IMMUNE THROMBOCYTOPENIA (ITP)













  • Reference [10,11,12]
Causes of Thrombocytopenia
Pseudothrombocytopenia
  • Pseudothrombocytopenia is clumping of platelets in a blood sample caused by EDTA which is an anticoagulant added to the samples
  • Diagnosis may be made by looking at a peripheral smear or by repeating the platelet count in citrate-anticoagulated blood (sometimes referred to as "blue-top platelet count" or "platelet count, citrated"
Infections
  • Hepatitis C, Hepatitis B, HIV, Cytomegalovirus, Epstein-Barr virus, H pylori, Parvovirus, Varicella zoster
  • Common cause in children
Medications
Autoimmune diseases
  • Systemic lupus erythematosus, rheumatoid arthritis, antiphospholipid antibody syndrome
Liver disease
  • Thrombocytopenia occurs in up to 85% of patients with cirrhosis. Platelet counts of < 50,000 occur in approximately 13% of cirrhotic patients.
Kidney disease
  • Thrombocytopenia is present in 16 - 55% of patients with uremia
Myelodysplastic syndromes
  • Other blood cell indices will also be abnormal
  • Diagnosed with peripheral smear and/or bone marrow biopsy
Leukemia and lymphoma
  • Other blood cell indices will also be abnormal
  • Diagnosed with peripheral smear and/or bone marrow biopsy
Immune disorders
  • Common variable immunodeficiency
  • IgA deficiency
Aplastic anemia
  • Marked by pancytopenia
  • Diagnosed with bone marrow biopsy
Thrombotic thrombocytopenic purpura
  • Rare condition where abnormal blood clots form in the small blood vessels and platelets are consumed
  • The blood clots can lead to organ ischemia and hemolytic anemia. Platelet consumption leads to thrombocytopenia and bleeding (purpura).
  • TTP has been associated with certain drugs. It also occurs secondary to decreased activity of the ADAMTS13 enzyme which is involved in breaking up von Willebrand factor that is bound to platelets. ADAMTS13 deficiencies can be inherited through genetic defects or acquired from autoantibodies to the enzyme.
  • Schistocytes (RBC fragments) on a peripheral smear and low ADAMTS13 levels can help distinguish it from ITP
Evans syndrome
  • Rare autoimmune disorder that causes Coombs' positive hemolytic anemia and thrombocytopenia
Bernard–Soulier syndrome
  • Very rare (1 in 1 million) genetic disorder that causes abnormally large and fewer platelets
  • Caused by a mutation in the genes that code the Glycoprotein Ib-IX-V complex found on the surface of platelets
MYH9-related disorder
  • Very rare genetic disorder that causes hearing loss, kidney disease, cataracts, and thrombocytopenia
  • Caused by a mutation in the MYH9 gene that codes for myosin, a protein involved in cell motility, maintenance of cell shape, and cytokinesis



























  • References [4,5,10,13]
American Society of Hematology 2019 ITP Treatment Recommendations for Children
First-line treatment
  • No bleeding or minor bleeding (skin manifestation such as petechiae and bruising)
    • Observation is recommended

  • Non-life-threatening mucosal bleeding and/or diminished health-related quality of life
    • Corticosteroids (preferred)
      • Dosing: Prednisone 2 - 4 mg/kg/day (maximum 120 mg/day) for 5 - 7 days
      • Effective in up to 75% of patients
      • Platelet count responds in 2 - 7 days
    • Intravenous immunoglobulin (IVIG)
      • Dosing: single dose of 0.8 - 1 g/kg OR 0.4 grams/kg/day for 2 - 5 days
      • Effective in > 80% of patients
      • Platelet count responds in 1 - 2 days. IVIG may be more beneficial in patients with active serious bleeding and in those with very low platelet counts (<10,000).
      • One-third of patients will fall below acceptable platelet count 2 - 6 weeks after treatment
    • Anti-Rh(D) immunoglobulin (WinRho®)
      • Dosing: 50 - 75 μg/kg IV
      • Only for use in Rh(D) positive, non-splenectomized patients. Anti-Rh(D) coats RBCs so that spleen sequesters RBCs instead of platelets.
      • Avoid in patients with decreased hemoglobin and/or autoimmune hemolysis
      • 50 - 77% of patients will respond and platelet count responds in ≥ 50% within 24 hours
      • Platelet count responds in 2 - 7 days
Second-line treatment
  • Thrombopoietin receptor agonists (first-line)
    • Thrombopoietin receptor agonists (TPO-RAs) stimulate megakaryocyte proliferation and differentiation. Side effects include possible increased risk of thromboembolism, increased bone marrow reticulin, rebound thrombocytopenia upon discontinuation, and hepatotoxicity (eltrombopag). Response is typically seen in 1 - 2 weeks.
      • Romiplostim (Nplate®) - romiplostim is a weekly SQ injection. In one trial, 88% of children treated with romiplostim achieved a platelet count ≥ 50,000. [PMID 21502541]
      • Eltrombopag (Promacta®) - eltrombopag is a once daily tablet. In trials, around 40% of children treated with eltrombopag achieved a durable platelet response of ≥ 50,000.
  • Rituximab (second-line)
    • Dosing: 100 mg/week for 4 weeks OR 375 mg/m2/week for 4 weeks
    • Response rate is highly variable (30 - 80%)
    • Platelet count responds within a few weeks
  • Splenectomy (third-line)
    • Effective in 60 - 70% of patients
    • Platelet response seen in 24 hours and 80% of responders maintain response over 4 years
    • Increases risk of Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae infections (see asplenic patients for more)
MMR-associated ITP
  • Children with a history of ITP who are unimmunized - should receive first scheduled MMR vaccine
  • Children with either nonvaccine or vaccine-related ITP who have received their first dose of MMR vaccine - check vaccine titer. If immune (90 - 95% of children), do not give another MMR vaccine. If not immune, give MMR at recommended age. [4]

