7.4 Platelet Disorders, Thrombocytopenia & the Bleeding Patient

Clinical evaluation of bleeding and thrombotic disorders requires distinguishing between abnormalities of primary hemostasis (platelet adhesion, activation, and aggregation) and secondary hemostasis (coagulation cascade activation and stable fibrin mesh generation).

1. Clinical Approach to Bleeding Disorders

2. Thrombocytopenia & Microangiopathic Disorders

Immune Thrombocytopenia (ITP)

• Pathophysiology: Acquired autoimmune destruction of platelets mediated by anti-glycoprotein IIb/IIIa (GPIIb/IIIa) or GPIb/IX autoantibodies, causing splenic macrophage phagocytosis and impaired megakaryocyte platelet production.
• Diagnosis: Isolated thrombocytopenia with normal coagulation studies and normal peripheral smear (large, young platelets may be seen). It is a diagnosis of exclusion (rule out HIV, HCV, H. pylori, SLE, CLL, and drug-induced causes).
• Treatment Thresholds & Regimens:
  • Platelets ≥ 30,000/mcL without bleeding: Observation and clinical monitoring.
  • Platelets < 20,000–30,000/mcL or active mucosal bleeding:
    • First-line: Oral Prednisone (1 mg/kg/day x 2–4 weeks with taper) or high-dose Dexamethasone (40 mg daily x 4 days every 14 days for 1–2 cycles) $\pm$ IVIG (1 g/kg/day x 1–2 days) or IV anti-D immunoglobulin (Rh-positive, non-splenectomized patients only).
    • Second-line: Thrombopoietin Receptor Agonists (TPO-RAs: Eltrombopag, Romiplostim, Avatrombopag), Rituximab (anti-CD20), or Splenectomy for chronic refractory disease.

Thrombotic Thrombocytopenic Purpura (TTP)

• Pathophysiology: Severe deficiency of ADAMTS13 (< 10% activity), a metalloprotease responsible for cleaving ultra-large von Willebrand factor (UL-vWF) multimers. Uncleaved UL-vWF multimers trigger spontaneous platelet adhesion, systemic microvascular thrombosis, consumptive thrombocytopenia, and shearing of erythrocytes (MAHA).
• Clinical Presentation: Classic "Pentad" (present in full in only 20–30% of patients; MAHA + thrombocytopenia alone is sufficient to suspect TTP and initiate emergency treatment):
  1. Microangiopathic Hemolytic Anemia (MAHA) with prominent schistocytes, elevated LDH, indirect hyperbilirubinemia, low haptoglobin.
  2. Severe Thrombocytopenia (usually < 30,000/mcL) with mucosal bleeding.
  3. Neurological Abnormalities (headache, confusion, transient aphasia, seizures, coma).
  4. Renal Insufficiency (mild-to-moderate hematuria/proteinuria; anuria/severe AKI is rare compared to HUS).
  5. Fever (low-grade).
• PLASMIC Score: Clinical prediction tool for ADAMTS13 deficiency < 10% (Score 6–7 indicates high probability: Platelets < 30k, Hemolysis markers, No active cancer, No organ transplant, MCV < 90, INR < 1.5, Creatinine < 2.0).
• EMERGENCY Management:
  • Immediate Therapeutic Plasma Exchange (PEX): Replaces ADAMTS13 enzyme and removes inhibitory autoantibodies. Perform daily until platelet count is normal (≥ 150,000/mcL) and LDH normalizes for 2 consecutive days.
  • High-Dose Corticosteroids: Methylprednisolone 1 g IV daily x 3 days, followed by oral Prednisone 1 mg/kg/day.
  • Caplacizumab: Humanized anti-vWF nanobody targeting the A1 domain of vWF; blocks vWF-platelet GPIb interaction, halting microvascular thrombosis.
  • CRITICAL CONTRAINDICATION: Platelet transfusions are STRICTLY CONTRAINDICATED (fuel to the fire; precipitates catastrophic stroke, myocardial infarction, and death) unless life-threatening intracranial hemorrhage is present.

Hemolytic Uremic Syndrome (HUS)

• Typical / STEC-HUS: Caused by Shiga toxin-producing Escherichia coli (STEC serotype O157:H7) or Shigella dysenteriae. Shiga toxin injures glomerular endothelial cells. Triad: bloody diarrhea prodrome, severe Acute Kidney Injury (AKI), and MAHA/thrombocytopenia. Management: Supportive fluid resuscitation and hemodialysis. Antibiotics and antimotility agents are contraindicated (they increase bacterial toxin release and worsen outcomes).
• Atypical HUS (aHUS): Uncontrolled alternative complement pathway dysregulation due to mutations in complement regulatory proteins (CFH, CFI, CD46) or anti-Factor H autoantibodies. Treated with Eculizumab or Ravulizumab (C5 inhibitors).

Heparin-Induced Thrombocytopenia (HIT Type II)

• Pathophysiology: IgG autoantibodies bind to complexes of Platelet Factor 4 (PF4) and Heparin. The antibody-PF4-heparin complex cross-links platelet FcγRIIa receptors, driving massive platelet activation, thrombin generation, and severe venous and arterial thrombosis.
• Clinical 4Ts Score:
  1. Thrombocytopenia: > 50% platelet drop (or nadir 20,000–100,000/mcL) (2 pts).
  2. Timing: 5 to 10 days post-heparin start (or < 24 hours if exposed to heparin within prior 30–100 days) (2 pts).
  3. Thrombosis: New confirmed VTE/ATE, skin necrosis at injection site, or acute systemic reaction (2 pts).
  4. oTher causes: No other apparent etiology for thrombocytopenia (2 pts).
• Diagnostic Testing: Step 1: PF4-Heparin Enzyme-Linked Immunosorbent Assay (ELISA) (high sensitivity, high NPV). Step 2: If ELISA positive (OD > 0.40–1.0), confirm with a functional gold-standard assay: Serotonin Release Assay (SRA) (demonstrates $^{14}\text{C}$-serotonin release from donor platelets at therapeutic heparin concentrations).
• Management Protocol:
  1. IMMEDIATELY DISCONTINUE ALL HEPARIN: Stop UFH infusions, LMWH injections, heparin flushes, and remove heparin-coated vascular catheters.
  2. Initiate Non-Heparin Parenteral Anticoagulation at Therapeutic Doses: Argatroban (direct thrombin inhibitor, cleared hepatically; titrate to aPTT 1.5–3.0x baseline; agent of choice in renal failure), Bivalirudin (cleared renally/enzymatically), or Fondaparinux (indirect factor Xa inhibitor; contraindicated if CrCl < 30 mL/min).
  3. Warfarin Rules: NEVER start Warfarin in acute HIT. Warfarin rapidly depletes Protein C (short half-life ~6 hours), creating an extreme prothrombotic state leading to warfarin-induced skin necrosis and venous limb gangrene. Warfarin can only be initiated AFTER platelets recover to ≥ 150,000/mcL, must be started at low maintenance doses (≤ 5 mg, NO loading dose), and must be overlapped with the non-heparin anticoagulant for at least 5 days and until INR is therapeutic for ≥ 2 consecutive days.