|Year : 2021 | Volume
| Issue : 2 | Page : 33-41
Steroid-Resistant immune thrombocytopenia: Challenges and solutions
Abhishekh Basavarajegowda1, Vinod K Vishwanath2, Ramamoorthy G Jaikumar3, Murali Subbaiah4
1 Department of Transfusion Medicine, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India
2 Department of General Medicine, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India
3 Department of Pediatrics, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India
4 Department of Obstetrics and Gynecology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India
|Date of Submission||07-Jan-2021|
|Date of Acceptance||04-Apr-2021|
|Date of Web Publication||19-Aug-2021|
Dr. Murali Subbaiah
Department of Obstetrics and Gynecology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry
Source of Support: None, Conflict of Interest: None
Immune Thrombocytopenic purpura (ITP) is an autoimmune disorder characterized by a platelet count of <100 × 109/L in the absence of other underlying causes of thrombocytopenia and increased risk of bleeding. Glucocorticoids are the mainstay drugs of treatment for ITP. The response rate to steroids is around 60%–70% in adults, but only 10%–15% of these patients will have a durable response. If patients do not respond to steroids by 4 weeks, they are considered to have steroid-resistant ITP. Some patients though they respond, need frequent courses of steroids to maintain a platelet count above 30 × 109/L or to avoid bleeding and are considered nonresponders to steroids. A number of potential mechanisms for this resistance to steroids have been suggested, including receptor downregulation by glucocorticoid exposure and negative inhibition by the beta-isoform of the glucocorticoid receptor. The available treatment options for these patients include various drugs including rituximab, thrombopoietin receptor agonists, fostamatinib, danazol, immunosuppressive drugs, and biological therapies including intravenous immunoglobulin, Rh immunoglobulins, and immunoadsorption. Splenectomy has been performed surgically, by radiation, or chemoembolization. Supportive treatment includes screening for osteoporosis and management, vaccination, and platelet therapy. Newer therapies such as veltuzumab, belimumab, and toralizumab which deplete B-cells have been tried. Nearly 70% of adult chronic ITP patients failing to respond to splenectomy still achieve stable remission with additional therapies.
Keywords: Immunosuppressives, intravenous immunoglobulin, Rh immunoglobulin, rituximab, steroid-resistant ITP
|How to cite this article:|
Basavarajegowda A, Vishwanath VK, Jaikumar RG, Subbaiah M. Steroid-Resistant immune thrombocytopenia: Challenges and solutions. J Appl Sci Clin Pract 2021;2:33-41
|How to cite this URL:|
Basavarajegowda A, Vishwanath VK, Jaikumar RG, Subbaiah M. Steroid-Resistant immune thrombocytopenia: Challenges and solutions. J Appl Sci Clin Pract [serial online] 2021 [cited 2023 Mar 29];2:33-41. Available from: http://www.jascp.org/text.asp?2021/2/2/33/324114
| Introduction|| |
Immune thrombocytopenia (ITP) is an autoimmune disorder characterized by a low platelet count and increased risk of bleeding. There has been a change in nomenclature for this disorder, and terms like idiopathic thrombocytopenic purpura are no longer used., Primary ITP has been defined as a platelet count <100 × 109/L in the absence of other underlying causes of thrombocytopenia. The incidence of ITP in adults has been estimated to be 3.3 per 100,000 adults every year and in children approximately 1.9–6.4 per 100,000 children every year.
Glucocorticoids are the mainstay among the first-line drugs for ITP. Intravenous immunoglobulin (IVIG) and anti-D antibody are the other two first-line drugs. The initial response rates to steroids can be as high as 60%–70% in adults. If patients have not responded to steroids by 4 weeks, it is highly likely that they have steroid-resistant ITP. On the other hand, steroid dependence is defined as the continuous need for steroid administration or frequent need of courses of steroids to maintain a platelet count above 30 × 109/L or to avoid bleeding. These patients are also considered nonresponders to steroids. In this article, we will review the therapeutic options available for these patients.
Complete response (CR) is defined as platelet count more than 100 × 109/L and the absence of bleeding. Platelet count between 30 and 100 × 109/L and at least doubling of the baseline count without any bleeding is termed response (R). If the platelet count is <30 × 109/L or if there is less than doubling of the baseline count, the term “no response” is used.
Patient characteristics which determine resistance
Studies have suggested that the pharmacokinetics of steroid absorption, distribution, and metabolism are generally the same in the steroid-sensitive, insensitive patients and the controls. Glucocorticoid receptors/cells' number as well does not differ among these groups. However, differences in the binding affinity of the glucocorticoid receptor have been described, with steroid dependent and steroid insensitive demonstrating progressively lower binding affinities, especially in asthmatics. Failure of the glucocorticoid receptor to translocate to the nucleus is an important contributor to steroid insensitivity. There is also a subgroup of steroid-insensitive patients in whom translocation occurs, but in whom a specific defect prevents the downstream events that result in either switching on of anti-inflammatory genes or switching off of pro-inflammatory genes.
ITP with active cytomegalovirus infection was known to have poorer response to preliminary therapy with steroids. However, the response rate improved on adding antiviral therapy to the regimen.
People with HLA-DR4 and DRB1*0410 were associated with poorer response to steroid treatment with more in the latter than the former. However, the authors state that the findings should be considered preliminary because of possible racial differences in HLA status between Japanese and other ITP patients.
Mechanism of resistance
A number of potential mechanisms for this resistance to steroids have been suggested, including receptor downregulation by glucocorticoid exposure, negative inhibition by the beta-isoform of the glucocorticoid receptor, or inhibition of the alpha-isoform of the receptor by the pro-inflammatory transcription factor nuclear factor-kappa B in inflammatory conditions.
| Therapeutic Options and Management|| |
- Surgical: Splenectomy
- Medical: Rituximab, thrombopoietin receptor agonists (TPO-RAs), fostamatinib, danazol, and immunosuppressive drugs
- Biological therapies: IVIG, Rh immunoglobulin, and platelet transfusions.
