Immune Thrombocytopenia (ITP) 

Updated: Jan 11, 2020
Author: Craig M Kessler, MD, MACP; Chief Editor: Srikanth Nagalla, MBBS, MS, FACP 

Overview

Practice Essentials

Immune thrombocytopenia (ITP) is a syndrome in which platelets become coated with autoantibodies to platelet membrane antigens, resulting in splenic sequestration and phagocytosis by mononuclear macrophages. The resulting shortened life span of platelets in the circulation, together with incomplete compensation by increased platelet production by bone marrow megakaryocytes, results in a decreased number of circulating platelets (thrombocytopenia; see the image below). 

Peripheral blood smear from a patient with immune Peripheral blood smear from a patient with immune thrombocytopenia (ITP) shows a decreased number of platelets, a normal-appearing neutrophil, and normal-appearing erythrocytes. ITP is diagnosed by excluding other diseases; therefore, the absence of other findings from the peripheral smear is at least as important as the observed findings. This smear demonstrates the absence of immature leukocytes (as in leukemia) and fragmented erythrocytes (as in thrombotic thrombocytopenic purpura) and no clumps of platelets (as in pseudothrombocytopenia).

Signs and Symptoms

ITP manifests as a bleeding tendency, easy bruising (purpura), or extravasation of blood from capillaries into skin and mucous membranes (petechiae). Although most cases of acute ITP, particularly in children, are mild and self-limited, intracranial hemorrhage may occur when the platelet count drops below 10 × 109/L (< 10 × 103/µL);[1]  this occurs in 0.5-1% of children, and half of these cases are fatal.[2]

ITP is a primary illness occurring in an otherwise healthy person. Signs of chronic disease, infection, wasting, or poor nutrition indicate that the patient has another illness. Splenomegaly excludes the diagnosis of ITP.

An initial impression of the severity of ITP is formed by examining the skin and mucous membranes, as follows:

  • Widespread petechiae and ecchymoses, oozing from a venipuncture site, gingival bleeding, and hemorrhagic bullae indicate that the patient is at risk for a serious bleeding complication.

  • If the patient's blood pressure was taken recently, petechiae may be observed under and distal to the area where the cuff was placed and inflated.

  • Suction-type electrocardiograph (ECG) leads may induce petechiae.

  • Petechiae over the ankles in ambulatory patients or on the back in bedridden ones suggest mild thrombocytopenia and a relatively low risk for a serious bleeding complication.

Findings suggestive of intracranial hemorrhage include the following:

  • Headache, blurred vision, somnolence, or loss of consciousness

  • Hypertension and bradycardia, which may be signs of increased intracranial pressure

  • On neurologic examination, any asymmetrical finding of recent onset

  • On fundoscopic examination, blurring of the optic disc margins or retinal hemorrhage

See Presentation for more detail.

Diagnosis

On complete blood cell count, isolated thrombocytopenia is the hallmark of ITP. Anemia and/or neutropenia may indicate other diseases. Findings on peripheral blood smear are as follows:

  • The morphology of red blood cells (RBCs) and leukocytes is normal

  • The morphology of platelets is typically normal, with varying numbers of large platelets

  • If most of the platelets are large, approximating the diameter of red blood cells, or if they lack granules or have an abnormal color, consider an inherited platelet disorder

Many children with acute ITP have an increased number of normal or atypical lymphocytes on the peripheral smear, reflecting a recent viral illness. Clumps of platelets on a peripheral smear prepared from ethylenediaminetetraacetic acid (EDTA)–anticoagulated blood are evidence of pseudothrombocytopenia.[3] This diagnosis is established if the platelet count is normal when repeated on a sample from heparin-anticoagulated or citrate-anticoagulated blood.

No single laboratory result or clinical finding establishes a diagnosis of ITP; it is a diagnosis of exclusion. The differential diagnosis includes such other causes of thrombocytopenia as leukemia, myelophthisic marrow infiltration, myelodysplasia, aplastic anemia, and adverse drug reactions. Pseudothrombocytopenia due to platelet clumping is also a diagnostic consideration.

Aspects of bone marrow aspiration and biopsy are as follows:

  • The value of bone marrow evaluation for a diagnosis of ITP is unresolved[4]

  • Biopsy in patients with ITP shows a normal-to-increased number of megakaryocytes in the absence of other significant abnormalities

  • In children, bone marrow examination is not required except in patients with atypical hematologic findings, such as immature cells on the peripheral smear or persistent neutropenia.[5]

  • In adults older than 60 years, biopsy is used to exclude myelodysplastic syndrome or leukemia

  • In adults whose treatment includes corticosteroids, a baseline pretreatment biopsy may prove useful for future reference, as corticosteroids can change marrow morphology

  • Biopsy is performed before splenectomy to evaluate for possible hypoplasia or fibrosis

  • Unresponsiveness to standard treatment after 6 months is an indication for bone marrow aspiration

See Workup for more detail.

Management

ITP has no cure, and relapses may occur years after seemingly successful medical or surgical management.[6] Most children with acute ITP do not require treatment, and the condition resolves spontaneously.[7, 8]

Treatment is as follows:

  • Corticosteroids remain the drugs of choice for the initial management of acute ITP

  • Oral prednisone, IV methylprednisolone, or high-dose dexamethasone may be used[9, 10, 11]

  • IV immunoglobulin (IVIG) has been the drug of second choice for many years[12, 13]

  • For Rh(D)-positive patients with intact spleens, IV Rho immunoglobulin (RhIG) offers comparable efficacy, less toxicity, greater ease of administration, and a lower cost than IVIG[14, 15]

  • RhIG can induce immune hemolysis (immune hemolytic anemia) in Rh(D)-positive persons and should not be used when the hemoglobin concentration is less than 8 g/dL

  • Sporadic cases of massive intravascular hemolysis,[16] disseminated intravascular coagulation (particularly in elderly individuals), and renal failure[17] have been reported with RhIG

  • Rituximab is third-line therapy

  • Platelet transfusions may be required to control clinically significant bleeding but are not recommended for prophylaxis

  • If 6 months of medical management fails to increase the platelet count to a safe range (about 30,000/µL), splenectomy becomes an option

  • Thrombopoietin receptor agonists (ie, eltrombopag, romiplostim) may maintain platelet counts at safe levels in adults with chronic ITP refractory to conventional medical management or splenectomy

Pregnant women require special consideration for delivery, as follows[18] :

  • If the platelet count is greater than 50 × 109/L (>50 × 103/µL), the risk of serious hemorrhage is low, but beginning oral prednisone a week before delivery is a reasonable precaution

  • If the platelet count is less than 50 × 109/L (50 × 103/µL) before delivery, treatment with oral prednisone and IVIG is recommended

  • Avoiding the use of IV RhIG in this situation until safety data are available is advisable

  • Rarely, splenectomy may be required to manage acute hemorrhage[19]

See Treatment and Medication for more detail.

For discussion of ITP in pregnancy, see Immune Thrombocytopenia and Pregnancy. For patient education information, see the Thrombocytopenia Directory

Background

Immune thrombocytopenia (ITP) was previously known as idiopathic thrombocytopenic purpura. The term "idiopathic" no longer applies, because the etiology is known: ITP is caused by a dysregulation of the immune system. The term "purpura" has been abandoned because it is misleading: almost one-third of patients with newly diagnosed ITP have no bleeding, despite their low platelet counts.[20]

Pathophysiology

In immune thrombocytopenia (ITP), an abnormal autoantibody, usually immunoglobulin G (IgG) with specificity for one or more platelet membrane glycoproteins, binds to circulating platelet membranes.[21, 22, 23]

Autoantibody-coated platelets induce Fc receptor-mediated phagocytosis by mononuclear macrophages, primarily but not exclusively in the spleen.[24] The spleen is the key organ in the pathophysiology of ITP, not only because platelet autoantibodies are formed in the white pulp, but also because mononuclear macrophages in the red pulp destroy immunoglobulin-coated platelets.[25]

If bone marrow megakaryocytes cannot increase production and maintain a normal number of circulating platelets, thrombocytopenia and purpura develop. Impaired thrombopoiesis is attributed to failure of a compensatory increase in thrombopoietin and megakaryocyte apoptosis.

Etiology

In children, most cases of immune thrombocytopenia (ITP) are acute, manifesting a few weeks after a viral illness. In adults, most cases of ITP are chronic, manifesting with an insidious onset, and occur in middle-aged women. These clinical presentations suggest that the triggering events may be different. However, in both children and adults, the cause of thrombocytopenia (destruction of antibody-coated platelets by mononuclear macrophages) appears to be similar.

Autoantibody stimulation

In chronic ITP, for unknown reasons, membrane glycoproteins (GPs) on the surface of platelets become immunogenic, stimulating the production of platelet autoantibodies. In acute ITP, the stimulus for autoantibody production is also unknown; platelet membrane cryptantigens may become exposed by the stress of infection, or pseudoantigens may be formed by the passive adsorption of pathogens on platelet surfaces

Autoantibody specificity

In persons with chronic ITP, approximately 75% of autoantibodies are directed against platelet GPIIb/IIIa or GPIb/IX GP complexes. Presumably, the remaining 25% are directed against other membrane epitopes, including GPV, GPIa/IIa, or GPIV

Role of the spleen

The spleen is the site of autoantibody production (white pulp); it is also the site of phagocytosis of autoantibody-coated platelets (red pulp). The slow passage of platelets through splenic sinusoids with a high local concentration of antibodies and Fc-gamma receptors on splenic macrophages lend to the uniqueness of the spleen as a site of platelet destruction. Low-affinity macrophage receptors, Fc gamma RIIA, and Fc gamma RIIIA bind immune-complexed IgG and are the key mediators of platelet clearance.

Platelet destruction

The mononuclear macrophage system of the spleen is responsible for removing platelets in ITP, as demonstrated by the fact that splenectomy results in prompt restoration of normal platelet counts in most patients with ITP. Platelets are sequestered and destroyed by mononuclear macrophages, which are neither reticular nor endothelial in origin. Therefore, the former designation of reticuloendothelial system is considered imprecise. Immune destruction of immunoglobulin-coated platelets is mediated by macrophage IgG Fc (Fc gamma RI, Fc gamma RII, and Fc gamma RIII) and complement receptors (CR1, CR3).

Epidemiology

United States

The annual incidence of immune thrombocytopenia (ITP) is estimated to be five cases per 100,000 children and two cases per 100,000 adults,[2] but those data are not from large population-based studies. Most cases of acute ITP, particularly in children, are mild and self-limited and may not receive medical attention. Therefore, estimated incidences of ITP are difficult to determine and are likely to understate the full extent of the disease. The age-adjusted prevalence of ITP in Maryland was reported as 9.5 per 100,000 persons by Segal and Powe.[26]

International

A French study reported an incidence of ITP of 2.9 cases per 100,000 person-years, with peaks in children and in those older than 60 years of age and a higher frequency of ITP in males in these subgroups. ITP showed seasonal variation, with a peak in winter and a nadir in summer. Persistence or chronicity occurred in 36% of children compared with 67% of adults. In adults, 18% of ITP cases were secondary, with malignancy the main cause.[27]

Mortality and morbidity

The primary cause of long-term morbidity and mortality in patients with immune thrombocytopenia (ITP) is hemorrhage.[28] Spontaneous or accidental trauma–induced intracranial hemorrhage is the most frequent cause of death in association with ITP. Most cases of intracranial hemorrhage occur in patients whose platelet counts are less than 10 × 109/L (< 10 × 103/µL).[1] This situation occurs in 0.5-1% of cases in children, and half of those are fatal.[2] In one study, 17% of children experienced a major hemorrhage.[29] The estimated frequency of intracranial hemorrhage in adults with ITP is 1.5%.[30]

Treatment-related morbidity may result from the need to maintain the platelet count in a safe range in patients with chronic treatment-resistant ITP. These patients may require a long-term course of corticosteroids, other immunosuppressive medications, or splenectomy, and thus may experience the complications of therapy with corticosteroids or splenectomy.

