Blue Toe Syndrome

Blue toe syndrome is sudden, painful blue or purple discolouration of one or more toes, with palpable foot pulses and an otherwise viable foot. It is a presentation, not a single disease, and means small vessel occlusion in the toes by emboli or by in situ microvascular thrombosis.

The causes by frequency are:

• Atheroembolism (cholesterol crystal embolism) from an ulcerated plaque in the aorta or iliac, femoral or popliteal arteries. This is the commonest cause. It occurs spontaneously, or after arterial catheterisation, vascular surgery, anticoagulation or thrombolysis.
• Thromboembolism from a proximal aneurysm (abdominal aorta, iliac, femoral, popliteal) or from the heart (atrial fibrillation, infective endocarditis, left ventricular thrombus, atrial myxoma).
• Hypercoagulable and blood disorders: antiphospholipid syndrome, heparin induced thrombocytopenia, polycythaemia vera, essential thrombocythaemia, cryoglobulinaemia, cold agglutinin disease, malignancy and disseminated intravascular coagulation.
• Vasculitis and vasospasm: polyarteritis nodosa, ANCA vasculitis, Buerger disease, Raynaud phenomenon, ergot or other vasoconstrictor drug effects.
• Others: chilblains (pernio, including post-viral), frostbite, calciphylaxis in dialysis, septic emboli, and low flow states.

Atheroembolism occurs mostly in men over 60 with widespread atherosclerosis. Renal involvement is the commonest visceral complication, and the 1-year mortality of multi-organ cholesterol embolism is high.

Pathophysiology.

In atheroembolism, cholesterol crystals and plaque debris, 100 to 200 micrometres in size, lodge in small arteries and arterioles. They provoke an intense inflammatory and foreign body response with endothelial injury and thrombosis, so the toe is ischaemic even though larger arteries stay open.

In thromboembolism, larger fragments occlude digital and plantar arteries. Pulses may be present because the emboli are small and distal.

In primary thrombotic and vasculitic states, small vessel thrombosis or inflammation occludes the digital circulation without a proximal source.

History:

• Timing and speed of onset, pain, and whether one or both feet are affected.
• Recent arterial procedures (catheterisation, stenting, aortic surgery) in the preceding weeks to months, and recent anticoagulant or thrombolytic therapy.
• Atrial fibrillation, previous embolic events, claudication, abdominal or back pain, fever, weight loss, joint pains, Raynaud symptoms, smoking, dialysis, and drugs (ergot, vasopressors, heparin).

Examination:

• Blue, purple or mottled painful toes, sometimes with ulceration or early gangrene. Livedo reticularis over the feet, legs or buttocks suggests cholesterol embolism.
• Palpable or Doppler audible foot pulses (absence suggests a larger arterial occlusion instead).
• Pulsatile mass or bruit (aneurysm or stenosis), irregular pulse, murmur, splinter haemorrhages, and retinal Hollenhorst plaques.
• Hypertension and oedema (renal involvement), abdominal tenderness (mesenteric emboli), and signs of connective tissue disease.

Step 1: assess limb threat.

• Ankle brachial index and toe pressures with handheld Doppler. A toe pressure under 30 mmHg means critical ischaemia.

Step 2: laboratory workup.

• Full blood count with differential (eosinophilia in 20 to 80% of cholesterol embolism), platelets, ESR and C-reactive protein, urea, creatinine and eGFR, urinalysis (protein, eosinophils), creatine kinase, liver tests, amylase, glucose and lipids.
• Complement (C3 and C4 are low in a minority of cholesterol embolism), antinuclear antibody, ANCA, antiphospholipid antibodies, cryoglobulins and cold agglutinins, protein electrophoresis, JAK2 testing when the haematocrit or platelets are raised, HIV and hepatitis serology.
• Blood cultures (three sets before antibiotics) when fever or a murmur is present.

Step 3: find the source.

• Duplex ultrasound of the aorta, iliac and lower limb arteries.
• CT angiography of the aorta and run off, showing ulcerated plaque, aneurysm and mural thrombus (cholesterol emboli arise from irregular, shaggy plaque).
• Echocardiography (transthoracic and, when negative with strong suspicion, transoesophageal for aortic arch atheroma, vegetation and thrombus), ECG and ambulatory ECG for atrial fibrillation.
• Imaging of the opposite leg, popliteal arteries and abdominal aorta.

Step 4: tissue diagnosis when the cause is uncertain.

• Skin, muscle (gastrocnemius) or renal biopsy showing biconvex needle shaped clefts of cholesterol in small arteries confirms atheroembolism.

Differential diagnosis.

