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Idiopathic Thrombocytopenic Purpura

para>Age: adult or pediatric

Phases: newly diagnosed (<3 months), persistent, and chronic (>12 months); or acute (<6 months) and chronic ITP (>6 months).

Etiology: primary (idiopathic) or secondary when occurring in association with another disorder

ITP is a relatively common disease of childhood that often follows viral infection or vaccination. Onset is within 1 week, and spontaneous resolution occurs within 2 months in 83% of patients.

In adults, ITP is usually a chronic disease and spontaneous remission is rare (9% in 1 series).

System(s) affected: heme, lymphatic, immunologic

Synonym(s): immune thrombocytopenia; immune thrombocytopenic purpura; and Werlhof disease

Epidemiology

• Peak age
  

  • Pediatric ITP: 2-4 years

  • Chronic ITP: >50 years with incidence 2 times higher in persons 60 years than those <60 years of age

• Predominant gender
  

  • Pediatric ITP: male = female

  • Chronic ITP: female > male (1.2-1.7:1)

Incidence

• Pediatric acute ITP, 1.9-6.4/100,000 children/year (1)
• Adult ITP, 3.3/100,000 per year

Prevalence
Limited data. In one population (in Oklahoma) (2):  

• Overall prevalence of 11.2/100,000 persons
• In children (<16 years), 8.1/100,000 with average age of 6 years
• In adults (>16 years), 12.1/100,000 persons with average age of 55 years.

Etiology and Pathophysiology

• Accelerated platelet uptake and destruction by reticuloendothelial phagocytes results from action of IgG autoantibodies against platelet membrane glycoproteins IIb/IIIa. There is also cell-mediated platelet destruction by CD8+ T cells.
• Autoantibodies interfere with megakaryocyte maturation, resulting in decreased production.

Risk Factors

• Autoimmune thrombocytopenia (e.g., Evan syndrome)
• Common variable immune deficiency
• Drug side effect (e.g., quinidine, gold, penicillin, procainamide, methyldopa, sulfamethoxazole)
• Infections: Helicobacter pylori, hepatitis C, HIV, varicella zoster
• Vaccination side effect
• Bone marrow transplantation side effect
• Connective tissue disease, such as systemic lupus erythematosus, antiphospholipid antibody syndrome
• Lymphoproliferative disorders

Commonly Associated Conditions

• Viral infections, such as measles, rubella, varicella, influenza, and EBV
• Live virus vaccinations carry a lower risk than natural viral infection: 2.6/100,000 cases MMR vaccine doses versus 6-1,200/100,000 cases of natural rubella or measles infections

Diagnosis

A careful history, physical exam, and review of CBC and peripheral blood smear remain the key components of the diagnosis of ITP.  

History

• Often asymptomatic; found incidentally on routine CBC
• Posttraumatic bleeding occurs at counts of 40-60 — 109/L.
• With counts <30 — 109/L, bruising tendency, epistaxis, menorrhagia, and gingival bleeding are common.
• GI bleeding, hematuria, and hemoptysis are less common.
• Spontaneous bleeding may occur with platelet count <20 — 109/L.
• Intracerebral bleeding is rare and may occur with counts <20 — 109/L and associated trauma or vascular lesions, resulting in neurologic symptoms.
• Constitutional symptoms are absent except for malaise. Symptoms are varied and most are asymptomatic at time of diagnosis.

Physical Exam

• Ecchymoses, petechiae, epistaxis, and bleeding from the gums are common.
• Abnormal uterine bleeding may be present.
• Hemorrhagic bullae on buccal mucosa reflect acute, severe thrombocytopenia.
• Absence of splenomegaly is an essential diagnostic criterion. Also absent: hepatomegaly, lymphadenopathy, stigmata of congenital disease

Differential Diagnosis

• Acute leukemia
• Thrombotic thrombocytopenic purpura
• Hemolytic uremic syndrome
• Factitious: platelet clumping on peripheral smear
• Thrombocytopenia secondary to sepsis
• Myelodysplastic syndrome, particularly in older patients
• Decreased marrow production: malignancy, drugs, viruses, megaloblastic anemia
• Posttransfusion
• Gestational thrombocytopenia
• Isoimmune neonatal purpura
• Congenital thrombocytopenias
• Disseminated intravascular coagulation
• Alcohol-induced thrombocytopenic purpura

Diagnostic Tests & Interpretation

Initial Tests (lab, imaging)

• CBC with differential and peripheral smear:
  

  • Isolated decreased platelet count <100 — 109/L

  • Giant platelets are usually present.

