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PA20.1-2 | Platelet & Vascular Bleeding Disorders — Part 2

Thrombotic Thrombocytopenic Purpura (TTP)

Thrombotic Thrombocytopenic Purpura: Pathogenesis, Pentad, and DIC Differentiation

Thrombotic Thrombocytopenic Purpura (TTP) is a life-threatening microangiopathy — recognising its pentad is a clinical emergency.

Pathogenesis:
• Deficiency (inherited or acquired via inhibitory antibodies) of ADAMTS13, the metalloprotease that cleaves ultra-large von Willebrand factor (UL-vWF) multimers.
• Uncleaved UL-vWF binds and activates platelets spontaneously → platelet thrombi in small vessels throughout the body.
• These microthrombi do NOT activate the coagulation cascade significantly → PT and aPTT are normal or near-normal (distinguishing TTP from DIC).

Classic Pentad of TTP:
1. Microangiopathic haemolytic anaemia (MAHA) — RBCs fragmented by fibrin strands in microthrombi → schistocytes on blood film (helmet cells, triangle cells). Elevated LDH, low haptoglobin.
2. Thrombocytopenia — platelet consumption in microthrombi.
3. Neurological abnormalities — TIAs, confusion, seizures (microthrombi in cerebral vessels).
4. Renal dysfunction — mild in TTP (more severe in HUS).
5. Fever.

Key differentiator from DIC: In TTP, PT and aPTT are essentially normal (consumption is limited to platelets + vWF). In DIC, both coagulation factors and platelets are consumed.

> Cross-reference: Cluster H5 (DIC) covers the coagulation factor consumption side; when you see schistocytes, always ask: normal PT/aPTT (TTP/HUS) or prolonged PT/aPTT (DIC)?

Qualitative Platelet Defects

Qualitative Platelet Defects: Glanzmann vs Bernard-Soulier

Normal platelet count but prolonged bleeding time / abnormal PFA-100 → think qualitative (functional) platelet disorder.

Inherited defects:

• Glanzmann thrombasthenia: autosomal recessive deficiency of GPIIb/IIIa (the fibrinogen receptor mediating platelet aggregation). Platelets adhere normally (GPIb intact) but cannot aggregate — aggregation assays show no response to ADP, collagen, or thrombin. Severe mucocutaneous bleeding; platelet count normal.

• Bernard-Soulier syndrome: autosomal recessive deficiency of GPIb-IX-V (the VWF receptor mediating platelet adhesion to sub-endothelium). Platelets cannot adhere to damaged vessel wall. Characteristically large platelets (giant platelets) + mild thrombocytopenia on film. Aggregation with ristocetin (which mimics VWF) is absent.

Disorder	Defective receptor	Defective step	Distinguishing lab
Glanzmann	GPIIb/IIIa	Aggregation	No aggregation with ADP/collagen; normal ristocetin
Bernard-Soulier	GPIb-IX-V	Adhesion	Giant platelets; no aggregation with ristocetin

Acquired defects:

• Aspirin: irreversibly inhibits COX-1 (cyclo-oxygenase), blocking thromboxane A2 synthesis → impairs platelet activation and aggregation for the platelet's lifespan (~7–10 days).
• Uraemia: retained metabolites (guanidinosuccinic acid, phenolic acids) impair platelet GPIb and granule release — a common and treatable bleeding risk in CKD. Corrected by dialysis or DDAVP.

Vascular Purpuras

Vascular Purpuras: Mechanisms and Clinical Patterns

Vascular purpuras arise from vessel wall fragility or structural defects — platelet count and coagulation tests are typically normal. The bleeding time may be prolonged.

Henoch-Schönlein Purpura (HSP) / IgA Vasculitis:
• Most common systemic vasculitis in children; follows upper respiratory infection.
• Pathogenesis: IgA-dominant immune complex deposition in small vessel walls → complement activation → leukocytoclastic vasculitis.
• Tetrad: palpable purpura (non-thrombocytopenic) over buttocks/lower limbs, arthralgia, colicky abdominal pain, and renal involvement (IgA nephropathy pattern).
• The purpura is palpable because of perivascular oedema — this distinguishes it from flat thrombocytopenic petechiae.

Scurvy (Vitamin C deficiency):
• Vitamin C is required for hydroxylation of proline and lysine in collagen synthesis → deficient collagen in vessel walls → perivascular haemorrhages.
• Features: perifollicular haemorrhages, corkscrew hairs, gingival swelling and bleeding, subperiosteal haemorrhages in children.

Senile purpura:
• Atrophy of perivascular connective tissue with ageing → purpura on sun-exposed areas (dorsum of hands, forearms) with minor trauma. Benign.

Hereditary Haemorrhagic Telangiectasia (HHT / Osler-Weber-Rendu):
• Autosomal dominant mutation in endoglin or activin receptor-like kinase (ALK1) — proteins involved in TGF-β vascular signalling.
• Abnormal arteriovenous communications (telangiectasias) in skin, mucosae, lungs, liver, brain.
• Recurrent epistaxis + telangiectasias on lips, tongue, fingertips; may cause right-to-left shunts via pulmonary AVMs.

Henoch-Schönlein Purpura: Distinguishing Palpable Purpura from Flat Petechiae