Thrombocytopenia and ITP

Decreased production (marrow problem)

• Marrow infiltration or failure: leukemia, myelodysplastic syndrome, metastatic carcinoma, aplastic anemia, myelofibrosis — expect other cytopenias, blasts, or teardrop cells rather than isolated thrombocytopenia
• Nutritional and toxic: B12/folate deficiency (megaloblastic, ineffective hematopoiesis), chronic alcohol use (direct megakaryocyte toxicity plus folate deficiency), cytotoxic chemotherapy, radiation, linezolid
• Congenital: Wiskott–Aldrich syndrome (small platelets, eczema, immunodeficiency), Bernard–Soulier and MYH9-related disorders (giant platelets)

Increased destruction — immune

• Primary ITP: anti-GPIIb/IIIa and anti-GPIb/IX IgG, as described above
• Secondary ITP: HIV, HCV, H. pylori, SLE, antiphospholipid syndrome, CLL, common variable immunodeficiency — the ASH 2019 ITP guideline supports testing for HIV, HCV, and (in endemic areas) H. pylori
• Drug-induced immune thrombocytopenia: heparin (HIT, anti-PF4/heparin antibodies causing platelet activation and thrombosis), quinine/quinidine, sulfonamides, vancomycin, valproate, GPIIb/IIIa inhibitors (abciximab can cause profound thrombocytopenia within hours)
• Alloimmune: post-transfusion purpura, neonatal alloimmune thrombocytopenia (anti-HPA-1a)

Increased destruction — non-immune (consumptive)

• Thrombotic microangiopathy: TTP (ADAMTS13 deficiency), Shiga toxin HUS, complement-mediated HUS, DIC, HELLP, malignant hypertension, mechanical valve shear — the smear shows schistocytes

Sequestration and dilution

• Cirrhosis/portal hypertension: splenic pooling plus reduced hepatic thrombopoietin synthesis
• Massive transfusion or volume resuscitation

Non-modifiable risk factors

• Female sex and young adulthood for chronic ITP; preceding viral illness or live vaccine in children for acute, self-limited ITP
• Pregnancy: gestational thrombocytopenia is the most common cause in pregnancy (ACOG), typically mild and late-gestation

Modifiable risk factors

• Heparin exposure, especially unfractionated heparin after cardiac or orthopedic surgery
• Quinine ingestion (including tonic water), alcohol, culprit antibiotics
• **Untreated HIV, HCV, or *H. pylori*** — treating the driver can correct the platelet count

• Autoimmune destruction in ITP: IgG autoantibodies bind to platelet surface antigens (primarily GPIb/IX and GPIIb/IIIa), leading to antibody-dependent cellular cytotoxicity (ADCC) and complement activation, resulting in accelerated platelet clearance primarily in the spleen and liver
• Abnormal megakaryopoiesis: T-cell dysfunction and Th1/Th2 imbalance lead to impaired thrombopoietin (TPO) production and reduced platelet production, compounding the loss from peripheral destruction; anti-TPO autoantibodies may also develop
• Loss of immune tolerance: Breakdown of regulatory T-cell function and loss of B-cell tolerance permits autoreactive B cells to persist and produce pathogenic anti-platelet antibodies
• Splenic sequestration: The spleen becomes the primary site of platelet destruction due to opsonization with IgG; this distinguishes ITP from other causes of thrombocytopenia like TTP or DIC where destruction is more systemic
• Enhanced thrombopoiesis in response: Bone marrow shows compensatory increase in megakaryocytes (typically >50% of normal), producing young, larger platelets; this distinguishes ITP from marrow failure states where megakaryocytes are decreased or normal

• Mucocutaneous bleeding (petechiae, purpura, epistaxis): Most common presenting symptom; typically follows an acute illness or medication exposure in acute ITP; in chronic ITP, bleeding may be absent despite severely low platelet counts
• Gingival bleeding and oral petechiae: Distinctive finding that helps distinguish ITP from other causes; patients often report bleeding gums when brushing teeth
• Menorrhagia or abnormal uterine bleeding: Very common presenting complaint in women; may be severe enough to cause secondary iron deficiency anemia
• Gastrointestinal bleeding: Less common than mucocutaneous bleeding but more clinically significant; hematemesis, melena, or hematochezia
• Intracranial hemorrhage (ICH): Rare but life-threatening complication occurring in <1% of chronic ITP cases; more common in acute ITP with platelets <10,000/μL; classic exam presentation is a patient with petechiae and sudden neurologic symptoms
• Asymptomatic thrombocytopenia: 10-15% of chronic ITP patients have no bleeding symptoms despite severe thrombocytopenia (<20,000/μL), likely due to young, more hemostatic platelets; this paradox is high-yield for boards
• Absence of splenomegaly or lymphadenopathy: Unlike other causes of thrombocytopenia, physical exam in ITP typically shows normal or slightly enlarged spleen; presence of lymphadenopathy or hepatomegaly should prompt consideration of alternate diagnoses (SLE, lymphoma, CLL)

