Idiopathic Thrombocytopenic Purpura: Comprehensive Overview
Definition
ITP is an autoimmune disorder characterized by immunologic destruction of otherwise normal platelets, resulting in isolated thrombocytopenia in the absence of other identifiable causes. 1 The condition is fundamentally a diagnosis of exclusion, defined by a low platelet count (typically <100 × 10⁹/L) without another apparent cause. 2 The disease involves a dual mechanism: both increased platelet destruction and impaired platelet production due to autoimmune mechanisms. 3, 1
Epidemiology
Incidence: ITP occurs at a rate of 2-5 cases per 100,000 population. 1
Age distribution: The acute form predominantly affects children between the second and fourth year of age, while chronic ITP is more common in adults and children older than 10 years. 4, 1
Sex distribution: In children, the disease affects both sexes equally, whereas in adults, females are affected approximately three times more often than males. 5, 4
Spontaneous remission rates are highly age-dependent: 1
- 74% in children <1 year of age
- 67% in children between 1-6 years
- 62% in children 10-20 years
- Adults have significantly lower remission rates and are more likely to develop chronic disease
Mortality: Adults with ITP have a 1.3-2.2-fold higher mortality than the general population due to cardiovascular disease, infection, and bleeding. 1
Pathophysiology
The pathophysiology of ITP involves multiple interconnected immune dysfunctions that ultimately lead to thrombocytopenia through both destructive and productive mechanisms. 3, 6
Primary Mechanisms
Antibody-mediated destruction: The immune system produces IgG antibodies against platelet surface glycoproteins, particularly GPIIb/IIIa, which opsonize platelets for destruction by the reticuloendothelial system in the spleen and liver. 5, 7, 4
Cytotoxic T cell involvement: Cytotoxic T cells directly contribute to platelet destruction alongside antibody-mediated mechanisms. 3
Impaired platelet production: Contrary to historical belief that ITP was solely a destructive process, newer evidence demonstrates that platelet production is decreased in many patients, as the bone marrow cannot adequately compensate for the accelerated destruction. 3, 1, 6
Shortened platelet lifespan: The half-life of platelets in ITP is markedly shortened due to opsonization and subsequent removal by reticuloendothelial cells. 4, 8
Immunology
ITP represents a multi-dysfunctional breakdown in immune regulation involving both cellular and humoral immunity. 7
Cellular Immune Dysfunction
T cell dysregulation: T cells play a pivotal role in the pathophysiology, with abnormalities in T cell function driving the autoimmune response. 7
Failure of self-antigen recognition and tolerance: The immune system loses its ability to recognize platelet antigens as "self," leading to autoantibody production. 7
Altered Th1/Th2 cytokine profiles: Imbalanced cytokine production contributes to the perpetuation of the autoimmune response. 7
Abnormal cell surface molecules: Alterations in cell surface markers on immune cells contribute to immune dysregulation. 7
Impaired cell-mediated cytotoxicity: Regulatory mechanisms that normally prevent autoimmunity are compromised. 7
Humoral Immune Dysfunction
Autoantibody production: B cells produce IgG antibodies directed against platelet membrane glycoproteins, with GPIIb/IIIa being the most common target. 7, 4
Impaired megakaryocytopoiesis: Autoantibodies may also target megakaryocytes in the bone marrow, further impairing platelet production. 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. 3, 1
Secondary ITP: Associated with identifiable triggers and underlying conditions. 3, 1
Triggers and Associated Conditions
Viral infections: Hepatitis C, HIV, and other viral infections are common triggers, particularly in children where acute ITP often follows viral illness. 3, 1, 4
Autoimmune diseases: Antiphospholipid antibody syndrome, systemic lupus erythematosus, and other autoimmune disorders. 3
Drugs: Quinidine, heparin, and various other medications can trigger secondary ITP. 3
Alcohol: Can cause thrombocytopenia through multiple mechanisms. 3
Helicobacter pylori infection: Associated with ITP in some patients. 9
Lymphoproliferative disorders: Can present with secondary thrombocytopenia. 9
Temporal Classification
- Newly diagnosed: Initial presentation
- Persistent: 3-12 months duration
- Chronic: ≥12 months duration 1
Clinical Features
Most patients with ITP present with platelet-related bleeding, though the condition may be first detected by incidental discovery of thrombocytopenia on routine blood counts. 2
Bleeding Manifestations
Cutaneous bleeding: Petechiae and purpura are the most common manifestations, often appearing suddenly without other signs of illness. 1, 4
- Epistaxis (nosebleeds)
- Oral bleeding
- Gastrointestinal hemorrhage
- Genitourinary bleeding (hematuria)
- Menorrhagia in adolescent females
Severe bleeding: Reported in 9.5% of adults and 20.2% of children. 1
Intracranial hemorrhage: The most serious complication, occurring in 1.4% of adults and 0.1-0.4% of children, with most cases occurring within the first 5 weeks of diagnosis. 1, 9
Correlation with Platelet Count
