This is accompanied by the application of new types of drugs and further research in pathophysiology. Previous guidelines for the diagnosis and treatment of primary immune thrombocytopenia need to be revised. Indeed, the choice of treatment continues to depend on clinical expertise or patient choice rather than on high-quality clinical trial evidence. The purpose of this consensus article is to review the newly published literature and thereby make recommendations for the diagnosis and treatment of ITP in adults, children, and pregnant women. The figures in the Conclusions section of this article, which are derived from data in the online appendix of the paper, are intended to aid in clinical decision making.
Preface Primary immune thrombocytopenia (ITP, primary immune thrombocytopenia) is an acquired immune-mediated disorder characterized by thrombocytopenia in which peripheral platelets are less than 100×109/L and there is no apparent primary and/or underlying disease causing the thrombocytopenia. Until recently, ITP was still seen as shorthand for idiopathic thrombocytopenic purpura (ITP). The mechanism of thrombocytopenia in ITP has changed from the traditional antibody-mediated increase in platelet destruction to a more complex, T-cell-mediated imbalance of action and platelet production. Recent epidemiological surveys have found that in adults, the prevalence is higher in women at the middle-aged stage (30-60 years), while at other stages, there is no difference in the prevalence of ITP between men and women.ITP can be classified as newly diagnosed, persistent (lasting 3-12 months) and chronic (lasting ≥12 months) depending on the duration. In adults, the typical case is usually insidious, with no obvious history of viral infection or other diseases before the disease, and the course of the disease is chronic. In children, the course is generally short, with at least 2/3 of children in spontaneous remission within 6 months. Signs and symptoms also vary widely. Many patients have no symptoms or only minor bleeding, while some have significant bleeding, such as from the gastrointestinal tract, extensive cutaneous mucosal bleeding, or intracranial bleeding. The severity of bleeding correlates in part, but not exclusively, with the degree of thrombocytopenia. A number of other factors, such as age, lifestyle factors, and uremia, are also associated with the risk of bleeding and should be fully considered when choosing the appropriate treatment.
This consensus was developed through an extensive survey of the diagnosis and management of patients with ITP. The purpose of this consensus is to review the newly published literature and to provide diagnostic and treatment recommendations. The final decision for the patient depends on the physician’s expertise and a detailed examination of the individual patient’s situation.
Methodology The 22 members of the expert panel were renowned clinical and research experts in ITP from North America (7 in the United States and 1 in Canada), Europe (1 in France, 1 in Italy, 1 in Spain, 1 in Switzerland, and 8 in the United Kingdom), and Australia (1).
The literature was evaluated with the terms “immune thrombocytopenic purpura”, “idiopathic thrombocytopenic purpura”, “ITP”, “autoimmune thrombocytopenic purpura”, “autoimmune thrombocytopenic purpura” and “autoimmune thrombocytopenic purpura”. “, “autoimmune thrombocytopenic purpura” were searched in NLM’s PubMed database for relevant English literature. The initial search results were then screened by applying the corresponding MedLineMeSH entries and cross-references. The relevant literature from the European Hematology Association (EHA), American Society of Hematology (ASH), and International Society on Thrombosis and Haemostasis (ISTH) annual meetings from 2003-2007 was also referenced. A special scoring system was applied to the level of evidence and level of recommendation in the consensus. Randomized controlled trials (RCTs) were considered to have the highest level of evidence, and conversely, case reports or expert opinion evidence had the lowest level. The recommended level of rating was based on the level of supporting evidence. Levels of evidence were reviewed throughout the consensus preparation process through face-to-face meetings of an expert committee. During the review process, authors of the literature were allowed to challenge the level of their literature. Relevant data and appendices of tables appearing in this consensus are available on the Blood website.
Diagnostic Approach to Patients with Suspected ITP
The diagnostic tools for adult and pediatric patients with suspected ITP are divided into 3 sections in the consensus. When the presenting history, physical examination, complete blood count, and peripheral blood film examination do not support other etiologic causes of thrombocytopenia. There is no “gold standard” test to definitively diagnose ITP; a response to ITP-specific therapy, such as IVIG or intravenous anti-D, may support the diagnosis, but a response does not exclude secondary ITP.
