What are the indications for anticoagulation in patients with nephrotic syndrome?

Anticoagulation in Nephrotic Syndrome

Full-dose anticoagulation is mandatory for any documented thromboembolic event in nephrotic syndrome, while prophylactic anticoagulation should be initiated when serum albumin falls below 20-25 g/L in the presence of additional risk factors. 1

Therapeutic Anticoagulation (Full-Dose)

Absolute indications requiring 6-12 months of full anticoagulation or for the duration of nephrotic syndrome include: 1

• Venous thrombosis (including deep vein thrombosis and renal vein thrombosis)
• Pulmonary embolism
• Arterial thrombosis
• Nonvalvular atrial fibrillation occurring in the context of nephrotic syndrome

Prophylactic Anticoagulation

High-Risk Criteria Requiring Prophylaxis

Prophylactic anticoagulation is indicated when serum albumin <20-25 g/L PLUS any one of the following additional risk factors: 1, 2

• Proteinuria >10 g/day
• Body mass index >35 kg/m²
• Heart failure (NYHA class III or IV)
• Recent orthopedic or abdominal surgery
• Prolonged immobilization
• Membranous glomerulonephritis (carries particularly high thrombotic risk)

Pathophysiologic Rationale

The hypercoagulable state results from urinary loss of antithrombotic proteins including antithrombin III, protein C, and protein S, which reduces natural anticoagulant defenses. 2 This creates a severe prothrombotic environment with reported VTE rates of 7-40% in untreated nephrotic patients. 3

Contraindications to Prophylactic Anticoagulation

Carefully assess for the following before initiating anticoagulation: 1, 2

• Absolute contraindications:

  • Active bleeding diathesis or hemorrhagic disorder
  • Recent gastrointestinal bleeding
  • CNS lesions that influence bleeding risk or warfarin metabolism
  • Severe frailty with high fall risk

• Relative contraindications:

  • Patient inability to adhere to monitoring requirements
  • Concurrent medications with high drug interaction potential

Recommended Anticoagulation Agents and Dosing

First-Line: Warfarin

Warfarin remains the anticoagulant of choice due to extensive long-term experience and predictable pharmacokinetics despite hypoalbuminemia. 1, 2

Initiation protocol: 1, 2

• Start with intravenous unfractionated heparin OR subcutaneous low-molecular-weight heparin as bridging therapy
• Higher than usual heparin dosing is required due to urinary loss of antithrombin III
• Transition to warfarin with target INR 2-3
• Monitor INR frequently (more often than standard protocols) because warfarin-protein binding fluctuates with changing serum albumin levels

Critical monitoring considerations: 1

• Check for drug interactions, particularly with antibiotics that can potentiate warfarin effects
• Reassess INR within 3-5 days when starting new medications

Prophylactic Dosing Options

For transient high-risk events or prophylaxis: 1

• Low-molecular-weight heparin (dose reduction advised when creatinine clearance <30 mL/min)
• Unfractionated heparin 5000 U subcutaneous twice daily
• Low-dose warfarin (target INR 2-3)
• Aspirin 75 mg daily for albumin 2.0-3.0 g/dL (lower risk tier) 3

Direct Oral Anticoagulants (DOACs): Use With Caution

Factor Xa inhibitors and direct thrombin inhibitors have NOT been systematically studied in nephrotic syndrome and should be used cautiously. 1

Pharmacokinetic concerns with DOACs: 1

• Apixaban: 92-94% protein-bound, 27% urinary clearance
• Rivaroxaban: 92-95% protein-bound, 66% urinary clearance
• Edoxaban: 55% protein-bound, 50% urinary clearance
• Hypoalbuminemia substantially affects drug half-lives in unpredictable ways

Limited clinical experience suggests potential safety: 4

• A 2022 case series of 21 nephrotic patients treated with apixaban or rivaroxaban showed no thromboembolic events and only minor bleeding in 5 patients
• Bleeding occurred more frequently in older patients, females, and those on longer treatment duration
• However, this evidence is insufficient to recommend DOACs as first-line therapy

Clinical Outcomes With Prophylaxis

Prophylactic anticoagulation effectively prevents thromboembolic events: 3, 5

• A 2014 study of 143 high-risk nephrotic patients (median albumin 1.5 g/dL, 40% with membranous nephropathy) showed zero VTE events in patients established on prophylaxis for >1 week
• A 2019 comparative study demonstrated significantly more TEs in non-anticoagulated patients (4 events) versus anticoagulated patients (0 events, P=0.035)

Bleeding risk remains acceptable: 3, 5

• Minor bleeding occurs in approximately 2-5% of patients
• Major bleeding is rare (0.7-1.4%) and primarily occurs when combining anticoagulation with antiplatelet agents
• Avoid combining prophylactic anticoagulation with aspirin or other antiplatelet agents to minimize major bleeding risk 5

Common Pitfalls to Avoid

• Do not wait for a thrombotic event to occur before anticoagulating patients with albumin <20 g/L and additional risk factors 2
• Do not use standard heparin dosing—higher doses are required due to antithrombin III losses 1, 2
• Do not assume stable INR on warfarin—albumin fluctuations require more frequent monitoring than typical warfarin protocols 1
• Do not combine prophylactic anticoagulation with antiplatelet therapy unless there is a separate compelling indication, as this significantly increases major bleeding risk 5
• Do not use DOACs as first-line agents until pharmacokinetic studies establish safety and efficacy in hypoalbuminemic states 1