Unilateral leg swelling

Unilateral leg swelling is an increase in the volume of one limb, which may be painful and red (the painful swollen calf) or painless.

Clinical relevance. Deep vein thrombosis affects about 1 in 1,000 adults a year and carries a risk of pulmonary embolism (up to 50% of untreated proximal deep vein thrombosis embolises) and post thrombotic syndrome (20% to 50%). Only 10% to 25% of patients referred with a swollen leg have a thrombosis; cellulitis, ruptured Baker cyst, muscle injury and chronic venous disease are common alternatives. Misdiagnosis in either direction is costly.

Classification by mechanism.

• Venous: deep vein thrombosis (proximal: iliac, femoral, popliteal; distal: calf veins), post thrombotic syndrome, superficial vein thrombosis, chronic venous insufficiency, venous obstruction (May-Thurner syndrome, pelvic tumour, retroperitoneal fibrosis, inferior vena cava thrombosis).
• Inflammatory and infective: cellulitis, erysipelas, necrotising fasciitis, abscess, septic arthritis, osteomyelitis, pyomyositis, insect bite, tropical pyomyositis, filariasis, lymphangitis.
• Musculoskeletal and traumatic: muscle tear and calf strain, haematoma, ruptured Baker cyst, fracture, compartment syndrome, Achilles tendon rupture, knee effusion, haemarthrosis, myositis ossificans.
• Lymphatic: primary and secondary lymphoedema, filariasis, tumour infiltration.
• Arterial and vascular: popliteal aneurysm with thrombosis or compression, acute limb ischaemia with reperfusion oedema, arteriovenous malformation and fistula, vascular tumour.
• Neurological and other: paralysed limb (stroke, spinal cord injury), complex regional pain syndrome, lipoedema (asymmetry), tumour (sarcoma), ruptured plantaris tendon, drug extravasation.

Mechanism. Venous thrombosis arises from stasis, endothelial injury and hypercoagulability (Virchow triad). Inflammation and infection increase permeability and lymphatic load. Compartment syndrome results from raised pressure within a closed fascial space.

History.

• Onset (hours, days, weeks), pain (type, calf or thigh, on walking or at rest), redness, warmth, fever and rigors, trauma, recent strenuous activity, insect or animal bite, skin break, ulcer, injection.
• Thrombosis risk: recent surgery or fracture, immobilisation (cast, bed rest over 3 days), long haul travel, hospitalisation, active cancer, previous venous thromboembolism, family history, thrombophilia, pregnancy and postpartum (6 weeks).
• Other thrombosis risk: oestrogen containing contraception and hormone therapy, obesity, age, heart failure, inflammatory bowel disease, nephrotic syndrome, HIV, central venous catheter, intravenous drug use.
• Symptoms of pulmonary embolism: breathlessness, pleuritic pain, haemoptysis, palpitations, syncope.
• Arterial symptoms: cold, pale or numb leg, sudden severe pain, claudication, known aneurysm.
• Knee disease: arthritis, effusion, Baker cyst history; recent injection or procedure.
• Lymphatic: previous radiotherapy or node surgery, prior cellulitis, residence in filarial endemic areas, barefoot exposure on volcanic soil.
• Systemic: weight loss, night sweats, bleeding, anticoagulant use.
• Drugs: anticoagulants, antiplatelets, oestrogen, tamoxifen, thalidomide, steroids, testosterone.

Examination.

• Vital signs (temperature, heart rate, respiratory rate, saturation, blood pressure).
• Both legs exposed from groin to toes: swelling, colour, warmth, tenderness along deep veins, venous distension, collateral veins.
• Also on both legs: calf circumference measured 10 cm distal to the tibial tuberosity (difference over 3 cm is significant), pitting, skin (erythema borders, bullae, crepitus, necrosis, venous eczema, ulcer), blue or pale discolouration (phlegmasia cerulea dolens, phlegmasia alba dolens), groin and popliteal masses.
• Pulses (femoral, popliteal, dorsalis pedis, posterior tibial), capillary refill, sensation, motor power, pain on passive stretch (compartment syndrome).
• Knee: effusion, popliteal fullness, range of movement; calf squeeze and Achilles tendon (Thompson test).
• Abdomen, pelvis and rectal or vaginal examination when a pelvic cause is suspected; breasts, lymph nodes, and signs of malignancy.
• Chest: signs of pulmonary embolism or pleural effusion.