• Complete blood count (CBC) with peripheral blood smear: Shows isolated thrombocytopenia (<150,000/μL, often <30,000/μL in symptomatic disease); normal or elevated mean platelet volume (MPV) is typical in ITP (young compensatory platelets), which helps distinguish from TTP/HUS or consumptive coagulopathies; smear shows absence of schistocytes, ruling out microangiopathic hemolytic anemia
• Antiplatelet antibody testing (anti-GPIb/IX and anti-GPIIb/IIIa): Positive in ~60% of ITP; specificity is good but sensitivity is limited, so negative testing does NOT exclude ITP; less commonly used as a diagnostic tool than in the past
• Bone marrow examination: Indicated when diagnosis is uncertain or when additional cytopenias are present; shows normal to increased megakaryocytes, ruling out hypoplastic/aplastic causes and other marrow disorders; NOT routinely needed if clinical presentation is classic
• Coagulation studies (PT, aPTT, fibrinogen): Normal in ITP; abnormalities suggest alternate diagnoses such as DIC or severe liver disease
• Peripheral blood smear evaluation for schistocytes and other cell abnormalities: Schistocytes or fragmented RBCs suggest TTP/HUS; spherocytes suggest autoimmune hemolytic anemia; atypical lymphocytes or blasts suggest leukemia/lymphoma
• Testing for secondary causes: Serologic testing for SLE (ANA), antiphospholipid syndrome, HAV/HBV/HCV, Helicobacter pylori, and HIV should be performed in appropriate clinical contexts, as some ITP is secondary to these conditions
• Diagnostic criteria for ITP: Isolated thrombocytopenia (platelet count <150,000/μL) without other explanations; normal or increased megakaryocytes on marrow; absence of splenomegaly, lymphadenopathy, or signs of other systemic disease

• Observation (watch-and-wait): Appropriate for asymptomatic patients with platelet counts >20,000-30,000/μL who have no bleeding risk; reassess clinical status and hemostatic demands periodically
• Corticosteroids (first-line therapy): Prednisone 0.5-2 mg/kg/day orally (typically 50-100 mg daily) or methylprednisolone 1 g IV daily for 3-5 days in severe/acute presentations; response rate ~80% with median time to response of 7-14 days; taper gradually over weeks to months; mechanism includes decreased antibody production and reduced FcγR-mediated platelet destruction; major limitation is corticosteroid dependence and side effects with long-term use
• Intravenous immunoglobulin (IVIG): Dose 1-2 g/kg (typically 2 g IV once or divided over 2-5 days); rapid onset within 24-48 hours making it ideal for acute presentations or severe bleeding; mechanism includes blockade of splenic Fc receptors and anti-idiotypic suppression; shorter duration of effect than corticosteroids (2-4 weeks); used as bridge therapy while awaiting corticosteroid response or for patients requiring rapid platelet increment
• Anti-D immunoglobulin (RhoGAM): Dose 50-75 μg/kg IV; effective in RhD-positive, non-splenectomized patients with hemolytic anemia; works similarly to IVIG; rapid onset (24-48 hours); cheaper and faster infusion than IVIG but shorter duration; contraindicated in RhD-negative or splenectomized patients
• Splenectomy: Considered second-line therapy in corticosteroid-dependent or resistant patients; response rate ~60-70% (durable complete response in ~50%); most effective when performed early (within 6 months of diagnosis); mechanism is removal of primary site of platelet destruction; preoperative assessment should include response to IVIG (responders have higher chance of splenectomy response)
• Thrombopoietin (TPO) receptor agonists (romiplostim, eltrombopag): Second-line agents increasingly used as alternatives to splenectomy or in patients failing corticosteroids; romiplostim is SC given weekly (initial 1 μg/kg, titrate to 10 μg/kg); eltrombopag is oral daily dosing (starting 25-50 mg); response rates 80-90%; advantages include avoiding surgery and corticosteroid dependence; limitations include cost, teratogenicity, and risk of thrombosis if overdosed
• **Rituximab (monoclonal anti-

