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Risk factors Definitions/Symptoms/Pathology Labs Diagnostic criteria Management/Prognosis
RISK FACTORS
  • Age
    • Adults ≥ 60 years
    • Children - peak incidence at age 5 - 6 years
  • Female sex - up until age 60 years, then equal
  • MMR vaccine - 0.87 to 4 cases per 100,000 doses
  • Infections
  • Cancers
    • Chronic lymphocytic leukemia (CLL)
    • Hodgkin’s disease
    • non-Hodgkin’s lymphomas
    • Large granulocytic leukemia (LGL)
  • Immune disorders
  • Post-organ transplantation
  • Family history - possible risk factor [1,2,3,4]

DRUGS ASSOCIATED WITH ITP
  • Heparin
  • Quinine
  • Penicillin
  • Vancomycin
  • Sulfonamide antibiotics
  • Valproic acid
  • NSAIDs
  • Gold salts
  • Procainamide
  • Tirofiban (Aggrastat®)
  • Eptifibatide
  • Abciximab (Reopro®) [1,2,6]
DEFINITIONS
  • NOTE: In the past, immune thrombocytopenia was referred to as "idiopathic thrombocytopenic purpura." In 2009, the International Working Group on ITP recommended that the condition be called "immune thrombocytopenia" and that the acronym "ITP" be retained.
  • Primary ITP - peripheral platelet count < 100 K/µL in the absence of other causes or disorders associated with thrombocytopenia. Primary ITP is a diagnosis of exclusion.
  • Secondary ITP - peripheral platelet count < 100 K/µL in the presence of a condition known to be associated with ITP
  • Newly diagnosed ITP - ITP diagnosed within 3 months
  • Persistent ITP - between 3 - 12 months from the diagnosis of ITP
  • Chronic ITP - ITP lasting more than 12 months
  • Severe ITP - ITP with bleeding that requires treatment [7]

SYMPTOMS
  • NOTE: Symptoms of ITP are highly-dependent upon the severity of the disease. In general, bleeding is uncommon when the platelet count is > 30 K/µL, so many of these patients may be asymptomatic.
  • Bleeding - epistaxis, menorrhagia, gingival and gastrointestinal bleeding
  • Purpura - bruising of the skin; typically occurs on the extremities (dry purpura) or on the oral mucosa (wet purpura)
  • Petechia - pinpoint microvascular hemorrhages that do not blanch (note: hemangiomas do blanch); typically occur on the hands and feet; more common when platelet count is < 15 K/µL
  • Intracranial hemorrhage - rare and serious complication that almost always occurs at a platelet count < 10 K/µL
  • Thrombosis - paradoxically, ITP has been associated with an increased risk of thrombosis; etiology unclear, but may be related to presence of antiphospholipid antibodies
  • Fatigue - nonspecific symptom that may be present in up to 40% of patients

PATHOLOGY
  • The estimated annual incidence of ITP is 100 cases per 1 million people with half of the cases occurring in children [3]

  • ITP is thought to occur through several mechanisms:
    • Platelet antibodies - the development of platelet antibodies (most commonly to glycoprotein IIb/IIIa) leads to accelerated clearance of platelets in the spleen.
    • Impaired platelet production - platelet production by megakaryocytes in the bone marrow is often suppressed in ITP. The mechanism by which this occurs is not completely understood.
    • Antibody-independent autoimmunity - destruction of platelets by cytotoxic T-cells has been demonstrated

DIAGNOSTIC LABS
  • Platelet count - platelet count < 100 K/µL
  • CBC - in ITP, erythrocytes and leukocytes are typically normal in count and morphology. If patient has experienced significant bleeding, anemia may be present
  • Peripheral smear - a peripheral smear should be performed to exclude other causes of thrombocytopenia like hematological cancers and thrombotic thrombocytopenic purpura (TTP). In TTP, signs of red blood cell destruction (e.g. schistocytes) will be present. [1,2,5]