The present history of thrombocytopenia can be caused by many reasons, such as systemic diseases, infections, drugs and diseases of the primary hematological system. In about 60% of pediatric cases there is a history of infection. There is an increased risk of ITP after measles mumps rubella vaccination. Bleeding after previous surgery, dentistry, or trauma should be considered with chronic thrombocytopenia or other hematologic disorders. If ITP has been diagnosed, contraindications and cautions for glucocorticoids should be noted. Hereditary thrombocytopenia is considered if the patient has chronic thrombocytopenia unresponsive to therapy and a familial thrombocytopenia or bleeding disorder.
Emergency physicians should be aware of the possibility of drug abuse in young patients presenting with bleeding and purpura at first diagnosis (level IV evidence). Children with infections such as those with S. meningitidis infection usually have other systemic symptoms that can be quickly identified.
Physical examination
Physical examination is performed as usual except for examination of bleeding manifestations. Mild enlargement of the spleen may be seen in younger patients, but in cases of moderate or severe enlargement other causes need to be considered. Some symptoms such as fever, weight loss, hepatomegaly, and lymph node enlargement require consideration of secondary diseases, such as HIV infection, systemic lupus erythematosus, and lymphoproliferative disorders, among others, are common.
Peripheral blood count ITP is characterized by peripheral blood with only reduced platelets and normal other lineages. Some patients may have anemia present due to blood loss, proportional to the degree of blood loss. Persistent bleeding can lead to iron deficiency (evidence level IV). Reticulocyte counts are helpful in clarifying whether there is insufficient red blood cell production or excessive destruction.
Evaluation of peripheral blood films by a hematologist or pathologist is paramount for the diagnosis of ITP. This can lead to the confirmation of other pathologies that are not compatible with ITP. For example, the presence of broken red blood cells in thrombotic thrombocytopenic purpura-hemolytic urotoxin syndrome, leukocyte inclusion bodies in MYH9-associated disease, and the excessive presence of giant or microplatelets require consideration of hereditary thrombocytopenia. Pseudo-thrombocytopenia due to EDTA-dependent platelet agglutination needs to be excluded (level of evidence III).
Bone marrow examination Bone marrow examination may provide additional information in patients older than 60 years of age. Bone marrow examination is required in patients with systemic symptoms and abnormal signs, some splenomegaly, and is usually performed simultaneously with bone marrow aspiration and biopsy. In addition to morphologic evaluation, flow cytometry and cytogenetic testing may be considered (Evidence Level IIb-IV). Flow cytometry is of particular interest in the differential diagnosis of patients with chronic lymphocytic leukemia secondary to ITP.
H. pylori testing H. pylori infection is best detected by urea breath test or fecal antigen test. It can be performed in adult patients with typical ITP (level of evidence IIa) and may have clinical implications. Serological tests may also be used, but are less sensitive and less specific than other tests. In addition, false positives can occur in patients treated with IVIg. H. pylori testing is not routinely performed in children with ITP except in highly endemic areas.
HIV and HCV screening Thrombocytopenia due to HIV and hepatitis C virus infection is difficult to distinguish from patients with primary ITP in the years before they develop other symptoms. HIV and HCV testing is recommended for adult patients suspected of having ITP, regardless of the presence or absence of local hyperendemicity or the patient’s history of high-risk exposure. Control of these infections may achieve complete hematologic recovery (Level of Evidence Level IIa).
Immunoglobulin quantification Basal levels of adult immunoglobulins (IgG, IgA, IgM) are required routinely (Level of Evidence IV). Basal levels may also be measured in children with ITP. Measurement in children with persistent or chronic ITP can be part of the reassessment evaluation. Low levels of immunoglobulins may suggest conditions such as common variable immunodeficiency
(CVID) or selective IgA deficiency. The application of immunosuppressive therapy for ITP and CVID can create some confusion. The best approach should be to measure Ig before applying IVIg, but in general the drug should be used before the results are known (evidence level IV).
Direct anti-human globulin test (DAT) has been documented to be positive in 22% (186 adults, 19 children) of 205 patients with ITP, but its clinical significance has not been clarified.DAT is considered in the following cases: anemia with elevated reticulocyte count and consideration of anti-D immunoglobulin.