Splenectomy essentially attacks multiple pathophysiologic mechanisms of ITP and modifies the course of the disease. It removes the major site of phagocytosis of antibody-coated platelets, as well as lymphocytes that might be responsible for producing antiplatelet antibodies that reside in the spleen. A large systematic study of 2623 cases treated with splenectomy showed that platelet counts normalized in 66% of individuals and platelet counts increase to >50,000/μL in an additional 22%, with a total response rate of 88%. The responses persisted up to 12 years and beyond. The younger the age, the better was the response. Pursuing for a diagnosis of an accessory spleen and removal is beneficial, especially in patients with persistent thrombocytopenia following splenectomy. Standard operative technique currently is a laparoscopic splenectomy based on the lower rates of morbidity and mortality reported in the systematic review. The risks are long-term infections and thromboembolic complications.
In patients who relapsed after splenectomy, they usually have benefitted from the combination of any of danazol, colchicine, dapsone, or vinblastine/interferon compared to the use of cyclophosphamide, azathioprine, cyclosporine, mycophenolate mofetil, or combination chemotherapy. The ones treated with them had a higher complete or partial remission (platelet count more than 30 × 109/L).
Intravenous immunoglobulin and anti-D
IVIG exerts its effect by various mechanisms, as given in [Table 1]. IVIG is reproducible enough in that the response in platelet count after treatment is used as a diagnostic criterion for ITP.
Anti-D when given to Rh-D-positive individuals would bind to the patient's red cells, and these complexes would saturate the Fc receptors of the macrophages, thereby sparing the immunoglobulin G (IgG)-bound platelets. The effects of both these treatments are compared in [Table 2].
|Table 2: Comparison of intravenous immunoglobulin and Rh immunoglobulin in treatment of steroid-resistant immune thrombocytopenia|
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Rituximab, the anti-CD20 monoclonal antibody, is a useful therapeutic option for patients failing to respond to first-line therapy (steroids, IVIG, and anti-Rh-D immunoglobulin) for ITP, especially in those situations where splenectomy is not being considered upfront after failure of steroid therapy. Rituximab may also reduce the need for splenectomy in steroid-resistant ITP patients. However, the response rates and the durability of response to rituximab therapy are generally inferior to that following splenectomy in steroid-resistant ITP patients.,, Rituximab is also useful for steroid-resistant ITP patients with inadequate response or relapse following splenectomy. Following rituximab therapy, a long-term response rate of 20%–40% in ITP patients, and a sustained stable platelet response of 20% at 5 years among those failing other therapies, have been reported. Low-dose rituximab therapy (100 mg weekly for 4 weeks) has also shown encouraging responses in adults similar to standard dose rituximab (375 mg/m2 weekly for 4 weeks) and significantly reduces the cost of treatment. Initial response to rituximab is seen between 7 and 56 days, and the peak response occurs between 14 and 180 days of therapy. Rituximab, when combined with high-dose dexamethasone (40 mg/day × 4 days) increases long-term response rates in adult ITP patients without significant increase in adverse effects. Although there is a dearth of data from controlled trials of rituximab in children, an overall response rate of 68% and a CR rate of 39% have been reported in children with primary and secondary ITP. Some patients require repeat courses of rituximab for maintenance of long-term remission. Rituximab is generally well tolerated by both children and adult ITP patients, the common adverse reactions being infusion-related reactions such as fever, chills, pruritus, and sore throat. More severe adverse reactions such as anaphylaxis, serum sickness, and infections (such as reactivation of latent hepatitis B infection and progressive multifocal leukoencephalopathy) are rare in ITP patients., Whether rituximab therapy must be considered upfront after failure of steroid treatment in ITP or after splenectomy/TPO-RAs is not established as there are no controlled trials to answer this question. However, in a survey of hematologists and oncologists managing ITP patients done at Oklahoma, United States, the choice of second-line treatments after failure of corticosteroids and IVIGs was almost equally divided between splenectomy and rituximab, followed by TPO-RAs.
Thrombopoietin receptor agonists
These stimulate megakaryocytic proliferation and growth, thereby increasing the production of platelets from the marrow. Romiplostim, an Fc-peptide fusion protein (peptibody, given as a once-weekly subcutaneous injection), and two nonpeptide oral TPO-RAs (eltrombopag and avatrombopag) have been approved for use in ITP patients. TPO RAs are indicated for ITP patients who have failed or shown an inadequate response to steroids, in whom splenectomy/rituximab is not among the therapeutic options under consideration or after the failure of these treatments to achieve remission.,, They are effective and safe second-line treatment options for improving platelet counts and reducing bleeding events and need for rescue therapies in pediatric and adult ITP patients., One general limitation of TPO-RAs is that they need to be continuously administered to maintain the counts and drug-free remissions are uncommon. However, uncommonly, sustained platelet response has been noted in some ITP patients after discontinuation of eltrombopag and romiplostim., Platelet counts start increasing after 5 days of treatment initiation and peak around 12–14 days. TPO-RAs have been approved for use both in adults and children with ITP. Both romiplostim (dose range: 1–10 μg/kg body weight and usual maintenance dose: 3–8 μg/kg) and eltrombopag improve platelet counts in ≈ 80% of ITP patients with or without prior splenectomy., TPO-RAs are associated with thrombocytosis, increased risk of thrombotic events, and bone marrow reticulin fibrosis (not clinically significant and readily reverses on discontinuation of the medication). Romiplostim is generally well tolerated and has minor adverse effects such as headache and gastrointestinal intolerance. Eltrombopag (usual starting dose: 50 mg once/day) has to be taken on an empty stomach for proper absorption, and the most frequently reported adverse effects are elevation of hepatic transaminases and headache. Avatrombopag absorption is not affected by food, and the clinical experience with this drug is limited. Platelet counts should be monitored periodically (initially weekly during treatment initiation and subsequently monthly, once stable maintenance doses are achieved) while being on TPO-RAs. The doses should be titrated to achieve a stable platelet count of ≥50,000/μl (and not to normalize the count), which will be sufficient to reduce the risk of bleeding in most, if not all patients.
