What is Idiopathic Thrombocytopenic Purpura (ITP), its epidemiology, pathophysiology, clinical features, diagnosis, management, and prognosis?

Idiopathic Thrombocytopenic Purpura: Comprehensive Overview

Definition

ITP is an autoimmune disorder where the immune system produces antibodies and cytotoxic T cells against platelet surface proteins, leading to both accelerated platelet destruction and impaired platelet production, resulting in isolated thrombocytopenia without another identifiable cause. 1

• The disease involves a dual mechanism: historically thought to be purely destructive, newer evidence demonstrates that platelet production is decreased in many patients, challenging the traditional understanding 1, 2
• The diagnosis is made by exclusion of other causes of thrombocytopenia, requiring a platelet count below the laboratory's normal range 3, 4

Epidemiology

• ITP affects both children and adults, with the median age in pediatric studies being approximately 9-10 years 5
• In pediatric populations studied, approximately 57-73% were female 5
• The condition can present at any age, with different clinical courses in children versus adults 3

Pathophysiology and Immunology

The central pathophysiologic mechanism involves autoantibodies, particularly IgG antibodies against platelet glycoproteins GPIIb/IIIa and GPIb/IX, leading to premature platelet destruction by the reticuloendothelial system in the spleen and liver. 6, 7

Immune Mechanisms:

• Antibody-coated platelets are destroyed by reticuloendothelial cells, overwhelming the bone marrow's compensatory capacity to increase platelet production 6, 8
• Cytotoxic T cells also contribute to platelet destruction, representing a cellular immune component beyond antibody-mediated destruction 4
• Multiple cellular immune dysfunctions occur, including failure of self-antigen recognition and tolerance, abnormal cell surface molecules, altered Th1/Th2 cytokine profiles, impaired megakaryocytopoiesis, and impaired cell-mediated cytotoxicity 7
• T cells play a pivotal role in the pathophysiology, with B cell production of autoantibodies depending on these cellular mechanisms 7

Classification and Triggers

Primary vs. Secondary ITP:

• Primary ITP occurs in isolation without an identifiable trigger, representing an autoimmune response to an unknown stimulus 1
• Secondary ITP is associated with identifiable triggers including autoimmune diseases (particularly antiphospholipid antibody syndrome), viral infections (hepatitis C, HIV), and certain drugs 1

Drug-Induced Thrombocytopenia:

• Drug-induced thrombocytopenia must always be considered and may be difficult to exclude 3, 1
• Most commonly implicated drugs include quinidine and heparin among hospitalized patients 3
• Other associated medications include sulfonamides, sulfonylureas, dipyridamole, salicylates, and aspirin 3
• Alcohol causes thrombocytopenia through multiple mechanisms, including chronic liver disease and platelet pooling 3, 1
• Discontinuation of the offending agent may resolve thrombocytopenia without need for immunosuppressive therapy 1

Clinical Features

Bleeding Manifestations by Severity:

Mild Thrombocytopenia (50-150 × 10⁹/L):

• Often asymptomatic and discovered incidentally during routine blood counts 9
• Many patients tolerate these levels without clinical bleeding 9

Moderate Thrombocytopenia (20-50 × 10⁹/L):

• Easy bruising, petechiae, and purpura are common manifestations 9
• Minor purpura may be the only finding 3

Severe Thrombocytopenia (<20 × 10⁹/L):

• Increased risk of serious bleeding including gastrointestinal bleeding and intracranial hemorrhage 9
• Mucous membrane bleeding that may require clinical intervention 3
• Spontaneous serious bleeding is rare (<5% of patients) with platelet counts >10,000, but occurs in approximately 40% with counts <10,000 3

Important Clinical Considerations:

• The risk of bleeding is not perfectly correlated with platelet count alone; additional factors such as age, lifestyle, and comorbidities significantly influence bleeding risk 9
• Intracranial hemorrhage risk is approximately 0.5% in children and 1.5% in adults 9
• Medications affecting platelet function (aspirin, NSAIDs) can increase bleeding risk independent of platelet count 9
• ITP can be asymptomatic despite low platelet counts 9

History and Physical Examination Elements:

Critical History Components:

