22.5 Thrombocytopenia & Thrombotic Microangiopathies

3. Thrombocytopenias & Thrombotic Microangiopathies

Immune Thrombocytopenia (ITP)

• Pathophysiology: Acquired autoimmune disorder characterized by isolated thrombocytopenia (<100 x 10^9/L) in the absence of other cytopenias or systemic illnesses (diagnosis of exclusion). Pathogenic IgG autoantibodies directed against platelet surface glycoprotein complexes (most commonly GpIIb/IIIa and GpIb-IX) opsonize platelets. Opsonized platelets undergo premature destruction via Fc-gamma receptors on splenic macrophages. In addition, autoantibodies bind to megakaryocytes in the bone marrow, inhibiting thrombopoiesis.
• Bone Marrow Findings: Not routinely required in young patients with typical presentations, but if performed, shows normal or increased megakaryocytes with normal erythroid and myeloid lineages.
• Management Guidelines (UK / ASH):
  • Platelets >30 x 10^9/L without bleeding: Conservative observation alone.
  • First-Line Therapy (platelets <30 x 10^9/L or active bleeding): Oral prednisolone (1 mg/kg/day) or high-dose pulsed dexamethasone (40 mg daily for 4 days). In severe, active, life-threatening mucosal or central nervous system bleeding, or before urgent surgery, administer Intravenous Immunoglobulin (IVIG, 1 g/kg) to rapidly saturate splenic macrophage Fc receptors within 24–48 hours.
  • Second-Line Refractory Therapy: Thrombopoietin Receptor Agonists (TPO-RAs: romiplostim, eltrombopag), rituximab, or laparoscopic splenectomy.

Thrombotic Thrombocytopenic Purpura (TTP)

• Pathophysiology: Severe deficiency of ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13), the plasma zinc metalloprotease that cleaves ultra-large von Willebrand factor (UL-vWF) multimers into physiological smaller forms. In adults, >90% is acquired autoimmune, driven by inhibitory IgG autoantibodies against ADAMTS13 (rare congenital form is Upshaw-Schulman syndrome). Deficient ADAMTS13 activity results in persistence of hyper-reactive UL-vWF multimers, which spontaneously bind to platelet GpIb receptors under physiological shear stress, generating widespread, disseminated platelet-rich microthrombi throughout the microcirculation.
• The Classical Clinical Pentad ("FAT RN"):
  1. F = Fever (~50%);
  2. A = Microangiopathic Haemolytic Anaemia (MAHA): Mechanical shearing of red blood cells passing through microvascular platelet thrombi produces abundant schistocytes (fragmented cells, helmet cells) on blood film (>1–2%), profound LDH elevation, unconjugated hyperbilirubinaemia, and absent haptoglobin; Direct Antiglobulin Test (DAT) is strictly negative;
  3. T = Thrombocytopenia: Severe consumptive thrombocytopenia (typically <20–30 x 10^9/L) causing extensive petechiae and purpura;
  4. R = Renal Impairment: Usually mild/moderate proteinuria or microscopic haematuria (severe anuric renal failure is uncommon);
  5. N = Neurological Deficits: Occurs in >60%; characteristically fluctuating and transient (waxing and waning confusion, fluctuating headache, expressive aphasia, visual field defects, seizures, hemiparesis, coma).
• COAGULATION PROFILE PEARL: The Prothrombin Time (PT/INR), aPTT, and fibrinogen levels are COMPLETELY NORMAL in TTP! The microvascular thrombi consist almost entirely of platelets and vWF, without significant consumption of plasma coagulation factors (in sharp contrast to DIC).
• Diagnostic Confirmation: Severe ADAMTS13 activity <10% and detection of anti-ADAMTS13 IgG antibodies.
• Emergency Treatment:
  • EMERGENT THERAPEUTIC PLASMA EXCHANGE (PEX): Must be started immediately upon clinical suspicion! PEX removes circulating anti-ADAMTS13 autoantibodies and replenishes active ADAMTS13 metalloprotease from donor plasma. Continued daily until platelet count >150 x 10^9/L for >=2 consecutive days.
  • High-dose systemic corticosteroids (IV methylprednisolone or oral prednisolone 1 mg/kg) and rituximab.
  • Caplacizumab: A bivalent humanized anti-vWF nanobody that specifically blocks the interaction between vWF A1-domains and platelet GpIb receptors, rapidly stopping further platelet consumption.
  • CRITICAL CONTRAINDICATION: PLATELET TRANSFUSIONS ARE STRICTLY CONTRAINDICATED IN TTP! Administering platelets "fuels the fire" by providing additional substrate for microvascular thrombosis, precipitating acute myocardial infarction, cerebral stroke, and sudden cardiac arrest. Platelet transfusion is restricted solely to catastrophic, life-threatening intracranial haemorrhage.