Blood group Rh(D) typing Testing is required if anti-D immunoglobulin is being considered.
Potentially useful tests
Anti-platelet antibody glycoprotein-specific antibody test. Antibody testing for platelet-specific glycoproteins is not routinely recommended because platelet-associated IgG is elevated in both immune and non-immune thrombocytopenia (evidence level IV).
Antiphospholipid antibodies
Antiphospholipid antibodies (APLA), which include anticardiolipin antibodies and lupus anticoagulants, can be found in approximately 40% of other patients with typical adult ITP. The presence of APLA does not affect the response to treatment in ITP. It is not used as a routine test in the absence of symptoms of antiphospholipid syndrome.
The presence of positive antinuclear antibody test (ANA) in pediatric ITP patients may indicate chronicity.
Antithyroid antibodies and thyroid function are found in 8-14% of patients with ITP followed up for the development of clinical hyperthyroidism. Others develop antithyroglobulin antibodies or eventually develop hypo- or hyperthyroidism. Mild thrombocytopenia has been reported in some cases of hypothyroidism (possibly with reduced platelet production) and hyperthyroidism (with shortened platelet survival). This is accompanied by recovery of thyroid function and normalization of platelets. Determination of thyroglobulin antibodies and thyroid-stimulating hormone (TSH) is relevant to identify patients presenting with clinical thyroid disease.
Screening for other acute and persistent infections Acute viral infections and some vaccinations (active attenuated virus) are associated with thrombocytopenia, which is usually transient. Some chronic infections, such as microviruses and cytomegalovirus (CMV), also present with thrombocytopenia.
Unproven or inconclusive diagnostic tests
A number of other tests have not usually proved to be of interest in the differential diagnosis of ITP and in guiding treatment.
Treatment of ITP in adults
Although RCT data provide new treatment modalities for ITP (e.g., romiplostin, eltrombopag), only a few RCT data evaluate the application of conventional treatment modalities in adults, and even fewer evaluate other treatment modalities. The present literature provides a wide range of treatment modalities. A general principle is that these treatments must be applicable to individual patients. All treatment modalities are listed in alphabetical order so as to reflect the absence of a preferred specific treatment. Different criteria for evaluating efficacy between studies have led to difficulties in direct comparison of treatment modalities applied to individual patients.
New treatments are becoming more expensive due to the rising cost of modern drugs, thus limiting the use of some new drugs in some countries. The source of health care spending, whether from individuals or public health fund systems, has an impact on the choice of treatment. In fact, more medical costs are offset based on the fact that these new drugs are not immunosuppressive, have undergone rigorous randomized controlled clinical trials and appear to have high efficacy.
Who should be treated?
Factors that have an impact on treatment decisions include the extent of bleeding, coexisting disease bleeding susceptibility, complications of specific treatments, function and lifestyle, tolerance of side effects, potential interventions to cause bleeding, feasibility of care, patient expectations, patient concerns and anxiety about the large burden of disease, and patient need for non-ITP medications that can create bleeding risk.
Although bleeding death was the main issue involved, an analysis of 17 adult case studies evaluated the results: the annual risk of bleeding death per adult patient was 0.0162-0.0389. patients over 60 years of age and those with prior bleeding had a higher risk of bleeding. Deaths due to bleeding and infection were comparable.
Patients with platelet counts greater than 50×109/L and with the following conditions are generally rarely treated. These conditions include bleeding due to abnormal platelet function or other coagulation defects, trauma, surgery, clearly identifiable co-morbidities causing bleeding, mandatory anticoagulation therapy, or in a population with trauma due to work or lifestyle. Patient thoughts must be considered when discussing treatment. Details of consensus-based recommendations: The number of platelets in adults undergoing surgery was previously discussed and has been further revised.
First-line therapy: initial treatment of newly diagnosed patients
Efficacy criteria vary from study to study, so comparison of individual patient response rates to treatment is not possible.
