Immune Thrombocytopenic Purpura

Immune thrombocytopenic purpura (ITP), formerly known as idiopathic thrombocytopenic purpura, is a condition that develops secondary to immune-mediated destruction of platelets, resulting in thrombocytopenia (platelet count < 100,000/mm³). Immune thrombocytopenic purpura can be either primary or secondary due to drugs or underlying disease. The diagnosis is usually one of exclusion. Many patients with ITP are asymptomatic. When present, symptoms are primarily related to bleeding (e.g., bruising, petechiae, epistaxis), but fatigue is also common. The severity of thrombocytopenia in patients with ITP is variable. When platelet counts drop to < 20,000/mm³, the risk of serious bleeding increases. Treatment may include platelet transfusion, steroids, IV immune globulins, and/or splenectomy. Some cases remit spontaneously; others generally have a good prognosis with appropriate therapy.

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Overview

Definition

Immune thrombocytopenic purpura (ITP) is an acquired thrombocytopenia that results from autoantibodies targeting platelet antigens.

Epidemiology

  • Annual prevalence in the United States:
    • 8 cases per 100,000 children
    • 12 cases per 100,000 adults
  • 40% of patients are younger than 10 years of age.
  • The peak incidence in children is 2–4 years of age.
  • The peak incidence in adults is 20–50 years of age.
  • In adults, women are affected more than men.
  • ⅕–⅓ of cases are asymptomatic.

Etiology

  • Antibody-mediated destruction of circulating platelets
  • Antibodies against platelet surface glycoprotein (GP)IIb/IIIa
  • An additional mechanism may include autoimmune destruction of megakaryocytes (platelet progenitors)
  • Primary: isolated thrombocytopenia (platelets < 100,000/mm³)
  • Secondary (following an inciting event):
    • Underlying infections (e.g., Helicobacter pylori (H. pylori), HCV, cytomegalovirus, varicella zoster virus, EBV, HIV)
    • Autoimmune disorders (e.g., systemic lupus erythematosus (SLE))
    • Lymphoproliferative disorders 
  • Drug-induced: quinine, sulfonamides, heparin

Pathophysiology and Clinical Presentation

Pathophysiology

  • Anti-GPIIb/IIIa are IgG antibodies produced by B cells.
  • The production is driven by CD4+ helper T cells.
  • Splenic macrophages are the major antigen-presenting cells.
  • Anti-GPIIb/IIIa antibodies bind to the platelet-surface glycoprotein.
  • Tagged platelets are sequestered in the spleen by splenic macrophages.
  • Platelet morphology in ITP is normal.
  • Impaired thrombopoiesis in the bone marrow cannot maintain a normal count of circulating platelets

Clinical presentation

Onset:

  • Acute:
    • Most common presentation
    • Usually follows a vaccination or viral illness (up to 6 months)
    • More common in children
    • Typically resolves in 6 months
    • Can be asymptomatic
  • Chronic:
    • Persists > 12 months
    • Insidious
    • Usually presents with an autoimmune disorder or chronic illness
    • More common in adults
    • More common in women

Clinical manifestations: 

  • Asymptomatic: 
    • Many patients are asymptomatic.
    • Patients with platelet counts > 50,000/mm³ rarely have bleeding symptoms.
    • Fatigue can be the only presenting symptom in some.
  • Mild: 
    • Platelet count 30,000–50,000/mm³ 
    • Petechiae
    • Prolonged bleeding post-injury
    • Excessive menstrual bleeding
    • Epistaxis
  • Moderate:
    • Platelet count 10,000–30,000/mm³ 
    • Easy bruising
    • Spontaneous bleeding
    • Purpura (nonpalpable; usually dependent areas)
  • Severe:
    • Platelet count less than 10,000/mm³ 
    • Intracranial hemorrhage
    • GI bleeding
    • Potential hemorrhagic shock

Diagnosis

History

  • Recent infection
  • Medications
  • Underlying chronic conditions
  • Spontaneous bruising, bleeding with minor trauma, and/or nosebleeds
  • Heavy menses
  • Unexplained fatigue
  • Family history (to rule out other causes of thrombocytopenia)

Physical exam

  • Skin and mucous membranes:
    • Petechiae
    • Bruises
    • Nonpalpable purpura
    • Hemorrhagic blisters in mucous membranes (“wet purpura”; a predictor of more severe bleeding)
  • Sometimes no physical exam findings
  • Splenomegaly is not the presenting symptom of ITP.