Sex- and Age-related Demographics

In children, ITP is more common in boys than in girls.[31] In middle-aged adults, women are affected more frequently than men.[2]

Children may develop ITP at any age, but the incidence peaks in children aged 1-6 years.[31] Adults may be affected at any age, but most cases are diagnosed in women aged 30-40 years.

Onset in a patient older than 60 years is uncommon, and a search for other causes of thrombocytopenia is warranted. The most likely causes in these persons are myelodysplastic syndromes, acute leukemia, and marrow infiltration (myelophthisis). Persons with ITP who are 70 years or older are at increased risk for spontaneous bleeding and treatment-related adverse events.[32]

Prognosis

Prognosis varies in children and adults.

Children

More than 80% of children with untreated immune thrombocytopenia (ITP) have a spontaneous recovery with completely normal platelet counts in 2-8 weeks. Fatal bleeding occurs in 0.9% upon initial presentation.

A systematic review and meta-analysis identified the following factors associated with higher risk of ITP in children becoming chronic[33] :

  • Female gender (odds ratio [OR] 1.17)
  • Age ≥11 years at presentation (OR 2.47)
  • No preceding infection or vaccination (OR 3.08)
  • Insidious onset (OR 11.27)
  • Platelet count ≥20 × 10 9/L at presentation (OR 2.15)
  • Presence of antinuclear antibodies (OR 2.87)
  • Treatment with methylprednisolone plus intravenous immunoglobulin (OR 2.67)

Factors associated with lower likelihood of developing chronic ITP were as follows:

  • Mucosal bleeding at diagnosis (OR 0.39)
  • Treatment with intravenous immunoglobulin alone (OR 0.71)

Adults

Approximately 60-90% of adults with ITP respond with an increased platelet count after treatment with prednisone or prednisone and IV RhIG or IVIG. Of those adults who do not maintain an increased platelet count and who require splenectomy, approximately two thirds have a sustained response and 10-15% have a partial response.[1, 34]

 

Presentation

History

The medical history in a patient with a clinical suspicion of immune thrombocytopenia (ITP) should focus on the following:

  • Factors that suggest another disease for which thrombocytopenia is a complication
  • Signs and symptoms that differentiate mild, moderate, and severe bleeding tendencies

Other systemic illnesses

Considerations include the following:

  • In adults, thrombocytopenia may be a manifestation of systemic lupus erythematosus [35] or acute or chronic leukemia
  • Thrombocytopenia may be a manifestation of a myelodysplastic syndrome, particularly in patients older than 60 years
  • In young children, ITP may manifest as a primary immune deficiency syndrome

Postviral illness

In children, most cases of ITP are acute, and onset seems to occur within a few weeks of recovery from a viral illness. The severity of symptoms of the viral illness does not correlate with the degree of thrombocytopenia.

Thrombocytopenia is a recognized complication after infection with Epstein-Barr virus, varicella virus, cytomegalovirus, rubella virus, or hepatitis virus (A, B, or C). However, the most typical association is with a vaguely defined viral upper respiratory infection or gastroenteritis.

Transient thrombocytopenia has been reported to be associated with recent immunization with attenuated live-virus vaccines.[36, 37]

Human immunodeficiency virus (HIV) infection

In persons infected with HIV, thrombocytopenia may occur during the acute retroviral syndrome coincident with fever, rash, and sore throat. However, thrombocytopenia may also be a manifestation of acquired immunodeficiency syndrome (AIDS), occurring late in the course of HIV infection. HIV-related thrombocytopenia is particularly likely to occur in people who abuse drugs

Drug-induced thrombocytopenia

Regard any medication taken by a person who develops thrombocytopenia as a potential causative agent. A history of all prescription and over-the-counter medications is required to exclude drug-related thrombocytopenia.[38]

More than 1444 currently approved drugs are listed in the US Food and Drug Administration's Adverse Event Reporting System (AERS) database, all of which have been suspected of causing clinical episodes of thrombocytopenia. However, only 573 of these agents have a statistically significant reporting association with thrombocytopenia and of these, perhaps only two dozen satisfy clinical and laboratory criteria for evidence of causality for drug-induced thrombocytopenia. Reese et al have published a useful online database of the drugs most likely to cause thrombocytopenia.[39]

For a diagnosis of drug-induced thrombocytopenia to be made with confidence, all of the following criteria must be met:

  • The development of the low platelet count should exhibit a strict temporal relationship with the initiation of the medication
  • The platelet count should recover when the offending medication is discontinued
  • The likelihood of drug-induced thrombocytopenia should be greater than any other plausible cause
  • Ideally, in vitro evidence of drug-dependent antibody formation should exist

Persons who have been sensitized (by previous exposure) to quinidine or quinine may develop immune-mediated drug purpura within hours to days of subsequent exposure. To exclude drug purpura in a person previously treated with quinidine or quinine, the history must include questions about possible exposure to over-the-counter medications, tonic water in cocktails, or bitter lemon beverages.

In patients who have been hospitalized and who develop acute thrombocytopenias, investigate the records for all of their medications that are listed and not listed in nursing charts. For example, patients who are at risk for heparin-induced thrombocytopenia because of current or recent treatment with heparin may be receiving heparin with the routine flushing of intravenous (IV) catheters, and this exposure may not be listed on the nursing medication sheet. Many catheters are also heparin impregnated, and unless checked, they can be a hidden cause of heparin-induced thrombocytopenia.

Antiplatelet drugs that are glycoprotein IIb/IIIa (GPIIb/IIIa) Inhibitors may result in ITP.  These include eptifibatide (Integrilin), and abciximab (ReoPro), which is a Fab fragment of the chimeric human-murine monoclonal antibody 7E3 directed against the platelet GPIIb/IIIa receptor.

Other drugs associated with drug purpura include the following:

  • Antibiotics (eg, cephalosporins, rifampicin)
  • Gold salts
  • Analgesics
  • Neuroleptics
  • Diuretics
  • Antihypertensives

Acute and chronic alcohol consumption may also be associated with thrombocytopenia. In persons with chronic liver disease, hypersplenism with secondary thrombocytopenia is not uncommon.

Bleeding tendency

Determine the extent and duration of the bleeding tendency to estimate the severity of the illness and the potential risk for a serious hemorrhage. Previous surgical history can often provide a useful clue regarding the acuteness of thrombocytopenia.

Query patients to elicit signs or symptoms of intracranial bleeding, such as headache, blurred vision, somnolence, or loss of consciousness.

Ask about any recent accidental head trauma.

Record any bleeding, including petechiae, ecchymoses, epistaxis, menorrhagia, melena, or hematuria. Determine whether bruising or bleeding is a recurrent problem.

 

Physical Examination

Like the medical history, the physical examination should focus on the following:

  • Findings that suggest another disease for which thrombocytopenia is a complication
  • Physical signs that suggest serious internal bleeding

General health

Immune thrombocytopenia (ITP) is a primary illness occurring in an otherwise healthy person. Signs of chronic disease, infection, wasting, or poor nutrition indicate that the patient has another illness

Vital signs: Hypertension and bradycardia may be signs of increased intracranial pressure and evidence of an undiagnosed intracranial hemorrhage.

Skin and mucous membranes

An initial impression of the severity of ITP is formed by examining the skin and mucous membranes. Widespread petechiae and ecchymoses, oozing from a venipuncture site, gingival bleeding, and hemorrhagic bullae indicate that the patient is at risk for a serious bleeding complication. If the patient's blood pressure was taken recently, petechiae may be observed under and distal to the area where the cuff was placed and inflated. Suction-type electrocardiograph (ECG) leads may similarly induce petechiae.

Mild thrombocytopenia and a relatively low risk for a serious bleeding complication may manifest as petechiae over the ankles in patients who are ambulatory or on the back in patients who are bedridden.

Other organ systems

On cardiovascular examination, distant low-amplitude heart sounds accompanied by jugular venous distention may be evidence of hemopericardium.

On abdominal examination, in children with acute ITP the presence of a readily palpable spleen is not typical. In an adult, hepatosplenomegaly is also atypical for ITP and may indicate chronic liver and other diseases; in fact, splenomegaly excludes the diagnosis of ITP.

Nervous system

  • Any asymmetrical finding of recent onset can indicate an intracranial hemorrhage

  • Pupils should be equal in size and patients should have intact extraocular muscles and symmetrical eye movements

  • Balance and gait should be intact

  • Funduscopic examination reveals whether the margins of the optic disc are blurred; examine the patient for the presence of retinal hemorrhages and other evidence of increased intracranial pressure

 

DDx

Diagnostic Considerations

Common differential diagnoses of immune thrombocytopenia purpura (ITP) and possible alternative causes of thrombocytopenia identified by patient history include the following[40] :

  • Previously diagnosed or possible high risk for conditions that may be associated with ITP (eg, infections such as from HIV, hepatitis C virus, hepatitis B virus), autoimmune/immunodeficiency disorders (common variable immunodeficiency, systemic lupus erythematosus, or antiphospholipid syndrome), and malignancy (eg, lymphoproliferative disorders)
  • Liver disease (including cirrhosis or portal hypertension)
  • Splenomegaly
  • Drugs (prescription or nonprescription), including heparin, alemtuzumab, programmed death–1 inhibitors, abciximab, valproate, alcohol abuse, consumption of quinine (tonic water), exposure to environmental toxins, or chemotherapy
  • Bone marrow diseases, including myelodysplastic syndromes, leukemias, other malignancies, metastatic disease, myelofibrosis, aplastic anemia, megaloblastic anemia, myelophthisis, and Gaucher disease
  • Recent transfusions (rare possibility of posttransfusion purpura) and recent vaccinations
  • Inherited thrombocytopenia - Thrombocytopenia–absent radius syndrome, radioulnar synostosis, congenital amegakaryocytic thrombocytopenia, Wiskott-Aldrich syndrome, MYH9-related disease, Bernard-Soulier syndrome, type IIB von Willebrand disease (vWD), or platelet-type VWD
  • Other thrombocytopenic disorders (eg, disseminated intravascular coagulation, thrombotic thrombocytopenic purpura, hemolytic-uremic syndrome, Evans syndrome)

Differential Diagnoses

 

Workup

Laboratory Studies

The workup for immune thrombocytopenia (ITP) starts with a complete blood cell (CBC) count. The hallmark of ITP is isolated thrombocytopenia; anemia and/or neutropenia may indicate other diseases

On peripheral blood smear, the morphology of red blood cells (RBCs) and leukocytes is normal. The morphology of platelets is typically normal, with varying numbers of large platelets. Some persons with acute ITP may have megathrombocytes or stress platelets, reflecting the early release of megakaryocytic fragments into the circulation. If most of the platelets are large, approximating the diameter of RBCs, or if they lack granules or have an abnormal color, consider an inherited platelet disorder.

Clumps of platelets on a peripheral smear prepared from ethylenediaminetetraacetic acid (EDTA)–anticoagulated blood are evidence of pseudothrombocytopenia.[3] The diagnosis of this type of pseudothrombocytopenia is established if the platelet count is normal when repeated on a sample from heparin-anticoagulated or citrate-anticoagulated blood.

In patients who have risk factors for HIV infection, a blood sample should be tested with an enzyme immunoassay for anti-HIV antibodies.[41] During the acute HIV retroviral syndrome, the results of the anti-HIV assay may be negative. In this situation, a polymerase chain reaction for HIV DNA is more reliable than the anti-HIV assay.

In selected women, the medical history may suggest a chronic, recurrent, multisystemic illness with vague, generalized signs or symptoms, such as recurrent, multiple, painful, tender, or swollen joints. In such cases, a negative antinuclear antibody (ANA) result is useful in diagnosing ITP if the patient's thrombocytopenia becomes chronic and resistant to treatment.

If anemia and thrombocytopenia are present, a positive direct antiglobulin (Coombs) test result may help establish a diagnosis of Evans syndrome.