Red flags.

• Massive swelling with pain, cyanosis or blanching (phlegmasia), venous gangrene, or arterial compromise.
• Pain out of proportion, tense swollen compartment, pain on passive stretch, paraesthesia, weak or absent pulses (compartment syndrome, arterial occlusion).
• Rapidly spreading erythema with severe pain, bullae, crepitus, skin necrosis, systemic toxicity (necrotising fasciitis).
• Breathlessness, pleuritic pain, haemoptysis, syncope, tachycardia or hypoxia (pulmonary embolism).
• Fever with rigors, hypotension, confusion (sepsis).
• Pregnancy or postpartum with left leg swelling or abdominal pain.
• Active cancer, unexplained weight loss, or pelvic mass.
• Anticoagulated patient with a rapidly enlarging tense swelling (haematoma).

Venous. Proximal deep vein thrombosis, distal (calf vein) thrombosis, upper iliac and femoral vein thrombosis (including pregnancy related and May-Thurner syndrome), inferior vena cava thrombosis, superficial thrombophlebitis, post thrombotic syndrome, chronic venous insufficiency with asymmetry, vein compression by pelvic mass, nodes, aneurysm or retroperitoneal disease.

Infective and inflammatory. Cellulitis, erysipelas, necrotising fasciitis, pyomyositis, septic arthritis, osteomyelitis, abscess, lymphangitis, insect bite reaction, tinea pedis with secondary infection, erythema nodosum, panniculitis, gout and pseudogout, acute inflammatory arthritis.

Musculoskeletal and traumatic. Calf muscle strain or tear, ruptured Baker cyst (pseudothrombophlebitis), haematoma (including on anticoagulation), fracture, Achilles tendon rupture, plantaris rupture, compartment syndrome (trauma, crush, tight cast, reperfusion, anticoagulant bleeding, exertion), knee effusion, haemarthrosis (haemophilia), rhabdomyolysis, osteosarcoma and soft tissue sarcoma.

Lymphatic. Secondary lymphoedema (cancer, surgery, radiotherapy), primary lymphoedema (often unilateral at presentation), filariasis, recurrent cellulitis, tuberculosis of lymph nodes.

Arterial and vascular. Popliteal aneurysm, acute limb ischaemia, arteriovenous fistula or malformation, vascular tumours (haemangioma), pseudoaneurysm after puncture, reperfusion oedema after revascularisation.

Neurological and other. Hemiplegic limb oedema, complex regional pain syndrome, lipoedema or lipohypertrophy asymmetry, drug extravasation, limb dependency from immobility, Klippel-Trenaunay syndrome.