ITP is an autoimmune disease where autoantibody coated platelets are phagocytosed and destroyed in the spleen, through spleen tyrosine kinase-mediated signal transduction in macrophages. Fostamatinib disodium inhibits splenic tyrosine kinase, thereby inhibiting platelet phagocytosis by splenic macrophages. Experience with fostamatinib in ITP is limited, and it has been approved for the treatment of ITP refractory to other treatments. Fostamatinib, compared to placebo, induced clinically meaningful platelet responses in adult persistent and chronic ITP patients who had not responded to splenectomy, TPO-RAs, and/or rituximab and was associated with acceptable adverse effect profile. Fostamatinib is an orally administered drug, administered at an initial dose of 100 mg twice/daily, which can be subsequently up titrated to 150 mg twice/day if required to achieve a platelet count of ≥50,000/μl. Gastrointestinal disturbances such as nausea, vomiting, diarrhea, and increased hepatic transaminases are the most common adverse reactions reported. Others included hypertension, dizziness, and rarely neutropenia and rash.
Dapsone (50–100 mg/day) is a cheaper and efficacious second-line treatment option in pediatric and adult ITP patients not responding to steroids, and nearly half of the patients treated showed response in retrospective analysis of patients started on dapsone., The median time to response was 29 days (24–41 days) in a study. However, adverse effects (hypersensitivity reactions such as skin rash, sulfone syndrome, peripheral neuropathy, and methemoglobinemia) need to be closely monitored during therapy, and prolonged drug-free remissions are uncommon. However, one study found no benefit of dapsone in ITP patients who had severe thrombocytopenia despite multiple earlier therapies.
It is an attenuated androgen whose mechanism of action is supposed to be due to reduced Fc receptor expression on monocytes which decreases the phagocytosis of platelets. It is usually started at a dosage of 200 mg, three times a day until response; the median time to response is usually 2–3 months. It can be tapered gradually to a dose of 200 mg per day once response is obtained. Response rates have been reported to be 40%–70%. Maloisel et al. reported a 10-year response rate of 42% and a relapse rate of 32%. The most frequent side effect reported is liver cytolysis; regular liver enzyme monitoring is recommended. The other side effects reported are peliosis, thrombosis, liver cancer, and pulmonary fibrosis. Response rates in the elderly have been found to be higher than in young patients. Danazol can be considered as one of the second-line drugs in the elderly, especially if they have contraindication for splenectomy. Being an androgenic drug, it is contraindicated in men with prostate cancer and not the preferred drug in prepubertal as it can accelerate bone growth.
Immunosuppressive drugs are a cheaper and noninvasive option in treatment of steroid-resistant ITP. They provide durable and sustained response despite their discontinuation. This class of drug is used either in isolation or in combination with other treatment options such as TPO agonists, splenectomy, or rituximab. The commonly used drugs, response rates, median time to response, and dosages utilized are given in [Table 3].
Clinically significant response was witnessed after few months whenever immunosuppressive drugs were used in isolation. On the contrary, immunosuppressive drugs in combination with other treatment options have produced clinically significant response sooner. The combination of oral cyclosporine A, low-dose rituximab, and high-dose dexamethasone achieved a 60% response. More importantly, the response was evident after median duration of 7 days, and it was sustained in 92% and 76% at the end of 12 and 24 months, respectively. Initiation of combination therapy is preferred whenever rituximab and/or splenectomy has failed. Combination therapy is expected to prevent the induction of multiple drug-resistance genes.
| Splenic Artery Embolization/Splenic Radiation|| |
Splenic artery embolization provides a prompt increase in platelet counts in life-threatening ITP. It is a safer, less invasive, and faster intervention than operative splenectomy in a sick thrombocytopenic patient. Availability of expertise and data regarding its use in ITP is limited. Splenic irradiation is utilized as an alternative to splenectomy to increase the platelet count in patients with life-threatening bleeding. A varying dose of 7.5–15 gy in 10–20 fractions has been administered in different case reports.,, Both splenic irradiation and splenic artery embolization lead to long-term splenic dysfunction. These patients need to be vaccinated against encapsulated organism and need to continue long-term antibiotic prophylaxis. Newer agents that have been tried are listed in [Table 4].
| Other Supportive Therapies|| |
Screening and management for osteoporosis in patients with steroid-refractory ITP is required as they may be at a higher risk of fragility fractures, particularly of the vertebrae. Dual-energy X-ray absorptiometry scan to assess the bone mineral density and screening for Vitamin D deficiency is needed. This should be treated promptly if detected by bisphosphonate (alendronate, risedronate, and zoledronic acid) therapy. This may aggravate thrombocytopenia. Adult patients should be advised to take 700–1200 mg of elemental calcium and 800 U of Vitamin D through diet/supplements, to maintain bone health. In addition, regular weight-bearing exercises, cessation of smoking, and moderation of alcohol intake to <2 units/day are also recommended to promote bone health.