In children with ITP who have already received their first dose of measles-mumps-rubella (MMR) vaccine, the American Society of Hematology recommends measuring vaccine titers. If the titers indicate full immunity (as is the case in up to 95% of children), then no further MMR vaccine should be given. If the titers indicate inadequate immunity, the child should receive further immunization with MMR vaccine at the recommended age.[42]

Assays for platelet antigen–specific antibodies, platelet-associated immunoglobulin, or other antiplatelet antibodies are available in some medical centers and certain mail-in reference laboratories. The reliability of the results of a platelet antibody test is highly specific to the laboratory used. A negative antiplatelet antibody assay result does not exclude the diagnosis of ITP.[43] The authors do not recommend this test as part of the routine evaluation. Testing for antiplatelet antibodies is not required to diagnose ITP.

Studies from Italy,[44, 45] Japan,[46, 47] and Korea[48] indicate that many persons with ITP have Helicobacter pylori gastric infections and that eradication of H pylori results in increased platelet counts. In the United States and Spain, however, the prevalence of H pylori infections does not appear to be increased in persons with ITP, and eradication of H pylori has not increased platelet counts.[49, 50] Therefore, routine testing for H pylori infections in adults and children with ITP is not recommended.

Results of a study from Taiwan suggest that ITP may be an early hematologic manifestation of HIV infection. Lai et al reported that patients with ITP were 6.47-fold more likely to have HIV infection than those without ITP, and recommended considering the possibility of undiagnosed HIV infection in patients presenting with ITP.[51]

Imaging Studies

Computed tomography (CT) scanning and magnetic resonance imaging (MRI) are relatively benign and useful noninvasive imaging studies that can be used to rule out other causes of thrombocytopenia. However, they are not part of the routine evaluation of patients who may have immune thrombocytopenia (ITP). However, prompt CT scanning or MRI is indicated when the medical history or physical findings suggest serious internal bleeding.

Histologic Findings

Bone marrow aspirate

The cellularity of the aspirate and the morphology of erythroid and myeloid precursors should be normal. The number of megakaryocytes may be increased. Because the peripheral destruction of platelets is increased, megakaryocytes may be large and immature, although in many cases the megakaryocyte morphology is normal. Older patients require a careful examination of megakaryocyte morphology to exclude an early myelodysplastic syndrome.

Bone marrow biopsy

Sections of a needle biopsy specimen or marrow clot should reveal normal marrow cellularity, without evidence of hypoplasia or increased fibrosis.

Splenic evaluation

The spleen reveals no specific findings. In adults, the microscopic finding of extramedullary hematopoiesis is atypical and indicates myeloid metaplasia. Spleens removed from patients with immune thrombocytopenia (ITP) should be carefully examined for a primary splenic lymphoma or granuloma or other signs of an undiagnosed infectious disease.

Bone Marrow Examination

Bone marrow aspiration and biopsy in patients with immune thrombocytopenia (ITP) demonstrates a normal-to-increased number of megakaryocytes in the absence of other significant abnormalities. The value of bone marrow evaluation for a diagnosis of ITP is unresolved, and more data are needed to establish clear guidelines.[4]

Recommendations for adult patients are as follows:

  • In adults who are thrombocytopenic and older than 60 years, examine the bone marrow to exclude myelodysplastic syndrome or leukemia.

  • In adults whose treatment includes corticosteroids, baseline pretreatment bone marrow aspiration may be useful for future reference. Many adults have treatment-resistant chronic ITP evident after 3-6 months of treatment, and an alternative diagnosis may be pursued vigorously at that time. Marrow aspirate obtained before any steroid-induced changes may have occurred can be useful.

  • Perform bone marrow aspiration and biopsy to evaluate for possible hypoplasia or fibrosis before splenectomy is performed.

American Society of Hematology guidelines advise that bone marrow examination is not necessary in children and adolescents with the typical features of ITP, or in children in whom intravenous immunoglobulin therapy fails. The guidelines suggest that bone marrow examination is also not necessary in similar patients before initiation of treatment with corticosteroids or before splenectomy.[42]

Bone marrow examination is indicated in children with atypical hematologic findings, such as immature cells on the peripheral smear or persistent neutropenia.[5] Many children with acute ITP have an increased number of normal or atypical lymphocytes on the peripheral smear, reflecting a recent viral illness. Unresponsiveness to standard treatment after 6 months is an indication for bone marrow aspiration.

 

Treatment

Medical Care

The goal of medical care for immune thrombocytopenia (ITP) is to increase the platelet count to a safe level, permitting patients to live normal lives while awaiting spontaneous or treatment-induced remission. ITP has no cure, and relapses may occur years after seemingly successful medical or surgical management.[6]

Although the paradigm may be shifting somewhat with the expanding experience with thrombopoietin receptor analogs in chronic ITP, the long-term consequences associated with their use remain to be established and the delayed platelet count responses these agents produce are not conducive to preventing or reversing the potential of acute bleeding complications in newly diagnosed ITP. Therefore, for the present, corticosteroids (ie, oral prednisone, intravenous [IV] methylprednisolone, or high-dose dexamethasone)[9, 10, 11] should remain the drugs of choice for the initial management of acute ITP. Treatment with corticosteroids may not only reduce the rate of platelet destruction but may also rapidly alter endothelial cell integrity to facilitate primary hemostasis and to reduce bleeding and bruising.

Because corticosteroid administration may change marrow morphology, performance of a bone marrow aspiration and biopsy should be considered to confirm the diagnosis of ITP if the clinical presentation, patient age, or other findings are atypical for acute ITP before the patient is treated with corticosteroids.

IV immunoglobulin (IVIG) has been the drug of second choice (after corticosteroids) for many years.[12, 13] However, for Rh(D)-positive patients with ITP and intact spleens, IV Rho immunoglobulin (RhIG) offers comparable efficacy, less toxicity, greater ease of administration, and a lower cost than IVIG.[14, 15]

The limitation of using IV RhIG is the lack of efficacy in Rh(D)-negative or splenectomized patients. Also, IV RhIG may induce immune hemolysis (immune hemolytic anemia) in Rh(D)-positive persons, which is the most common adverse effect, and should not be used when the hemoglobin concentration is less than 8 g/dL. Sporadic cases of massive intravascular hemolysis[16] disseminated intravascular coagulation (particularly in elderly individuals), and renal failure[17] have been reported.

Treatment in children

Most children with acute ITP do not require treatment, and thrombocytopenia resolves spontaneously.[7] The American Society of Hematology (ASH) recommends that children who have no bleeding or minor bleeding (eg, cutaneous manifestations such as bruising and petechiae) be managed with observation alone regardless of platelet count.[8] A retrospective review by Schultz et al found that this approach did not lead to an increase in later treatment or an increase in delayed bleeding.[52]

For pediatric patients requiring treatment, ASH suggests a short course of corticosteroids for first-line treatment rather than IVIG or anti-D immunoglobulin.[8]

The ASH guidelines acknowlege the risk of hemolysis with IV RhoD immune globulin (RhIG, anti-D immune) and the black box warning related to fatal intravascular hemolysis, but notes these are rare events.[8]  An advantage of IV RhIG is that if bone marrow aspiration is unacceptable to parents and if the diagnosis of acute ITP is equivocal, IV RhIG is an effective treatment that avoids the problem of a misdiagnosis of acute leukemia because of steroid-related changes in the marrow.

For children or adolescents with ITP who have significant ongoing bleeding despite treatment with IVIG, RhIG, or conventional doses of corticosteroids, the ASH suggests a thrombopoietin receptor agonist (TPO-RA) rather than rituximab or splenectomy as second-line treatment. Rituximab may also be considered as an alternative to splenectomy.[8]

Treatment in adults

In adults, treatment is recommended for a platelet count < 30×109/L. The ASH recommends that if treatment is needed, shorter courses of corticosteroids (≤6 weeks) are preferred over prolonged courses (> 6 weeks including treatment and taper) as first-line treatment. The guidelines suggest either prednisone (0.5-2.0 mg/kg per day) or dexamethasone (40 mg per day for 4 days) as the type of corticosteroid for initial therapy. [8]

In adults with ITP lasting ≥3 months who are corticosteroid-dependent or have no response to corticosteroids, the ASH guidelines suggest either splenectomy or a TPO-RA. In adults who are going to be treated with aTPO-RA, either eltrombopag or romiplostim is suggested by the ASH guidelines. ASH also suggests rituximab over splenectomy.[8]

Gudbrandsdottir et al reported that treatment with the combination of dexamethasone and rituximab resulted in higher response rates than with dexamethasone monotherapy (58%, versus 37% with dexamethasone alone; P = 0.02), as well as longer time to relapse ( P = 0.03) and longer time to rescue treatment (P = 0.007). However, the incidence of grade 3 to 4 adverse events was higher in the rituximab plus dexamethasone group (P = 0.04). The study included 113 adult patients with newly diagnosed, symptomatic primary ITP.[53]

Additional precautions are required for patients with hypertension, peptic ulcers, recent aspirin ingestion, or other risk factors for increased bleeding. Considerations are as follows:

  • Aspirin inhibits platelet function by acetylating platelet cyclooxygenase, increasing the risk of bleeding because it adds a platelet functional defect to the quantitative defect already present from the severe thrombocytopenia. In addition, platelet dysfunction may be induced by the platelet antibody, which is potentiated by the superimposition of the aspirin-platelet defect. Because of this effect, aspirin is contraindicated in persons with ITP.

  • Adults whose platelet counts are greater than 50× 109/L typically have minimal purpura, and the risk of a severe hemorrhage is low. They may be treated without a specific medication.

  • Platelet transfusions may be required to control clinically significant bleeding but are not recommended for prophylaxis. Transfused platelets also have decreased circulation, and repeated platelet transfusions may lead to platelet alloimmunization.

Fostamatinib was approved by the FDA in April 2018 for thrombocytopenia in adults with chronic ITP who have had an insufficient response to a previous treatment. It is the first spleen tyrosine kinase (SYK) inhibitor approved in the US. Approval was based on the FIT clinical program (n=163), which included 2 randomized placebo-controlled phase 3 trials and an open-label extension trial. Results from the randomized trials showed more patients experienced a platelet response with fostamatinib than with placebo (18% vs 0% and 16% vs 4%). In the open-label expansion trial, 23% of patients who had received placebo in the previous randomized trials experienced a platelet response. Fewer bleeding episodes were observed in patients in the fostamatinib arm compared with placebo (29% vs 37%).[54]

Treatment in pregnant women

Pregnant women with no bleeding manifestations whose platelet counts are  30 × 109/L or higher do not require any treatment until 36 weeks' gestation, unless delivery is imminent. For pregnant women with platelet counts below 30 × 109/L, or clinically relevant bleeding, first-line therapy is oral corticosteroids or IVIG. Oral prednisone and prednisolone cross the placenta less readily than dexamethasone. Although ASH guidelines recommend a starting dose of prednisone of 1mg/kg daily, other experts recommend a starting dose of 0.25 to 0.5 mg/kg, as there is no evidence that a higher starting dose is better. The recommended starting dose of IVIG is 1 g/kg.[18]

Refractory ITP in pregnancy can be treated with corticosteroids and IVIG in combination, or splenectomy (in the second trimester).[18] Rarely, splenectomy may be required to manage acute hemorrhage.[19]  

Azathioprine and RhIG are relatively contraindicated in pregnancy. The standard dose of IV RhIG for ITP contains approximately 10-fold the concentration of anti-D that is in the standard antepartum dose of intramuscular RhIG for Rh immunoprophylaxis. Other third-line agents that are not recommended in pregnancy, but whose use in this setting has been described, include the following agents (all of them pregnancy category C)[18] :

  • Cyclosporine
  • Dapsone
  • Thrombopoietin receptor agonists
  • Alemtuzumab
  • Rituximab

For more information, see Immune Thrombocytopenia and Pregnancy.