Glucocorticoid therapyGlucocorticoids are the standard initial treatment. In addition, they can also reduce bleeding and increase platelet count independently by acting directly on the vessel wall. However, the side effects of this class of drugs appear quickly and produce significant side effects. Over time, the side effects often outweigh their effectiveness. Prednisone is the standard first-line treatment for ITP and is generally given at 0.5-2 mg/kg/d until the platelet count rises (30-50×109/L), which takes several days to several weeks. This treatment is effective, but patients are at risk for glucocorticoid-related complications, which vary with dose and duration of therapy. To avoid glucocorticoid-related complications, prednisone must be rapidly tapered and often discontinued in those who are effective, especially in those who are ineffective, and should be discontinued after 4 weeks.
Dexamethasone Although dexamethasone has been abandoned in the treatment of patients with chronic refractory ITP, the results of 2 recent large clinical studies applying dexamethasone as first-line therapy have shown that treatment with dexamethasone produces high rates of initial remission and reliable rates of sustained response (effectiveness). Application of dexamethasone 40 mg/d for 4 days (equivalent to prednisone 400 mg/d) produced a 50% sustained response in newly diagnosed adult ITP patients. In another study, dexamethasone 40 mg/d4 days given every 14 days for 4 courses had an 86% response rate and 74% response median duration of 8 months. the RCT study needs to clearly evaluate these encouraging results and also distinguish whether the addition of dexamethasone is the best glucocorticoid treatment in terms of efficacy, duration of efficacy and toxicities.
High-dose methylprednisolone administered parenterally in different regimens is 80% effective in patients with ITP who have failed first-line therapy, but its duration of efficacy is short and oral glucocorticoid maintenance therapy is required (Level IV evidence).
IV anti-D IVanti-D is indicated for Rh(D)-positive, non-splenectomy ITP patients. Avoid in patients with autoimmune hemolytic anemia because it can exacerbate hemolysis. Blood group, DAT and reticulocyte count need to be checked before applying IVanti-D.
IVanti-D can be an effective alternative treatment to IVIG because it can be infused in a shorter period of time, the product comes from a smaller donor pool, and has the potential to be effective for a longer maintenance period while potentially reducing the requirement for splenectomy. Two studies have demonstrated that administration of IVanti-D 75ug/kg instead of the standard 50ug/kg increases the total platelet count compared to the application of IVIG. The recommended administration of acetaminophen/p-acetaminophen or glucocorticoids (e.g., prednisone 20 mg) prior to the application of this drug may reduce the febrile/chill response, especially at higher doses. Mild anemia may occur and is dose-related. Severe side effects, even death, can occur in rare cases, and cases of intravascular hemolysis, DIC, and renal failure have been reported (Evidence Class Ib-III). IVanti-D is a mixed biological blood product, and the risks of its application must be clearly explained with the patient. Safety concerns have increased recently and for some reasons have led to its rapid withdrawal from the European market. This product must be used with caution until the nature of its adverse effects has been fully assessed. A more convenient and potentially more tolerable treatment route, anti-D immunoglobulin intramuscularly or subcutaneously, has been used in restricted, open-label clinical trials of chronic ITP in adults and children, with results showing that most patients showed an increase in platelets within one week without serious reactions. Controlled prospective trials are needed to establish subcutaneous or intramuscular anti-D as the recommended treatment for ITP.
IVIG. Since the introduction of high-dose IVIG more than 20 years ago, there have been many controlled studies with glucocorticoids for ITP, which shorten the time to onset of action compared to the latter. In patients with ITP with CVID, 0.3-0.4 g/kg should be given as maintenance therapy at 3-4 week intervals after the application of high-dose IVIG.
Despite the high toxicity of IVIG, especially headache, and the need for prolonged infusion (at least several hours), patients receiving this treatment are more likely to experience platelet elevation within 24 hours of application of 1 g/kg (1-2 injections over 2 days) compared to previous treatment modalities (0.4 g/kg/d for 5 days). Rare but serious toxic reactions include renal failure and thrombosis. Fear of blood-borne disease persists, but no recent transmission of HIV, HBV, or human T-lymphotropic virus type 1 (HTLV-1) has occurred. In some patients, glucocorticoids may promote the efficacy of IVIG. In addition, concomitant glucocorticosteroids may reduce infusion reactions and avoid aseptic meningitis.
