Differential Diagnosis of Purpura

Introduction

Purpura refers to the visible extravasation of red blood cells into the skin or mucous membranes, manifesting as non-blanching (does not disappear with pressure) red-purple discoloration. Unlike erythema (which blanches because blood is within dilated vessels), purpura persists because blood has leaked outside vessels into the dermis.

The size of purpuric lesions provides initial classification:

• Petechiae: Pinpoint lesions <2-3mm
• Purpura: 3mm to ~1cm
• Ecchymoses: >1cm (bruises)

The fundamental diagnostic approach is to distinguish Palpable Purpura (raised, indicating vasculitis with vessel wall inflammation) from Non-Palpable (Macular) Purpura (flat, indicating bleeding without significant vessel wall destruction).

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22.1 Diascopy: Essential Test

[!IMPORTANT] Technique: Press a glass slide firmly against the lesion.

• Blanching: Lesion disappears → Erythema (blood in vessels).
• Non-Blanching: Lesion persists → Purpura (blood extravasated).

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22.2 Palpable vs. Non-Palpable Purpura

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22.3 Causes of Palpable Purpura (Vasculitis)

Palpable purpura almost always indicates small vessel vasculitis.

22.3.1 IgA Vasculitis (Henoch-Schönlein Purpura)

• Epidemiology: Most common vasculitis in children (peak 4-6 years). Rare in adults. Often follows upper respiratory tract infection (streptococcal).
• Pathogenesis: IgA-dominant immune complex deposition in small vessels.
• Clinical Features (Tetrad):
  1. Palpable Purpura: Non-thrombocytopenic. Symmetric, lower extremities and buttocks (dependent areas). Lesions may become confluent or necrotic.
  2. Arthritis/Arthralgia: Large joints (knees, ankles). Transient, non-deforming.
  3. Abdominal Pain: Colicky. GI bleeding (occult or overt). Risk of intussusception (ileo-ileal).
  4. Nephritis: Hematuria (macroscopic or microscopic), proteinuria. Usually self-limited but may progress to CKD (especially adults).
• Diagnosis:
  • Clinical criteria.
  • Skin biopsy: Leukocytoclastic vasculitis.
  • DIF: Granular IgA deposits in vessel walls (pathognomonic).
  • Normal platelets.
• Prognosis: Usually self-limited (weeks). Long-term renal monitoring essential.

22.3.2 Leukocytoclastic Vasculitis (LCV) / Hypersensitivity Vasculitis

• Definition: Small vessel vasculitis characterized histologically by fibrinoid necrosis and neutrophilic infiltrate with nuclear dust (leukocytoclasis = fragmented neutrophil nuclei).
• Triggers:
  • Drugs (most common in adults): Penicillins, Sulfonamides, NSAIDs, Thiazides.
  • Infections: Streptococcal, Hepatitis B/C.
  • Autoimmune diseases: SLE, RA, Sjögren's.
  • Malignancy (paraneoplastic).
• Clinical Features:
  • Crops of palpable purpura, predominantly on lower legs (dependent areas).
  • May have papules, vesicles, pustules, ulcers.
  • Symmetric.
• Course: Usually single episode if drug-induced. Chronic if associated with systemic disease.

22.3.3 Cryoglobulinemic Vasculitis

• Pathogenesis: Cryoglobulins (immunoglobulins that precipitate at cold temperatures) deposit in small vessels.
• Types:
  • Type I: Monoclonal (myeloma, Waldenström). Causes hyperviscosity, acral ischemia.
  • Type II/III: Mixed. Strongly associated with Hepatitis C (>90% of mixed cryoglobulinemia).
• Clinical Features:
  • Palpable purpura.
  • Livedo.
  • Peripheral neuropathy (mononeuritis multiplex).
  • Arthralgia.
  • Renal involvement (membranoproliferative GN).
  • Raynaud's phenomenon.
• Diagnosis: Cryoglobulin assay (sample MUST be collected and transported at 37°C). Hepatitis C serology.