Thrombopoietin receptor agonists

For many years, the only treatment options after corticosteroids, IV RhIG, IVIG, and rituximab were cyclophosphamide, azathioprine, and danazol. Interventions with decreased certain efficacy and with conflicting reports in the literature include alemtuzumab, azathioprine, danazol, dapsone, vinblastine, vincristine, ascorbic acid, colchicine, and interferon alfa.[55, 56, 57, 58, 59, 60, 61]  In the past decade, thrombopoietin (TPO) receptor agonists have entered clinical practice as second-line agents. Three of these agents are currently available: romiplostin (Nplate), eltrombopag (Promacta), and avatrombopag (Doptelet).

Romiplostin

The TPO receptor agonist romiplostim became available for patients with chronic ITP in 2008. Romiplostinm is administered weekly via subcutaneous injection and increases platelet counts within 5 to 8 days, with levels returning to baseline after 28 days. 

In one prospective, randomized controlled study comparing romiplostin with the standard of care for the treatment of chronic ITP, romiplostim administration was associated with higher rates of platelet count responses, decreased need for splenectomy, fewer episodes of serious bleeding and blood transfusions, and decreased need for initiating additional medical treatments. Romiplostim therapy was also associated with improved quality of life.[62] In a study of long-term romiplostim treatment, a small cohort of children with severe chronic ITP increased and maintained platelet counts for over 4 years, with good tolerability and without significant toxicity.[63]

In a phase III double-blind study of 62 symptomatic children with persistent or chronic ITP who were randomly assigned to receive weekly romiplostim or placebo for 24 weeks, durable platelet response was seen in 52% of patients receiving romiplostim vs.10% of those in the placebo group (p=0.002, odds ratio 9.1). However, further studies are needed to determine long-term efficacy, safety, and remission rates.[64]  

A systematic review concluded that romiplostim is effective and generally well tolerated in patients 65 years of age and older with ITP. Complications included nonsignificant trends toward increased risks of grade ≥3 bleeding and thromboembolic events.[65]

Eltrombopag

Like romiplostim, eltrombopag also became available in 2008. In August 2015, the US Food and Drug Administration expanded the indication for eltrombopag to include treatment of chronic ITP in patients 1 year of age and older who have not achieved an appropriate response with other medical therapy or splenectomy.[66]  An oral TPO receptor agonist, eltrombopag increases platelet counts after 8 days of daily dosing.

Eltrombopag was studied in a phase III double-blind trial in adults with previously treated ITP lasting more than 6 months and with platelet counts lower than 30,000/µL. Patients received treatment with local standard care plus eltrombopag (50 mg) or placebo for 6 months. Of 196 patients in the study, 106 (79%) patients in the eltrombopag group responded to treatment at least once, compared with 17 (28%) in the placebo group. Toxic reactions in the eltrombopag group included thromboembolic events (2%), mild increases in alanine aminotransferase levels (3%), and increased total bilirubin levels (4%).[67]

Eltrombopag has a boxed warning for the risk of severe and potentially life‐threatening hepatotoxicity.  

Avatrombopag

Avatrombopag, an oral TPO receptor agonist, was approved by the FDA in June 2019 for adults with chronic ITP who have had an insufficient response to a previous treatment. Results from a phase III randomized trial that supported the approval showed avatrombopag administration resulted in a platelet count of at least 50,000/µL at day eight of therapy in the majority of patients, with efficacy superior to placebo in maintaining platelet counts in the target range during the 6-month treatment period.[68]

Unlike romiplostim, which must be taken on an empty stomach, avatrombopag can be administered with food; unlike eltrombopag, it has not been associated with hepatotoxicity.

Surgical Care

In persons with acute immune thrombocytopenia (ITP), splenectomy usually results in rapid, complete, and life-long clinical remission. In persons with chronic ITP, the results of splenectomy are typically less predictable than they are in patients with acute ITP. Platelet counts may not fully revert to normal values, and relapses are not uncommon after 5 years. Studies suggest that the initiation of thrombopoietin mimetics may obviate splenectomy in a significant number of  adults with chronic ITP.[69]

Laparoscopic splenectomy is an interventional approach that is less invasive than traditional splenectomy and offers the promise of decreased postoperative morbidity and shorter recovery.[70, 71, 72] However, the ultimate role for laparoscopic splenectomy in ITP depends on long-term follow-up to determine whether this approach is as effective as conventional splenectomy for visual scrutiny of the abdominal cavity to identify accessory spleens.

Splenectomy results in a lifelong increased risk of sepsis from infection by encapsulated bacteria[73, 74, 75] and Babesia, as follows[76] :

  • In adults, this risk is estimated to be approximately 1%, with a fatal outcome in approximately 1 per 1500 patient-years.

  • In children, the risk of bacterial sepsis after splenectomy is estimated to be 1-2%. Many pediatricians recommend delaying splenectomy until children are 5 years of age.

  • These estimates are presumably based on early data and may be inflated, given the increased alertness to the importance of early treatment, availability of more effective antibiotics, and availability of vaccines against specific encapsulated bacteria.

  • Before one concludes that medical management and splenectomy have failed and that treatment with alternative options is needed, perform an imaging study to ensure that the problem is not associated with an accessory spleen.

In addition, splenectomy has been associated in adults with an increased incidence of venous and arterial thrombosis,[77] a twofold increase in deaths from cardiovascular disease,[78] and an increased rate of pulmonary hypertension[79] .

If elective splenectomy is planned for a child or an adult, initiate immunization with Haemophilus influenzae type b vaccine at least 14 days before surgery.[80]

Immunize adults and children older than 2 years with polyvalent Streptococcus pneumoniae vaccine and quadrivalent meningococcal polysaccharide vaccine.

Evaluate patients who have a relapse after having an initially satisfactory response to splenectomy for the possible presence of an accessory spleen.[81, 82]

  • An accessory spleen is strongly suggested if Howell-Jolly bodies appeared on the peripheral smear after splenectomy but are no longer present. However, the continued presence of Howell-Jolly bodies does not exclude an accessory spleen.

  • Imaging techniques using radionucleotide-labeled sulfur colloid, heat-damaged RBCs, or, preferably, autologous platelets provide more useful information than standard imaging with CT scanning or MRI.

Consultations

Selecting a treatment program for immune thrombocytopenia (ITP) requires knowledge of current options and consultation with a hematologist.

If 6 months of medical management fails to increase the platelet count to a safe range (about 30,000/µL), splenectomy becomes an option. Early consultation with a surgeon is useful for planning management.[83, 84]

If the platelet count is less than 10 × 109/L (< 10 × 103/µL) or if the patient has other evidence of a clinically significant risk of serious hemorrhage, consult a radiologist to determine what noninterventional imaging procedures are available in case of emergency.

 

Guidelines

Guidelines Summary

In 2019, the American Society of Hematology (ASH) published an update to its 2011 evidence-based practice guideline for immune thrombocytopenia (ITP). The 2019 guideline comprises strong recommendations and conditional recommendations/suggestions. Recommendations and suggestions are provided separately for pediatric and adult patients. Some of the 2011 recommendations remain unchanged and were not included in the 2019 review and update.[8]  In 2013, ASH issued a clinical practice guide on the treatment of thrombocytopenia in pregnancy, based in part on the 2011 guideline.[18, 42]

In 2019, an international group of experts published an International Consensus Report on the investigation and management of primary immune thrombocytopenia, covering adult, pediatric, obstetric, neonatal, and emergency management. The report updates an earlier guideline published in 2010.[40]

American Society of Hematology Guidelines

Pediatric ITP

Diagnosis

ASH recommendations are that bone marrow examination is not necessary in children and adolescents with the typical features of ITP, or in children in whom intravenous immunoglobulin (IVIG) therapy fails. ASH suggests that bone marrow examination is not necessary in similar patients before initiation of treatment with corticosteroids or before splenectomy, and that testing for antinuclear antibodies is not necessary in the evaluation of children and adolescents with suspected ITP.[42]

Treatment

ASH has moved away from recommending treatment on the basis of the platelet count. The 2019 ASH guidelines recommend that children with no bleeding or mild bleeding (ie, skin manifestations only, such as bruising and petechiae) be managed with observation alone regardless of platelet count.[8]

ASH suggestions include the following for children with non–life-threatening mucosal bleeding and/or diminished health-related quality of life (HRQoL)[8] :

  • A short course of corticosteroids over anti-D immunoglobulin or IVIG for first-line treatment 
  • Thrombopoietin receptor agonists (TPO-RAs) over rituximab or splenectomy for second-line treatment
  • Rituximab over splenectomy for second-line treatment

Adult ITP

Diagnosis

ASH recommends testing adult patients with ITP for hepatitis C virus and HIV. ASH suggests further investigations if the blood count or peripheral blood smear reveals abnormalities other than thrombocytopenia and perhaps findings of iron deficiency. ASH suggests that a bone marrow examination is not necessary irrespective of age in patients presenting with typical ITP.[42]

Treatment

The 2019 ASH guidelines recommend against treatment of patients with a platelet count ≥30×109/L. For newly diagnosed adult patients with a platelet count < 30×109/L, the guidelines suggest treatment with corticosterioids. For adults with a platelet count < 20×109/L who are asymptomatic or have minor mucocutaneous bleeding, the guidelines suggest hospital admission for newly diagnosed patients but outpatient treatment for those with an established diagnosis of ITP. [8]

For first-line treatment, the guidelines recommend a short course (≤6 weeks) of steroids over a prolonged course (> 6 weeks, including treatment and taper). Additional first-line treatment suggestions include the following[8] :

  • Either prednisone (0.5-2.0 mg/kg per day) or dexamethasone (40 mg per day for 4 days) as the type of corticosteroid 
  • Corticosteroids alone rather than rituximab and corticosteroids

The following 2011 ASH treatment suggestions remain unchanged[42] :

  • IVIG may be used with corticosteroids when a more rapid increase in platelet count is required
  • Either IVIG or anti-D (in appropriate patients) may be used if corticosteroids are contraindicated
  • If used, IVIG should be administered in a single dose of 1 g/kg; the dose may be repeated if necessary

For adults with ITP for ≥3 months who are corticosteroid dependent or unresponsive to corticosteroids, the 2019 second-line treatment suggestions include the following, in order of preference[8] :

  • A TPO-RA (either eltrombopag or romiplostim)
  • Rituximab
  • Splenectomy

The 2011 recommendation that for medically suitable patients, laparoscopic and open splenectomy offer similar efficacy, also remains unchanged.[8]

ASH recommends the following tests for thrombocytopenia in pregnant patients[18] :

  • Complete blood count
  • Reticulocyte count
  • Peripheral blood smear
  • Liver function tests
  • Viral screening (HIV, HCV, HBV)

Tests to consider if clinically indicated include the following:

  • Antiphospholipid antibodies
  • Antinuclear antibody (ANA)
  • Thyroid function tests
  • Helicobacter pylori testing
  • Disseminated intravascular coagulation testing—prothrombin time (PT), partial thromboplastin time (PTT), fibrinogen, fibrin split products
  • Von Willebrand disease type IIB testing*
  • Direct antiglobulin (Coombs) test
  • Quantitative immunoglobulin levels

The following studies are not recommended:

  • Antiplatelet antibody testing
  • Bone marrow biopsy
  • Thrombopoeitin (TPO) levels

Treatment

Treatment considerations include the following:

  •  Women with no bleeding manifestations and platelet counts ≥30×10 9/L do not require any treatment until 36 weeks’ gestation (sooner if delivery is imminent).
  •  If platelet counts are < 30×10 9/L or clinically relevant bleeding is present, first-line therapy is oral corticosteroids or intravenous immunoglobulin (IVIG).
  • The recommended starting dose of IVIG is 1 g/kg.
  • Prednisone and prednisolone are preferred to dexamethasone, which crosses the placenta more readily.
  • Recommended starting doses of prednisone by different experts vary from 0.25 to 0.5 to 1 mg/kg daily; no evidence exists that a higher starting dose is better.
  • Medications should be adjusted to maintain a safe platelet count.

