What is the most likely diagnosis and recommended work‑up for a patient with a livedo‑type rash, skin tenderness, fatigue and brain fog, who has normal partial thromboplastin time, normal activated partial thromboplastin time, normal erythrocyte sedimentation rate and mildly elevated C‑reactive protein?

Diagnostic Approach to Livedo-Type Rash with Normal Coagulation Studies and Mildly Elevated CRP

The most likely diagnosis is antiphospholipid syndrome (APS) or Sneddon syndrome, and you should immediately order antiphospholipid antibodies (lupus anticoagulant, anticardiolipin antibodies, anti-β2-glycoprotein I antibodies, and anti-phosphatidylserine-prothrombin complex antibodies) along with neuroimaging to assess for cerebrovascular involvement. 1, 2, 3

Critical Distinction: Livedo Reticularis vs. Livedo Racemosa

The pattern of the rash determines both the differential diagnosis and urgency of workup:

• Livedo reticularis presents as a regular, symmetric, fishnet pattern primarily on the trunk and proximal extremities, often physiologic or benign 2, 4
• Livedo racemosa shows an irregular, broken, asymmetric pattern with wider loops and is pathologic, strongly associated with systemic disease including APS, Sneddon syndrome, and vasculitis 2, 5

Livedo racemosa is significantly associated with cutaneous vasculitis (P = 0.0014), higher CRP levels, skin ulceration, arthralgia, and ischemic cerebrovascular events compared to regular livedo reticularis 5

Immediate Laboratory Workup

Antiphospholipid Antibody Panel (Priority Testing)

• Lupus anticoagulant (LAC) - Note that a prolonged aPTT from lupus anticoagulant is NOT a contraindication to anticoagulation and actually indicates increased thrombotic risk requiring indefinite anticoagulation if thrombotic events occur 6
• Anticardiolipin antibodies (aCL) - IgG and IgM isotypes 5, 3
• Anti-β2-glycoprotein I antibodies - IgG and IgM isotypes 5
• Anti-phosphatidylserine-prothrombin complex (anti-PS/PT) antibodies - IgM anti-PS/PT antibodies are significantly elevated in livedo racemosa (19.2 ± 17.0 U/ml) versus regular livedo reticularis (8.93 ± 8.48 U/ml, P = 0.0013) and may be implicated in disease susceptibility 5

Additional Essential Testing

• Complete blood count with differential - assess for thrombocytopenia, anemia, or leukocytosis 7, 8
• Comprehensive metabolic panel - evaluate renal function (azotemia can falsely elevate ESR) and liver function 7, 8, 9
• ANA panel and rheumatoid factor - screen for systemic lupus erythematosus, which can present with livedo racemosa and APS 8, 2
• Serum ferritin - if Still's disease is suspected based on fever pattern 6, 7

Neuroimaging and Cardiovascular Assessment

• Brain MRI with and without contrast - essential to evaluate for cerebrovascular events, as livedo is significantly associated with cerebral or ocular ischemic arterial events (OR 10.8,95% CI 5.2-22.5) 3
• Echocardiography - livedo reticularis is significantly associated with heart valve abnormalities (OR 7.3,95% CI 3.6-14.7) 3
• Blood pressure monitoring - livedo is associated with arterial systemic hypertension ≥160/90 mm Hg (OR 2.9,95% CI 1.5-5.7) 3

Skin Biopsy Considerations

Early detection of cutaneous vasculitis in skin biopsies is useful for prognostic evaluation, including risk of ischemic cerebrovascular events 5

• Perform punch biopsy of affected skin if livedo racemosa pattern is present or if diagnosis remains unclear after initial workup 5
• Cutaneous vasculitis is significantly more prevalent in livedo racemosa and is closely related to pathogenic factors triggering disease progression 5

Interpretation of Normal Coagulation Studies

Your patient's normal PTT and aPTT do NOT exclude antiphospholipid syndrome:

