Hypercoagulability in Nephrotic Syndrome

Hypercoagulability in nephrotic syndrome is a thrombophilic state in which heavy proteinuria produces a high risk of venous and, less often, arterial thrombosis. Venous thromboembolism develops in about 7% of adults with nephrotic syndrome overall and in 25 to 30% of those with membranous nephropathy (with a peak in the first 6 months), compared with about 1 to 3% in minimal change disease and focal segmental glomerulosclerosis.

Renal vein thrombosis occurs in 5 to 25% of adult nephrotic patients (higher in membranous nephropathy), and pulmonary embolism in a third of those with deep vein thrombosis. Children have lower rates (about 3%), with a higher share of arterial and cerebral venous events.

Pathophysiology. Urinary loss of antithrombin, protein C, protein S and plasminogen, with raised hepatic synthesis of fibrinogen and of factors V, VII, VIII and X, reduced fibrinolysis, platelet hyperreactivity and thrombocytosis, haemoconcentration from diuretics, hyperlipidaemia and, in membranous nephropathy, direct complement mediated endothelial effects. The risk rises sharply when albumin falls under 25 g/L in membranous nephropathy and under 20 g/L in other lesions.

• Deep vein thrombosis: unilateral leg swelling, pain and warmth; may be hard to separate from oedema.
• Pulmonary embolism: pleuritic chest pain, dyspnoea, haemoptysis, tachycardia, syncope.
• Renal vein thrombosis: flank pain, macroscopic haematuria, a sudden rise in creatinine or proteinuria, an enlarged kidney; often silent when chronic.
• Cerebral venous sinus thrombosis (headache, seizures, focal signs), mesenteric, portal or hepatic vein thrombosis (abdominal pain), and arterial events (stroke, limb ischaemia, myocardial infarction), especially in children and with antiphospholipid antibodies.
• Central venous catheter thrombosis in children and dialysis patients.

Red flags

• Albumin under 20 g/L with proteinuria above 10 g daily.
• Sudden dyspnoea, chest pain or collapse.
• Flank pain with haematuria and a rapid creatinine rise.
• Severe headache, seizures or focal neurological signs.
• Heparin resistance (low antithrombin).

• Compression Doppler ultrasound of the legs; CT pulmonary angiography (weigh contrast risk in acute kidney injury) or ventilation perfusion scan for pulmonary embolism; renal Doppler ultrasound, CT venography or MR venography for renal vein thrombosis; MR or CT venography for cerebral sinus thrombosis.
• D-dimer is raised in nephrotic syndrome and has poor specificity.
• Antithrombin activity, fibrinogen, full blood count, platelet count, coagulation screen (activated partial thromboplastin time can be prolonged by antiphospholipid antibodies), antiphospholipid antibodies (lupus anticoagulant, anticardiolipin, anti-beta-2 glycoprotein I); inherited thrombophilia testing only when it will change management and not during acute thrombosis or on anticoagulants.
• Underlying cause of nephrotic syndrome by the usual workup (biopsy, anti-phospholipase A2 receptor, lupus and infection screen).
• Bleeding risk assessment: previous bleeding, liver disease, uncontrolled hypertension, anaemia, platelet count, concurrent antiplatelets, falls risk.

Differential diagnosis

• Pitting oedema without thrombosis, cellulitis, heart failure, nephrotic syndrome from lupus with antiphospholipid syndrome, malignancy associated thrombosis, polycythaemia, paroxysmal nocturnal haemoglobinuria, heparin induced thrombocytopenia.