Expected responses to first-line therapy are as follows:

  • Oral corticosteroids—initial response 2-14 days, peak response 4-28 days
  • IVIG—initial response 1-3 days, peak response 2-7 days

Second-line therapy for refractory ITP is with combined corticosteroids and IVIG or, in the second trimester, splenectomy.  For third-line therapy, anti-D immunoglobulin and azathioprine are relatively contraindicated. Agents that are not recommended, but whose use in pregnancy has been described, include the following:

  • Cyclosporine
  • Dapsone
  • Thrombopoietin receptor agonists
  • Alemtuzumab
  • Rituximab

Contraindicated agents include the following:

  • Mycophenolate mofetil
  • Cyclophosphamide
  • Vinca alkaloids
  • Danazol

Management at the time of delivery

ASH recommendations are as follows:

  • Because of the possible need for cesarean delivery, the recommended target platelet count prior to labor and delivery is ≥50×10 9/L.
  • A woman whose platelet count is < 8010 9/L but who has not required therapy during pregnancy can be started on oral prednisone (or prednisolone) 10 days prior to anticipated delivery at a dose of 10-20 mg daily and titrated as necessary.
  • The mode of delivery should be determined by obstetric indications.
  • Although the minimum platelet count for the placement of regional anesthesia is unknown and local practices may differ, many anesthesiologists will place a regional anesthetic if the platelet count is ≥80×10 9/L.
  • While platelet transfusion alone is generally not effective in ITP, its use in conjunction with IVIG can be considered if an adequate platelet count has not been achieved and delivery is emergent.
  • Percutaneous umbilical blood sampling (PUBS) or fetal scalp blood sampling is not recommended, as it is not helpful in predicting neonatal thrombocytopenia and is potentially harmful.
  • In the newborn, the platelet count reaches its nadir 2-5 days after delivery and rises spontaneously by day 7.
  • Postpartum thromboprophylaxis should be considered, as women with ITP are at increased risk of venous thromboembolism.

International Consensus Report Guidelines - Adults

Diagnosis

Basic evaluation in all patients should consist of the following[40] :

  • Patient history
  • Family history
  • Physical examination
  • CBC and reticulocyte count 
  • Peripheral blood film
  • Quantitative Ig level measurement
  • Blood group (Rh)
  • HIV serology - Recommended by the majority of the panel for adult patients in the appropriate geographic setting
  • Hepatitis C virus serology - Recommended by the majority of the panel for adult patients in the appropriate geographic setting 
  • Hepatitis B virus serology

Tests of potential utility in patients with ITP include the following:

  • Glycoprotein-specific antibody (can be used in difficult cases, but has poor sensitivity and is not a primary diagnostic test)
  • Antiphospholipid antibodies (including anti-cardiolipin and lupus anticoagulant) if there are clinical features of antiphospholipid syndrome
  • Anti-thyroid antibodies and thyroid function
  • Pregnancy test in women of childbearing potential
  • Antinuclear antibodies (ANA) – A positive ANA may be a predictor of chronicity; hydroxychloroquine may be an effective treatment if ANAs are present, especially in young women; ANA testing can be considered before splenectomy because of the increased risk for thrombosis
  • Polymerase chain reaction (PCR) testing for Epstein-Barr virus, cytomegalovirus, and parvovirus
  • Bone marrow examination (may be informative in patients with systemic symptoms, abnormal signs, or with suspicion of a different diagnosis)
  • Direct antiglobulin test Helicobacter pylori testing (should be considered in adults with typical ITP, in those with digestive symptoms, and those from areas of high prevalence)

The following tests have no proven role in the differential diagnosis of ITP from other thrombocytopenias and do not guide patient management:

  • Thrombopoietin level
  • Reticulated platelets/immature platelet fraction
  • Bleeding time
  • Serum complement

Therapy

Recommendations for initial treatment of newly diagnosed patients are as follows:

  • Corticosteroids are the standard initial treatment for adults with ITP who need treatment and do not have a relative contradiction: prednisone or prednisolone at 1 mg/kg (maximum dose 80 mg, even in patients weighing >80 kg) for 2 weeks, to a maximum of 3 weeks; or dexamethasone 40 mg/d for 4 days, repeated up to 3 times
  • If a response is seen (eg, platelets > 50 × 10 9/L), taper the prednisone/prednisolone, aiming for discontinuation by 6 weeks (maximum 8 weeks), even if the platelet count drops during the taper.
  • If there is no response to the initial dose within 2 weeks, taper the prednisone/prednisolone rapidly over 1 week and discontinue.
  • Longer courses of steroids should be avoided, although occasional patients may benefit from continuous low-dose corticosteroids (eg, ≤5 mg/d).
  • Use of IVIG (1 g/kg on 1 or 2 consecutive days or 0.4 g/kg per day for 5 days), or IV anti-D (50-75 µg/kg once) where available, may be appropriate in patients with bleeding, at high risk for bleeding, who require a surgical procedure, or who are unresponsive to prednisone/prednisolone. If using anti-D, exercise consideration over potential triggering of disseminated intravascular coagulation (DIC) or hemolysis, and consider steroid premedication to minimize acute infusion reactions (eg, headaches, fever-chills, and/or intravascular hemolysis).
  • Patients with contraindications to high-dose corticosteroid therapy (eg, insulin-dependent diabetes, uncontrolled diabetes, psychiatric disorders, active infection) may be managed with only IVIZG or IV anti-D as initial therapy.
  • TPO receptor agonists (TPO-RAs) and rituximab are not considered initial therapies.

For subsequent therapy, medications with robust evidence of efficacy are as follows:

  • Rituximab
  • TPO-RAs: eltrombopag, avatrombopag, romiplostim
  • Fostamatinib

Medical therapies with less robust evidence are as follows:

  • Azathioprine
  • Cyclophosphamide
  • Cyclosporine
  • Danazol
  • Dapsone
  • Mycophenolate mofetil (MMF)
  • Switching from one TPO-RA to another
  • Vinca alkaloids

​Consensus-based recommendations for target platelet counts (× 109/L) for dental procedures in adults are as follows:

  • Dental prophylaxis (descaling, deep cleaning):  ≥20 to 30
  • Simple extractions:  ≥30
  • Complex extractions:  ≥50
  • Regional dental block: ≥30  

Consensus-based recommendations for target platelet counts (× 109/L) for surgery in adults are as follows:

  • Minor surgery: ≥50 
  • Major surgery: ≥80
  • Major neurosurgery: ≥100

Treatment of life-threatening bleeding:

  • In emergency situations in which there is an urgent need to increase the platelet count within 24 hours, a combination of initial treatments, including IV corticosteroids and, usually, IVIG, should be used. Platelet transfusions may be helpful and must not be postponed in cases of life-threatening bleeding, especially intracranial hemorrhage (ICH).
  • In the case of life-threatening bleeding and the absence of a significant response to IVIG and platelet transfusion in a patient on corticosteroids, consider use of a TPO-RA.
  • Additional options may include IV anti-D; vincristine or vinblastine; antifibrinolytics in combination with other initial therapies; and, rarely, emergency splenectomy.

Surgical therapy for persistent and chronic ITP:

  • Splenectomy is associated with long-term treatment-free remissions. However, deferring splenectomy for ≥12 to 24 months from diagnosis before performing splenectomy is recommended because of the chance of remission or stabilization of the platelet count at a hemostatic level; up to one third of patients may remit in 1 year, and up to 80% may remit in 5 years. 
  • When available, indium-labeled autologous platelet scanning may be useful prior to splenectomy to confirm that the spleen is the main site of platelet sequestration.
  • Laparoscopic splenectomy is as effective as open splenectomy in terms of response and is more comfortable for the patient.
  • Postoperative thromboprophylaxis should be considered in patients undergoing splenectomy as long as the platelet count is > 30 to 50 × 10 9/L.
  • Splenectomy should be performed by a surgeon experienced in identifying accessory splenic tissue, which is common and should be removed.
  • Appropriate vaccination against Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae must be provided ≥2 weeks before splenectomy and maintained according to national guidelines; recent treatment (within 6 months) with rituximab may impair vaccination efficacy.
  • Patients should be informed of the long-term risks of splenectomy (ie, increased rates of thrombosis, infection, and cancer) and educated to follow advice aimed at mitigating these complications.
  • Antibiotic prophylaxis should be given as per national guidelines.

Approach when multiple treatments have failed:

  1. Reconsider the diagnosis
  2. Perform bone marrow examination if not already done
  3. Reassess the need for treatment (consider platelet count/bleeding risk)
  4. Consider referral to an ITP treatment center
  5. Reassess the adequacy of prior therapies (eg, was the full dose of TPO-RA explored? Did the addition of a small dose of corticosteroid improve response?)
  6. Assess the risks and benefits of further treatment
  7. Reassess the possibility of splenectomy if not already performed
  8. Consider other medical therapies if not already attempted (eg, MMF, fostamatinib, rituximab, azathioprine, dapsone, danazol)
  9. Consider enrollment in a clinical trial
  10. In patients who relapse >1 year after responding to splenectomy, an accessory spleen should be searched for and, if found, resected.
  11. Switching from one TPO-RA to another and sequential therapy have been shown to have a positive effect on response and adverse effects.
  12. Other therapies that have been used as last resorts include combination chemotherapy, alemtuzumab, and hematopoietic stem cell transplantation (HSCT). The side effects of these treatment options may be severe, and the data supporting their use are limited.

Assessment and management of health-related quality of life outcomes

The 10-scale ITP-patient assessment questionnaire (ITP-PAQ) is an ITP-specific questionnaire that can be used to measure HRQoL, with estimated minimally important differences (MIDs) aiding interpretation. Additional measures of patient-reported outcomes (PROs) that have been studied in adult patients with ITP include the following:

  • 36-item Short Form Health Survey (SF-36)
  • EuroQol tool (EQ-5D)
  • Hamilton anxiety and expression rating scales
  • Motivation and energy inventory-short form (MEI-SF)
  • Fatigue subscale of the functional assessment of chronic illness therapy (FACIT-Fatigue)
  • Functional assessment of cancer therapy–thrombocytopenia (FACT-Th6)

Impaired HRQoL is multifactorial and includes (but is not limited to) issues around actual bleeding, fear of bleeding, reduced energy, depression, treatment side effects, and additive influences of underlying or comorbid diseases. Patients who respond to treatment have improved HRQoL, with those who respond to TPO-RA improving more than those who respond to other therapies; in particular, romiplostim may improve fatigue.

Other HRQoL recommendations are as follows:

  • Participation in high-risk activities (eg, BMX racing, boxing, American football, ice hockey, lacrosse, motorcycle riding, motocross racing, power lifting, outdoor rock climbing, rodeo, rugby, snowmobiling, trampoline, wrestling) should be discouraged unless the patient has a near-normal platelet count on a consistent and stable basis. Alternatively, treatment should be administered to provide a safe platelet count during the activity.
  • Intermittent or continuous treatment may be given to cover activities with appropriate discussion of risks vs benefits of the activity and treatment, with emphasis on psychological well-being and risks for injury, despite treatment.
  • Choice of treatment and target platelet count must be carefully evaluated and based on extensive consultation and consideration of the specific activity desired and the bleeding tendency.

International Consensus Report Guidelines - Pregnancy and Neonatal

Diagnosis of ITP in pregnancy

Recommendations for investigation of suspected ITP in pregnancy include the following[40] :

  • Patients with a history suggestive of ITP or those with a platelet count < 80 × 10 9/L should be investigated for possible ITP (Grade C recommendation).
  • As in nonpregnant patients, the diagnosis of ITP is one of exclusion using the patient’s history, physical examination, blood counts, and blood smear examination.
  • Laboratory evaluation is similar to the nonpregnant patient, but special consideration should be given to rule out hypertensive, microangiopathic, coagulopathic, and hepatic disorders associated with pregnancy. Recommended tests should be based on the clinical features and may include review of the blood smear, reticulocyte count, coagulation screen, liver function, thyroid function, ANAs, and antiphospholipid antibodies.
  • Bone marrow examination is not recommended unless atypical features are present.
  • Anti-platelet antibody testing does not predict the course of maternal or neonatal thrombocytopenia or distinguish ITP from gestational thrombocytopenia and is not recommended.
  • Testing of TPO levels is not recommended.