• For patients with history, exam, CBC, and peripheral smear typical of ITP, only the following tests may be needed:
  

  • PT/PTT is normal.

  • In adults, serologies for hepatitis B, hepatitis C, and HIV infections are recommended (3)[B].

  • In pediatric ITP, immunoglobulin levels to exclude common variable immunodeficiency are commonly obtained (3)[B].

  • Other tests are not necessary for patients with typical ITP presentation (3): antiplatelet, antinuclear, antiphospholipid antibodies; H. pylori testing; thrombopoietin; platelet parameters; direct antiglobulin test; reticulocyte count; urinalysis; and thyroid function tests.

Diagnostic Procedures/Other

• Imaging is not necessary.
• Bone marrow aspiration/biopsy
  

  • Not part of routine workup and not necessary for diagnosis irrespective of age of patients presenting with typical ITP or for children failing first-line therapy (pediatric (3)[B]; adult (3)[C])

  • Can be considered for a patient with atypical symptoms, such as fever and weight loss and multiple abnormalities in blood count

Test Interpretation

• Peripheral smear: normal red and white cells with large or giant platelets but diminished in number
• Marrow reveals abundant megakaryocytes with normal erythroid and myeloid precursors.

Treatment

General Measures

• Management with observation alone in children with no or mild bleeding (not more than bruising and petechiae) regardless of platelet count (3)
• Outpatient management unless patient has platelet count <20 — 109/L and is at risk for bleeding (3)
• Admit patients with active bleeding.

Medication

First Line

• Pediatric
  

  • First-line treatment:
    

    • For children with no or mild bleeding (bruising and petechiae only and no mucosal bleeding), observation alone regardless of platelet count (3)[B]

    • For children with significant bleeding
      

      • Single-dose intravenous immunoglobulin (IVIG) 0.8-1 g/kg, especially when a more rapid increase in platelet count is desired (3)[B]. Do not administer in patients with IgA deficiencies because of anaphylaxis risk.

      • A short course of corticosteroids (e.g., PO prednisone 2 mg/kg/day for 2 weeks with 3 weeks taper) (3)[B]

      • For nonsplenectomized children who are Rh-positive, single dose of anti-Rho(D) immunoglobulin (anti-D), 50-75 g/kg. Do not use in children with low hemoglobin or evidence of hemolysis (3)[B].

  • Second and other treatments for pediatric and adolescent persons with ITP (3)
    

    • Splenectomy for chronic or persistent ITP (3)[B]

    • Rituximab (Rituxan) 375 mg/m2 weekly for 4 weeks (3)[C]

    • High-dose dexamethasone 0.6 mg/kg/day for 4 days every 4 weeks (3)[C]

    • Others without adequate data: azathioprine, cyclosporin A, danazol, mycophenolate mofetil, anti-CD52 monoclonal antibody, and interferon

• Adult
  

  • First line, adult ITP
    

    • Treatment is recommended for newly diagnosed patients with platelet count <30 — 109/L (3)[C].

    • Longer course of corticosteroids preferred (e.g., PO prednisone 1 mg/kg/day for 21 days then tapered with addition of IVIG to corticosteroids when a more rapid increase in platelet count is required) (3)[B]

    • If corticosteroids are contraindicated
      

      • IVIG, 1-2 g/kg once, repeating as necessary (3)[C]

      • OR anti-D, 50-75 εg/kg once, repeating as necessary for Rh+, nonsplenectomized patients. Do not use anti-D in patients with low hemoglobin or evidence of hemolysis (3)[C].

