What is the relationship between Deep Vein Thrombosis (DVT) and nephrotic syndrome?

Relationship Between Deep Vein Thrombosis and Nephrotic Syndrome

Nephrotic syndrome creates a hypercoagulable state that significantly increases the risk of venous thromboembolism, including DVT, with patients experiencing up to 29% risk of renal vein thrombosis and 17-28% risk of pulmonary embolism. 1

Pathophysiology of Hypercoagulability

The thrombotic risk in nephrotic syndrome results from multiple mechanisms that create an imbalance favoring clot formation:

• Loss of anticoagulant proteins in urine (particularly antithrombin III) while procoagulant factors are retained or increased, creating a net prothrombotic state 2, 3
• Increased platelet aggregation and activation occurs as a consequence of the nephrotic state 4
• Hypoalbuminemia is the single most significant independent predictor of thrombotic risk, especially when serum albumin falls below 2.0-2.5 g/dL 2, 3
• Urinary loss of immunoglobulins and complement factors contributes to the overall prothrombotic milieu 1

Risk Stratification

The risk of DVT and other thromboembolic events varies substantially based on specific factors:

High-Risk Features for VTE:

• Serum albumin <20-25 g/L (using bromocresol green method) or <20 g/L (using bromocresol purple method) 2
• Proteinuria >10 g/day 2
• Membranous nephropathy carries particularly high thrombotic risk compared to other causes of nephrotic syndrome 2, 5
• Body mass index >35 kg/m² 2
• Heart failure NYHA class III or IV 2
• Recent orthopedic or abdominal surgery 2
• Prolonged immobilization 2

Duration of Risk:

• Thromboembolic events occur most commonly within the first 6 months of diagnosis 2
• Duration of severe hypoalbuminemia (albumin <20 g/L) directly correlates with VTE risk 6

Clinical Management Algorithm

For Established DVT/Thromboembolic Events:

Full-dose anticoagulation is mandatory for 6-12 months and/or for the duration of nephrotic syndrome 2

Preferred anticoagulation approach:

• Initiate with intravenous unfractionated heparin followed by bridging to warfarin 2
• Higher than usual heparin dosing may be required due to urinary loss of antithrombin III 2
• Target INR 2-3 with frequent monitoring since warfarin-protein binding fluctuates with changing serum albumin 2
• Low-molecular-weight heparin is an effective alternative for both inpatient and outpatient treatment, though dose reduction may be needed with creatinine clearance <30 mL/min 2, 7

For Prophylactic Anticoagulation:

Prophylactic anticoagulation should be employed when thromboembolism risk exceeds bleeding risk 2

Decision-making algorithm (based on KDIGO 2021):

1. Assess serum albumin level:

   • If albumin <25 g/L (BCG method) or <20 g/L (BCP method), proceed to step 2 2
   • If albumin ≥25 g/L (BCG) or ≥20 g/L (BCP), no prophylactic anticoagulation unless other high-risk features present 2

2. Evaluate for additional VTE risk factors (proteinuria >10 g/day, BMI >35, immobilization, recent surgery) 2

3. Assess bleeding risk using validated tools (available at www.med.unc.edu/gntools/bleedrisk.html) 2

4. If high VTE risk and low bleeding risk:

   • Initiate warfarin with target INR 2-3 2
   • Alternative: low-molecular-weight heparin during transient high-risk periods 2
   • Consider low-molecular-weight heparin + aspirin for 3 months before switching to warfarin to allow assessment of proteinuria trajectory 2

Contraindications to Prophylactic Anticoagulation:

• Patient preference/inability to adhere 2
• Bleeding diathesis or propensity to hemorrhage 2
• CNS lesions that could influence warfarin metabolism/efficacy 2
• Frailty with fall risk 2
• Prior gastrointestinal bleeding 2

Important Caveats and Pitfalls

Novel Oral Anticoagulants (DOACs):

Factor Xa inhibitors (apixaban, rivaroxaban, edoxaban) and direct thrombin inhibitors (dabigatran) are NOT recommended for nephrotic syndrome despite favorable case reports 2

Rationale for avoiding DOACs:

• Heavy protein binding (55-95%) results in unpredictable urinary losses in nephrotic-range proteinuria 2
• Pharmacokinetic properties have not been systematically studied in hypoalbuminemic states 2
• Effects of fluctuating albumin levels on drug half-lives are unknown 2

Warfarin-Specific Considerations:

• Monitor INR more frequently than in non-nephrotic patients due to fluctuating protein binding with changing albumin levels 2
• Glucocorticoids increase thrombotic risk, so anticoagulation should not be omitted when starting prednisone 2
• Watch for drug interactions, particularly with antibiotics that can potentiate warfarin effects 8
• Consider starting with low-dose low-molecular-weight heparin before folding in warfarin to avoid increased thrombosis risk immediately after starting high-dose warfarin 2

Monitoring During Treatment:

• Assess volume status carefully as hypovolemia increases thrombotic risk 8
• Counsel patients to hold diuretics during illness (sick day rules) to prevent volume depletion that could precipitate thrombosis 2, 8
• Continue anticoagulation for the duration of nephrotic syndrome, as optimal duration extends to persistence of the nephrotic state 5