There have been some isolated reports of the use of rFVIIa at a dose of 90–120 mcg/kg every 2–3 h till the bleeding arrests for management of severe bleeding episodes and achievement of hemostasis postoperatively in ITP patients who were refractory to multiple other therapies.,, However, routine off-label use of rFVIIa for management of severe bleeding episodes in ITP patients is not recommended. Care must be exercised to monitor for the development of new thrombosis.
| Vaccination for Patients with ITP|| |
In patients planned for elective splenectomy, vaccination should be completed 2 weeks before the performing splenectomy. In patients undergoing emergency splenectomy, vaccination should be initiated 2 weeks after the procedure. The recommended vaccines are pneumococcal conjugate vaccine (PCV), Haemophilus influenzae b conjugate, typhoid conjugate, and meningococcal polysaccharide vaccine together. Pneumococcal polysaccharide vaccine 23 (PPSV23) should be given 8 weeks after PCV dose. Vaccination recommended for patients during chronic immunosuppression therapy is annual inactivated influenza vaccine. Six months after completion of immunosuppressive therapy, the following vaccines should be administered: PCV, PPSV23, and typhoid conjugate vaccine.
| Immunoadsorption|| |
Extracorporeal immunoadsorption using columns of staphylococcal protein A-silica removes IgG and circulating immune complexes (CICs) from the plasma. This was evaluated as a therapy for adults with treatment-resistant immune thrombocytopenic purpura (ITP). Patients who had failed to improve with two therapies and platelet count remaining <50,000/μl received an average of 6 treatments which involved 0.25–2 L of plasma per procedure over 2–3 weeks. The median time to response was 2 weeks. Responses were transient (≤1 month) in only 10% of the patients. Additional relapses were not seen on follow-up of up to 26 months (mean of 8 months). Clinical responses were also associated with significant decreases in specific serum platelet autoantibodies (including anti-glycoprotein IIb/IIIa), platelet-associated Ig, and CIC. The side effects were noted in about 30% of patients which were usually only mild to moderate commonly presenting as a hypersensitivity-type reaction. Continued administration of low-dose corticosteroids (530 mg/d) had not much influence on the effectiveness of this treatment but did reduce the incidence and severity of adverse effects. The effectiveness of immunoadsorption by protein A columns in patients with treatment-resistant ITP looks promising. Further controlled studies are warranted in this patient population for the same.
| Platelet Transfusion|| |
Platelet transfusion is recommended in a patient with clinical bleeding. Other factors which contribute to bleeding including surgical or anatomic defects, fever, infection or inflammation, coagulopathy, and acquired or inherited platelet function defect should also be addressed.
The general principle is to treat the clinical setting rather than the count. Platelets in circulation in patients with ITP are known to be highly functional and hence usually do not bleed even with counts as <30,000 or less. A platelet count of 50,000/μl must be achieved in patients with active bleeding. A count of 100,000/μl is to be maintained in central nervous system bleeds.
The determinants of the extent of bleeding are usually prior bleeding history and older age.
A standard dose of platelet is approximately 1 unit of random donor platelet (RDP) per 10 kg of body weight of the patient. For an average adult patient weighing 60 kg, it translates to 6 units of RDPs or 1-unit apheresis platelet (single-donor platelet [SDP]) which provides around 3–4 × 1011 platelets. The increment in the platelet count, as well as hemostatic effects of RDPs and SDP, is comparable. For pediatric patients, the dose can be calculated as the fraction of a unit of RDP proportionate to 10 kg body weight. This one dose is expected to raise the platelet count in the patient by 30,000/μl. Usually, one dose is sufficient per day. However, subsequent doses may be required on the same day if patients are having ongoing bleed or have rapidly/steady drop in platelet counts.
| Treating Steroid-Resistant ITP in Pregnancy|| |
ITP is estimated to occur in 1–2/1000 pregnant women. Corticosteroids are usually used as the first-line drugs in treating ITP in pregnancy. In steroid-resistant ITP patients in pregnancy, options are limited. IVIG is the drug of choice in this scenario. The advantage of IVIG is the rapid onset of action, but its effects tend to be transient. The other disadvantage of this agent is the theoretic risk of blood-borne infections. Response rates in pregnant patients are similar to those in nonpregnant patients.
Anti-D antibody can be used only in nonsplenectomized Rh (D)-positive patients. It has been found to be safe and effective during pregnancy. It is contraindicated in women with anemia. Neonatal monitoring for jaundice, anemia, and direct antiglobulin test positivity is recommended after delivery.
Splenectomy if indicated is best performed in the second trimester. It can be performed laparoscopically but is technically challenging beyond 20 weeks' gestation.
Rituximab usage in pregnancy has been described in several studies, primarily in the treatment of lymphomas and autoimmune diseases including ITP. It has been found to have an acceptable safety profile in pregnancy in these studies, but more studies are needed before it can be recommended routinely in pregnancy. Moreover, it crosses the placenta and may result in B-cell depletion in the neonate, especially when given within 6 months before delivery.
Experience with TPO mimetics is limited in pregnancy, and therefore, it is not possible to endorse their safety or efficacy. There are several case reports describing the successful usage of eltrombopag and romiplostim in steroid-resistant ITP in pregnancy., Recombinant human TPO has also been used in steroid-resistant ITP in pregnancy in a recent study involving 31 women; the response rate was 74.2% and no neonatal adverse effects or congenital malformation were reported.