Emergency management
Immediate platelet elevation is required for thrombocytopenic patients requiring emergency surgery, high-risk bleeding, or active central nervous system (CNS), GI, or genitourinary bleeding. In emergency management, a change from glucocorticoids to IVIG or anti-D may be effective and is more appropriate in conjunction with first-line therapy: prednisone + IVIG as the recommended therapy for emergency management of uncontrolled bleeding, and high-dose methylprednisolone (HDMP) is also effective at this time. Other rapid and effective treatments include platelet transfusions, potentially in combination with IVIG, and emergency splenectomy. There is evidence that vincristine analogs also have a rapid onset of action.
General measures These include discontinuation of drugs that reduce platelet function, control of blood pressure, suppression of menstruation, and efforts to minimize trauma (Level IV of evidence). In fact, some patients require oral anticoagulants or antiplatelet agents (e.g., aspirin and/or clopidogrel in patients with cardiac stents), which require elevated platelet thresholds. In patients with reduced renal function, desmopressin is applied to increase hemostasis and maintain hemoglobin at a minimum of 100 g/L.
Platelet transfusion and application with or without IVIG. in 42% of patients with bleeding ITP platelet transfusion can increase the platelet count by more than 20 x
109/L platelets while reducing bleeding. In a retrospective study, 40 patients (Level IIb of evidence) with concomitant platelet transfusion and application of IVIG had reduced bleeding, adequate rapid platelet return, and minimal side effects (Level III/IV of evidence).
Vincristine as a stand-alone agent, vincristine elevates platelets in a small percentage of patients with chronic ITP (Level of Evidence IV). In fact, the combination of vincristine and other drugs is a potentially effective approach in patients requiring urgent treatment (Level IIb).
For emergency splenectomy, see “Splenectomy” in “Second-line treatment: surgery”.
Antifibrinolytic drugs. Antifibrinolytic drugs, such as tranexamic acid and aminocaproic acid, administered orally or intravenously, may stop recurrent bleeding in patients with severe thrombocytopenia. In fact, the effectiveness of such drugs in patients with ITP has not been evaluated in randomized controlled trials. Tranexamic acid (1 g orally 3 times/day) and aminocaproic acid (1-4 g every 4-6 hours, maximum dose 24 g/day) are particularly effective in dentistry and surgery.
Emergency treatment modalities without clear efficacy
Plasmapheresis. Plasmapheresis has been performed in small cohort studies of patients with ITP. Partly in acute ITP. no effect seen in patients with chronic ITP (evidence level III).
Second-line treatment of ITP in adults
Splenectomy and a large number of drugs have been used as second-line treatment for ITP, with widely varying efficacy. Physicians should individualize treatment based on the patient’s bleeding history, co-morbidities, patient expectations, and compliance. An important goal of second-line therapy is to increase the patient’s platelets to the point where they are maintained in the absence of bleeding. The available treatments have completely different mechanisms of action and they can be generally classified into the following categories: a single treatment (or only one course of therapy) in the hope of achieving long-term remission (splenectomy, rituximab), the need for long-term or continuous application (glucocorticoids, immunosuppressants, platelet receptor agonists).
According to clinical applications, splenectomy is usually performed after 6 months. This is due to patient selection, other co-morbidities and the knowledge that some patients experience spontaneous platelet elevation or delayed remission 6-12 months after diagnosis. Some patients even experience spontaneous remission several years after diagnosis.
Second-line treatment: internal medicine approach. Treatments are listed in alphabetical order, indicating that there is no preference for treatment.
Azathioprine Despite the absence of new information, the consensus is that this drug remains effective. The investigators reported a median of 18 months of treatment with azathioprine (150 mg/d) in 53 patients (40 had splenectomy) with a 45% complete response. Although continuous therapy is usually required, the dose was gradually reduced. Rare cases of azathioprine causing leukemia have been seen in the treatment of other diseases, but to date, no leukemia has been reported with azathioprine for ITP (Level of Evidence III).
Cyclosporine A Cyclosporine A (2.5-3 mg/kg/d) is effective as a single agent or in combination with prednisone in the treatment of ITP. However, its side effects are unsuitable for some patients (e.g., elderly with renal insufficiency). Clinical improvement has been observed in more than 80% of patients resistant to first-line drugs, with 42% achieving complete remission (evidence class IIa). Remission was long-term (median time 29 months) after cessation of treatment (Level IIb of evidence). Side effects were generally moderate and transient; these were mainly malaise, renal insufficiency, hypertension and neuropathy.