• Bleeding history including hemostasis with prior surgeries and pregnancies 3
• Systemic symptoms: weight loss, fever, headache, symptoms of autoimmune disorders (arthralgias, skin rash, alopecia, venous thrombosis) 3
• Complete medication history, including heparin, alcohol, quinidine/quinine, sulfonamides, and aspirin 3
• Risk factors for HIV infection 3
• Family history of thrombocytopenia and autoimmune disorders 3
• Comorbid conditions increasing bleeding risk (gastrointestinal disease, CNS disease, urologic disease) 3
• Lifestyle activities, particularly vigorous and potentially traumatic activities 3
• Transfusion history 3

Physical Examination Focus:

• Assessment of type and severity of bleeding 3
• Splenomegaly provides evidence against ITP; less than 3% of ITP patients have splenomegaly, corresponding with the 3% of healthy young adults with palpable spleens 3
• Signs of liver disease or lymphadenopathy suggesting lymphoproliferative or autoimmune disorders 3
• Evidence for infection, particularly bacteremia or HIV 3
• Evidence for autoimmune disease (arthritis, goiter, nephritis, cutaneous vasculitis) 3
• Evidence for thrombosis 3
• Neurologic function and funduscopic examination to establish baseline 3
• Hearing impairment and skeletal anomalies suggesting congenital thrombocytopenia 3

Laboratory Findings

Initial Blood Work:

• Thrombocytopenia must be confirmed by direct examination of the peripheral blood smear to distinguish true thrombocytopenia from pseudothrombocytopenia 3
• Pseudothrombocytopenia occurs in approximately 0.1% of adults, most commonly due to platelet agglutinins causing clumping in EDTA anticoagulant 3

Tests of Uncertain Necessity at Presentation (Per Expert Panel):

For establishing diagnosis in adults, tests with uncertain appropriateness include: 3

• ANA (antinuclear antibody)
• Direct antiglobulin test
• Lupus anticoagulant/antiphospholipid antibodies
• Chemistry profile
• Coagulation studies
• HIV testing
• Bone marrow examination

The panel considered platelet-associated IgG assay both unnecessary and inappropriate for diagnosis 3

Peripheral Smear Findings

Consistent with ITP Diagnosis:

• Thrombocytopenia with platelets normal in size or larger than normal; consistently giant platelets (approaching the size of red blood cells) should be absent 3
• Normal red blood cell morphology 3
• Normal white blood cell morphology 3

Findings NOT Consistent with ITP:

• Red blood cell poikilocytosis, schistocytes, or predominant giant platelets 3
• Red blood cell poikilocytosis, schistocytes, polychromatophilia (unless response to bleeding) 3
• Leukocytosis or leukopenia with immature or abnormal cells (though atypical lymphocytes and eosinophilia may occur in children with ITP) 3

Bone Marrow Findings

• Bone marrow examination is of uncertain necessity for establishing diagnosis at presentation in both children and adults 3
• When performed, typically shows normal or increased megakaryocytes with normal morphology 8
• The bone marrow demonstrates impaired megakaryocytopoiesis as part of the disease pathophysiology 7

Complications

Bleeding Complications:

• Life-threatening bleeding, particularly intracranial hemorrhage, represents the most serious complication 3, 9
• Gastrointestinal bleeding in severe thrombocytopenia 9
• Central nervous system bleeding requiring baseline neurologic assessment 3

Paradoxical Thrombotic Risk:

• Certain thrombocytopenic conditions can paradoxically increase thrombotic risk rather than just bleeding risk 10
• In some patient populations, the risk of venous thromboembolism is not reduced despite low platelet counts 10

Differential Diagnosis

Key Conditions to Exclude:

Drug-Induced Thrombocytopenia:

• Must always be considered; may be difficult to exclude 3, 1
• Requires thorough medication history 1

Pseudothrombocytopenia:

• EDTA-induced platelet clumping 3
• Confirmed by peripheral smear review 3

Secondary Causes:

• HIV infection (commonly associated with thrombocytopenia) 3
• Bacteremia or viral infection 3
• Thrombotic thrombocytopenic purpura (suggested by acute anemia, neurologic, or renal abnormalities) 3
• Autoimmune disorders (lupus, antiphospholipid syndrome) 3, 1
• Chronic liver disease with splenomegaly 3
• Lymphoproliferative disorders 3

Congenital Thrombocytopenias:

• Suggested by hearing impairment and skeletal anomalies 3
• Family history of thrombocytopenia 3