OTHER POTENTIALLY HELPFUL LABS
  • Antiplatelet antibody assays
    • Specific antigen tests - tests for antibodies that are bound to platelet-specific glycoproteins llb/llla, lb/IX, or la/lla. Test has a sensitivity of around 53% and a specificity around 72%. Because of the low sensitivity, the test is generally not recommended as part of the routine workup.
    • Nonspecific antigen tests - also called platelet-associated immunoglobulin G (PAIgG assay). Tests for total platelet-associated IgG. Test has a sensitivity of around 91% and a specificity around 27%. Because of the low specificity, the test is generally not recommended as part of the routine workup.
  • Blood type - if Anti-Rh(D) immunoglobulin is being considered for treatment, blood typing is indicated. Anti-Rh(D) is only effective in Rh(D) positive individuals.
  • Direct antiglobulin test (direct Coombs test) - if anemia is present, may help distinguish autoimmune hemolytic anemia from other conditions
  • Reticulocyte count - if anemia is present, reticulocyte count may help decipher if anemia is from red blood cell destruction (ex. TTP) or poor production
  • Bone marrow biopsy - bone marrow biopsy may be useful to exclude other myelodysplastic disorders in select patients
  • Antiphospholipid antibodies - found in up to 40% of adults with ITP
  • Antinuclear antibodies (ANA) - lupus is associated with ITP. A positive ANA test may be a predictor of chronic ITP in childhood.
  • TSH (thyrotropin) receptor antibody and thyroid function tests - up to 14% of chronic ITP patients will develop hyperthyroidism at some point. Hypothyroidism also is prevalent. [1,2,5,8]

ASSOCIATED DISEASE TESTING
  • H pylori testing - H pylori testing may be useful in adults but is not routinely recommended in children. In the U.S., treatment of H pylori generally does not improve ITP.
  • Hepatitis C testing - hepatitis C infection is present in up to 20% of patients with ITP
  • HIV testing - HIV testing is recommended in patients with ITP
  • Quantitative antibody testing (IgG, IgA, IgM) - ITP is associated immunodeficiencies including common variable immunodeficiency (CVID) and IgA deficiency [1,5]

American Society of Hematology recommended testing in typical ITP
  • Children
    • Bone marrow biopsy and other testing is not recommended in children with typical ITP
  • Adults
    • Testing for hepatitis C and HIV are recommended
    • Bone marrow biopsy is not recommended irrespective of age in patients with typical ITP [4]
OVERVIEW
  • There is no single "gold standard" test or set of criteria that can be used to establish a diagnosis of ITP
  • The diagnosis should be considered in patients who have a platelet count of < 100 K/µL
  • ITP is divided into two types - Primary ITP and Secondary ITP

PRIMARY ITP
  • Primary ITP is an autoimmune disorder characterized by isolated thrombocytopenia (< 100 K/µL) in the absence of other causes or disorders that are associated with thrombocytopenia
  • Primary ITP is a diagnosis of exclusion

SECONDARY ITP
  • Secondary ITP is an immune-mediated thrombocytopenia (platelet count < 100 K/µL) that occurs in the presence of a specific condition, infection, or drug that has been associated with thrombocytopenia
  • See RISK FACTORS and DRUGS ASSOCIATED WITH ITP for specific causes [7]

CHILDREN
  • PROGNOSIS
    • ITP resolves spontaneously in 80% of children, usually within 6 months
    • Only 3% of children with ITP have clinically significant bleeding such as severe epistaxis or GI bleeding
    • Children > 10 years old are more likely to develop chronic ITP [4,5]