Immunosuppressive and cytotoxic drugs are potentially teratogenic. Cyclophosphamide, Vinca alkaloids, and danazol are contraindicated in pregnancy. Experience with azathioprine in pregnant women with renal transplant indicates that it is a safe drug but may be associated with fetal growth restriction, preterm delivery, and neonatal immunosuppression. Recent studies have found the drug to be nonteratogenic. Calcineurin inhibitors (cyclosporine and tacrolimus) are also considered relatively safe in pregnancy. They have not been associated with congenital malformations but may increase the risk of preterm birth, low birth weight, reversible nephrotoxicity, and hyperkalemia in the newborn.
| Monitoring of Disease|| |
While monitoring of steroid-resistant ITP patients, the treating physician/hematologist should focus on bleeding symptoms, psychological burden of disease, adverse effects of medications, and quality of life of affected patients. The frequency of platelet count monitoring depends not only on the degree of thrombocytopenia but also on bleeding episodes. Patients with stable platelet counts >20,000/μl and without bleeding need infrequent monitoring (once in 2–3 weeks), and those with bleeding and platelet counts <20,000/μl need more frequent (i.e., weekly) platelet count monitoring. In addition to monitoring treatment response, treatment-related adverse effects such as infections, thrombotic events, and hepatotoxicity should also be monitored.
| Prognosis|| |
Spontaneous remissions have been reported in up to about 10% of adult ITP patients, and these are more likely to occur within 6 months of diagnosis. Population-based studies have shown increased mortality among adult ITP patients compared to the general population, the mortality related to the severity of disease. A Danish study found 1.5-fold increased mortality among ITP patients, compared to the general population, the mortality being attributable mainly to increased infections (relative risk [RR]: 6.2) and bleeding (RR: 2.4), apart from hematologic malignancies (RR: 5.7). The risk of bleeding, especially that of serious intracranial bleeds, is more in the elderly and those with prior significant hemorrhage. The overall risk for developing intracranial bleeds among adults is 1.5%–1.8%, which is more than that in children (<1%)., Severe bleeding events contribute to a smaller number of deaths compared to infections and other complications related to treatment in ITP patients. There is in addition a definite increase in risk of thromboembolic events among ITP patients. Nearly 70% of adult chronic ITP patients failing to respond to splenectomy still achieved stable remission with additional therapies, and the subpopulation with severe and resistant disease had increased morbidity and mortality in a study. Development of autoimmune disorders such as systemic lupus erythematosus and autoimmune thyroiditis in ITP patients is uncommon. Splenectomy for ITP did not increase the risk of cardiovascular events and malignancy and did not significantly reduce survival but increased the risk of infections and thrombotic events in a study.
| Conclusion|| |
The principal choices as of today available for steroid-resistant ITP are splenectomy, rituximab, and TPO-RAs. There are no prospective randomized trials which have compared them with each other, and hence, the choice of therapy is to be based on the patient and the physician preferences and feasibility. The goal is to be to prevent clinically significant bleeding rather than normalizing platelet count. The threshold count target for initiating therapy also is lower than the first-line therapy. Splenectomy is usually suggested for patients who can tolerate the surgery, and risks are acceptable as this has the greatest chance of producing CR. For others, rituximab is appropriate. TPO-RAs are usually reserved for patients with persistent thrombocytopenia after splenectomy/rituximab or unable to tolerate these treatments. Immunosuppressants, danazol, or other modalities can be used, but data supporting them are limited. IVIG can be used as rescue treatment rather than a routine therapy. Drugs such as fostamatinib and alemtuzumab though promising more data are needed before putting them to regular practice.
We like to thank Prof. T. K. Dutta, Department of Medicine, MGMCRI, Puducherry, our mentor and guide who helped us throughout this work with timely inputs.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Provan D, Stasi R, Newland AC, Blanchette VS, Bolton-Maggs P, Bussel JB, et al
. International consensus report on the investigation and management of primary immune thrombocytopenia. Blood 2010;115:168-86.
Neunert C, Lim W, Crowther M, Cohen A, Solberg L Jr., Crowther MA, et al
. The American Society of Hematology 2011 evidence-based practice guideline for immune thrombocytopenia. Blood 2011;117:4190-207.
Rodeghiero F, Stasi R, Gernsheimer T, Michel M, Provan D, Arnold DM, 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;113:2386-93.
Terrell DR, Beebe LA, Vesely SK, Neas BR, Segal JB, George JN. The incidence of immune thrombocytopenic purpura in children and adults: A critical review of published reports. Am J Hematol 2010;85:174-80.
Stasi R, Stipa E, Masi M, Cecconi M, Scimò MT, Oliva F, et al
. Long-term observation of 208 adults with chronic idiopathic thrombocytopenic purpura. Am J Med 1995;98:436-42.
Lo E, Deane S. Diagnosis and classification of immune-mediated thrombocytopenia. Autoimmun Rev 2014;13:577-83.
Adcock IM, Lane SJ, Brown CR, Peters MJ, Lee TH, Barnes PJ. Differences in binding of glucocorticoid receptor to DNA in steroid-resistant asthma. J Immunol 1995;154:3500-5.
Shimanovsky A, Patel D, Wasser J. Refractory immune thrombocytopenic purpura and cytomegalovirus infection: A call for a change in the current guidelines. Mediterr J Hematol Infect Dis 2016;8:e2016010.
Nomura S, Matsuzaki T, Ozaki Y, Yamaoka M, Yoshimura C, Katsura K, et al
. Clinical significance of HLA-DRB1*0410 in Japanese patients with idiopathic thrombocytopenic purpura. Blood 1998;91:3616-22.
Adcock IM, Barnes PJ. Molecular mechanisms of corticosteroid resistance. Chest 2008;134:394-401.
Rodeghiero F. A critical appraisal of the evidence for the role of splenectomy in adults and children with ITP. Br J Haematol 2018;181:183-95.
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;104:2623-34.
McMillan R, Durette C. Long-term outcomes in adults with chronic ITP after splenectomy failure. Blood 2004;104:956-60.
Chaigne B, Mouthon L. Mechanisms of action of intravenous immunoglobulin. Transfus Apher Sci 2017;56:45-9.