Management and Treatment

Hospitalization Criteria:

Appropriate for Hospitalization:

• Children with severe, life-threatening bleeding regardless of platelet count 3
• Children with platelet count <20,000 and mucous membrane bleeding that may require clinical intervention 3
• Children with platelet counts <20,000 who may be inaccessible or noncompliant 3

Inappropriate for Hospitalization:

• Children with platelet count 20,000-30,000 who are asymptomatic 3
• Children with platelet count >30,000 who are either asymptomatic or have only minor purpura 3

Treatment Goals and Principles:

The goal of treatment is to raise the platelet count to high enough levels to prevent bleeding using the least toxic therapy, recognizing the generally benign nature of the illness. 6

• Treatment is clearly required only for patients with severe bleeding and/or extremely low platelet counts (<10 × 10⁹/L) 8
• Many mild cases (platelets >30 × 10⁹/L) do not require treatment 4
• The primary goal is to maintain platelet count at a safe level with minimal side effects 4
• Essentially all evidence regarding treatment efficacy is indirect, inferred by measuring surrogate outcomes (platelet count) rather than clinical bleeding endpoints 3

Treatment Modalities:

First-Line Therapies:

• Corticosteroids remain a mainstay of treatment, aiming to reduce platelet destruction through immunosuppression 6, 4
• Intravenous immunoglobulin (IVIG) for patients requiring rapid platelet count elevation 6, 4
• Anti-D immunoglobulin (in Rh-positive, non-splenectomized patients) 5, 4

Splenectomy:

• Splenectomy is the single most effective treatment of ITP 4
• Recommended after 3-6 months if spontaneous remission has not occurred and side effects from medical therapy are significant 4
• Performed in patients who fail to respond to primary treatment 3

Newer Thrombopoietic Agents:

• Romiplostim (Nplate) and eltrombopag are thrombopoietin receptor agonists that stimulate platelet production in ITP patients not responsive to standard treatments 2
• These agents bear no structural resemblance to thrombopoietin but bind and activate the thrombopoietin receptor 2
• Romiplostim dosing starts at 1 mcg/kg weekly, titrated up to maximum 10 mcg/kg to maintain target platelet count 50-200 × 10⁹/L 5
• In pediatric studies, 52% achieved durable platelet response (≥6 weekly counts ≥50 × 10⁹/L during weeks 18-25) versus 10% with placebo 5
• Long-term pediatric data shows mean 50.6% of time with platelet response (≥50 × 10⁹/L) within first 6 months 5

Rituximab:

• Newer therapy remodeling conventional treatment algorithms 6
• Used in refractory cases 6

Refractory ITP Management:

• Patients failing splenectomy and first- and second-line therapies present a management dilemma 4
• Therapeutic options are limited, available treatments potentially toxic, and chances of sustained response low 4
• Observation with no active treatment is a reasonable option for refractory patients 4
• Immune suppressant medications and cytotoxic drugs continue to be used with some success, though estimates are limited by lack of randomized trials using clinical endpoints 6

Activity Restrictions:

• Patients with platelet counts below 50 × 10⁹/L should avoid contact sports and activities that increase trauma risk 10
• Lifestyle considerations should influence treatment goals; sedentary individuals may tolerate lower platelet counts than those with high-exertion activities or potential trauma 3

Emergency Treatment:

• For life-threatening bleeding, multiple regimens are justified despite lack of published efficacy data, given the serious consequences of severe hemorrhage 3
• Conventional critical care measures should be implemented 3
• Rescue medications (corticosteroids, platelet transfusions, IVIG, azathioprine, anti-D immunoglobulin, danazol) are permitted for severe cases 5

Prognosis

Natural History:

• The disease is heterogeneous with regard to severity and clinical course, and unpredictable in response to therapy 8
• After 3-6 months, spontaneous remission may occur 4
• In pediatric long-term studies, 29.6% of patients required rescue medications over extended treatment periods 5
• The generally benign nature of the illness should be recognized when making treatment decisions 6

Response to Treatment:

• Splenectomy provides the highest likelihood of sustained response 4
• Thrombopoietic agents offer good prospects for maintaining safe long-term platelet counts in refractory patients 4
• Early aggressive therapy may alter the natural history of this self-perpetuating illness 6