Complications of the disease

• Intracranial hemorrhage — emergency: rare but the feared outcome, usually at counts <10,000/μL; signaled by headache, vomiting, or focal deficit in a patient with petechiae. Treat simultaneously with IV corticosteroids, IVIG, and platelet transfusion (the one setting where transfusion is indicated in ITP despite rapid antibody-mediated clearance)
• Severe GI or genitourinary bleeding — emergency: melena, gross hematuria, or hemodynamic instability; wet purpura (hemorrhagic oral blisters) is the classic bedside marker of imminent serious bleeding
• Iron deficiency anemia: from chronic menorrhagia; microcytosis with low ferritin in a woman with ITP
• Evolution to secondary ITP: emergence of arthritis, rash, lymphadenopathy, or a rising lymphocyte count suggests SLE, APS, or CLL was the real driver

Complications of treatment

• Corticosteroids: hyperglycemia, hypertension, osteoporosis, avascular necrosis, adrenal suppression, insomnia and steroid psychosis; ASH 2019 explicitly favors short courses to limit toxicity
• IVIG: aseptic meningitis, volume overload, acute kidney injury (sucrose-containing products), hemolysis from passive anti-A/anti-B, and arterial/venous thrombosis from hyperviscosity
• Anti-D immunoglobulin: carries a boxed warning for intravascular hemolysis with DIC and renal failure — signaled by back pain, dark urine, and a falling hemoglobin after infusion
• Splenectomy: overwhelming post-splenectomy infection — emergency, from encapsulated organisms (S. pneumoniae, N. meningitidis, H. influenzae type b); CDC/ACIP recommends vaccinating in advance, ideally at least two weeks preoperatively. Also portal/splenic vein thrombosis and lifelong VTE risk
• TPO receptor agonists: thrombosis if the count overshoots, marrow reticulin deposition, rebound thrombocytopenia on abrupt withdrawal; eltrombopag causes hepatotoxicity and requires LFT monitoring
• Rituximab: hepatitis B reactivation (screen HBsAg/anti-HBc before dosing), hypogammaglobulinemia, infusion reactions, and rare progressive multifocal leukoencephalopathy

• ITP is a diagnosis of exclusion: isolated thrombocytopenia with a normal smear, normal PT/aPTT, and no splenomegaly. Neither bone marrow biopsy nor antiplatelet antibody testing is required in a classic presentation (ASH 2019)
• Schistocytes change the answer: microangiopathic hemolytic anemia plus thrombocytopenia is TTP until proven otherwise. The single best next step is urgent therapeutic plasma exchange, not platelet transfusion — transfusing platelets can fuel microthrombi. ADAMTS13 activity <10% confirms it, but never wait for the result (ISTH 2020)
• HIT presents with thrombosis, not bleeding: a ~50% platelet fall 5–10 days after heparin exposure. Score with the 4Ts, stop all heparin including flushes, and start a non-heparin anticoagulant — a direct thrombin inhibitor such as argatroban. Do not start warfarin until the platelet count recovers, because protein C depletion causes venous limb gangrene (ASH 2018)
• Pseudothrombocytopenia is the classic distractor: an asymptomatic patient with a surprisingly low count and platelet clumping on the EDTA smear. Repeat the count in a citrate or heparin tube before any workup
• Pediatric ITP after a viral illness or vaccine is usually self-limited: ASH 2019 supports observation over drugs in children without significant bleeding, regardless of how low the number looks
• Platelet transfusion thresholds (AABB): roughly 10,000/μL prophylactically in hypoproliferative thrombocytopenia, about 50,000/μL for most invasive procedures, and about 100,000/μL for neurosurgical or ocular surgery — but these apply to production failure, not to ITP, where transfused platelets are destroyed within hours
• The association examiners love: mucocutaneous bleeding (petechiae, epistaxis, menorrhagia) means a platelet problem; hemarthrosis and deep muscle hematomas mean a coagulation factor problem such as hemophilia
• Pregnancy: gestational thrombocytopenia is far more common than ITP and needs no treatment; maternal ITP antibodies cross the placenta and can cause neonatal thrombocytopenia (ACOG)