Laboratory studies

  • Hematology:
    • CBC: thrombocytopenia (platelets < 100,000 /mm³) with no other abnormalities
    • Bleeding time: prolonged
    • PT, aPTT, INR: normal
  • Serology:
    • HIV/HCV to rule out disease-associated thrombocytopenia
    • H. pylori (associated with ITP)
    • ANA if SLE suspicion
  • Blood smear: large platelets (not a universal finding)
  • Bone marrow aspirate:
    • Does not need to be performed routinely for ITP diagnosis
    • Only done to rule out other bone marrow disorders
    • Shows normal or increased number of megakaryocytes (normal morphology)

Management

Treatment

Indications: 

  • Platelets < 30,000/mm³ 
  • Active bleeding

Mild bleeding:

  • Platelet transfusion
  • Glucocorticoids

Severe bleeding (GI/intracranial; platelet count: < 10,000/mm³):

  • Platelet transfusion
  • Intravenous immune globulin
  • Anti-D/Rho(D) immune globulin:
    • For patients with rhesus factor (Rh)+ blood type
    • Saturates macrophages with anti-D–coated RBCs
    • Some hemolysis is expected but slows down platelet destruction.

Additional therapies for active/persistent bleeding:

  • IV fluid resuscitation/blood transfusion
  • Remove precipitating trauma (if any)
  • Stop offending drugs
  • Antifibrinolytic therapy (tranexamic acid)
  • Recombinant factor Ⅶa 
  • Thrombopoietin receptor agonists
  • Emergent splenectomy is a last resort for failure of medical management.

No bleeding and platelet count > 30,000/mm³:

  • Monitor, observe, educate
  • Treatment is not required.

Avoid:

  • Antiplatelet medications
  • Anticoagulants
  • Trauma

Recurrent/refractory episodes:

  • If steroid dependent: Splenectomy is a reasonable option.
  • Thrombopoietin receptor agonists may be considered if splenectomy is contraindicated.

Post-splenectomy ITP/refractory to steroids:

  • Thrombopoietin (romiplostim, eltrombopag)
  • Immunomodulators (azathioprine, cyclophosphamide, rituximab)

Prognosis

  • 80% of children have spontaneous remission.
  • 10% of adults have spontaneous remission (usually within the 1st 6 months).
  • ⅓–⅔ of patients will achieve stable, safe platelet counts with 1st-line therapies.
  • Mortality is only marginally higher than the general population.

Differential Diagnosis

  • Von Willebrand’s disease (VWD): the most common inherited bleeding disorder caused by von Willebrand factor (VWF) abnormality. Bruising and mucocutaneous bleeding are common manifestations of VWD. Most individuals with VWD have a normal CBC and many have normal coagulation studies, but some have prolonged aPTT. Treatment is usually with desmopressin. 
  • Disseminated intravascular coagulation (DIC): A complication of many diseases, DIC is an imbalance between pro- and anticoagulants. Thrombus formation creates an excessive consumption of platelets, coagulation factors, and fibrinogen. Presentation includes signs and symptoms of thrombocytopenia. High morbidity and mortality are common and DIC requires emergent care involving blood product transfusion and treatment of the underlying process. 
  • Thrombotic thrombocytopenic purpura: a congenital or acquired disorder due to a deficiency in the metalloproteinase responsible for breaking down VWF. Thrombotic thrombocytopenic purpura falls into the differentials with ITP and DIC (all present with thrombocytopenia). The diagnosis is clinical and supported by blood studies and blood smear. Thrombotic thrombocytopenic purpura is more acute than ITP requiring urgent plasmapheresis.
  • Henoch-Schönlein purpura: an autoimmune, small-vessel vasculitis typically presenting as a tetrad of abdominal pain, hematuria, arthritis, and purpuric rash. Diagnosis is commonly established clinically and management is mostly supportive and focused on symptoms.
  • Infections and drugs: Many infections and medications can cause thrombocytopenia by several nonimmune mechanisms. Examples include bone marrow suppression, hypersplenism, and platelet consumption.

References

  1. Arnold, D., and Cunker, A. (2021). Immune thrombocytopenia (ITP) in adults: Clinical manifestations and diagnosis. In Leung, L. (Ed.), UpToDate. Retrieved March 03, 2021, from https://www.uptodate.com/contents/immune-thrombocytopenia-itp-in-adults-clinical-manifestations-and-diagnosis
  2. Arnold, D., and Cunker, A. (2021). Immune thrombocytopenia (ITP) in adults: Initial treatment and prognosis. In Leung, L. (Ed.), UpToDate. Retrieved March 03, 2021, from https://www.uptodate.com/contents/immune-thrombocytopenia-itp-in-adults-initial-treatment-and-prognosis
  3. Cines DB, Blanchette VS. Immune thrombocytopenic purpura. (2002). N Engl J Med 2002; 346:995. Retrieved March 03, 2021, from https://www.uptodate.com/contents/immune-thrombocytopenia-itp-in-adults-clinical-manifestations-and-diagnosis
  4. Rodeghiero F, Stasi R, Gernsheimer T, et al. (2009). Standardization of terminology, definitions and outcome criteria in immune thrombocytopenic purpura of adults and children: report from an international working group. https://www.uptodate.com/contents/immune-thrombocytopenia-itp-in-adults-clinical-manifestations-and-diagnosis/

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