  • TREATMENT (American Society of Hematology 2011 guidelines)
    • OBSERVATION
      • Children with no bleeding or minor bleeding (defined as skin manifestation only such as petechiae and bruising) should be managed with observation only regardless of platelet count [4]
    • MEDICATIONS - first-line (one of the following)
      • IVIG - single dose of 0.8 - 1 g/kg; effective in > 80% of patients; platelet count responds in 1 - 2 days; one-third of patients will fall below acceptable platelet count 2 - 6 weeks after treatment
      • Prednisone - 1 - 2 mg/kg/day for a maximum of 14 days OR 4 mg/kg/day for 3 - 4 days; effective in up to 75% of patients; platelet count responds in 2 - 7 days
      • Anti-Rh(D) immunoglobulin (WinRho®) - 50 - 75 μg/kg IV; 50 - 77% of patients will respond; platelet count responds in ≥ 50% within 24 hours; anti-Rh(D) coats RBCs so that spleen sequesters RBCs instead of platelets; only for use in Rh(D) positive, non-splenectomized patients; avoid in patients with decreased hemoglobin and/or autoimmune hemolysis [4,5]
    • NONRESPONDERS (one of the following)
      • Rituximab - 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
      • High-dose dexamethasone - 28 mg/m2/day; effective in up to 80% of patients; platelet count responds in 3 days [4,5]
    • CHRONIC ITP
      • Splenectomy - effective in 60 - 70% of patients; platelet response seen in 24 hours; 80% of responders maintain response over 4 years; increases risk of Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae infections; see asplenic patients for more. [4,5]
    • 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]
ADULTS
  • PROGNOSIS
    • In adults, spontaneous remission of primary ITP is much less likely than in children with only 9 - 28% of adults achieving remission without splenectomy [4]
    • Despite the low remission rate, the prognosis is generally favorable. In one study, 134 patients with primary ITP were followed for 10 years. 85% of patients achieved platelet counts > 30,000 K/µL while off of all therapies and had an overall mortality equal to the general population. 9% of patients had refractory disease, and their overall mortality was higher than the general population. [9]

  • TREATMENT (American Society of Hematology 2011 guidelines)
    • OVERVIEW
      • Adults with platelet counts < 30,000 K/µL should be treated
    • MEDICATIONS - first-line (one of the following)
      • Corticosteroids (longer course) - e.g. prednisone 1 mg/kg for 21 days then taper; effective in 70 - 80% of patients; platelet count responds in several days to several weeks; sustained response rate is highly variable; repeated cycles are often necessary
      • Corticosteroids + IVIG - IVIG can be added to corticosteroids when a more rapid platelet response is required; IVIG dose is 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®) - may be used in patients where corticosteroids are contraindicated; recommended dose is 50 - 75 μg/kg IV; up to 80% of patients will respond; platelet count responds in 4 - 5 days; effect typically lasts 3 - 4 weeks; anti-Rh(D) coats RBCs so that spleen sequesters RBCs instead of platelets; only for use in Rh(D) positive, non-splenectomized patients; avoid in patients with decreased hemoglobin and/or autoimmune hemolysis [4,5]
    • NONRESPONDERS/RELAPSERS
      • Splenectomy - splenectomy is recommended in patients who do not respond to corticosteroids and in those who relapse after corticosteroids; 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
      • Thrombopoietin receptor agonists (romiplostim, eltrombopag) - may be considered in patients who relapse after splenectomy or who have a contraindication to splenectomy and have failed at least one other therapy; TRAs stimulate megakaryocyte proliferation and differentiation; romiplostim is a weekly SQ injection and eltrombopag is a once daily oral tablet; response rate is 70 - 90%; TRAs do not typically produce sustained remission; side effects include possible increased risk of thromboembolism, increased bone marrow reticulin, rebound thrombocytopenia upon discontinuation, and hepatotoxicity (eltrombopag)
      • Rituximab - may be considered in patients at risk for bleeding who have failed corticosteroids, IVIg, or splenectomy; dose is 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
    • SPECIAL CASES
      • Pregnancy - treatment with corticosteroids or IVIG is recommended
      • Hepatitis C-associated - if treatment is required, IVIG is recommended; hepatitis C infection should be treated



  • References:
  • 1 - PMID 23714309 - Hematol Oncol Clin North Am review
  • 2 - PMID 21632906 - Cleveland Clinic review
  • 3 - PMID 11919310 - NEJM review
  • 4 - PMID 21325604 - ASH 2011 GL for ITP
  • 5 - PMID 19846889 - BSH GL 2010
  • 6 - PMID 17687133 - Drug-induced ITP
  • 7 - PMID 19005182 - ITP standardization
  • 8 - LabCorp website
  • 9 - PMID 11313240 - Morbidity and mortality in adults with idiopathic thrombocytopenic purpura, Blood, 2001