  • Second line, adult ITP
    

    • Splenectomy for patients who failed corticosteroid therapy (3)[B]

    • For patients for whom splenectomy is contraindicated, thrombopoietin receptor agonists (3)[B]: eltrombopag (Promacta), 50 mg/day PO ORromiplostim (Nplate), 1 μg/kg SC weekly; may be used for patients at high risk of bleeding.

    • Rituximab, 375 mg/m2 IV weekly for 4 weeks, for patients at high risk of bleeding who have failed one line of therapy or post splenectomy (3)[C]

    • Consider combination therapy with dexamethasone and rituximab (4)[C].

    • Thrombopoietin receptor agonists can be considered for patients at risk of bleeding who failed first line of therapy (3)[C].

    • Others to consider: azathioprine, cyclosporine A, cyclophosphamide, danazol, dapsone, mycophenolate mofetil, and vincristine

• ITP in pregnancy
  

  • Preeclampsia or gestational thrombocytopenia may cause thrombocytopenia unrelated to ITP.

  • Corticosteroids or IVIG are considered safe and are considered first line (4)[C].

  • ITP management at time of delivery is based on maternal bleeding risks, and mode of delivery should be based on obstetric indications (4)[C]. Platelet autoantibodies can cross the placenta and cause neonatal thrombocytopenia.

  • Caesarean section can be considered if platelet count >50 — 109/L.

  • Prednisone and/or IVIG may be considered 2-3 weeks prior to delivery.

• ITP secondary to HIV
  

  • Antivirals should be considered before other treatment (3)[C].

  • If treatment is required, corticosteroids, IVIG, or anti-D are 1st-line options; and splenectomy is a 2nd-line option (3)[C].

• ITP secondary to HCV
  

  • Antivirals should be considered before other treatment (3)[C].

  • If treatment required, IVIG is initial treatment (3)[C].

• EMERGENCY TREATMENT
  

  • Patients with intracranial or GI bleeding, massive hematuria, internal hematoma, or who need emergent surgery.

  • IV corticosteroids (e.g., IV methylprednisolone, 1 g/day for 3 days) (3)[B] with caution in patients with GI bleeding and/or IVIG 1 g/kg, repeat following day for count <50 — 109/L (3)[B].

  • Platelet transfusions with IVIG may also be considered for significant bleeding (3)[C].

  • Other agents that may be considered: Recombinant factor VIIa (3)[C] not only promotes hemostasis but also increases risk of thrombosis. Efficacy of antifibrinolytic agents, aminocaproic acids, and tranexamic acid, is unproved; they may be used as adjunctive treatments only. Emergent splenectomy has been reported.

Issues for Referral

Hematology consultation is recommended for acute bleeding or for those who fail to respond to first-line therapies.  

Additional Therapies

Proprietary traditional Chinese medicines: Dihuang Zhixue (blend of Rehmannia root and others herbs) showed benefit for childhood refractory ITP in a single, small, randomized controlled trial (5); limited evidence for Kami-kihi-to, minor decoction of Bupleurum, replenishing qi and tonifying kidney, roasted licorice decoction, Sairei-to, Shengxueling, and Zhinu-I and Zhinu-II (6). Unclear evidence for active hexose correlated compound, berberine, dong quai, ginseng, licorice, melatonin, and periwinkle. (7)  

Surgery/Other Procedures

Splenectomy  

• Mortality rate is very low (<1%) even in patients with severe thrombocytopenia.
• Necessary vaccinations prior to splenectomy: polyvalent pneumococcal vaccine and quadrivalent meningococcal vaccine every 3-5 years and 1-time Haemophilus influenzae B (Hib).
• Consider lifelong prophylactic antibiotics with penicillin or erythromycin.
• Should raise the platelet count to at least 20 — 109/L prior to surgery
• Reported 5-10-year efficacy is ~65% for all patients.
• Laparoscopic splenectomy has similar long-term outcomes compared to open splenectomy and has better short-term outcomes (8)[C].

Ongoing Care

Follow-up Recommendations

Patient Monitoring
Platelet counts weekly for patients on prednisone and monthly for stable patients are reasonable.  