22.3.4 Urticarial Vasculitis

• Definition: Vasculitis presenting with urticaria-like lesions that last >24 hours and leave residual purpura or hyperpigmentation.
• Key Features Differentiating from Simple Urticaria:
  • Individual lesions persist >24 hours (urticaria usually resolves within hours).
  • Lesions may burn or hurt rather than itch.
  • Residual purpura, ecchymosis, or hyperpigmentation when lesion resolves.
• Associations: Hypocomplementemic urticarial vasculitis → associated with SLE or Anti-C1q antibodies.

22.3.5 ANCA-Associated Vasculitides (AAV)

Can cause palpable purpura as cutaneous manifestation. Primarily medium-small vessel involvement.

• Granulomatosis with Polyangiitis (GPA, Wegener's): Upper/Lower respiratory tract + Nephritis + Purpura. c-ANCA (anti-PR3).
• Microscopic Polyangiitis (MPA): Nephritis + Pulmonary hemorrhage + Purpura. p-ANCA (anti-MPO).
• Eosinophilic Granulomatosis with Polyangiitis (EGPA, Churg-Strauss): Asthma + Eosinophilia + Purpura. p-ANCA (40%).

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22.4 Causes of Non-Palpable (Macular) Purpura

Flat purpura indicates extravasation without significant vessel wall inflammation.

22.4.1 Thrombocytopenia (Low Platelets)

Immune Thrombocytopenia (ITP)

• Mechanism: Autoantibodies (usually anti-GPIIb/IIIa) cause platelet destruction.
• Clinical Features: Petechiae, purpura, mucosal bleeding (epistaxis, menorrhagia). No hepatosplenomegaly.
• Diagnosis: Isolated thrombocytopenia (<100,000/μL). Exclusion of other causes.

Thrombotic Thrombocytopenic Purpura (TTP)

[!CAUTION] MEDICAL EMERGENCY

• Pathogenesis: Deficiency of ADAMTS13 (a metalloprotease that cleaves vWF multimers) → Uncleaved large vWF multimers → Platelet aggregation → Microthrombi → Microangiopathic Hemolytic Anemia (MAHA).
• Pentad (classic but not all required):
  1. Thrombocytopenia
  2. Microangiopathic Hemolytic Anemia (schistocytes, elevated LDH, low haptoglobin)
  3. Neurological symptoms (confusion, stroke, seizure)
  4. Fever
  5. Renal impairment
• Presentation: Purpura + Confusion + Anemia.
• Diagnosis: ADAMTS13 activity <10%.
• Treatment: Urgent plasma exchange. DO NOT delay. High mortality if untreated.

Heparin-Induced Thrombocytopenia (HIT)

• Pathogenesis: Antibodies to platelet factor 4-heparin complexes → Platelet activation → Thrombosis (paradoxically!).
• Timing: 5-14 days after heparin exposure (or earlier if prior exposure).
• Hallmark: Thrombocytopenia + Thrombosis (NOT just bleeding).
• Diagnosis: 4Ts score, Anti-PF4 antibodies, Serotonin release assay.

Bone Marrow Failure

• Causes: Aplastic anemia, Leukemia, Myelodysplasia, Chemotherapy.
• Clue: Pancytopenia (low WBC, RBC, Platelets). Petechiae/purpura + Fatigue + Infections.

22.4.2 Coagulation Disorders

Disseminated Intravascular Coagulation (DIC)

• Definition: Systemic activation of coagulation → Widespread microthrombi → Consumption of platelets and clotting factors → Bleeding + Thrombosis.
• Causes: Sepsis, Obstetric complications (abruption, amniotic embolism), Malignancy, Severe trauma.
• Clinical Features:
  • Widespread purpura, ecchymoses.
  • Bleeding from multiple sites (IV sites, incisions, mucosal).
  • End-organ damage from microvascular thrombosis.
• Labs: Low platelets, Prolonged PT/PTT, Low fibrinogen, Elevated D-dimer, Schistocytes.

Vitamin K Deficiency / Warfarin Overdose

• Mechanism: Reduced production of Vitamin K-dependent clotting factors (II, VII, IX, X).
• Clinical Features: Ecchymoses, Prolonged bleeding from cuts.
• Clue: Elevated PT/INR with normal platelet count.

