ITP – What the Sources Say

ASH SAP*Up-To-Date**DynaMed**
DefinitionITP is an autoimmune disorder characterized by thrombocytopenia and a variable risk of bleeding. 

A platelet count < 100 × 109/L is required for the diagnosis of ITP because mild thrombocytopenia may occur in normal individuals and uncommonly results in development of more severe thrombocytopenia or other autoimmune disease. 
ITP (also called idiopathic thrombocytopenic purpura, immune thrombocytopenic purpura) is an acquired thrombocytopenia caused by autoantibodies against platelet antigens. It is one of the more common causes of thrombocytopenia in otherwise asymptomatic adults.

Threshold for ITP is a platelet count <100 × 109/L.
ITP is an acquired autoimmune disorder characterized by immune-mediated destruction of otherwise normal platelets and with inadequate compensatory platelet production.

ITP is defined by a platelet count < 100 × 109/L in absence of other causes of thrombocytopenia.1
PathophysiologyAntiplatelet antibodies in mediating the enhanced clearance of platelets in patients with ITP. These antibodies recognize GPs on the platelet surface, most commonly GPIIb-IIIa and GPIb-IX. Antibody-coated platelets are cleared from the circulation by phagocytes in the reticuloendothelial system, primarily the spleen. 

Antiplatelet antibodies may recognize the same targets on megakaryocytes, leading to impairment of megakaryocyte proliferation and differentiation and proplatelet production. 
Reduced platelet lifespan due to antibody-mediated destruction is the predominant hypothesis. However, other mechanisms are likely important, including autoreactive cytotoxic T cells, as well as humoral and cellular autoimmunity directed at megakaryocytes, causing impaired platelet production.In ITP, thrombocytopenia results from immune-mediated clearance of platelets and decreased platelet production due to cross-reactivity of antiplatelet antibodies with megakaryocytes.

Primary ITP in adults has no known trigger or obvious cause.

Secondary ITP may develop due to underlying condition such as other autoimmune disorders, lymphoproliferative disorders, or infections (e.g., H. pylori, HCV, HIV).
Risk factorsIn adults, the incidence and prevalence of ITP is greatest in the elderly, with a female preponderance in the middle-adult years and a slight male preponderance in patients >70 years of age. More common in young women. Similar incidence in males and females > 60 years of age.Incidence of primary ITP similar in men and women except between ages 20 and 30 years, where women are slightly more commonly affected.
Clinical presentationAlthough patients with more severe thrombocytopenia may present with mucocutaneous bleeding, those diagnosed with thrombocytopenia on a routine blood count are often asymptomatic. 

The most common symptom of ITP is mucocutaneous bleeding, which may manifest as petechiae, ecchymoses, epistaxis, menorrhagia, oral mucosal, or gastrointestinal bleeding. 

Intracranial hemorrhage reported in 1.4% of adults.

Nonhemorrhagic clinical manifestations common among patients with ITP include fatigue and reduced health-related quality of life.

Mounting epidemiologic evidence suggests that ITP is associated with an increased risk of venous thromboembolism. 
Many patients with ITP are asymptomatic. For those who do have symptoms, these are primarily related to thrombocytopenia and bleeding, but patients can also experience fatigue and a reduced quality of life.

Thrombocytopenia in people with ITP is not necessarily protective against thrombosis. Several studies have documented an increased risk of thrombosis in people with ITP compared with controls.
Most patients are either asymptomatic at diagnosis, or present with mucocutaneous bleeding.
OverviewThere is no gold-standard laboratory test for ITP. The diagnosis of ITP is primarily made by excluding nonimmune causes of thrombocytopenia and investigating potential secondary causes. The most compelling evidence supporting a diagnosis of ITP is a platelet response to ITP-specific therapy.

Major diagnostic concerns in an adult with suspected ITP are twofold:

Distinguishing ITP from other causes of thrombocytopenia, which often have a similar presentation but may require completely different management approaches.

Determining whether the ITP is primary or secondary to an underlying condition that might also benefit from treatment.
Diagnosis of ITP is made only after other causes of thrombocytopenia are ruled out.
Suspect diagnosisThe diagnosis of ITP rests on a consistent clinical history, physical examination, and exclusion of other causes of thrombocytopenia.“We make a presumptive diagnosis of primary ITP when the history, physical examination, and laboratory testing (including review of the peripheral blood smear) do not reveal other potential etiologies for thrombocytopenia.”