• Acute limb ischaemia from a major artery occlusion (absent pulses).
• Chilblains and pernio, frostbite, Raynaud phenomenon and acrocyanosis.
• Vasculitis, antiphospholipid syndrome, cryoglobulinaemia and calciphylaxis.
• Diabetic neuroischaemic foot, cellulitis, gout and warfarin skin necrosis.

Immediate measures (first hours).

• Keep the foot warm, level and protected from pressure, and do not apply heat. Stop smoking.
• Analgesia: paracetamol 1 g orally every 6 hours (maximum 4 g daily; 3 g daily when weight is under 50 kg or in hepatic impairment); add morphine 2.5 to 5 mg orally every 4 hours as needed (reduce in renal impairment). Neuropathic pain: gabapentin 300 mg orally at night, increased by 300 mg every 1 to 3 days to a maximum of 3600 mg daily (reduce at eGFR under 60).
• Stop unnecessary anticoagulants and thrombolytics in suspected cholesterol embolism, because they may release more emboli. Continue them where there is a clear indication such as a mechanical valve or atrial fibrillation with thromboembolism.
• Tetanus status review when there is an ulcer or gangrene.

Treat by cause.

• Atheroembolism:
  • Aspirin 75 to 100 mg orally once daily and atorvastatin 40 to 80 mg once daily (LDL cholesterol under 1.4 mmol/L), with ALT at baseline and lipids at 4 to 12 weeks.
  • Control blood pressure (under 130/80 mmHg), glucose and smoking.
  • Treat the source: endovascular or surgical exclusion of an ulcerated or aneurysmal segment (stent graft, endarterectomy, bypass or ligation with extra-anatomical bypass).
  • Corticosteroids are not routine because evidence is weak, and are considered by a specialist for eosinophilia with kidney or systemic inflammation.
  • Avoid further catheter procedures and anticoagulation where possible.
• Aneurysmal or cardiac thromboembolism: unfractionated heparin 80 units/kg intravenous bolus then 18 units/kg/h (aPTT 1.5 to 2.5 times control), then long term anticoagulation (apixaban 5 mg twice daily, 2.5 mg twice daily if two of age 80 or over, weight 60 kg or under, creatinine 133 micromol/L or over; or warfarin to INR 2.0 to 3.0), with repair of the aneurysm. Treat endocarditis with the usual antibiotics and surgical indications.
• Antiphospholipid syndrome: warfarin to INR 2.0 to 3.0 (direct oral anticoagulants avoided in triple positive disease).
• Heparin induced thrombocytopenia: stop all heparin and give argatroban 2 microgram/kg/min intravenously (0.5 microgram/kg/min in hepatic impairment or critical illness; maximum 10 microgram/kg/min; aPTT 1.5 to 3 times baseline), then warfarin once platelets exceed 150 x 10^9/L.
• Myeloproliferative disease: aspirin 75 to 100 mg daily and cytoreduction (hydroxycarbamide 500 mg to 1 g orally daily, titrated by blood count; venesection to a haematocrit under 45% in polycythaemia vera) under haematology.
• Vasculitis: prednisolone 0.5 to 1 mg/kg orally daily (usual 40 to 60 mg) with a steroid sparing drug under rheumatology direction.
• Vasospasm and pernio: amlodipine 5 to 10 mg once daily or nifedipine modified release 30 to 60 mg once daily; remove triggers (ergot, cold).
• Severe digital ischaemia unresponsive to vasodilator and antithrombotic therapy: iloprost 0.5 to 2 ng/kg/min intravenously over 6 hours daily for 3 to 5 days (limited evidence; monitor blood pressure and heart rate).

Toe care.

• Wound care and offloading. Allow dry gangrene to demarcate (autoamputation) and amputate only when demarcated, infected or painful. Treat infection with antibiotics by culture. Revascularise a proximal lesion first when one is found.

Monitoring. Daily toe and foot assessment during admission. Creatinine and eosinophils weekly for 4 weeks (renal decline can follow over weeks). Duplex or CT surveillance of the treated source at 1, 6 and 12 months. Lipids at 4 to 12 weeks.

Referral and escalation. Refer every patient on the same day to a vascular surgeon. Refer to nephrology for rising creatinine, to cardiology for a cardiac source, to haematology or rheumatology for a systemic cause. Immediate review for abdominal pain (mesenteric emboli), confusion, or a rapidly worsening foot.

Special groups.

• Pregnancy: use low molecular weight heparin (enoxaparin 1 mg/kg subcutaneously every 12 hours) and aspirin 75 mg; avoid statins, warfarin and direct oral anticoagulants.
• Dialysis: calciphylaxis is possible, so check calcium, phosphate and parathyroid hormone; treat with sodium thiosulfate 25 g intravenously three times each week after dialysis by specialist direction.
• Older adults: consider frailty when choosing between repair and conservative care.
• Region specific: where angiography is unavailable, duplex, echocardiography and clinical examination often find the source.