22.4.3 Vascular Fragility (Normal Platelets and Coagulation)

Senile (Actinic) Purpura

• Epidemiology: Elderly patients (>60 years).
• Distribution: Dorsal forearms and hands (sun-exposed, mechanically vulnerable areas).
• Mechanism: Age-related atrophy of dermal collagen and loss of subcutaneous fat → Vessels poorly supported → Minor trauma causes hemorrhage.
• Appearance: Dark purple, irregular ecchymoses. Often preceded by minor trauma.
• Course: Benign. Lesions resolve with brownish hemosiderin staining.

Steroid-Induced Purpura

• Similar mechanism to senile purpura. Long-term systemic or topical corticosteroids cause skin atrophy.

Scurvy (Vitamin C Deficiency)

• Mechanism: Vitamin C is essential for collagen synthesis. Deficiency → Weak vessel walls.
• Clinical Features:
  • Perifollicular purpura: Hemorrhage around hair follicles.
  • Corkscrew hairs: Coiled, fragmented hairs.
  • Gum swelling/bleeding (if teeth present).
  • Wound dehiscence.
• At-Risk Groups: Elderly, Alcoholics, Psychiatric patients, Fad diets.

Ehlers-Danlos Syndrome (EDS)

• Inheritance: Group of connective tissue disorders (various types).
• Mechanism: Defective collagen leads to fragile skin and vessels.
• Clinical Features: Easy bruising, Skin hyperextensibility, Joint hypermobility, "Cigarette paper" scars.

22.4.4 Pigmented Purpuric Dermatoses (Capillaritis)

A group of chronic, benign conditions characterized by petechial hemorrhage from capillary inflammation (minimal inflammation, primarily capillary damage).

• Common to All: Petechiae, Hemosiderin deposition (orange-brown), Lower legs.
• Variants:
  • Schamberg's Disease (Progressive Pigmented Purpura): Most common. "Cayenne pepper" petechiae on orange-brown background. Non-pruritic.
  • Majocchi's Disease (Purpura Annularis Telangiectoides): Annular pattern with central clearing.
  • Lichen Aureus: Golden-brown patch, often solitary.
  • Gougerot-Blum (Pigmented Purpuric Lichenoid Dermatitis): Lichenoid papules + purpura.
• Histology: Red cell extravasation, hemosiderin, mild lymphocytic infiltrate.

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22.5 Emergencies in Purpura

[!CAUTION] Life-Threatening Conditions

1. Meningococcemia: Fever + Rapidly progressive petechiae/purpura + Shock. IV Ceftriaxone IMMEDIATELY.
2. TTP: Purpura + MAHA + Neuro symptoms. Urgent plasma exchange.
3. DIC: Multi-site bleeding + Thrombosis + Critical illness. Treat underlying cause.
4. Purpura Fulminans: Symmetric limb purpura/necrosis in setting of severe sepsis (meningococcus, pneumococcus) or Protein C/S deficiency.

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22.6 Diagnostic Algorithm

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22.7 Summary Comparison Table

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22.8 Clinical Pearls

1. Palpable purpura = Vasculitis until proven otherwise. Biopsy for histology and DIF.
2. IgA Vasculitis (HSP): Child + Purpura (lower limbs/buttocks) + Abdominal pain + Arthritis. Monitor kidneys long-term.
3. Drug-induced LCV: Onset 7-21 days after starting drug. Resolves with drug withdrawal.
4. Cryoglobulinemia: Think Hepatitis C. Check cryoglobulins (warm transport).
5. TTP is an emergency: Purpura + Confusion + MAHA → Urgent ADAMTS13, Plasma exchange.
6. DIC: Sick patient + Bleeding from everywhere + Thrombosis → Check PT, PTT, Fibrinogen, D-dimer.
7. Senile purpura: Common, benign. Elderly forearms. No workup needed unless atypical.
8. Perifollicular purpura + Corkscrew hairs → Scurvy. Ask about diet.