Cyclophosphamide is applied as cyclophosphamide immunosuppressive therapy, either orally (1-2 mg/kg/d for at least 16 weeks) or intravenously (0.3-1 g/m2
1-3 doses 2-4 weeks apart), which is used mainly in patients who have failed glucocorticoid therapy and/or splenectomy, with response rates ranging from 24%-85% and mild to moderate toxicity. The application of cyclophosphamide for the treatment of patients with ITP and SLE developing acute myeloid leukemia has been reported. Infertility together with treatment of ITP has not received sufficient attention.
Danazol Danazol is a decongestant hormone given orally at 200 mg 2-4 times/day (10-15 mg/kg/d) with a reported response rate of 60-67% (in 57 patients given splenectomy ITP >50 x 109/L over 2 months). Response rates were highest in elderly women and post-splenectomy patients.
Aminophenazone Aminophenazone is a moderately effective preserved glucocorticoid usually given at 75-100 mg/d orally. This drug can delay splenectomy for up to 32 months in patients who have failed to respond to first-line drug glucocorticoid therapy. However, the drug has a low response rate in post-splenectomy patients.
Male patients at risk for glucose-6-phosphate dehydrogenase deficiency were screened prior to application of the drug for treatment and tested for hemolysis and hemoglobinuria during treatment (evidence level III).
The enzyme phenolate lipase phenolate lipase (MMF) is an antiproliferative immunosuppressant that has been shown to be effective in some patients with ITP. MMF therapy requires a gradual increase in dose (250 mg gradually preferably to 1000 mg/d twice/w over 3 weeks) and can result in a 39% increase in platelet count in patients with refractory ITP that is not maintained (Level of Evidence IIb). In a retrospective analysis, the overall response rate was 78% (maximum response at 3 months >
80 x 109/L; median response 30-80 x 109/L).
Several formal publications have reported the use of rituximab in patients with ITP. These are based on previously published consensus. It is considered effective in 60% of patients and complete remission occurs in approximately 40% of patients. Response occurs between 1-2 weeks and 6-8 weeks after dosing, with duration of effectiveness ranging from 2 months to 5 years in some patients, and up to 5 years or more in 15-20% of primary care patients. Most patients can maintain complete remission for more than 1 year. If relapse occurs, response to treatment remains (Evidence IIa-III). A prospective, open-label, single-arm phase 2 clinical trial with 2-year follow-up found that 33% of patients had platelet counts above 50 x 109/L and 40% had counts above 30 x 109/L without other treatment. Although the current study applied a dose of 375 mg/m2, a smaller dose (100 mg IV once a week for 4 weeks) was also considered effective, but a prolonged response time was observed. To date, the standard dose of rituximab for the treatment of ITP remains unclear, and furthermore, due to potential toxicity and high drug prices, future studies will need to clarify the optimal dose. Recent studies have shown high response rates with high-dose dexamethasone combined with rituximab as initial therapy.
Rituximab is not indicated for patients with evidence of active hepatitis B (e.g., B/C core antibody positive). Side effects associated with rituximab are generally mild or moderate, with a low rate of infection. More than 50 cases of progressive multifocal leukoencephalopathy have been reported in patients treated with rituximab for lymphoma, and several cases have recently been reported in the literature in patients treated for SLE and ITP. Therefore, additional long-term safety observations are warranted. Most of the patients in these cases had severe immunosuppression and were given combination therapy.
Romiplostim and eltrombopag are not immunomodulators and their mode of action is to stimulate platelet production. Thrombopoietin (TPO) is an important regulator of platelet production. Several TPO receptor agonists have been developed to activate TPO receptors and increase platelet counts. Both of these drugs have been approved by the FDA for the treatment of ITP. romiplostim is administered at 1-10µg/kg once a week by subcutaneous injection. eltrombopag is an oral non-peptide TPO receptor agonist given at 25, 50 or 75mg daily (Exhibit Ib/IIa).