Treatment of ITP in pregnancy

Recommendations for the treatment of ITP during pregnancy include the following[40] :

  • A platelet count of 20 to 30 × 10 9/L in a nonbleeding patient is safe for most of pregnancy. A platelet count ≥50 × 10 9/L is preferred for delivery.
  • Initial treatment is with oral steroids or IVIG.
  • In Rh(D)-positive nonsplenectomized women, IV anti-D appears to be well tolerated and effective; however, it may potentially cause maternal or fetal hemolysis.
  • IVIG can provide a rapid, but often very transient, increase in platelet count and can be used to urgently increase platelet counts during bleeding or for delivery.
  • Combining therapies (prednisone with IVIg and/or IV anti-D) may elicit a response in patients refractory to single agents alone (Grade C recommendation). High-dose methylprednisolone, in combination with IVIg and/or azathioprine, is suggested for patients refractory to oral corticosteroids or IVIg alone (Grade C recommendation).
  • Rituximab can be considered in pregnancy for very severe cases, but perinatal and neonatal immunosuppression and subsequent infection are potential complications and require monitoring.
  • TPO-RAs may be considered in late pregnancy when other treatments have failed, but published information is limited.
  • In the rare instances when splenectomy is required, it should be performed in the second trimester.
  • Vinca alkaloids, danazol, and immunosuppressive drugs not listed in these recommendations should be avoided in pregnancy.

Recommendations for obstetric analgesia and anesthesia

Recommendations for obstetric analgesia and anesthesia in women with ITP include the following[40] ​:

  • At a platelet count ≥70 × 10 9/L, in the absence of other hemostatic abnormalities, regional axial anesthesia can be safely performed.
  • Nonsteroidal anti-inflammatory drugs (NSAIDs) should be avoided for postpartum or postoperative analgesia in women with platelet counts < 70 × 10 9/L because of increased hemorrhagic risk.
  • A platelet count ≥50 × 10 9/L should be obtained for delivery.
  • All women, despite having ITP, who are at an increased risk for thromboembolism should receive appropriate prophylaxis for venous thromboembolism.
  • The mother with a rapidly falling platelet count should be observed more closely than those with low, but stable, levels.

Recommendations for management of delivery and newborn infants

Recommendations for delivery of women with ITP include the following [40]  ​:

  • Cordocentesis and fetal scalp blood sampling should be avoided in the management of the fetus/neonate of a mother with ITP in pregnancy.
  • Neonatal alloimmune thrombocytopenia should be excluded by parental testing if the neonate presents with severe thrombocytopenia.
  • The mode of delivery should be determined by obstetric indications, not by anticipation of the neonatal platelet count.
  • Procedures during labor that may be associated with increased hemorrhagic risk to the fetus should be avoided, specifically the use of fetal scalp electrodes, fetal blood sampling, ventouse delivery, and rotational forceps.
  • Previous splenectomy has been associated with worsening of maternal ITP in pregnancy and a higher risk for neonatal thrombocytopenia.
  • A mother with a previous newborn, thrombocytopenic or not, is likely to have a second baby with a similar platelet count.

Recommendations for management of neonates born to women with ITP

Recommendations for the management of neonates born to women with ITP include the following[40] :

  • Obtain umbilical cord platelet count at the time of delivery or as soon as possible.
  • Repeat the platelet count as needed depending on platelet levels, trends in the count, and response to treatment (if any). If cord platelet count is < 100 × 10 9/L, repeat the platelet count daily until stable. The incidence of pseudothrombocytopenia is high in neonates because of the difficulties encountered in obtaining unclotted blood with blood draws.
  • If platelet count is < 50 × 10 9/L at birth, perform a cranial ultrasound. A magnetic resonance imaging for confirmation or clarification can be performed without anesthesia using the sleep and swaddle approach 30 to 60 minutes prior.
  • In the case of ICH, give IVIG and limited steroids to maintain platelet count >100 × 10 9/L for 1 week if possible and >50 × 10 9/L for another week. The use of platelet transfusion may increase neonatal risk.
  • If there is symptomatic bleeding or if platelet count is < 30 × 10 9/L, with or without platelet transfusion, give IVIG.
  • If severe thrombocytopenia continues for >1 week in a breast-fed infant, consider pausing breastfeeding for a few days to see whether platelet count increases.
  • Women who had a splenectomy may have a thrombocytopenic newborn, even if their platelet count is normal.
  • The only currently reliable predictor of whether a baby will be thrombocytopenic is if a previous sibling was thrombocytopenic.

 

International Consensus Report Guidelines - Pediatric

Diagnosis

Recommendations for initial investigation of suspected childhood ITP are as follows[40] :

  • Perform a complete history, physical examination, full blood count, and expert analysis of the peripheral blood smear at initial diagnosis.
  • A direct anti-globulin test (DAT) is recommended to exclude coexistent autoimmune hemolytic anemia, especially prior to therapy.
  • Baseline Ig levels, to exclude coexisting immunodeficiency, is recommended prior to therapy.
  • When a child's CBC shows isolated thrombocytopenia, the peripheral blood smear shows no abnormal features beyond thrombocytopenia, and signs of bleeding are present on physical examination, a bone marrow aspiration/biopsy is not required, even prior to steroid therapy.
  • Children with newly diagnosed ITP, especially with atypical features, should be referred to, or their case discussed with, a hematologist experienced in assessment and treatment of children with ITP.
  • Bone marrow aspiration, biopsy, and cytogenetics should be performed if abnormal or potentially malignant cells are visualized on smear and carefully considered if there are other abnormalities of the hemoglobin and/or white cell count (with the exception of microcytic anemia) or if there is hepatosplenomegaly and/or adenopathy. In addition, failure to acutely respond to ITP therapy merits a bone marrow examination.
  • Additional investigations are based on clinical assessment and may include tests insuch as molecular genetics, autoantibody screening, liver-spleen imaging, and other laboratory testing

Recommendations for subsequent investigation of children with persistent or chronic ITP are as follows:

  • Perform a repeat history, physical examination, full blood count, and expert analysis of the peripheral blood smear to reassess the diagnosis.
  • Perform bone marrow aspiration, biopsy, and cytogenetics if no spontaneous platelet increase and no response to treatment has occurred after 3 to 6 months, or earlier if there is no response to treatment within the expected timeframe. Consider next-generation sequencing or targeted sequencing, if available.
  • A bone marrow biopsy is not indicated prior to further therapy (eg, with TPO), but should be included in reevaluation of the diagnosis in the setting of increasingly difficult-to-treat persistent or chronic ITP.

Additional evaluation could include testing for the following:

  • Lupus and other markers of autoimmune diseases that might require specific treatment (eg, test for APLAs, ANAs, anti-cardiolipin antibody, lupus anticoagulant, and serum Igs)
  • Chronic infections (hepatitis, cytomegalovirus, HIV, and/or H pylori in at-risk populations or when there is no other explanation)
  • Complex immunodeficiency diseases
  • Genetic screening for inherited thrombocytopenia and bone marrow failure syndromes

Management

A bleeding scale for pediatric patients with ITP is shown in Table 1, below.

Table 1. Bleeding scale for pediatric patients with ITP (Open Table in a new window)

Grade

Bleeding

Management approach

Grade 1 (minor) 

Minor bleeding, few petechiae (≤100 total) and/or ≤5 small bruises (≤3 cm in diameter), no mucosal bleeding 

Consent for observation 

Grade 2 (mild) 

Mild bleeding, many petechiae (>100 total) and/or >5 large bruises (>3 cm in diameter), no mucosal bleeding 

Consent for observation 

Grade 3 (moderate) 

Moderate bleeding, overt mucosal bleeding, troublesome lifestyle 

Intervention to reach grade 1 or 2 

Grade 4 (severe) 

Severe bleeding, mucosal bleeding leading to decrease in Hb > 2 g/dL or suspected internal hemorrhage 

Intervention

Watch-and-wait

Recommendations for a watch-and-wait policy, based on clinical classification, are as follows:

  • At diagnosis, children and adolescents with ITP and mild or even moderate bleeding on a pediatric bleeding assessment tool (grade 1-3) may be managed expectantly with supportive advice and a 24-hour contact point, irrespective of platelet count
  • Those with grade 3 bleeding are more likely to require therapy because of the higher rates of serious bleeding requiring hospital admission and emergency treatment.
  • All patients need regular reevaluation to monitor for worsening, including health-related quality of life (HRQoL) and evolution to a serious bone marrow disorder or a secondary form of ITP. The frequency of clinical and laboratory monitoring should be based on bleeding, HRQoL, trend in platelet counts, and impression of family reliability.
  • The same monitoring and 24-hour access are needed with persistent and chronic ITP, depending upon the factors listed above, but at less frequent intervals in a stable patient. Observation or watch-and-wait is less validated in patients with persistent and chronic ITP because it is based on the expectation of spontaneous future improvement.

Indications for treatment

Recommendations for when to start initial treatment in children newly diagnosed with ITP are as follows:

  • Any severe (grade 4) bleeding requires immediate hospital admission and treatment to increase platelet levels until bleeding has decreased.
  • Any moderate (grade 3) bleeding requires hospital review and consideration for admission and therapy.

Administer treatment and strongly consider hospitalization in the following cases:

  • Worsening bleeding or significant comorbidities
  • Risk of ICH (eg, head trauma or unexplained headaches); patients at higher risk for ICH include those with a history of moderate or severe bleed in the preceding 28 days, recent administration (within 8 hours) of NSAIDs, and another clinically significant coagulopathy (eg, von Willebrand disease). In the case of head trauma, treatment should precede a head computed tomography scan.
  • A change in behavior or mood consistent with significant depression or irritability
  • Parents are anxious about bleeding and do not believe that they can control (young child) or restrict (older child) their child’s activity.
  • Parents cannot be relied upon to bring the child back readily if there is an emergency (eg, they live too far away, they cannot afford to return, there are additional social concerns).
  • Child has not spontaneously improved and must be overly restricted in activities.
  • Child needs to take an anticoagulant or antiplatelet agent.
  • Higher risk of bleeding due to another medical or psychological issue

Initial treatment regimens:

  • If the patient has moderate or severe bleeding, IVIG and anti-D can often increase the platelet count to hemostatic levels (>50 × 10 9/L) within 24 to 48 hours. IVIGg is effective when given as a single dose of 0.8 to 1.0 g/kg. Anti-D has similar efficacy to IVIG when given as a single dose of 75 µg/kg and is rarely associated with severe hemolysis. High-dose steroid premedication is recommended for IV anti-D and is useful for IVIG.
  • A second dose of IVIg or anti-D may be administered if there is a suboptimal initial response and/or ongoing bleeding.
  • Give prednisone/prednisolone at 4 mg/kg per day in 3 or 4 divided doses for 4 days with no taper, with a maximum daily dose of 200 mg or at 1 to 2 mg/kg, with an 80-mg maximum daily dose, even in patients weighing >80 kg, for 1 to 2 weeks. If a response is seen (eg, platelets > 50 × 10 9/L), taper the prednisone/prednisolone, aiming to stop it by 3 weeks, even if the platelet count drops during the taper.
  • If there is no response to the initial dose within 2 weeks, taper the prednisone/prednisolone rapidly over 1 week and stop it.
  • In general, corticosteroids are used for grade 1 or 2 bleeding or for patients not responsive to IVIG.
  • IV anti-D can be used if the patient is Rh positive, not splenectomized, does not have a positive direct Coombs test (DAT), and has hemoglobin ≥9 g/dL.