Diet

• Evidence demonstrating benefit of an anti-inflammatory diet in ITP is lacking.
• The following foods and supplements can cause significant bleeding: garlic, ginger, Gingko biloba, and saw palmetto.
• Some foods and supplements that may inhibit platelets: evening primrose oil, fish oil, feverfew, ginseng, licorice, soy, vitamin C, vitamin E, and wintergreen.
• Partial list of foods and supplements with coumarin or salicylate components: alfalfa, angelica, anise, asafetida, aspen bark, birch, black cohosh, celery, chamomile, cinnamon, dandelion, fenugreek, heartsease, horse chestnut, meadowsweet, poplar, prickly ash, quassia, sarsaparilla, sweet birch, sweet clover, and willow bark.

Patient Education

• Modified activity to prevent injury or bruising; avoid contact sports.
• Avoid anticoagulants, aspirin and other platelet-inhibiting drugs, and NSAIDs.

Prognosis

• Acute ITP
  

  • ~80-85% of patients completely recover within 2 months.

  • 15% proceed to chronic ITP.

• Chronic ITP
  

  • ~10-20% of the patients recover spontaneously.

  • Remainder with diminished platelets for months to years

  • May see spontaneous remissions (5%) and relapses

• ~10% are refractory (fail medical therapy and splenectomy).

Complications

• Related to thrombocytopenia: 1% mortality due to intracranial hemorrhage and severe blood loss
• Related to treatment: for example, corticosteroid adverse effects, anaphylaxis and renal failure with IVIG, hepatotoxicity with eltrombopag, reports of progressive multifocal leukoencephalopathy with rituximab, hemolysis with anti-D, and septicemia for splenectomized patients

References

1.Terrell  DR, Beebe  LA, Vesely  SK, et al. The incidence of immune thrombocytopenic purpura in children and adults: a critical review of published reports. Am J Hematol.  2010;85(3):174-180.  [View Abstract]2.Terrell  DR, Beebe  LA, Neas  BR, et al. Prevalence of primary immune thrombocytopenic purpura in Oklahoma. Am J Hematol.  2012;87(9):848-852.  [View Abstract]3.Neunert  C, Lim  W, Crowtha  M, et al. The American Society of Hematology 2011 evidence-based practice guideline for immune thrombocytopenia. Blood.  2011;117(16):4190-4207.  [View Abstract]4.Gudbrandsdottir  S, Birgens  HS, Frederiksen  H, et al. Rituximab and dexamethasone vs dexamethasone monotherapy in newly diagnosed patients with primary immune thrombocytopenia. Blood.  2013;121(11):1976-1981.  [View Abstract]5.Liu  QC, Wu  WH, Wu  DY, et al. Clinical observation on the treatment of childhood refractory idiopathic thrombocytopenic purpura with Dihuang Zhixue Capsule. Chin J Integr Med.  2008;14(2):132-136.  [View Abstract]6.Platelet Disorder Support Association. http://www.pdsa.org/. Accessed on August 10, 2014.7.Natural Standard. https://naturalmedicines.therapeuticresearch.com/databases.aspx. Accessed on August 10, 2014.8.Qu  Y, Xu  J, Jiao  C, et al. Long-term outcomes of laparoscopic splenectomy versus open splenectomy for idiopathic thrombocytopenic purpura. Int Surg.  2014;99(3):286-290.  [View Abstract]

Codes

ICD10

• D69.3 Immune thrombocytopenic purpura

ICD09

• 287.31 Immune thrombocytopenic purpura

SNOMED

• 32273002 Idiopathic thrombocytopenic purpura (disorder)
• 13172003 chronic idiopathic thrombocytopenic purpura (disorder)
• 28505005 acute idiopathic thrombocytopenic purpura (disorder)

Clinical Pearls

• ITP: platelet counts of <100 — 109/L caused by accelerated destruction and/or impaired thrombopoiesis by antiplatelet antibodies
• Pediatric ITP: relatively common, with spontaneous remission in 2 months
• Adult ITP: usually persistent; requires treatment, with rare spontaneous remission

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