Thrombocytopenia

Definition

Causes (Mechanistic Classification)

1. Decreased Production

• Generalized bone marrow dysfunction: aplastic anemia (congenital or acquired), marrow infiltration (leukemia, metastatic cancer)
• Selective impairment of platelet production: drugs (alcohol, thiazides, cytotoxic agents), infections (measles, HIV)
• Ineffective megakaryopoiesis: megaloblastic anemia, paroxysmal nocturnal hemoglobinuria (PNH)

2. Decreased Platelet Survival — Immunologic Destruction

• Autoimmune: Immune thrombocytopenic purpura (ITP), SLE
• Alloimmune: post-transfusion purpura, neonatal alloimmune thrombocytopenia
• Drug-associated: quinidine, heparin (HIT), sulfa compounds
• Infections: infectious mononucleosis, HIV, CMV

3. Decreased Platelet Survival — Non-immunologic Destruction

• Disseminated intravascular coagulation (DIC)
• Thrombotic thrombocytopenic purpura (TTP)
• Hemolytic uremic syndrome (HUS)
• Microangiopathic hemolytic anemias

4. Sequestration

• Hypersplenism

5. Dilutional

• Massive transfusions

Key Clinical Entities

Immune Thrombocytopenic Purpura (ITP)

• Most common in women aged 20–40
• Caused by IgG autoantibodies against platelet surface antigens (GPIIb/IIIa most common)
• Antibody-coated platelets phagocytosed by splenic macrophages (Fc receptor–mediated)
• Bone marrow: increased megakaryocytes (reactive, compensatory)
• Presents with: petechiae, easy bruising, epistaxis, gingival bleeding; no splenomegaly
• Platelet counts typically 10,000–75,000/μL

• Mostly in children after viral infection
• Self-limited; resolves in weeks to months
• Caused by immune complex deposition or cross-reactive antibodies against platelet antigens

1. First-line: Corticosteroids (prednisone 1 mg/kg/day) — responses in ~80%
2. IVIG — short-term platelet boost; useful perioperatively or for acute bleeding
3. Anti-D (anti-Rh) immunoglobulin — in Rh+ non-splenectomized patients
4. Splenectomy — durable response in 65–70%; no test predicts response; lifelong risk of infection (encapsulated organisms) and small thrombosis risk
5. Rituximab (375 mg/m² × 4 weeks) — ~60% response rate; risk of hepatitis B reactivation
6. TPO receptor agonists — eltrombopag (oral, daily), romiplostim (SC, weekly), avatrombopag (oral, daily) — effective even in splenectomized/refractory patients; risks include bone marrow fibrosis and thromboembolism
7. Fostamatinib (oral Syk kinase inhibitor) — for multiply refractory ITP; 40–45% initial response rate
8. Severe ITP (< 5,000/μL or internal bleeding): pulse corticosteroids + IVIG ± platelet transfusions

Heparin-Induced Thrombocytopenia (HIT)

• Type I (non-immune): Mild, transient thrombocytopenia from direct platelet aggregation by heparin. Occurs within the first few days, self-resolves; no clinical significance.
• Type II (immune-mediated): Serious disorder caused by IgG antibodies against complexes of heparin + platelet factor 4 (PF4). The antibody–heparin–PF4 complex activates platelets via Fc receptors → paradoxical thrombocytopenia + thrombosis (venous > arterial). Typically occurs 5–14 days after heparin exposure (or sooner with prior sensitization).

Thrombotic Thrombocytopenic Purpura (TTP)

1. Thrombocytopenia
2. Microangiopathic hemolytic anemia (schistocytes on smear)
3. Fever
4. Neurologic symptoms (confusion, headache, seizure)
5. Renal dysfunction

• Acquired (immune): autoantibodies against ADAMTS13 (most common form)
• Hereditary (Upshaw-Schulman syndrome): inherited ADAMTS13 deficiency
• Secondary: drugs (quinine, clopidogrel, ticlopidine, cyclosporine), pregnancy, HIV, SLE

Gestational Thrombocytopenia

• Most common cause of thrombocytopenia in pregnancy (~75% of cases)
• Mild, asymptomatic; occurs late in pregnancy
• Mechanism: hemodilution (expanded plasma volume) + mildly accelerated platelet clearance
• Platelet count rarely < 70,000/μL; resolves postpartum
• No treatment required; does not affect fetus

Thrombocytopenia in HIV

• One of the most common hematologic manifestations of HIV
• Multifactorial: immune complex–mediated platelet destruction, antiplatelet autoantibodies, direct HIV suppression of megakaryocyte development and survival
• Incidence has fallen sharply with effective antiretroviral therapy (ART)

Diagnostic Approach

1. History: medications, infections, family history, alcohol use, bleeding symptoms
2. CBC with differential + peripheral blood smear — rule out pseudothrombocytopenia (platelet clumping), look for schistocytes (TTP/HUS/DIC), blasts (leukemia), large platelets (ITP/congenital)
3. Coagulation studies (PT, aPTT, fibrinogen, D-dimer) — abnormal in DIC; normal in ITP/TTP
4. Bone marrow biopsy — if production defect suspected (aplasia, infiltration)
5. ADAMTS13 activity — for TTP diagnosis
6. Heparin-PF4 antibody (ELISA) + serotonin release assay (SRA) — for HIT
7. HIV testing, ANA, hepatitis serologies as indicated

Summary Table