Am. 2007;21(4):743-759.

Q: I run a foster home for Chinese orphans in Xian China. I had one of my baby girls in the PICU yesterday with ITP, a very low platelet count (15) and anemia (64). She is still on milk only. Firstly, is ITP a reasonable diagnosis and how could we confirm it? Secondly, what can I do once she comes home to help her recover?

A: The combination of anemia and thrombocytopenia without bleeding as the cause of anemia makes ITP unlikely. Evans syndrome, with immune thrombocytopenia and Coombs-positive hemolytic anemia may be the cause, and steroids may resolve this. A careful look at the peripheral blood smear is key to make sure RBC and WBC morphology are normal and to define the reticulocyte count; Coombs, LDH, and haptoglobin will help define if there is red cell destruction. PNH, a rare disease, may produce hemolytic anemia and bone marrow failure. Flow cytometry measuring CD55 and CD59 will make the diagnosis. There is new therapy to correct PNH anemia. In this situation, if all is negative, a bone marrow exam is warranted.

Q: Have you ever seen a case similar to one that we have been following for the last 8 months or so? The baby is 8 months old now and was seen with petechiae and bruises in the neonatal period. The mother had thrombocytopenia with both pregnancies (older sibling had no issues). The mom was treated with IVGG and baby was delivered via C/S. Baby was treated with IVGG for her bleeding but failed to respond; we then started her on oral steroids, thinking that soon the infant would lose the passively acquired antibodies and her platelet counts would normalize. The issue is that she has been running platelet counts that swing wildly from week to week, from the low 20s to as high as 340,000 regardless of the amount of steroids she is on (currently she is on a homeopathic dose of steroids 0.2 mg/kg). During the vast majority of tests, her MPV is either > 10 or close to it (normal and abnormal platelet counts), and it was < 10 only on 2 occasions with normal counts. It is those swings that leave us a bit puzzled. We twice used ultrasound to visualize her belly to ensure that her spleen was not enlarged and that she didn't have some sort of visceral hemangiomata that trapped platelets; both U/S tests were normal. We never investigated her marrow but it's hard to see how that would shed any light on the question. Clearly she is able to manufacture platelets. Luckily, she never has had any bleeding symptoms beyond some bruises. Any thoughts?

A: The syndrome you have described is rare. Passive transfer of antibody from mother to child is well described in mothers who have ITP. Neonatal thrombocytopenia is seen in maternal child platelet (PLA1) incompatibility. This is acute, treated with platelet transfusion and short-lived. Infection at birth or thereafter is a further cause of thrombocytopenia, abating with appropriate antibiotic therapy. Wiskott-Aldrich syndrome is a rare inherited disorder with fluctuating platelet levels, eczema, and IgE deficiency. Uncommonly, a type IIB von Willebrand (vW) patient will present with fluctuating platelet levels. Measuring Factor VIII, ristocetin cofactor (or vW factor), vWF antigen and vW multimers would be helpful. Chronic ITP, although uncommon in children, may require other treatments, such as repeated IVIG or anti-D if the patient is RH+.

Q: I have a patient with ITP who is 37 years old. IVIG and splenectomy have failed to stably increase her platelet count, and she is now on chronic steroid therapy. She wants to stop the steroids, as she has gained weight and is concerned about the diabetes that runs in her family. Is one of the thrombopoiesis stimulating agents (TSAs) an appropriate choice at this point?

A: The new agents have been very useful in a wide variety of patients, and there is no suggestion from clinical trials that the efficacy is age dependent. After FDA approval and increased use of new drugs, much more patient information surfaces that was not available with phase 1, phase 2, or phase 3 clinical studies. These data help us evaluate several important issues. We can see if rare adverse events are significantly higher among patients receiving the drug, and whether these events are attributable to the drug. If the events are rare, these linkages may become apparent only with widespread use.

The other type of information is longitudinal. Some adverse side effects may become significant only when patients are exposed to the medication for a long period of time. This might be of concern in the case you present, as the patient is relatively young. Her treatment course could last 30 or 40 years. Monitoring her physiology with LFTs may be useful, but events can be unpredictable, for example hepatic problems with the withdrawn diabetes drug troglitazone.

Some have suggested treating ITP for a defined period and then weaning the patient off the drug, but such protocols have not been validated. I would urge caution for long-term treatment with TSAs until more clinical data can be collected.

Q: I have a 68-year-old patient with ITP who has failed steroids, IVIG and splenectomy. Is a thrombopoeisis stimulating drug such as romiplostim or eltrombopag the proper next therapeutic option?

A: A number of new therapies for ITP have emerged as the result of improved understanding of the immunopathologic mechanisms involved in the disorder. One of these, the use of thrombopoietin (TPO) to increase platelet production, is based on the recognition that neither platelet production nor TPO levels are increased in most patients. TPO is a glycoprotein hormone synthesized in the liver that promotes the viability and growth of megakaryocyte colony-forming cells and megakaryocyte progenitors, thus increasing the production of maturemegakaryocytes and platelets. Recombinant TPO is a viable therapeutic approach, but was found to be associated with the formation of neutralizing antibodies that cross-reacted with endogenous TPO and resulted in thrombocytopenia.

Two TPO mimetics, romiplostim (Nplate®) and eltrombopag (Promacta®) were recently approved by the FDA. Romiplostim is an injectable peptide and eltrombopag is an orally available nonpeptide drug.

Either of these agents may be a good option for your patient. The long term effects are not known and the benefits and risks should be discussed with a hematologist before making this therapeutic choice.