1. Pre-test probability with the two level Wells score for deep vein thrombosis:
   • active cancer (treatment within 6 months or palliative) 1
   • paralysis, paresis or recent plaster immobilisation 1
   • recently bedridden over 3 days or major surgery within 12 weeks 1
   • localised tenderness along the deep venous system 1
   • entire leg swollen 1
   • calf swelling over 3 cm greater than the asymptomatic side (measured 10 cm distal to the tibial tuberosity) 1
   • pitting oedema confined to the symptomatic leg 1
   • collateral superficial veins (non varicose) 1
   • previous documented deep vein thrombosis 1
   • alternative diagnosis at least as likely as deep vein thrombosis minus 2
   • A score of 2 or more means thrombosis is likely; 1 or less means unlikely.
2. Thrombosis unlikely (score 1 or less): high sensitivity D-dimer (cut off 500 ng/mL fibrinogen equivalent units; age adjusted cut off in over 50s is age multiplied by 10 ng/mL). A negative D-dimer excludes deep vein thrombosis; a positive D-dimer needs ultrasound.
3. Thrombosis likely (score 2 or more): proximal compression ultrasound (or whole leg ultrasound) without waiting for D-dimer; if the scan is delayed more than 4 hours, give a first dose of anticoagulant while awaiting it.
   • A positive scan (non compressible vein) confirms deep vein thrombosis.
   • If the proximal scan is negative and D-dimer is positive, repeat scan in 5 to 7 days or perform a whole leg scan.
   • A normal scan with a negative D-dimer excludes thrombosis.
4. D-dimer is unreliable in pregnancy, cancer, infection, recent surgery, trauma, inflammation and older age; in these settings, proceed directly to imaging (compression ultrasound with iliac vein Doppler in pregnancy; MR venography or CT venography for suspected iliac or inferior vena cava thrombosis).
5. Alternative causes found at ultrasound: Baker cyst, haematoma, muscle tear, effusion, abscess, lymph nodes, aneurysm; arterial duplex and ankle brachial pressure index for suspected arterial disease.
6. Blood tests when infection or systemic disease is suspected: full blood count, C reactive protein, urea, creatinine, electrolytes, creatine kinase, lactate, blood cultures; liver function; urinalysis; coagulation screen; pregnancy test.
7. Compartment pressure measurement (over 30 mmHg, or within 30 mmHg of diastolic pressure, supports diagnosis; clinical diagnosis is usually enough).
8. Radiograph for fracture or soft tissue gas; MRI for necrotising infection, muscle injury, tumour or osteomyelitis.
9. Extended work up for unprovoked thrombosis:
   • age appropriate cancer screening (history, examination, full blood count, chest radiograph, urinalysis, calcium, liver function; further imaging by symptoms)
   • thrombophilia tests (antiphospholipid antibodies; others only in selected young patients, family history or recurrent events, and not during acute thrombosis or anticoagulation).
10. Pulmonary embolism assessment with CT pulmonary angiography when symptomatic.
11. Lymphoscintigraphy, magnetic resonance lymphangiography and filarial antigen testing for lymphoedema.

Limits. Clinical examination alone is unreliable: no sign has adequate sensitivity or specificity for deep vein thrombosis. A single negative proximal ultrasound does not exclude distal thrombus that may extend. D-dimer has high negative predictive value only in low probability patients. Cellulitis and thrombosis can coexist, and bilateral ultrasound is needed to find asymmetry.

Emergency recognition. Phlegmasia, compartment syndrome, necrotising fasciitis, acute arterial ischaemia, pulmonary embolism with instability, septic shock: urgent vascular, orthopaedic or general surgical and critical care input.

Deep vein thrombosis.