Application of both of these agents in healthy volunteers and patients with ITP has been shown to rapidly increase platelet counts from phase 1-3 clinical studies. In 2 parallel, double-blind, randomized controlled phase 3 clinical trials in 63 post-splenectomy and 62 non-splenectomy patients administered romiplostim for 6 months, the overall platelet response rates (4 out of 24 study weeks > 50×109/L) were 79% and 88% in the romiplostim group and 0% and 14% in the corresponding control group. Similar findings were seen in patients with chronic refractory or recurrent ITP (114 patients) administered eltrombopag, and at 43 days of the study, platelets above 50×109/L were 59% in the study group compared to 16% in the control group.
In the second romiplostim study, 87% of patients reduced or stopped using concurrent therapy including glucocorticoids and IVIG. Long-term observational data suggest that in patients on continuous treatment, responses can exceed 4 years and most patients can reduce or discontinue concomitantly given glucocorticoid therapy. This is an important finding that will have implications especially for those patients on long-term immunosuppressive therapy. TPO receptor agonists may minimize morbidity and mortality in these patients.
Although most of the side effects are mild, it has been proposed that application of this class of drugs can increase sclerostin in the bone network, appearing in 10 cases in a study of more than 271 applications of romiplostim and 7 cases in 117 applications of eltrombopag. Long-term studies will clarify the significance of this finding and determine the need for routine testing. Although studies applying eltrombopag in rodent ITP models showed no increase in cataracts. Liver function abnormalities were seen in 13% of eltrombopag-treated patients.
Considering the mechanism of action of these drugs, TPO receptor agonists are generally used as maintenance therapy. Once treatment is discontinued, platelets decrease to lower levels in most patients (transient reduction of platelet counts below basal levels in 10%), and a small percentage of patients can successfully discontinue treatment.
Vincristine Vincristine analogs cause transient platelet count elevations lasting 1-3 weeks in 2/3 of patients. Approximately 50% of post-splenectomy patients are effective on vincristine therapy, but cannot be maintained.
Second-line treatment: surgical approach. Splenectomy. 80% of patients with a skin splenectomy are effective, 66% of whom do not require additional therapy, with efficacy lasting at least 5 years. Many patients achieve less than complete remission, but also achieve the expected partial or transient response. Approximately 14% of patients are not effective with this treatment. Approximately 20% of those who respond relapse after weeks, months, or years (evidence level IIb).
Complications of splenectomy Complications of splenectomy include bleeding, infection, thrombosis, prolonged hospitalization, readmission, and the application of other interventions. Complication rates are reported to vary considerably, while complications are more likely to occur in patients older than 65 years of age. A recent systematic analysis showed complication rates of 12.9% and 9.6% for splenectomy by caesarean section and 1.0% and 0.2% for mortality by laparoscopic surgery, respectively. Because of the risk of thromboembolism in both ITP and splenectomy, patients with ITP should be treated with appropriate thromboprophylaxis after surgery.
Prediction of the efficacy of splenectomy treatment There is no widely accepted way to predict the efficacy of splenectomy. The efficacy of oral glucocorticoids or high-dose IVIG has only low predictive value (Level IIb of evidence). Indium-labeled autologous platelet scans may be the most sensitive predictive method, but the findings are too different. When the scan revealed splenic platelet destruction, approximately 90% of patients were effective for splenectomy. This test is currently performed in only a few study centers, but may be meaningful if applied prior to splenectomy (Level of Evidence III).
Parasplenium (Evidence Level III/IV) Imaging reveals the presence of a parasplenium in up to 12% of patients undergoing splenectomy, and almost all parasplenium is removed at surgery. The presence or absence of a parasplenium should be considered in patients presenting with recurrence who were initially effective for splenectomy. In fact, it is very rare for splenectomy to be effective in patients who have not been treated with splenectomy.
Prevention of infection after splenectomy. Patients after splenectomy are at lifetime risk of developing pneumococcal, diplococcal meningitis, and Haemophilus influenzae infections that are not easily controlled and have a poor prognosis. According to nationalized recommendations (level of evidence IV), patients should be given prophylactic multivalent pneumococcal, meningococcal C conjugate, and H influenzae b (Hib) vaccines starting at least 4 weeks prior to surgery (preferably) or revaccination starting 2 weeks after surgery. Vaccination may not be effective in patients who have had rituximab within the past 6 months. These patients should be revaccinated after recovery of B-cell function.