“We make a presumptive diagnosis of secondary ITP in a patient with ITP and an underlying associated condition.”
Suspect diagnosis of primary ITP if isolated thrombocytopenia (peripheral blood platelet count < 100 × 109/L)

Suspect diagnosis of secondary ITP if isolated thrombocytopenia (peripheral blood platelet count < 100 × 109/L) and identifiable underlying immune-mediated cause.
Complete blood cell and reticulocyte count, examination of the peripheral blood smearAll patientsAll patientsAll patients
Screening for hepatitis C and HIV2All patientsAll patientsAll patients
Optional tests depending on clinical scenarioNMCoagulation studies, testing for H. pylori, antinuclear antibodies,3 Quantitative immunoglobulin levels,4 and thyroid function testing.Consider testing for quantitative immunoglobulin (Ig) levels and H. pylori testing where it may have clinical impact (in cases where eradication therapy would be used).

Hepatitis B virus testing.

There is insufficient evidence to support routine testing for bleeding time, antiplatelet antibodies, antiphospholipid antibodies, antinuclear antibodies, antithyroid antibodies and thyroid function testing, thrombopoietin levels, serum complement, platelet parameters on automated analyzers, or acute and persistent infections other than hepatitis B, hepatitis C, and HIV.
Bone marrow examinationBone marrow examination is not required routinely and is generally not useful for diagnosing ITP, but should be performed to exclude other causes of thrombocytopenia when atypical features such as unexplained anemia, lymphadenopathy, or splenomegaly are present. 

Failure to respond to first line therapy should prompt consideration of bone marrow examination and other causes of thrombocytopenia.

Bone marrow examination may also be warranted in elderly patients in whom myelodysplasia is suspected. 
Bone marrow examination may be indicated for patients with other unexplained cytopenias (anemia, leukopenia), dysplasia on the peripheral blood smear, other unexpected hematologic findings, or other causes of thrombocytopenia, when suspected.

Patients whose platelet counts do not respond to ITP therapy may warrant a bone marrow examination to investigate for myelodysplastic syndrome or other platelet production abnormalities such as acquired amegakaryocytic thrombocytopenia.
International Consensus Report 2019 states that a bone marrow examination should be considered in: 1) patients not responding to first-line therapy, 2) patients relapsing after remission, 3)
when splenectomy considered, 4) when other abnormalities are detected in the blood count or morphology.

American Society of Hematology (ASH) 2011 guideline states that a bone marrow examination is not necessary in adults of any age presenting with typical ITP (not addressed in 2019 guideline update).
OverviewIn contrast to children, ITP in adults evolves into a chronic disease in approximately 75% of patients. The goal of ITP management in adults is to maintain a hemostatic platelet count while minimizing the toxicity of therapy. The goal of treatment is to treat or prevent significant bleeding, not to normalize the platelet count. However, bleeding risk can be difficult to estimate.The goal of treatment is to achieve platelet count sufficient to manage and prevent severe bleeding (typically > 30 × 109/L).
Where to treatNMCritical or severe bleeding is treated in the hospital, often in the intensive care unit.

Most individuals with established ITP who have a platelet count ≥10 x 109/L without bleeding can be treated as outpatients.

Individuals with newly diagnosed ITP who have platelet counts >30 × 109/L and are not having bleeding symptoms generally do not require hospitalization.

Individuals with newly diagnosed ITP and platelet counts <10 × 109/L are typically hospitalized. 
Most patients can be treated in an outpatient setting. However, consider hospitalizing patients with newly diagnosed ITP and a platelet count of < 20 × 109/L, who are asymptomatic or have minor mucocutaneous bleeding.
Who to treatPlatelet counts <30 × 109/L may be associated with an increased bleeding risk. This platelet count threshold has been suggested by some experts as a cutoff for considering treatment of ITP. However, there is significant variability in bleeding among patients and therapy should be individualized. In individuals with ITP, the need for therapy to raise the platelet count is based on a rapid clinical assessment that includes: 1) presence of bleeding, and if present, the site, acuity, and severity, 2) platelet count, 3) other bleeding risk factors, 4) what treatments have been given previously for bleeding or thrombocytopenia, and their effectiveness, and 5) what treatment has been given for the current episode.