Despotovic JM, Lambert MP, Herman JH, Gernsheimer TB, McCrae KR, Tarantino MD, et al
. RhIG for the treatment of immune thrombocytopenia: Consensus and controversy (CME). Transfusion 2012;52:1126-36.
Godeau B, Chevret S, Varet B, Lefrère F, Zini JM, Bassompierre F, et al
. Intravenous immunoglobulin or high-dose methylprednisolone, with or without oral prednisone, for adults with untreated severe autoimmune thrombocytopenic purpura: A randomised, multicentre trial. Lancet 2002;359:23-9.
Newman GC, Novoa MV, Fodero EM, Lesser ML, Woloski BM, Bussel JB. A dose of 75 mug/kg/d of i.v. anti-D increases the platelet count more rapidly and for a longer period of time than 50 mug/kg/d in adults with immune thrombocytopenic purpura. Br J Haematol 2001;112:1076-8.
Gaines AR. Disseminated intravascular coagulation associated with acute hemoglobinemia or hemoglobinuria following Rh(0)(D) immune globulin intravenous administration for immune thrombocytopenic purpura. Blood 2005;106:1532-7.
Bierling P, Godeau B. Intravenous immunoglobulin for autoimmune thrombocytopenic purpura. Hum Immunol 2005;66:387-94.
Bussel JB, Eldor A, Kelton JG, Varon D, Brenner B, Gillis S, et al
. IGIV-C, a novel intravenous immunoglobulin: Evaluation of safety, efficacy, mechanisms of action, and impact on quality of life. Thromb Haemost 2004;91:771-8.
Rizk A, Gorson KC, Kenney L, Weinstein R. Transfusion-related acute lung injury after the infusion of IVIG. Transfusion 2001;41:264-8.
Auger S, Duny Y, Rossi JF, Quittet P. Rituximab before splenectomy in adults with primary idiopathic thrombocytopenic purpura: A meta-analysis. Br J Haematol 2012;158:386-98.
Palandri F, Polverelli N, Catani L, Sollazzo D, Romano M, Levorato M, et al
. The choice of second-line therapy in steroid-resistant immune thrombocytopenia: Role of platelet kinetics in a single-centre long-term study. Am J Hematol 2014;89:1047-50.
Moulis G, Sailler L, Sommet A, Lapeyre-Mestre M, Derumeaux H, Adoue D. Rituximab versus splenectomy in persistent or chronic adult primary immune thrombocytopenia: An adjusted comparison of mortality and morbidity. Am J Hematol 2014;89:41-6.
Khellaf M, Charles-Nelson A, Fain O, Terriou L, Viallard JF, Cheze S, et al
. Safety and efficacy of rituximab in adult immune thrombocytopenia: Results from a prospective registry including 248 patients. Blood 2014;124:3228-36.
Patel VL, Mahévas M, Lee SY, Stasi R, Cunningham-Rundles S, Godeau B, et al
. Outcomes 5 years after response to rituximab therapy in children and adults with immune thrombocytopenia. Blood 2012;119:5989-95.
Zaja F, Volpetti S, Chiozzotto M, Puglisi S, Isola M, Buttignol S, et al
. Long-term follow-up analysis after rituximab salvage therapy in adult patients with immune thrombocytopenia. Am J Hematol 2012;87:886-9.
Zaja F, Vianelli N, Volpetti S, Battista ML, Defina M, Palmieri S, et al
. Low-dose rituximab in adult patients with primary immune thrombocytopenia. Eur J Haematol 2010;85:329-34.
Wang J, Li Y, Wang C, Zhang Y, Gao C, Lang H, et al
. Efficacy and safety of the combination treatment of rituximab and dexamethasone for adults with primary immune thrombocytopenia (ITP): A meta-analysis. Biomed Res Int 2018;2018:1316096.
Liang Y, Zhang L, Gao J, Hu D, Ai Y. Rituximab for children with immune thrombocytopenia: A systematic review. PLoS One 2012;7:e36698.
Lu KH, George JN, Vesely SK, Terrell DR. Management of primary immune thrombocytopenia, 2012: A survey of Oklahoma hematologists-oncologists. Am J Med Sci 2014;347:190-4.
Nieto M, Calvo G, Hudson I, Feldschreiber P, Brown D, Lee CC, et al
. The European Medicines Agency review of eltrombopag (Revolade) for the treatment of adult chronic immune (idiopathic) thrombocytopenic purpura: Summary of the Scientific Assessment of the Committee for Medicinal Products for Human Use. Haematologica 2011;96:e33-40.
Zeng Y, Duan X, Xu J, Ni X. TPO receptor agonist for chronic idiopathic thrombocytopenic purpura. Cochrane Database Syst Rev. 2011: CD008235.
Wang L, Gao Z, Chen XP, Zhang HY, Yang N, Wang FY, et al
. Efficacy and safety of thrombopoietin receptor agonists in patients with primary immune thrombocytopenia: A systematic review and meta-analysis. Sci Rep 2016;6:39003.
González-López TJ, Pascual C, Álvarez-Román MT, Fernández-Fuertes F, Sánchez-González B, Caparrós I, et al
. Successful discontinuation of eltrombopag after complete remission in patients with primary immune thrombocytopenia. Am J Hematol 2015;90:E40-3.
Kuter DJ. The biology of thrombopoietin and thrombopoietin receptor agonists. Int J Hematol 2013;98:10-23.
Kuter DJ, Bussel JB, Lyons RM, Pullarkat V, Gernsheimer TB, Senecal FM, et al
. Efficacy of romiplostim in patients with chronic immune thrombocytopenic purpura: A double-blind randomised controlled trial. Lancet 2008;371:395-403.