In some studies, spleen-free patients were given long-term prophylactic antibiotics (penicillin V250-500 mg bid or equivalent; erythromycin 500 mg
bid). In practice, there is no proven benefit of lifelong prophylactic antibiotics and the risk of developing late infections is low. Therefore there is no consensus on this point. A practical approach is to have antibiotics (penicillin V potassium, erythromycin, levofloxacin) available at home for fever in post-splenectomy patients. Patients should be taught about post-splenectomy infections, including the importance of having a body temperature above 101°F
(38°C) should be brought to the hospital for emergency care. In addition, a medical card should be carried at all times to alert the physician that the patient is a spleen-free patient. Some patients may wish to wear a warning bracelet or accessory (evidence level IV).
Treatment of first- and second-line treatment-naïve ITP in adults
Approximately 20% of patients who fail first- and second-line therapy fail to achieve a platelet count that can be stopped after first- and second-line therapy or splenectomy. In addition, 10-20% of patients who are effective for splenectomy eventually relapse (Level IV evidence). These patients may tolerate severe thrombocytopenia (e.g., thrombocytopenia to 10×109/L) and have a quality of life (QoL) that is relatively similar to normal. In fact, some patients have consistent and statistically significant deficits in QoL tests, bleeding, and increased risk of death. Patients for whom these standard treatments are ineffective but require continued treatment are less selective. In such cases, further treatment must be discussed with the patient and the benefits of treatment compared. In addition, other potential causes of thrombocytopenia need to be exhaustively ruled out. In some patients, low platelet counts are chosen as a substitute for further toxic therapy.
Combination chemotherapy may be effective in chronic refractory ITP. Application of cyclophosphamide (100-200 mg/d IV) d1-5 or 7 days, prednisone (0.5-1.0 mg/kg/dpo) d1-5 or 7 days and vincristine (1-2 mg IV) d1 with one of the following, azathioprine (100 mg /d po) d1-5 or 7 days, etoposide (50 mgdpo) d1-7 The study has been concluded and in treating 31 patients, with an overall with efficiency of 68%, including 42% complete remission. The treatment was well tolerated (evidence level IIb). The duration of treatment remission and the risk of secondary tumors are subject to long-term follow-up.
Campath-1HCampath-1H may be used as a form of selective treatment for severe refractory ITP. The drug has the potential to cause severe and potentially life-threatening immunosuppression in patients and therefore requires long-term antifungal, antibacterial and antiviral prophylaxis.
Hematopoietic stem cell transplantation with autologous or allogeneic hematopoietic stem cells (HSCT) in some patients with chronic refractory ITP can lead to disease remission (Evidence Level IIb/III). Potentially fatal toxic effects such as neutrophil deficiency fever, intracranial hemorrhage, and sepsis may occur, and HSCT has only been used in patients with severe chronic refractory ITP with bleeding complications for whom other treatment modalities have failed. Few reports of long-term efficacy have emerged.
3.5.1.4 TPO receptor agonists: romiplostim and eltrombopag. the efficacy of TPO receptor agonists in patients after splenectomy has been studied with an overall efficacy close to 79% (level of evidence Ib). TPO receptor agonists are costly and thrombocytopenia returns to pre-treatment levels at the end of treatment. In fact, only RCTs with refractory ITP applying platelet receptor agonists have been shown to be effective. Given the apparently low toxicity and the very good tolerability of these treatments, many patients opt for long-term application. To date, romiplostim has been applied consistently for 4 years with no diminution in efficacy and no cumulative toxicity.
Empiric treatment in ITP applying the following therapies has been reviewed as empiric treatment due to evidence confirming lack of efficacy or excessive toxicity. These treatments include colchicine, interferon-, protein A immunosorbent columns, plasma removal as a method of isolation, vitamin C, and recombinant factor VIIa.
Supportive therapy
Antifibrinolytic therapy See “Emergency treatment” (Evidence Level IV).
Menstrual suppression. Progesterone-containing IUDs and oral contraceptives can reduce the frequency and volume of menstrual bleeding. (Evidence Level IIb).
Other methods Patient organizations (e.g., ITP Help Society, Platelet Disorders Help Society, ITP Foundation) provide psychological assistance to patients by distributing information about their condition, available treatments, and how to go about their daily lives.