Prevent thrombosis in high risk patients

• Indications for prophylaxis: albumin under 25 g/L in membranous nephropathy, or under 20 g/L in other lesions, with at least one additional risk, when bleeding risk is low.
• Additional risks: proteinuria above 10 g daily, previous venous thromboembolism, immobility, obesity with body mass index above 35, heart failure, congenital thrombophilia, nephrotic syndrome with lupus and antiphospholipid antibodies, recent surgery, central venous catheter.
• First line: enoxaparin 40 mg subcutaneously daily (20 mg daily when eGFR is under 30; check anti-Xa activity in kidney impairment).
• Or warfarin to INR 2 to 3 (start with 5 mg daily, check INR on days 3 and 5; avoid with interacting drugs).
• Alternative for patients who cannot inject or monitor INR: apixaban 2.5 mg twice daily (limited evidence in nephrotic syndrome; avoid when eGFR is under 15).
• Add aspirin 75 mg daily when anticoagulation is contraindicated and thrombosis risk is intermediate.
• Continue until albumin is above 30 g/L (or above 25 g/L in membranous nephropathy) and the nephrotic syndrome is in remission.
• Mobilise early, avoid dehydration and over diuresis, avoid unnecessary central lines and immobility.

Treat established thrombosis

• Enoxaparin 1 mg/kg subcutaneously twice daily (or 1.5 mg/kg once daily) for at least 5 days.
• Reduce to 1 mg/kg once daily when eGFR is under 30 with anti-Xa monitoring (target peak 0.5 to 1.0 units/mL at 4 hours after the third dose).
• Use unfractionated heparin (80 units/kg bolus, then 18 units/kg each hour, adjusted to a ratio of 1.5 to 2.5 times control) when eGFR is under 15, when bleeding risk is high or if thrombolysis may be needed.
• Low antithrombin may cause heparin resistance: increase the dose with anti-Xa monitoring; antithrombin replacement is rarely needed.
• Warfarin overlapped with heparin for at least 5 days and until INR is above 2 for 24 hours, target INR 2 to 3.
• Or apixaban 10 mg twice daily for 7 days then 5 mg twice daily.
• Or rivaroxaban 15 mg twice daily for 21 days then 20 mg once daily (use with caution when eGFR is under 30; avoid when under 15).
• Duration: at least 6 months, and continue while albumin remains under 30 g/L (under 25 g/L in membranous nephropathy). Continue indefinitely when thrombosis was unprovoked, recurrent or with antiphospholipid antibodies (warfarin only in antiphospholipid syndrome).
• Thrombolysis (alteplase 100 mg intravenously over 2 hours, or catheter directed therapy) for haemodynamically unstable pulmonary embolism, phlegmasia or limb threatening occlusion.
• Inferior vena cava filter only when anticoagulation is contraindicated or fails.
• Renal vein thrombosis: anticoagulate; catheter directed thrombolysis is reserved for acute bilateral thrombosis with acute kidney injury.

Treat the nephrotic syndrome. Remission is the best prevention: treat the underlying lesion with the regimen that suits it (for example, rituximab 1 g on days 1 and 15 for membranous nephropathy; prednisolone 1 mg/kg daily, maximum 80 mg, for minimal change disease).

Supportive care. Sodium under 2 g daily; avoid high dose diuretics that cause haemoconcentration; use albumin infusion only for hypovolaemia; ramipril 2.5 to 10 mg daily; atorvastatin 20 mg daily; correct hypovolaemia; avoid oestrogen containing contraceptives.

Monitoring. Albumin and proteinuria every 2 to 4 weeks; platelets weekly during heparin for 2 weeks (heparin induced thrombocytopenia); INR 2 to 3 times weekly then weekly during warfarin initiation; anti-Xa for enoxaparin in kidney impairment; creatinine and haemoglobin.

Referral and escalation. Haematology and nephrology for recurrent thrombosis, heparin resistance, antiphospholipid syndrome, pregnancy and thrombolysis decisions; emergency care for pulmonary embolism, cerebral thrombosis or limb ischaemia.

Special groups

• Children: lower risk but higher in adolescents, steroid resistant disease and with central lines; prophylaxis only for high risk patients; enoxaparin 1 mg/kg twice daily for treatment (specialist dosing).
• Pregnancy: use enoxaparin (prophylactic 40 mg daily, increasing to 1 mg/kg twice daily for treatment); avoid warfarin (first trimester and after 36 weeks) and direct oral anticoagulants; plan delivery with obstetric anaesthesia.
• Older adults: balance bleeding risk; lower enoxaparin doses with anti-Xa monitoring.
• Membranous nephropathy: highest risk in the first 6 months; low threshold for prophylaxis.