Saleh MN, Bussel JB, Cheng G, Meyer O, Bailey CK, Arning M, et al
. Safety and efficacy of eltrombopag for treatment of chronic immune thrombocytopenia: Results of the long-term, open-label EXTEND study. Blood 2013;121:537-45.
Jurczak W, Chojnowski K, Mayer J, Krawczyk K, Jamieson BD, Tian W, et al
. Phase 3 randomised study of avatrombopag, a novel thrombopoietin receptor agonist for the treatment of chronic immune thrombocytopenia. Br J Haematol 2018;183:479-90.
Newland A, Lee EJ, McDonald V, Bussel JB. Fostamatinib for persistent/chronic adult immune thrombocytopenia. Immunotherapy 2018;10:9-25.
Bussel J, Arnold DM, Grossbard E, Mayer J, Treliński J, Homenda W, et al
. Fostamatinib for the treatment of adult persistent and chronic immune thrombocytopenia: Results of two phase 3, randomized, placebo-controlled trials. Am J Hematol 2018;93:921-30.
Patel AP, Patil AS. Dapsone for immune thrombocytopenic purpura in children and adults. Platelets 2015;26:164-7.
Estève C, Samson M, Guilhem A, Nicolas B, Leguy-Seguin V, Berthier S, et al
. Efficacy and safety of dapsone as second line therapy for adult immune thrombocytopenia: A retrospective study of 42 patients. PLoS One 2017;12:e0187296.
Lee JY, Lee JO, Jung JY, Bang SM. Dapsone therapy for refractory immune thrombocytopenia patients: A case series. Blood Res 2017;52:95-9.
Schreiber AD, Chien P, Tomaski A, Cines DB. Effect of danazol in immune thrombocytopenic purpura. N Engl J Med 1987;316:503-8.
Audia S, Godeau B, Bonnotte B. Is there still a place for “old therapies” in the management of immune thrombocytopenia? Rev Med Interne 2016;37:43-9.
Maloisel F, Andrès E, Zimmer J, Noel E, Zamfir A, Koumarianou A, et al
. Danazol therapy in patients with chronic idiopathic thrombocytopenic purpura: Long-term results. Am J Med 2004;116:590-4.
Weinblatt ME, Kochen J, Ortega J. Danazol for children with immune thrombocytopenic purpura. Am J Dis Child 1988;142:1317-9.
Quiquandon I, Fenaux P, Caulier MT, Pagniez D, Huart JJ, Bauters F. Re-evaluation of the role of azathioprine in the treatment of adult chronic idiopathic thrombocytopenic purpura: A report on 53 cases. Br J Haematol 1990;74:223-8.
Emilia G, Morselli M, Luppi M, Longo G, Marasca R, Gandini G, et al
. Long-term salvage therapy with cyclosporin A in refractory idiopathic thrombocytopenic purpura. Blood 2002;99:1482-5.
Verlin M, Laros RK Jr., Penner JA. Treatment of refractory thrombocytopenic purpura with cyclophosphamine. Am J Hematol 1976;1:97-104.
Kotb R, Pinganaud C, Trichet C, Lambotte O, Dreyfus M, Delfraissy JF, et al
. Efficacy of mycophenolate mofetil in adult refractory auto-immune cytopenias: A single center preliminary study. Eur J Haematol 2005;75:60-4.
Szczepanik AB, Sikorska A, Slomkowski M, Konopka L. The use of vinca alkaloids in preparation for splenectomy of corticosteroid refractory chronic immune thrombocytopenic purpura patients. Int J Lab Hematol 2007;29:347-51.
Sobota A, Neufeld EJ, Lapsia S, Bennett CM. Response to mercaptopurine for refractory autoimmune cytopenias in children. Pediatr Blood Cancer 2009;52:80-4.
Choi PY, Roncolato F, Badoux X, Ramanathan S, Ho SJ, Chong BH. A novel triple therapy for ITP using high-dose dexamethasone, low-dose rituximab, and cyclosporine (TT4). Blood 2015;126:500-3.
Puapong D, Terasaki K, Lacerna M, Applebaum H. Splenic artery embolization in the management of an acute immune thrombocytopenic purpura-related intracranial hemorrhage. J Pediatr Surg 2005;40:869-71.
Bansal D, Rajendran A, Singhi S. Newly diagnosed immune thrombocytopenia: Update on diagnosis and management. Indian J Pediatr 2014;81:1033-41.
Callis M, Palacios C, López A, Giralt J, Juliá A. Splenic irradiation as management of ITP. Br J Haematol 1999;105:843-4.
Calverley DC, Jones GW, Kelton JG. Splenic radiation for corticosteroid-resistant immune thrombocytopenia. Ann Intern Med 1992;116:977-81.
Caulier MT, Darloy F, Rose C, Camier G, Morel P, Bauters F, et al
. Splenic irradiation for chronic autoimmune thrombocytopenic purpura in patients with contra-indications to splenectomy. Br J Haematol 1995;91:208-11.
Shih A, Nazi I, Kelton JG, Arnold DM. Novel treatments for immune thrombocytopenia. Presse Med 2014;43:e87-95.
Robak T, Windyga J, Trelinski J, von Depka Prondzinski M, Giagounidis A, Doyen C, et al
. Rozrolimupab, a mixture of 25 recombinant human monoclonal RhD antibodies, in the treatment of primary immune thrombocytopenia. Blood 2012;120:3670-6.
Fan H, Zhu HL, Li SX, Lu XC, Zhai B, Guo B, et al
. Efficacy of amifostine in treating patients with idiopathic thrombocytopenia purpura. Cell Biochem Biophys 2011;59:7-12.
Davidson A. Targeting BAFF in autoimmunity. Curr Opin Immunol 2010;22:732-9.