  • References [4,5,10,13]
American Society of Hematology 2019 ITP Treatment Recommendations for Adults
Whom to treat
  • Newly diagnosed ITP in adults who are asymptomatic or have minor mucocutaneous bleeding
    • Platelet count < 30,000/μL - corticosteroids are favored over observation
    • Platelet count ≥ 30,000/μL - observation is favored over corticosteroids
First-line treatment
  • Corticosteroids (course ≤ 6 weeks)
    • Dosing: prednisone 0.5 - 2 mg/kg then taper OR dexamethasone 40 mg/day for 4 days
    • Effective in 70 - 80% of patients
    • Platelet count responds in several days to several weeks. Sustained response after discontinuation only seen in 30 - 50% of patients. Repeated cycles are often necessary.
  • If corticosteroid-dependent or unresponsive for ≥ 3 months, proceed to second-line treatment
Second-line treatments
  • Thrombopoietin receptor agonists
    • Thrombopoietin receptor agonists (TPO-RAs) stimulate megakaryocyte proliferation and differentiation. Side effects include possible increased risk of thromboembolism, increased bone marrow reticulin, rebound thrombocytopenia upon discontinuation, and hepatotoxicity (eltrombopag). Response is typically seen in 1 - 2 weeks. Avatrombopag was not included in the recommendation because it was relatively new at the time the guidelines were published.
      • Romiplostim (Nplate®) - romiplostim is a weekly SQ injection. In one trial, 38% of splenectomized patients and 61% of nonsplenectomized patients achieved a durable platelet response with romiplostim [PMID 18242413]
      • Eltrombopag (Promacta®) - eltrombopag is a once daily tablet. In one trial, 73% of ITP patients achieved a platelet count ≥ 50,000 with eltrombopag. [PMID 19231632]
      • Avatrombopag (Doptelet®) - avatrombopag is a once daily tablet. In one small trial, avatrombopag was superior to placebo for cumulative number of weeks with platelet count ≥ 50,000. [PMID 30191972]
  • Rituximab
    • Dosing: 100 mg/week for 4 weeks OR 375 mg/m2/week for 4 weeks
    • Response seen in 60% of patients with long-term response achieved in 18 - 35%. Median time to response is 5.5 weeks.
    • In one study, rituximab was no better than placebo in preventing treatment failure (defined as splenectomy or meeting criteria for splenectomy) in patients with corticosteroid-resistant ITP. [PMID 25662413]
  • Splenectomy
    • If possible, splenectomy should be delayed for at least 1 year after diagnosis because of the potential for spontaneous remission in the first year
    • Response rate is 80% with two-thirds of patients achieving a lasting response. Response seen in 1 - 24 days.
    • Increases risk of Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae infections (see asplenic patients for more)
Other treatments (not addressed in 2019 guidelines)
  • Corticosteroids + IVIG
    • IVIG dosing: 1 gram/kg given as a one-time dose and repeated if necessary
    • Effective in up to 80% of patients
    • Platelet count responds in 1 - 4 days. Effect of IVIG typically lasts 1 - 2 weeks.
  • Anti-Rh(D) immunoglobulin (WinRho®)
    • Dosing: 50 - 75 μg/kg IV
    • Only for use in Rh(D) positive, non-splenectomized patients. Anti-Rh(D) coats RBCs so that spleen sequesters RBCs instead of platelets.
    • Avoid in patients with decreased hemoglobin and/or autoimmune hemolysis
    • Up to 80% of patients will respond
    • Platelet count responds in 4 - 5 days and effect typically lasts 3 - 4 weeks
  • Fostamatinib (Tavalisse™)
    • Fostamatinib is a tyrosine kinase inhibitor with demonstrated activity against spleen tyrosine kinase (SYK). The major metabolite of fostamatinib, R406, inhibits signal transduction of Fc-activating receptors and B-cell receptors. The fostamatinib metabolite R406 reduces antibody-mediated destruction of platelets. Major side effects of fostamatinib include hypertension, neutropenia, diarrhea, and hepatotoxicity
    • Fostamatinib is a tablet that is taken twice daily
    • In one trial, 18% of ITP patients treated with fostamatinib achieved a durable platelet count ≥ 50,000 compared to 2% of placebo-treated patients. [PMID 29696684]
Special cases
  • Pregnancy - treatment with corticosteroids or IVIG is recommended
  • Hepatitis C-associated ITP - if treatment is required, IVIG is recommended; hepatitis C infection should be treated