• Start anticoagulation as soon as thrombosis is likely, before imaging if imaging is delayed, unless bleeding risk is prohibitive.
• Direct oral anticoagulants are first line:
  • rivaroxaban 15 mg twice daily with food for 21 days, then 20 mg once daily with food
  • apixaban 10 mg twice daily for 7 days, then 5 mg twice daily
  • edoxaban 60 mg once daily (30 mg if weight 60 kg or under, creatinine clearance 15 to 50 mL/min or interacting drugs) after at least 5 days of parenteral anticoagulation
  • dabigatran 150 mg twice daily after at least 5 days of parenteral anticoagulation (110 mg twice daily if aged 80 or over).
• Low molecular weight heparin: enoxaparin 1 mg/kg subcutaneously twice daily (or 1.5 mg/kg once daily).
• Continue enoxaparin for at least 5 days and until INR is 2 or more on two consecutive days when bridged to warfarin (start 5 mg daily, target INR 2.0 to 3.0, adjusting by INR).
• Special groups:
  • Pregnancy: enoxaparin 1 mg/kg twice daily throughout.
  • Cancer: apixaban or rivaroxaban or edoxaban (or enoxaparin 1 mg/kg twice daily if gastrointestinal or genitourinary cancer bleeding risk is high).
  • Renal impairment (creatinine clearance under 30 mL/min): unfractionated heparin (80 units/kg bolus then 18 units/kg/hour, adjust by activated partial thromboplastin time) or warfarin.
  • Antiphospholipid syndrome: warfarin (target INR 2.0 to 3.0).
• Duration:
  • At least 3 months for all.
  • Stop at 3 months for a provoked deep vein thrombosis from a major transient risk (surgery, trauma, immobility).
  • At least 3 to 6 months and consider extended treatment (indefinite with annual review) for unprovoked disease, persistent risk factors, cancer (while active), antiphospholipid syndrome and recurrent disease.
  • After 6 months extended apixaban 2.5 mg twice daily or rivaroxaban 10 mg once daily can reduce bleeding risk.
• Distal (calf vein) thrombosis: anticoagulate for 3 months when symptomatic or with risk factors (severe symptoms, extension risk, cancer, previous thrombosis, positive D-dimer); alternatively repeat ultrasound at 1 week to detect extension.
• Compression: not routinely needed for prevention of post thrombotic syndrome; use graduated stockings 20 to 30 mmHg for symptomatic relief; early mobilisation is safe.
• Extensive iliofemoral thrombosis with severe symptoms or limb threat: catheter directed thrombolysis (alteplase 0.5 to 1 mg/hour for up to 24 to 48 hours at specialist centres) or mechanical thrombectomy.
• Surgical thrombectomy for phlegmasia.
• Inferior vena cava filter only when anticoagulation is contraindicated (bleeding) or fails (recurrent embolism on adequate therapy), with retrieval when possible.
• Pulmonary embolism: confirm and treat by risk (anticoagulation; alteplase 100 mg over 2 hours for shock).
• Superficial vein thrombosis:
  • If 5 cm or longer, or within 3 cm of the saphenofemoral junction, anticoagulation.
  • Fondaparinux 2.5 mg subcutaneously daily for 45 days for 5 cm or longer and more than 3 cm from the junction.
  • Therapeutic anticoagulation if within 3 cm of the junction.
  • For shorter segments NSAID (ibuprofen 400 mg three times daily for 7 to 14 days), compression and mobilisation.
• Outpatient management for haemodynamically stable patients without severe symptoms, high bleeding risk, kidney failure, cancer related complications, pregnancy or social barriers; admission otherwise.
• Heparin induced thrombocytopenia: stop heparin and use a non heparin anticoagulant (argatroban, fondaparinux, or a direct oral anticoagulant after recovery).
• Bleeding risk assessment and drug interaction review; avoid NSAIDs and aspirin during anticoagulation unless indicated; patient education (warfarin card, direct oral anticoagulant card).

Cellulitis and erysipelas. Mark the margin; elevate the leg; treat the portal of entry (tinea, ulcer, eczema). Mild: flucloxacillin 500 mg to 1 g orally four times daily for 5 to 7 days (extend to 10 to 14 days if slow).

Penicillin allergy: clarithromycin 500 mg twice daily, or doxycycline 200 mg on the first day then 100 mg daily, or clindamycin 300 to 450 mg four times daily. Suspected MRSA: doxycycline or co-trimoxazole 960 mg twice daily.

Severe or systemic features: admit; flucloxacillin 1 to 2 g intravenously four times daily, or ceftriaxone 2 g intravenously once daily, plus clindamycin 600 mg every 8 hours in toxic features. Vancomycin 15 to 20 mg/kg every 8 to 12 hours if MRSA risk or severe penicillin allergy.

Treat diabetes, venous disease, oedema and lymphoedema to reduce recurrence; penicillin prophylaxis (phenoxymethylpenicillin 250 to 500 mg twice daily, or benzathine penicillin 1.2 MU intramuscularly every 3 to 4 weeks) after two episodes a year.

Necrotising fasciitis. Emergency surgical debridement within hours.

• Broad spectrum antibiotics: piperacillin-tazobactam 4.5 g every 6 hours plus clindamycin 600 to 900 mg every 8 hours, plus vancomycin or linezolid 600 mg every 12 hours if MRSA risk; carbapenem alternative: meropenem 1 g every 8 hours.
• Resuscitation, intravenous immunoglobulin 1 to 2 g/kg for streptococcal toxic shock, and critical care.

Pain out of proportion is the key clue and imaging must not delay surgery.

Compartment syndrome. Remove constrictive bandages, casts and dressings, position at heart level, oxygen, analgesia, avoid hypotension. Urgent fasciotomy for confirmed or strongly suspected disease; monitor for rhabdomyolysis (creatine kinase, potassium, creatinine) and give intravenous crystalloid 1 to 2 litres to maintain urine output over 0.5 to 1 mL/kg/hour.