Solanilla A, Pasquet JM, Viallard JF, Contin C, Grosset C, Déchanet-Merville J, et al
. Platelet-associated CD154 in immune thrombocytopenic purpura. Blood 2005;105:215-8.
Nomura S, Kurata Y, Tomiyama Y, Takubo T, Hasegawa M, Saigo K, et al
. Effects of bisphosphonate administration on the bone mass in immune thrombocytopenic purpura patients under treatment with steroids. Clin Appl Thromb Hemost 2010;16:622-7.
Hill QA, Grainger JD, Thachil J, Provan D, Evans G, Garg M, et al
. The prevention of glucocorticoid-induced osteoporosis in patients with immune thrombocytopenia receiving steroids: A British Society for Haematology Good Practice Paper. Br J Haematol 2019;185:410-7.
Dilber C, Dagdemir A, Albayrak D, Albayrak S, Kalayci AG, Aliyazicioglu Y, et al
. Reduced bone mineral density in childhood chronic idiopathic thrombocytopenic purpura treated with high-dose methylprednisolone. Bone 2004;35:306-11.
Salama A, Rieke M, Kiesewetter H, von Depka M. Experiences with recombinant FVIIa in the emergency treatment of patients with autoimmune thrombocytopenia: A review of the literature. Ann Hematol 2009;88:11-5.
Davies JM, Lewis MP, Wimperis J, Rafi I, Ladhani S, Bolton-Maggs PH, et al
. Review of guidelines for the prevention and treatment of infection in patients with an absent or dysfunctional spleen: Prepared on behalf of the British Committee for Standards in Haematology by a Working Party of the Haemato-Oncology Task Force. Br J Haematol 2011;155:308-17.
Snyder HW Jr., Cochran SK, Balint JP Jr., Bertram JH, Mittelman A, Guthrie TH Jr., et al
. Experience with protein A-immunoadsorption in treatment-resistant adult immune thrombocytopenic purpura. Blood 1992;79:2237-45.
Cortelazzo S, Finazzi G, Buelli M, Molteni A, Viero P, Barbui T. High risk of severe bleeding in aged patients with chronic idiopathic thrombocytopenic purpura. Blood 1991;77:31-3.
Schiffer CA, Anderson KC, Bennett CL, Bernstein S, Elting LS, Goldsmith M, et al
. Platelet transfusion for patients with cancer: Clinical practice guidelines of the American Society of Clinical Oncology. J Clin Oncol 2001;19:1519-38.
Segal JB, Powe NR. Prevalence of immune thrombocytopenia: Analyses of administrative data. J Thromb Haemost 2006;4:2377-83.
Stavrou E, McCrae KR. Immune thrombocytopenia in pregnancy. Hematol Oncol Clin North Am 2009;23:1299-316.
Sieunarine K, Shapiro S, Al Obaidi M, Girling J. Intravenous anti-D immunoglobulin in the treatment of resistant immune thrombocytopenic purpura in pregnancy. BJOG 2007;114:505-7.
Chakravarty EF, Murray ER, Kelman A, Farmer P. Pregnancy outcomes after maternal exposure to rituximab. Blood 2011;117:1499-506.
Das G, Damotte V, Gelfand JM, Bevan C, Cree BA, Do L, et al
. Rituximab before and during pregnancy: A systematic review, and a case series in MS and NMOSD. Neurol Neuroimmunol Neuroinflamm 2018;5:e453.
Purushothaman J, Puthumana KJ, Kumar A, Innah SJ, Gilvaz S. A case of refractory immune thrombocytopenia in pregnancy managed with elthrombopag. Asian J Transfus Sci 2016;10:155-8.
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Decroocq J, Marcellin L, Le Ray C, Willems L. Rescue therapy with romiplostim for refractory primary immune thrombocytopenia during pregnancy. Obstet Gynecol 2014;124:481-3.
Kong Z, Qin P, Xiao S, Zhou H, Li H, Yang R, et al
. A novel recombinant human thrombopoietin therapy for the management of immune thrombocytopenia in pregnancy. Blood 2017;130:1097-103.
Alami Z, Agier MS, Ahid S, Vial T, Dautriche A, Lagarce L, et al
. Pregnancy outcome following in utero
exposure to azathioprine: A French comparative observational study. Therapie 2018;73:199-207.
Ponticelli C, Moroni G. Fetal toxicity of immunosuppressive drugs in pregnancy. J Clin Med 2018;7:552.
Lambert MP, Gernsheimer TB. Clinical updates in adult immune thrombocytopenia. Blood 2017;129:2829-35.
Frederiksen H, Maegbaek ML, Nørgaard M. Twenty-year mortality of adult patients with primary immune thrombocytopenia: A Danish population-based cohort study. Br J Haematol 2014;166:260-7.
Neunert C, Noroozi N, Norman G, Buchanan GR, Goy J, Nazi I, et al
. Severe bleeding events in adults and children with primary immune thrombocytopenia: A systematic review. J Thromb Haemost 2015;13:457-64.
Schoonen WM, Kucera G, Coalson J, Li L, Rutstein M, Mowat F, et al
. Epidemiology of immune thrombocytopenic purpura in the General Practice Research Database. Br J Haematol 2009;145:235-44.
Doobaree IU, Nandigam R, Bennett D, Newland A, Provan D. Thromboembolism in adults with primary immune thrombocytopenia: A systematic literature review and meta-analysis. Eur J Haematol 2016;97:321-30.
Thai LH, Mahévas M, Roudot-Thoraval F, Limal N, Languille L, Dumas G, et al
. Long-term complications of splenectomy in adult immune thrombocytopenia. Medicine (Baltimore) 2016;95:e5098.
[Table 1], [Table 2], [Table 3], [Table 4]