Immune thrombocytopenia

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Immune thrombocytopenia (ITP) is a type of thrombocytopenia involving the formation of autoantibodies against platelets. ITP may be a primary disease or occur secondary to a known trigger (e.g., SLE, HIV, hepatitis C, medications). It is commonly seen in children as a self-limiting illness following a viral infection, and in adults as a chronic illness. Most patients are asymptomatic, however, patients may occasionally present with minor mucocutaneous bleeding (e.g., petechiae, purpura, epistaxis) or, rarely, with severe bleeding (e.g., gastrointestinal or intracranial hemorrhage). Treatment recommendations vary depending on the presence and severity of symptoms. First-line medical therapy consists of corticosteroids, IVIG, or anti-D immunoglobulin, and is indicated for patients with non-life-threatening symptoms affecting their quality-of-life, and for adults with little-to-no symptoms and platelet counts below 30,000/mm³. Children with little-to-no symptoms can typically be managed with observation alone regardless of platelet count. Second-line treatments (i.e., thrombopoietin receptor agonists, rituximab, splenectomy) may be required for refractory, persistent or chronic cases. Patients with life-threatening hemorrhage, neurological symptoms, or those requiring urgent surgical interventions should receive immediate combination medical therapy (i.e., corticosteroids plus IVIG) along with platelet transfusions and hemostatic control interventions when necessary.

See also “Thrombocytopenia.”

Immune thrombocytopenia has previously been referred to as idiopathic thrombocytopenic purpura, however, this term is outdated.

• Primary immune thrombocytopenia: : an autoimmune disorder characterized by isolated thrombocytopenia (< 100,000/mm³) with no known precipitating cause [2]
• Secondary immune thrombocytopenia: an autoimmune hematologic disorder causing isolated thrombocytopenia that is secondary to an identifiable trigger (see “Etiology”).
• Newly diagnosed ITP: all cases within the first 3 months of diagnosis [2]
• Persistent ITP: ITP lasting 3–12 months
• Chronic ITP: ITP lasting > 12 months

• Prevalence: up to ∼ 10 per 100,000 [3][4]
• ♀ > ♂ [3]
• Children
  • Highest prevalence in children < 5 years of age [3]
  • Typically self-limiting after a viral infection; 80% of cases resolve within 12 months [5]
• Adults
  • Highest prevalence in individuals > 55 years of age [3]
  • 80% of patients develop chronic ITP. [5]
  • An incidental finding on a routine CBC in 25% of cases [6]

Epidemiological data refers to the US, unless otherwise specified.

• Primary ITP: idiopathic (most common) [7]
• Secondary ITP associated with:
  • Autoimmune disorders: SLE, antiphospholipid syndrome
  • Malignancy: lymphoma, leukemia (particularly CLL)
  • Infection: HIV, HCV
  • Drugs: e.g., quinine,; beta-lactam antibiotics, carbamazepine, heparin, vaccines, linezolid, sulfonamides, vancomycin, TMP-SMX, antiepileptics [8]

Antiplatelet antibodies (mostly IgG directed against, e.g., GpIIb/IIIa, GpIb/IX) bind to surface proteins on platelets → sequestration by spleen and liver → ↓ platelet count → bone marrow megakaryocytes and platelet production increase in response (in most cases) [9]

Clinical features can correlate with platelet count (see also “Clinical features of thrombocytopenia” and “Clinical features of bleeding disorders”).

• Most commonly
  • Asymptomatic
  • Splenomegaly is typically absent. [10]
• Minor mucocutaneous bleeding (less common)
  • Subcutaneous: e.g., bruising, petechiae, purpura
  • Mucosal: e.g., mild epistaxis, gingival bleeding
• Other types of bleeding (rare)
  • Gastrointestinal: e.g, melena
  • Genitourinary: e.g., hematuria, menorrhagia
  • CNS: e.g., features of intracranial hemorrhage
  • Prolonged or excessive traumatic or surgical bleeding

Splenomegaly is very unusual in ITP and makes other diagnoses more likely!

There should be suspicion for ITP in a child with thrombocytopenia and petechiae following a viral illness!

ITP is a diagnosis of exclusion; patients typically have a low platelet count with no other abnormalities. [5]

Laboratory studies [10][11][12]

Routine

• CBC: ↓ platelet count (< 100,000/mm³)
• Coagulation panel: usually normal
• Bleeding time: may be prolonged
• Peripheral blood smear: normal to large platelets [13]

Additional investigations

• All adults: HIV and HCV screening
• Bone marrow biopsy
  • Consider in atypical cases or if there is diagnostic uncertainty
  • Findings: normal or ↑ megakaryocytes [5]
• Additional testing as required: consider in suspected secondary ITP, e.g., antinuclear antibodies in SLE or H. pylori testing if the patient has GI symptoms or is from a high prevalence area

See “Differential diagnosis of platelet disorders.”

The differential diagnoses listed here are not exhaustive.

Approach

These recommendations are consistent with the 2019 American Society of Hematology ITP guidelines and the 2019 International Consensus Report on primary ITP investigation and management. [14][15]

Patients that can be managed as outpatients should receive expedited hematology follow-up within 24–72 hours. [14]

Conservative management [14][15]

• Indications for observation
  • Children: no symptoms or only mild mucocutaneous bleeding with any platelet count
  • Adults: no symptoms or minor mucocutaneous bleeding with a platelet count of ≥ 30,000/mm³
• All patients: Refer to hematology for regular monitoring and counseling on bleeding risks.

First-line medical therapy [14][15]

• Preferred: Corticosteroids [17]
  • Dexamethasone [14]
  • OR prednisone [14][15]
• Alternatives: if contraindication, non-response, or intolerance to corticosteroids
  • Intravenous immunoglobulin (IVIG)
  • OR anti-Rho(D) immunoglobulin
    • FDA black box warning: risk of intravascular hemolysis
    • In-hospital monitoring: recommended for at least 8 hours after administration
      • Urinalysis for hematuria and hemoglobinuria prior to therapy, and at 2 hours and 4 hours after administration.
      • Order hemolysis workup in patients with characteristic clinical features (e.g., back pain, chills, urine discoloration)
  • Side effects [17]
    • IVIG: e.g., thrombosis, aseptic meningitis, infusion reactions
    • Anti-Rho(D) immunoglobulin: e.g., intravascular hemolysis that can cause anemia, multiorgan dysfunction, AKI, renal failure, DIC, or death

Anti-Rho(D) immunoglobulin can cause potentially fatal intravascular hemolysis in patients with ITP. Close monitoring is recommended.

Subsequent therapeutic options [15]

The following options should be considered in consultation with a specialist for patients with newly-diagnosed ITP refractory to first-line medical therapy, or persistent/chronic ITP.

• Thrombopoietin receptor agonists (TPO-RAs)
  • Romiplostim
  • Eltrombopag
  • Avatrombopag
• Rituximab [2]
• Splenectomy
  • Indications
    • Treatment-resistant thrombocytopenia lasting > 12 months
    • Severe bleeding that does not respond to any other treatment
  • Procedure: Minimally invasive laparoscopic surgery is preferred.
  • Complications: See “Asplenic sepsis.”
  • Prevention of complications: See “Management of asplenic patients.”