Ruptured Baker cyst and muscle injury. Rest, ice, compression, elevation, analgesia (paracetamol 1 g every 6 hours, ibuprofen 400 mg every 8 hours to a maximum of 2.4 g, with food). Treat knee arthritis; image-directed aspiration and intra articular corticosteroid injection (methylprednisolone 40 mg) for cyst; early mobilisation; exclude associated deep vein thrombosis.

Haematoma on anticoagulation. Pressure, rest, review of dose and interacting drugs; reverse life threatening bleeding (andexanet alfa or prothrombin complex concentrate 25 to 50 units/kg with vitamin K 5 to 10 mg intravenously for warfarin; idarucizumab 5 g intravenously for dabigatran); surgical drainage if compartment syndrome.

Acute limb ischaemia. Unfractionated heparin bolus 5,000 units (70 to 100 units/kg), analgesia, urgent vascular assessment, thrombolysis, thrombectomy or bypass within hours.

Lymphoedema, popliteal aneurysm and other causes.

• Lymphoedema: complex decongestive therapy and compression garments
• Popliteal aneurysm: vascular surgery (repair for size 2 cm or more or thrombosis)
• Post thrombotic syndrome: graduated compression 30 to 40 mmHg, exercise, leg elevation, venous ulcer care, and venous stenting for iliac obstruction
• May-Thurner syndrome: anticoagulation plus iliac vein stenting after thrombolysis
• Neurological or immobility related oedema: elevation, positioning, compression, physiotherapy
• Tumour: oncology referral.

Monitoring.

• Review at 1 week after starting anticoagulation (symptoms, bleeding, adherence), at 3 months (decide on duration), then every 6 to 12 months.
• Full blood count, creatinine, liver function at baseline and at least annually (every 3 to 6 months if aged over 75 or renal impairment).
• INR as required on warfarin (weekly at first, then up to every 12 weeks when stable).
• For cellulitis, mark and review at 48 hours.
• For compartment syndrome, serial neurovascular checks.
• Follow up of unprovoked thrombosis for cancer screening.

Referral and escalation.

• Vascular surgery for phlegmasia, limb ischaemia, iliofemoral thrombosis needing intervention, popliteal aneurysm and venous obstruction
• Orthopaedics for compartment syndrome, fracture and tendon rupture
• General surgery or plastics for necrotising infection
• Haematology for thrombophilia, recurrent thrombosis, pregnancy, antiphospholipid syndrome and anticoagulant complications
• Oncology for cancer associated thrombosis
• Obstetrics for pregnancy.
• Lymphoedema service.
• Infectious diseases for severe infection and filariasis.

Admission. Phlegmasia, extensive thrombosis with severe symptoms, high risk pulmonary embolism, severe cellulitis or systemic toxicity, necrotising infection, compartment syndrome, limb ischaemia, serious bleeding risk, renal failure, pregnancy, intravenous drug use, or inability to self inject or reliably take drugs and attend follow up.

Safety netting. Return urgently for increasing pain, a cold or blue limb, loss of sensation, spreading redness, fever, breathlessness, chest pain, coughing blood, fainting, bleeding (black stools, vomiting blood, severe headache), or a head injury while on anticoagulants. Do not stop anticoagulants without advice, take every dose, and keep appointments.

Special groups. Pregnancy and postpartum: left leg and iliofemoral thrombosis are common; use ultrasound with iliac Doppler and enoxaparin 1 mg/kg twice daily (avoid warfarin and direct oral anticoagulants). Continue for the rest of pregnancy and at least 6 weeks postpartum with a minimum total of 3 months. Cancer: apixaban or rivaroxaban or edoxaban for at least 6 months, with caution in gastrointestinal and genitourinary cancers.

Children: rare and usually line related; specialist care. Older adults: higher bleeding risk, check renal function and weight, use apixaban where possible. Intravenous drug use: consider septic thrombophlebitis and abscess.

Endemic regions: filariasis, pyomyositis, tuberculosis of bone and joints, schistosomal and filarial lymphatic disease, snake bite compartment syndrome and sickle cell related crises and thrombosis.