Emergency treatment:

  • Combination therapy, including platelet transfusions, IV corticosteroids, and IVIG, with or without anti-D, is recommended. Administer platelet transfusions as a bolus, followed by continuous infusion in combination with IV high-dose steroids (eg, IV methylprednisone/prednisolone, 30 mg/kg per day). For ICH or other life-threatening or serious bleeding, give IVIG (0.8-1.0 g/kg per day, with or without single-dose IV anti-D (75 µg/kg). A second dose of IVIG and IV steroids may be required if a platelet response is not seen within 24 hours of the initial dose.
  • IVIG, steroids, and IV anti-D (if available) can be used to attempt to ensure the most likely and fastest platelet increase. Antifibrinolytics may be given if bleeding continues despite therapy.
  • In patients with an ICH, emergency splenectomy and/or neurosurgical control of bleeding should be considered in conjunction with emergency platelet-raising therapy, but medical treatment should never be delayed because of surgical or radiologic intervention if at all possible.
  • TPO-RAs should be considered, as they may aid the acute response in patients and prevent a decrease in platelet count if initial response to emergency therapy is lost.

Treatment of persistent or chronic ITP:

  • Most children with persistent or chronic ITP can be managed with watchful waiting. If an acute bleeding episode occurs, rescue therapy with corticosteroids, IVIG, and/or IV anti-D can be used.
  • Children who are having frequent or severe bleeding episodes or impaired HRQoL (including reduction in important activities) require referral to a hematologist experienced in treating pediatric ITP.
  • TPO-RAs often produce a good response and reduction in bleeding frequency, with an absence of adverse effects in the majority of patients. If the patient does not respond to a TPO-RA or loses response, switch to an alternative TPO-RA and/or consider combining with MMF or another immunosuppressant.
  • Consider rituximab and dexamethasone for patients, especially adolescent girls, in whom TPO-RAs fail.

Splenectomy:

  • Splenectomy is very rarely indicated in childhood ITP, and should be undertaken in consultation with a hematologist experienced in the management of children with ITP. It should only be considered in children who have failed all available medical therapies, are having thrombocytopenia-related bleeding, and whose life is at risk or whose HRQoL is substantially impaired.
  • Splenectomy should be avoided if at all possible before 5 years of age and within 1 year of disease onset.
  • Before considering splenectomy, reassess the diagnosis of ITP by excluding alternative diagnoses, including inherited thrombocytopenia, bone marrow failure, drug-induced thrombocytopenia, subclinical viral infections, immunodeficiency syndromes (eg, common variable immune deficiency [CVID], autoimmune lymphoproliferative syndrome), and myelodysplastic syndrome.
  • Prior to splenectomy, ensure that vaccinations are up to date according to national policy. Vaccination, as a minimum, should include pneumococcal 13-valent conjugate vaccine, followed by pneumococcal 23-valent vaccine 4 weeks later; H influenzae type B; and both meningococcal vaccines to cover all 5 species subtypes.
  • If there is any concern for an immunodeficiency-related ITP, even if undocumented, reducing the risk for postsplenectomy sepsis by assessing response to pneumococcal vaccines preprocedure is advisable.

Health-related quality of life considerations:

  • HRQoL should be reported using the Kid’s ITP Tool (KIT) or another validated scale before and after treatment, to assess the effect of treatment beyond the platelet count.
  • Corticosteroids may worsen HRQoL in children with ITP; TPO-RAs may improve their HRQoL, and romiplostim especially appears to improve parental burden.

School and participation in sporting activities:

  • Children and adolescents 5 to 18 years old need ≥60 minutes of physical activity per day, ≥3 d/wk. This should include exercises or sports to promote strong muscles and bones.
  • Normal attendance and play at kindergarten, school, or college, depending on age, is essential. The risk of bleeding and information about ITP should be provided to the school in a way that facilitates inclusion, not isolation.
  • Active participation in low-risk activities should be maintained, irrespective of platelet count and treatment.
  • Participation in non–low-risk activities must be discussed with the family, school, and coach. A number of factors must be considered prior to participation, including age of the child, platelet count, bleeding history, and physical nature of the activity.
 

Medication

Medication Summary

The treatment of acute immune thrombocytopenia (ITP) requires considerable individualization.[85] General approaches for children with acute ITP and adults with chronic ITP are discussed below.

Recommended general approach for children with acute immune thrombocytopenia

For initial (induction) treatment, in patients with a platelet count of 20-30 × 109/L [20-30,000/µL] and/or mucocutaneous bleeding), one regimen is prednisone 4-8 mg/kg/d with the intent of a rapid and complete taper after 7-10 days or when the platelet count reaches 50 × 109/L (50,000/µL), whichever occurs first. In critical situations, an IV infusion of a corticosteroid may be preferable.

Second-line (maintenance) treatment is IV Rh immune globulin (IG), 75/µg/kg (off-label dose) for the Rh-positive patient or IVIG 1.0 g/kg for the Rh-negative patient. If the patient has clinically significant purpura or bleeding at presentation, consider infusing the first dose of IV RhIG or IVIG at the time of initial therapy with corticosteroids.

Repeat the infusions at 3- to 4-week intervals (maintenance) until a satisfactory platelet count is achieved. If the platelet count is not maintained after 3-4 infusions, the case might be refractory, and a different treatment should be considered. Conditions refractory to IV RhIG may respond to IVIG, and vice versa. If the patient's hemoglobulin level decreases to 8.0 g/dL during treatment with IV RhIG, temporarily switch to IVIG until the level recovers. In this situation, the patient's condition should not be considered refractory to IV RhIG.

Conventional third-line treatment is splenectomy. However, recognizing the life-long potential adverse effects of splenectomy and the promising reports of responses to rituximab,[86, 87] the authors consider a course of rituximab 375 mg/m2 per week for four doses (off-label indication) before splenectomy (which becomes fourth-line therapy).[88] Rituximab at a standard dose of 375 mg/m2 per week for 4 weeks appears to be safe and effective, allowing nearly 40% of patients with ITP to achieve a long-term response and splenectomy-sparing effect in one study.[89]

Recommended general approach for adults with chronic immune thrombocytopenia

Adults whose disease is not controlled with a prednisone-induced increase in platelet count that is maintained by IV RhIG or IVIG and whose conditions do not respond to four weekly infusions of rituximab are candidates for splenectomy. After these serial experiences, such patients are likely to have had thrombocytopenia for at least 6 months and, therefore, are categorized as having chronic ITP. Eltrombopag or romiplostim offer potential maintenance of safe levels of platelet counts for adults who qualify by having ITP for at least 6 months and whose conditions are refractory to conventional medical management (prednisone, IV RhIG, IVIG, rituximab), and whose platelet count is not maintained in a satisfactory range after splenectomy.[90]

The treatment of chronic, refractory ITP may introduce risks of toxicity from medications that are comparable in severity to the risks of untreated thrombocytopenia. These treatments also may impact adversely on the patient's quality of life.[91]

Fostamatinib was approved by the FDA in April 2018 for thrombocytopenia in adults with chronic ITP who have had an insufficient response to a previous treatment. It is the first spleen tyrosine kinase (SYK) inhibitor approved in the US. Approval was based on the FIT clinical program (n=163), which included 2 randomized placebo-controlled phase 3 trials and an open-label extension trial.[54]

For patients with chronic refractory ITP who have access to investigational programs, the authors encourage them to participate in controlled clinical trials to support the development of effective treatments for this category.

Thrombopoietin-receptor agonists

Most conventional treatments for ITP act by decreasing destruction of autoantibody-coated circulating platelets. In contrast, thrombopoietin mimetics increase platelet counts in persons with ITP by increasing the number of platelets produced and released by the bone marrow. Agents in this class include the thrombopoietin peptide mimetic romiplostim (Nplate) and the nonpeptide mimetic eltrombopag (Promacta).[92, 93]

Avatrombopag, an oral TPO agonist, was approved by the FDA in June 2019 for thrombocytopenia in adults with chronic ITP who have had an insufficient response to a previous treatment.[68]

Romiplostim was approved by the FDA in August 2008. It is a thrombopoiesis-stimulating protein Fc-peptide fusion protein ("peptibody") that increases platelet counts in patients with acute and chronic ITP without reports of significant toxicity.[94, 34, 95]

Eltrombopag is indicated for treatment of thrombocytopenia in patients with chronic ITP who have shown insufficient response to corticosteroids, immunoglobulins, or splenectomy. This drug was also approved by the FDA in 2008.[96, 97] In August 2015, the FDA expanded the indication for eltrombopag to include treatment of chronic ITP in patients 1 year of age and older who have not achieved an appropriate response with other medical therapy or splenectomy.[66]

Corticosteroids

Prednisone (Deltasone, Orasone, Sterapred)

Oral corticosteroid that is used most frequently because of its relatively low cost, known adverse effects, and long-term clinical record. DOC for initial treatment of ITP in children and adults. For aggressive treatment, may be combined with IV RhIG or IVIG. In emergency, replace PO prednisone with IV methylprednisolone.

Methylprednisolone (Solu-Medrol)

DOC for the initial management of severe bleeding tendency in ITP. IV is recommended when the most rapid and reliable treatment of ITP is required. In this situation, combine with IV RhIG in qualified Rh(D)-positive patients or IVIG in Rh(D)-negative patients or unqualified Rh(D)-positive patients.

Blood Products

IV RhIG (WinRho SDF)

Specialized immunoglobulin product manufactured from pools of plasma from Rh(D)-negative persons and alloimmunized to D blood group antigen. Subjected to anion-exchange column chromatography to permit IV infusion and solvent-detergent treatment and nanofiltration to reduce infectivity by lipid-enveloped viruses. Induces immune RBC hemolysis in Rh(D)-positive recipients, decreasing function of mononuclear macrophages (reticuloendothelial blockade) and sparing immunoglobulin-coated platelets from splenic destruction.

IVIG (Gamimune, Gammagard, Sandoglobulin)

Large dose of 1 g/kg induces decreased function of mononuclear macrophages (reticuloendothelial blockade), sparing immunoglobulin-coated platelets from splenic destruction. Used with IV methylprednisolone to manage acute ITP in children. Decreased time to an increased platelet count compared with IV RhIG, but the difference does not appear to be clinically significant. Compared with IV RhIG, associated with more adverse effects, longer infusions, and increased cost, causing many hematologists to prefer IV RhIG as a supplement to corticosteroids, at least for Rh(D)-positive patients.

Immunosuppressive Antimetabolites

Azathioprine (Imuran)

May be effective in some patients with ITP whose conditions do not or no longer have response to corticosteroids, IV RhIG, or IVIG. May be used with prednisone to reduce dose of prednisone or as another PO medication to delay splenectomy.

Synthetic Antineoplastic Drugs

Cyclophosphamide (Cytoxan)

May be useful in some patients whose conditions do not or no longer have a response to corticosteroids, IV RhIG, IVIG, or splenectomy. Induces less of a decrease in platelet count than other immunosuppressive alkylating agents.

Androgens

Danazol (Danocrine)

May impair the clearance of immunoglobulin-coated platelets and decreases autoantibody production. Increased platelet counts in 40-50% of patients, particularly postmenopausal women.

Monoclonal Antibodies

Rituximab (Rituxan)

Chimeric monoclonal antibody directed against the CD20 antigen on the surface of normal and malignant B lymphocytes. Antibody is IgG kappa immunoglobulin with murine light- and heavy-chain variable sequences and human constant region sequences.

Thrombopoietic Agents

Avatrombopag (Doptelet)

Second-generation orally administered thrombopoietin receptor agonist (TPO-RA). Stimulates proliferation and differentiation of megakaryocytes from bone marrow progenitor cells, resulting in an increased production of platelets. It is indicated for thrombocytopenia in adults with chronic immune thrombocytopenia (ITP) who have had an insufficient response to a previous treatment.

Romiplostim (Nplate)

An Fc-peptide fusion protein (peptibody) that increases platelet production through binding and activation of the thrombopoietin (TPO) receptor, a mechanism similar to endogenous TPO. Indicated for chronic immune thrombocytopenia (ITP) in adults who are newly diagnosed or those who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy.