Haemolytic Uraemic Syndrome (HUS)

• Typical / STEC-HUS: Primarily affects children <5 years following an enteric prodrome with Shiga-toxin-producing Escherichia coli (STEC, serotype O157:H7) or Shigella dysenteriae. Shiga toxin binds to globotriaosylceramide (Gb3) receptors on glomerular endothelial cells, triggering endothelial apoptosis and localized microvascular thrombosis.
• Clinical Triad: (1) Microangiopathic haemolytic anaemia with schistocytes; (2) Severe acute oliguric/anuric acute kidney injury (AKI); and (3) Consumptive thrombocytopenia. Preceded by abdominal pain and bloody diarrhoea. Coagulation tests (PT/aPTT) are normal.
• Management: Supportive: Careful fluid and electrolyte management and renal replacement therapy (haemodialysis). Antibiotics and antimotility agents are contraindicated in STEC gastroenteritis because they induce bacterial lysis, increasing Shiga toxin release and heightening HUS severity.

Disseminated Intravascular Coagulation (DIC)

• Pathophysiology: Systemic, uncontrolled activation of the coagulation cascade triggered by massive exposure of tissue factor or procoagulant toxins into the circulation (sepsis, severe trauma, obstetric emergencies, APML). Results in widespread microvascular fibrin deposition causing multiorgan failure, alongside simultaneous consumptive exhaustion of platelets and clotting factors and hyperfibrinolysis, precipitating severe systemic bleeding.
• Laboratory Hallmarks: Prolonged PT/INR, prolonged aPTT, severe thrombocytopenia, profoundly depleted fibrinogen (<1.5 g/L), and massively elevated D-dimer / FDPs.

Heparin-Induced Thrombocytopenia (HIT Type II)

• Pathophysiology: A life-threatening, immune-mediated prothrombotic drug reaction. Exposure to unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH) stimulates formation of pathogenic IgG autoantibodies directed against multimolecular complexes of Platelet Factor 4 (PF4) and heparin. The Fc portions of these IgG-PF4-heparin complexes bind to Fc-gamma-RIIa receptors on adjacent platelets, inducing massive platelet activation, aggregation, and release of prothrombotic microparticles and thrombin.
• Clinical Presentation: Classically occurs 5 to 10 days after starting heparin (or within 24 hours if heparin exposure occurred within the preceding 100 days). Defined by a >=50% fall in platelet count from the post-heparin peak (even if the absolute platelet count remains within the normal reference range, e.g. falling from 340 to 150 x 10^9/L).
• Paradoxical Thrombosis: HIT is NOT a bleeding disorder; it is an aggressive prothrombotic state! Up to 50% of untreated patients develop catastrophic venous thromboembolism (deep vein thrombosis, pulmonary embolism) or arterial thrombosis (limb ischaemia, stroke, myocardial infarction), known as "white clot syndrome", alongside skin necrosis at heparin injection sites.
• Immediate Management Protocol:
  1. IMMEDIATELY STOP ALL HEPARIN PRODUCTS (including LMWH, heparin line flushes, and heparin-coated catheters);
  2. SWITCH TO A NON-HEPARIN PARENTERAL ANTICOAGULANT: Direct thrombin inhibitor (Argatroban) or Factor Xa inhibitor (Fondaparinux, danaparoid);
  3. ABSOLUTE CONTRAINDICATION - WARFARIN: Warfarin must NEVER be commenced during acute HIT! Warfarin rapidly depletes endogenous Protein C (half-life ~6 hours) before clearing prothrombin, creating an extreme procoagulant state that precipitates microvascular thrombosis and catastrophic venous limb gangrene or skin necrosis. Warfarin may only be introduced once the platelet count has completely normalized (>=150 x 10^9/L) and must be overlapped with a non-heparin anticoagulant for >=5 days.

4. Comparative Table: TTP vs. HUS vs. DIC vs. HIT