The platelet count threshold for initiating ITP treatment should be individualized and may vary based on bleeding history, age, comorbidities, occupation, lifestyle, need for antithrombotic therapy, and values and preferences.

Therapy to increase the platelet count in individuals who are not bleeding is generally appropriate if the platelet count is <20 x 109/L and generally not used if the platelet count is ≥30 x 109/L.

We treat the majority of individuals with platelet counts <20 x 109/L, and especially those with counts <10 x 109/L, even if they have no bleeding symptoms. This is based on the increased risk of bleeding with counts below 20 x 109/L and the greater risk below 10 x 109/L.

We treat the majority of individuals with minor bleeding. The platelet count is typically <50 x 109/L, often lower.
The 2019 International Consensus Report suggests treating patients to achieve minimum platelet count of > 20-30 × 109/L in asymptomatic patients.

The 2019 ASH guideline suggests treating newly diagnosed patients with platelet count < 30 × 109/L who are asymptomatic or have minor mucocutaneous bleeding with corticosteroids.
How to treatAlthough several first-line therapies are available, corticosteroids remain the initial treatment of choice because of their efficacy and low cost. Glucocorticoids and IVIG both raise the platelet count; they differ in their mechanisms of action, rapidity of platelet count increase, adverse effects, and costs.

In severe bleeding, minor bleeding, elective surgery, or severe thrombocytopenia without bleeding, we typically give glucocorticoids or IVIG. We generally prefer glucocorticoids because they are less expensive and can be easily administered in the outpatient setting without the need for an appointment in an infusion center. 
In nonemergency setting, patients with newly diagnosed ITP and bleeding should receive corticosteroids.
CorticosteroidsAlthough several first-line therapies are available, corticosteroids remain the initial treatment of choice because of their efficacy and low cost. At least 75% of patients initially respond to corticosteroids, although tapering usually precipitates relapse, and ultimately only 20% to 25% of patients are able to maintain a durable platelet response after steroid discontinuation. Standard corticosteroid regimens include prednisone 1 mg/kg/day (typically tapered over ∼6 weeks) and high-dose dexamethasone (40 mg daily for 4 days given over 1 to 6 cycles repeated every 2 to 4 weeks). Typical initial treatment involves administration of a glucocorticoid (dexamethasone, 40 mg orally or intravenously once per day for four days, or prednisone, 1 mg/kg daily for one to two weeks, followed by a gradual taper).In nonemergency setting, patients with newly diagnosed ITP and bleeding should receive corticosteroids.
IVIGFor patients who do not achieve a response with corticosteroids, therapy may be supplemented with intermittent IVIG or anti-D.5“We generally reserve IVIG for settings in which there is a need to raise the platelet count within 12 to 24 hours, or for individuals who cannot tolerate glucocorticoids (eg, due to diabetes mellitus or significant adverse effects).”In patients who have contraindications to steroids.
Second-line therapy for patients who do not respond to first-line therapy or relapse after it is taperedOptions for second-line therapy include rituximab, TPO receptor agonists, or splenectomy. NMNM
Emergency treatment of ITPPatients with new-onset, severe thrombocytopenia (<20 × 109/L) and bleeding should be hospitalized.

Management of bleeding may require platelet transfusions in combination with high doses of parenteral corticosteroids (methylprednisolone 1 g intravenously daily for 2 to 3 days) supplemented with IVIG (1 g/kg for 1 to 2 days).
Immediate treatment is required for critical bleeding (bleeding into a critical anatomical site or that causes hemodynamic instability or respiratory compromise), includes: 1) platelet transfusions,6 2) IVIG,7 3) glucocorticoids. One or more of the following: 1) combination high-dose IV corticosteroids plus IVIG, 2) platelet transfusions, especially if the patient presents with intracranial hemorrhage, 3) thrombopoietin receptor agonists (TPO-RAs) may be used, although responses may require 5-10 days, 4) additional options include anti-D immune globulin, vincristine, antifibrinolytics, and emergency splenectomy.
*American Society of Hematology Self-Assessment Program, Seventh Edition. ** Accessed April 2022. Abbreviations: ITP, immune thrombocytopenia; GPs, glycoproteins; CVID, common variable immune deficiency; IVIG, intravenous immune globulin.

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