• A prolonged aPTT from lupus anticoagulant is paradoxically associated with increased thrombotic risk, not bleeding risk 6
• The aPTT prolongation occurs through interference with phospholipids in the test reagent, not actual coagulation factor deficiency 6
• Normal aPTT can occur in APS patients without lupus anticoagulant but with other antiphospholipid antibodies 5, 3

Interpretation of Normal ESR with Mildly Elevated CRP

The discordance between normal ESR and elevated CRP (9.7 mg/L) suggests:

• Acute or subacute inflammation - CRP rises within 12-24 hours and peaks at 48 hours, while ESR rises more slowly 7, 9
• Early disease phase - CRP normalizes faster (half-life 19 hours) than ESR (half-life 4-7 days) 9
• Absence of chronic systemic inflammation - conditions like giant cell arteritis, polymyalgia rheumatica, or Still's disease typically show ESR >40-60 mm/h 6, 7

However, normal ESR and CRP do not exclude APS or Sneddon syndrome, as these are primarily thrombotic rather than inflammatory conditions 1, 2, 3

Differential Diagnosis Priority List

High Probability (Require Immediate Workup)

1. Antiphospholipid syndrome - livedo reticularis is the most frequent dermatologic manifestation (25.5% of APS patients) and is significantly associated with arterial events (OR 6,95% CI 2.9-12.6) 3
2. Sneddon syndrome - characterized by livedo racemosa with cerebrovascular accidents, affecting young adults 1, 2
3. Systemic lupus erythematosus - can present with livedo racemosa and antiphospholipid antibodies 2, 3

Moderate Probability (Consider Based on Additional Features)

1. Livedoid vasculopathy - presents with painful purpuric lesions and ulceration 2
2. Cholesterol embolization syndrome - typically follows vascular procedures, presents with livedo racemosa and renal dysfunction 2
3. Polyarteritis nodosa - medium vessel vasculitis with livedo racemosa, would typically show higher inflammatory markers 2

Lower Probability (Given Normal ESR)

1. Giant cell arteritis - ESR >40 mm/h has 93.2% sensitivity; normal ESR makes this unlikely 7
2. Polymyalgia rheumatica - ESR typically >40 mm/h; normal ESR argues against this diagnosis 7, 8
3. Still's disease - ESR elevated in 95-98% of cases; normal ESR makes this very unlikely 6, 7

Management Algorithm

If Antiphospholipid Antibodies Are Positive

• With history of thrombotic events: Initiate indefinite anticoagulation therapy regardless of aPTT prolongation 6
• Without thrombotic events: Close monitoring with repeat antibody testing in 12 weeks to confirm persistent positivity; consider low-dose aspirin 3
• With neurologic symptoms: Urgent neurology consultation and consideration of anticoagulation even without documented thrombosis 1, 3

If Initial Workup Is Negative

• Repeat antiphospholipid antibody panel in 12 weeks, as transient positivity can occur 3
• Consider alternative diagnoses including hematologic disorders, cryoglobulinemia, or medication-induced livedo 2
• Avoid cold exposure and vasoconstricting substances; consider calcium channel blocker if symptoms are bothersome 4

Critical Pitfalls to Avoid

• Do not dismiss normal aPTT as excluding prothrombotic state - lupus anticoagulant causes aPTT prolongation but increases thrombotic risk 6
• Do not delay anticoagulation in patients with APS and thrombotic events - prolonged aPTT from lupus anticoagulant is not a contraindication 6
• Do not assume benign etiology based on normal inflammatory markers - APS and Sneddon syndrome are thrombotic, not inflammatory conditions 1, 3
• Do not overlook neuroimaging - cutaneous vasculitis in livedo patients is significantly associated with ischemic cerebrovascular events 5
• Do not confuse livedo reticularis with livedo racemosa - the latter has much stronger association with systemic disease and requires more aggressive workup 2, 5