No strict correlation exists between platelet count and bleeding volume, though bleeding risk increases significantly when platelet count falls below 10 × 10⁹/L. 4, 9
Many patients remain asymptomatic with minimal symptoms such as bruising and petechiae despite low platelet counts. 1
Physical Examination
Physical examination should be normal except for bleeding manifestations. 9
The presence of splenomegaly, hepatomegaly, or lymphadenopathy excludes primary ITP and mandates investigation for secondary causes. 9, 1
Fever, weight loss, bone pain, or other systemic symptoms suggest alternative diagnoses. 9
Laboratory Findings
A complete blood count and examination of the peripheral blood smear are essential in ITP. 2
Complete Blood Count
Isolated thrombocytopenia (platelet count <100 × 10⁹/L) is the defining feature of ITP. 9
Hemoglobin and hematocrit are normal unless anemia results from chronic blood loss (which would be microcytic). 9
White blood cell count and differential are normal, though atypical lymphocytes and eosinophilia may occur in children with ITP. 2, 9
Coagulation Studies
Bleeding time is prolonged. 4
Clot retraction may be prolonged or completely absent. 4
PT, aPTT, and fibrinogen are normal, as ITP is a disorder of platelet destruction, not coagulation factor deficiency. 9
The Rumpel-Leede test is positive. 4
Platelet-Associated Antibodies
Detection of antiplatelet antibodies is technically difficult and established in only about 30% of cases. 4
Platelet antigen-specific antibody testing has uncertain appropriateness for routine diagnosis. 2
Anti-platelet antibodies have insufficient evidence for routine diagnostic use and do not change management. 9
Peripheral Smear Findings
The peripheral blood smear serves multiple critical diagnostic functions: confirming true thrombocytopenia, identifying characteristic ITP features, and excluding alternative diagnoses. 9
Findings Consistent with ITP 2
Thrombocytopenia with platelets that are normal in size or may appear larger than normal, but consistently giant platelets (approaching the size of red blood cells) should be absent.
Normal red blood cell morphology without poikilocytosis or schistocytes.
Normal white blood cell morphology without immature or abnormal cells (although atypical lymphocytes and eosinophilia may occur in children with ITP).
Findings NOT Consistent with ITP 2
Red blood cell poikilocytosis, schistocytes, or polychromatophilia (unless response to bleeding) suggest thrombotic microangiopathy or other disorders.
Leukocytosis or leukopenia with immature or abnormal cells suggest bone marrow disorders such as leukemia or myelodysplastic syndrome.
Predominantly giant platelets approaching red blood cell size suggest inherited thrombocytopenias such as MYH9-related disease or Bernard-Soulier syndrome.
Critical Importance
Never diagnose ITP without personally reviewing the peripheral blood smear, as automated counts can miss pseudothrombocytopenia, giant platelets, or schistocytes. 9
Pseudothrombocytopenia (EDTA-dependent platelet clumping) must be excluded by manual peripheral blood smear examination by a qualified hematologist or pathologist. 9
Bone Marrow Findings
Bone marrow examination is generally unnecessary in patients with typical ITP features but becomes mandatory in specific clinical situations. 1, 9
When Bone Marrow Examination is NOT Necessary 2, 1, 9
- Children and adolescents with typical ITP features (isolated thrombocytopenia, normal physical exam, no systemic symptoms)
- Patients with typical ITP presentation who respond to IVIg therapy
- Young adults (<60 years) with classic presentation and no atypical features
When Bone Marrow Examination IS Mandatory 1, 9
- Age ≥60 years (to exclude myelodysplastic syndromes, leukemias, or other malignancies)
- Systemic symptoms present (fever, weight loss, bone pain)
- Abnormal blood count parameters beyond thrombocytopenia (anemia, leukopenia, leukocytosis)
- Atypical peripheral smear findings (schistocytes, leukocyte inclusion bodies, predominant giant platelets)
- Before splenectomy in patients with persistent disease
- Minimal or no response to first-line ITP therapies (to exclude alternative diagnoses)
Expected Bone Marrow Findings in ITP
- Normal or increased megakaryocytes (compensatory response to peripheral platelet destruction)
- Otherwise normal marrow cellularity and morphology
- Absence of dysplasia, fibrosis, or infiltrative processes
Complications
Hemorrhagic Complications
Intracranial hemorrhage: The most serious complication with significant mortality risk, occurring in 1.4% of adults and 0.1-0.4% of children. 1, 9
Severe mucosal bleeding: Gastrointestinal hemorrhage, severe epistaxis, and hematuria can lead to significant anemia and require intervention. 1
Risk factors for serious bleeding include: 9
- Platelet count <10 × 10⁹/L
- Head trauma
- Concurrent use of medications affecting platelet function (aspirin, NSAIDs)
Long-Term Complications
Increased mortality in adults: 1.3-2.2-fold higher than the general population due to cardiovascular disease, infection, and bleeding. 1
Chronic disease burden: Approximately 10-15% of children and a higher proportion of adults develop chronic ITP requiring long-term management. 4, 1
