Immune (or Idiopathic) Thrombocytopenia

Links:

American Society of Hematology 2019 guidelines for immune thrombocytopenia

Acquired thrombocytopenia from autoantibodies against platelet antigens; also known as primary immune thrombocytopenia, previously referred to as immune thrombocytopenic purpura

  • One of the more common causes of thrombocytopenia (TCP) in adults (especially asymptomatic TCP)
  • Pathogenesis:
    • Incompletely understood; likely combination of reduced platelet lifespan due to antibody-mediated destruction and impaired platelet production.
    • Most due to IgG antibodies directed against platelet membrane glycoproteins (e.g.: GP IIb/IIIa)
    • Specific triggering events not always definable, but genetic and acquired factors likely both contribute – infection and other immunity altering conditions
  • Epidemiology:
    • Annual incidence approximately 1-3 per 100,000 adults
    • 20-33% of cases are asymptomatic
    • Incidence increases with age (especially >60 years old), with older men > older women; for cases in young adults, women > men
  • Clinical manifestations:
    • Bleeding in up to 60-70% of cases, typically occurring in skin or mucus membranes
    • Severity of bleeding variable, ranging from mild petechiae to life threatening hemorrhage
    • Onset of symptoms most often insidious, though can be acute
  • Bleeding:
    • Petechiae: flat, red lesions that do not blanch, most often in dependent areas of body
    • Purpura: lesions caused by coalescence of petechiae
      • “Wet purpura”: hemorrhagic blisters in mucus membranes; predict more severe bleeding – should trigger re-assessment and consideration of therapy
    • Epistaxis: minimal epistaxis common, generally not clinically important; continuous epistaxis may predict more serious bleeding
    • Severe hemorrhage: hematuria, overt GI bleding, and intracranial hemorrhage (ICH)
      • Seen in <10% of ITP cases
      • Risk factors: platelet count <20,000/µL, previous minor bleeding, chronic (>12 months) ITP
    • b.: Correlation between platelet count and bleeding risk is weak!
      • Circulating platelets in ITP are younger and more hemostatically effective, so bleeding events in ITP less severe at equivalent platelet counts than TCP due to other conditions
    • Thrombocytopenia:
      • Ranges from mild (<150,000/µL) to severe (<20,000/µL)
        • No obvious factors determine degree of TCP in a given patient
      • Counts tend to remain at steady, albeit low, levels in the absence of therapy or exacerbating events/hemostatic challenges
      • No distinctive platelet morphology on peripheral blood smear
    • Absence of other hematologic pathology:
      • ITP not characterized by WBC or RBC abnormalities or by abnormal coags
      • If such abnormalities are present, other conditions should be investigated (e.g.: leukemia, TTP, DIC)
      • Bone marrow biopsy not routinely useful (findings tend to be normal) unless other unexplained cytopenias are present
  • Laboratory Testing:
    • Once other conditions associated with TCP excluded by history, few further tests are needed or useful
    • Peripheral blood smear:
      • Review important to validate presence of TCP (not just from platelet clumping) and rule out platelet morphological abnormalities (as seen with inherited platelet disorders)
    • HIV & HCV testing:
      • TCP common presentation of both infections, and treatment of HIV/HCV can improve platelet counts
    • Other testing (coags, thyroid studies, bone marrow biopsy, immune studies, vitamin B12/folate) reserved for specific settings only (i.e.: suspicion of associated/underlying conditions)
    • Anti-platelet antibody testing is NOT RECOMMENDED
      • Multiple studies have shown low sensitivity and specificity for ITP
  • Diagnosis:
    • Overall, Dx of ITP is one of exclusion – isolated TCP without another apparent cause
      • Primary ITP: acquired thrombocytopenia due to autoimmune platelet destruction not triggered by underlying condition
      • Secondary ITP: ITP associated with an underlying condition
        • Common causes: Autoimmune diseases (SLE), Infections (HIV, HCV), Chronic Lymphocytic Leukemia (CLL)
      • DDx:
        • Drug-induced ITP: TCP due to drug-dependent platelet antibodies leading to platelet destruction
          • Clinically indistinguishable from ITP
          • Should resolve following drug discontinuation
        • HIT
        • Infection/Sepsis
          • Can be “post-viral” where TCP is typically transient or due to sepsis, where TCP can be severe and persist beyond other systemic sepsis symptoms/findings
          • Variety of mechanisms – bone marrow suppression, hypersplenism, and accelerated platelet consumptions
        • Chronic liver disease and/or hypersplenism
        • Microangiopathies (TTP, HUS, DIC)
        • Inherited thrombocytopenias
          • Suspect if morphological abnormalities in platelets detected
          • Mild TCP also seen in Type 2B von Willebrand Disease
        • Myelodysplastic syndromes or other acquired bone marrow disorders
        • Vasculitic purpura
          • Due to capillary inflammation
          • Presents with palpable, non-dependent purpura often in the absence of TCP
        • Gestational TCP
  • Treatment:
    • Different approaches to treatment depending on whether or not severe bleeding is present
    • If severe bleeding (ICH, active GIB, profound hematuria) is present and platelet count is <30,000/µL consider the following treatment package:
      • Platelet transfusion (goal >50,000/µL)
        • Contrary to myth, platelet transfusions do not increase risk of thrombosis in ITP
        • May be clinically effective despite lack of platelet count rise in post-transfusion CBC
      • IVIG, 1 g/kg x 1 (may repeat daily if platelet count still low)
      • Glucocorticoids (methylprednisolone 1g IV daily x 3 days or dexamethasone 40mg PO/OV daily x 4 days)
      • Romiplostim (Nplate, TPO) 500µg SQ x 1
      • Surgical/endoscopic/IR procedures to control bleeding site
      • If bleeding is not responding to platelet transfusions, try tranexamic acid (PO: 1-1.5g q6-8h; IV: 1g bolus, 1g IV gtt per 8 hours) or aminocaproic acid (Amicar; 4-12 g/day PO/IV)
    • If severe hemorrhage is not present, treatment can be more step-wise
      • 1st line: glucocorticoids (dexamethasone 40mg PO daily x 4 days)
        • similar response rates overall to IVIG
      • 2nd line: IVIG (1 g/kg daily for 1-2 days)
        • more rapid response rate, so preferred over steroids if active bleeding, need for urgent procedure/surgery or if significant side effects with steroids
        • effect usually transient
      • Anti-D (WinRho, RhoGam, RhIG): 50-75 µg/kg IV x 1
        • Alternative to IVIG if patient is Rh(D) positive (i.e.: Rh+ on blood typing)
        • Some mild RBC hemolysis after infusion is to be expected
        • Monitor recipients carefully for acute hemolytic transfusion reaction
      • If the above therapies are unsuccessful, second-line treatments include splenectomy, rituximab, thrombopoietin (TPO) receptor agonists (e.g.: romiplostim), other immunosuppressant therapy.
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