It is also indicated in children aged ≥1 year with ITP for ≥6 months who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy.

Eltrombopag (Promacta)

Oral thrombopoietin (TPO) receptor agonist. Interacts with transmembrane domain of human TPO receptor and induces megakaryocyte proliferation and differentiation from bone marrow progenitor cells. Indicated for thrombocytopenia associated with chronic idiopathic thrombocytopenic purpura in patients experiencing inadequate response to corticosteroids, immunoglobulins, or splenectomy. Not for use to normalize platelet counts, but used when clinical condition increases bleeding risk.

SYK Inhibitors

Fostamatinib (Tavalisse)

Fostamatinib is a spleen tyrosine kinase (SYK) inhibitor. The major active metabolite of fostamatinib (ie, R406) inhibits signal transduction of Fc-activating receptors and B-cell receptor, thereby reducing antibody-mediated destruction of platelets. It is indicated for thrombocytopenia in patients with chronic immune thrombocytopenia (ITP) who have had an insufficient response to a previous treatment.

 

Questions & Answers

Overview

What is immune thrombocytopenia (ITP)?

What are the signs and symptoms of immune thrombocytopenia (ITP)?

Which symptoms can be used to exclude a diagnosis of immune thrombocytopenia (ITP)?

Which physical findings indicate the severity of immune thrombocytopenia (ITP)?

Which findings suggest intracranial hemorrhage in immune thrombocytopenia (ITP)?

What is the role of lab testing in the diagnosis of immune thrombocytopenia (ITP)?

How is immune thrombocytopenia (ITP) diagnosed?

What is the role of bone marrow aspiration and biopsy in the diagnosis of immune thrombocytopenia (ITP)?

How is immune thrombocytopenia (ITP) treated?

How is immune thrombocytopenia (ITP) managed during pregnancy and delivery?

Why was the term "immune thrombocytopenic purpura" abandoned?

What is the pathophysiology of immune thrombocytopenia (ITP)?

What causes immune thrombocytopenia (ITP)?

What causes autoantibody stimulation in the pathogenesis of immune thrombocytopenia (ITP)?

Which platelet complex is most commonly involved in the pathogenesis of immune thrombocytopenia (ITP)?

What is the role of the spleen in the pathogenesis of immune thrombocytopenia (ITP)?

How are platelets destroyed in thrombocytopenia (ITP)?

What is the annual incidence of immune thrombocytopenia (ITP) in the US?

What is the global prevalence of immune thrombocytopenia (ITP)?

What is the primary cause of morbidity and mortality in immune thrombocytopenia (ITP)?

What is the cause of treatment-related morbidity in immune thrombocytopenia (ITP)?

How does the prevalence of immune thrombocytopenia (ITP) vary by sex?

How does the incidence of immune thrombocytopenia (ITP) vary by age?

How does the prognosis of immune thrombocytopenia (ITP) vary?

What is the prognosis of immune thrombocytopenia (ITP) in children?

Which factors increase the risk of developing chronic immune thrombocytopenia (ITP)?

Which factors decrease the risk of developing chronic immune thrombocytopenia (ITP)?

What is the prognosis of immune thrombocytopenia (ITP) in adults?

Presentation

What should be the focus of medical history in the evaluation of immune thrombocytopenia (ITP)?

Which systemic illnesses may manifest as immune thrombocytopenia (ITP)?

Which clinical history findings are characteristic of immune thrombocytopenia (ITP) in children?

What are the manifestations of immune thrombocytopenia (ITP) in patients with HIV infection?

Which medications may cause immune thrombocytopenia (ITP)?

How is drug-induced thrombocytopenia diagnosed?

What is the role of quinidine and quinine in the etiology of immune thrombocytopenia (ITP)?

How should heparin use be assessed in the evaluation of immune thrombocytopenia (ITP)?

Which antiplatelet drugs may cause immune thrombocytopenia (ITP)?

Which types of medications are associated with drug-induced immune thrombocytopenia (ITP)?

Which hepatic history findings are characteristic of immune thrombocytopenia (ITP)?

How is bleeding tendency assessed in suspected immune thrombocytopenia (ITP)?

What should be the focus of the physical exam for suspected immune thrombocytopenia (ITP)?

Which general health findings are useful in the evaluation of immune thrombocytopenia (ITP)?

Which skin and mucous membrane findings are characteristic of immune thrombocytopenia (ITP)?

Which cardiovascular findings are significant in the evaluation of immune thrombocytopenia (ITP)?

What does a finding of splenomegaly indicate in the evaluation of immune thrombocytopenia (ITP)?

Which nervous system findings are characteristic of immune thrombocytopenia (ITP)?

DDX

Which conditions are included in the differential diagnosis of immune thrombocytopenia (ITP)?

What are the differential diagnoses for Immune Thrombocytopenia (ITP)?

Workup

What is the initial lab test performed in the evaluation of immune thrombocytopenia (ITP)?

What is the role of peripheral blood smear in the diagnosis of immune thrombocytopenia (ITP)?

What is the significance of clumps of platelets on peripheral blood smear in the evaluation of immune thrombocytopenia (ITP)?

When is HIV testing indicated in the evaluation of immune thrombocytopenia (ITP)?

What medical history suggests immune thrombocytopenia (ITP) in women?

What is the role of measles-mumps-rubella (MMR) immunization in children with suspected immune thrombocytopenia (ITP)?

What is the role of platelet antigen assays in the evaluation of immune thrombocytopenia (ITP)?

What is the role of Helicobacter (H) pylori infection testing in the evaluation of immune thrombocytopenia (ITP)?

What is the risk of undiagnosed HIV infection in patients with immune thrombocytopenia (ITP)?

What is the role of imaging studies in the diagnosis of immune thrombocytopenia (ITP)?

What are the histologic findings characteristic of immune thrombocytopenia (ITP)?

Which bone marrow biopsy results are characteristic of immune thrombocytopenia (ITP)?

What should be included in the evaluation of the spleen in patients with immune thrombocytopenia (ITP)?

What is the role of bone marrow aspiration and biopsy in the diagnosis of immune thrombocytopenia (ITP)?

When is bone marrow exam indicated in adults with suspected immune thrombocytopenia (ITP)?

What are the ASH guidelines for bone marrow exam in the evaluation of immune thrombocytopenia (ITP)?

When is bone marrow exam indicated in children with suspected immune thrombocytopenia (ITP)?

Treatment

What is the goal of medical care for immune thrombocytopenia (ITP)?

What is the role of corticosteroids in the treatment of immune thrombocytopenia (ITP)?

Which diagnostic procedures should be considered to confirm the diagnosis of immune thrombocytopenia (ITP)?

What is the role of IV immunoglobulin (IVIG) in the treatment of immune thrombocytopenia (ITP)?

What is the role of IV Rho immunoglobulin (RhIG) in the treatment of immune thrombocytopenia (ITP)?

How is immune thrombocytopenia (ITP) managed in children?

How is immune thrombocytopenia (ITP) treated in adults?

How are bleeding risk factors managed in the treatment of immune thrombocytopenia (ITP) in adults?

What is the role of fostamatinib in the treatment of immune thrombocytopenia (ITP) in adults?

How is immune thrombocytopenia (ITP) managed during pregnancy?

How is refractory immune thrombocytopenia (ITP) treated during pregnancy?

Which medications are contraindicated in the treatment of immune thrombocytopenia (ITP) during pregnancy?

What is the role of thrombopoietin receptor agonists in the treatment of immune thrombocytopenia (ITP)?

What is the role of romiplostin in the treatment of chronic immune thrombocytopenia (ITP)?

What is the role of eltrombopag in the treatment of immune thrombocytopenia (ITP)?

What is the role of avatrombopag in the treatment of immune thrombocytopenia (ITP)?

When is splenectomy indicated in the treatment of immune thrombocytopenia (ITP)?

What are the risks of splenectomy in immune thrombocytopenia (ITP)?

What is the role of immunization in the treatment of immune thrombocytopenia (ITP)?

What are signs of an accessory spleen following splenectomy for immune thrombocytopenia (ITP)?

Which specialist consultations are needed for the management of immune thrombocytopenia (ITP)?

Guidelines

What guidelines are available for immune thrombocytopenia (ITP)?

What are the ASH recommendations for diagnosis of pediatric immune thrombocytopenia (ITP)?

What are the ASH recommendations for the treatment of immune thrombocytopenia (ITP) in children?

What are the ASH recommendations for the workup of immune thrombocytopenia (ITP) in adults?

What are the ASH recommendations for treatment of immune thrombocytopenia (ITP) in adults?

What are the ASH recommendations for diagnosis of thrombocytopenia during pregnancy?

Which tests may be clinically indicated for the diagnosis of thrombocytopenia during pregnancy?

Which studies are not recommended by ASH for the diagnosis of thrombocytopenia during pregnancy?

What are the ASH recommendation for treatment of immune thrombocytopenia (ITP) during pregnancy?

What are the expected responses to first-line therapy for immune thrombocytopenia (ITP) during pregnancy?

What are the ASH recommendations for second and third-line therapy for immune thrombocytopenia (ITP) during pregnancy?

Which drugs are contraindicated in the treatment of immune thrombocytopenia (ITP) during pregnancy?

What are the ASH recommendations for the treatment of immune thrombocytopenia (ITP) during delivery?

What are the International Consensus Report recommendations for the diagnosis of immune thrombocytopenia (ITP) during pregnancy?

What are the International Consensus Report recommendations for the treatment of immune thrombocytopenia (ITP) during pregnancy?

What are the International Consensus Report recommendations for the workup of immune thrombocytopenia (IPT) in adults?

Which tests are not recommended by the International Consensus Report for the diagnosis of Immune Thrombocytopenia (IPT) in adults?

What are the International Consensus Report recommendations for the initial treatment of immune thrombocytopenia (ITP) in adults?

What are the International Consensus Report guidelines for ongoing treatment of immune thrombocytopenia (IPT)?

What are the International Consensus Report recommendations for treatment of life threatening bleeding in adults with immune thrombocytopenia (ITP)?

What are the International Consensus Report recommendations for the surgical treatment of immune thrombocytopenia (ITP)?

What are the International Consensus Report guidelines for the treatment of immune thrombocytopenia (ITP) after multiple treatment failures?

What are the International Consensus Report recommendations for the assessment of quality of life outcomes in adults with immune thrombocytopenia (ITP)?

What are the International Consensus Report recommendations for participation in high-risk activities for adults with immune thrombocytopenia (ITP)?

Medications

What is required for the treatment of acute immune thrombocytopenia (ITP)?

What is the initial treatment of acute immune thrombocytopenia (ITP) in children?

What is the second-line treatment for acute immune thrombocytopenia (ITP) in children?

What is the third-line treatment for acute immune thrombocytopenia (ITP) in children?

What are the treatment options for chronic immune thrombocytopenia (ITP)?

How are thrombopoietin mimetics used in the treatment of immune thrombocytopenia (ITP)?

Which medications in the drug class Corticosteroids are used in the treatment of Immune Thrombocytopenia (ITP)?

Which medications in the drug class Blood Products are used in the treatment of Immune Thrombocytopenia (ITP)?

Which medications in the drug class Immunosuppressive Antimetabolites are used in the treatment of Immune Thrombocytopenia (ITP)?

Which medications in the drug class Synthetic Antineoplastic Drugs are used in the treatment of Immune Thrombocytopenia (ITP)?

Which medications in the drug class Androgens are used in the treatment of Immune Thrombocytopenia (ITP)?

Which medications in the drug class Monoclonal Antibodies are used in the treatment of Immune Thrombocytopenia (ITP)?

Which medications in the drug class Thrombopoietic Agents are used in the treatment of Immune Thrombocytopenia (ITP)?

Which medications in the drug class SYK Inhibitors are used in the treatment of Immune Thrombocytopenia (ITP)?