Quality of life impact: Bleeding manifestations, activity restrictions, and treatment side effects significantly affect quality of life. 9
Differential Diagnosis
ITP is a diagnosis of exclusion requiring systematic evaluation to rule out other causes of thrombocytopenia. 1, 9
Pseudothrombocytopenia
- EDTA-dependent platelet clumping can falsely lower automated platelet counts and must be excluded by peripheral blood smear review. 9
Drug-Induced Thrombocytopenia
Numerous medications can cause thrombocytopenia, including heparin, quinidine, sulfonamides, antibiotics (vancomycin, cefazolin, oxacillin), and many others. 3, 9
A thorough medication history is essential, as discontinuation of the offending agent may resolve thrombocytopenia without need for immunosuppressive therapy. 3
Heparin-induced thrombocytopenia (HIT) typically presents 5-10 days after heparin exposure with moderate thrombocytopenia (30-70 × 10⁹/L) and paradoxical thrombosis risk. 9
Viral Infections
HIV and hepatitis C can cause thrombocytopenia that is clinically indistinguishable from primary ITP and may precede other symptoms by years. 9
Testing for HIV and HCV is mandatory in all adults with suspected ITP, regardless of risk factors. 9
Thrombotic Microangiopathies
Thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS) cause platelet consumption through microvascular thrombosis and present with schistocytes on peripheral smear. 2, 9
Disseminated intravascular coagulation (DIC) causes consumption of platelets and coagulation factors with abnormal coagulation studies. 9
Bone Marrow Disorders
Myelodysplastic syndromes, leukemias, and other malignancies can impair megakaryocyte function and present with thrombocytopenia, often with other cytopenias or abnormal cells. 9
Aplastic anemia presents with pancytopenia rather than isolated thrombocytopenia. 4
Inherited Thrombocytopenias
- MYH9-related disease, Wiskott-Aldrich syndrome, thrombocytopenia-absent radius syndrome, and other inherited conditions can mimic ITP but typically have characteristic features on peripheral smear (giant platelets) or associated physical findings. 9, 4
Autoimmune Disorders
Systemic lupus erythematosus, antiphospholipid syndrome, and other autoimmune diseases can cause secondary ITP. 3, 9
Testing for ANA, lupus anticoagulant/APLA has uncertain appropriateness but may be considered in patients with suggestive features. 2
Pregnancy-Related Thrombocytopenia
Gestational thrombocytopenia is the most common cause of thrombocytopenia in pregnancy, typically presenting with mild thrombocytopenia (platelet count >70 × 10⁹/L). 9
Preeclampsia/HELLP syndrome can cause thrombocytopenia in pregnant patients. 9
Other Causes
Chronic alcohol use can cause thrombocytopenia through bone marrow suppression. 9
Hypersplenism from any cause can sequester platelets and cause thrombocytopenia. 9
Common variable immune deficiency (CVID) can present with ITP as an initial manifestation. 9
Prognosis
The prognosis of ITP varies dramatically by age, with children having a generally favorable prognosis and high spontaneous remission rates, while adult ITP is more likely to become chronic. 1
Pediatric ITP
Spontaneous remission rates are age-dependent: 1
- 74% in children <1 year of age
- 67% in children between 1-6 years
- 62% in children 10-20 years
Acute ITP occurs in 80-90% of pediatric cases, with bleeding episodes lasting days to weeks but no longer than 6 months. 4
Mortality in pediatric ITP is low, almost exclusively due to intracranial hemorrhage (0.1-0.4% of cases). 1, 4
Severe bleeding occurs in 20.2% of children, though most cases are self-limited. 1
Adult ITP
Adults have significantly lower spontaneous remission rates and are more likely to develop chronic disease requiring long-term management. 1
Adults with ITP have a 1.3-2.2-fold higher mortality than the general population due to cardiovascular disease, infection, and bleeding. 1
Severe bleeding occurs in 9.5% of adults. 1
Intracranial hemorrhage occurs in 1.4% of adults, representing a more significant risk than in children. 1
Factors Affecting Prognosis
Age at presentation: Younger children have better prognosis than older children and adults. 1
Acute vs. insidious onset: Acute onset following viral infection (typical in children) has better prognosis than insidious onset (typical in adults). 4
Platelet count at presentation: While not strictly correlated with bleeding risk, very low counts (<10 × 10⁹/L) increase risk of serious hemorrhage. 9, 4
Response to initial therapy: Patients who respond well to first-line treatments generally have better long-term outcomes. 1
Presence of secondary causes: Secondary ITP associated with HIV, HCV, or autoimmune diseases may have different natural history depending on the underlying condition. 3, 9
Long-Term Outcomes
Regular monitoring of platelet counts and bleeding symptoms is essential throughout the disease course. 1
The intermittent form of ITP (rarest form) is characterized by periods of normalization in platelet counts with relapses at intervals of 1-3 months. 4
Quality of life considerations are paramount, as many patients with chronic ITP require ongoing management and activity modifications. 9