Causes of Thrombosis in Nephrotic Syndrome
Nephrotic syndrome creates a severe hypercoagulable state through multiple mechanisms, with urinary loss of antithrombotic proteins being the primary driver, compounded by increased hepatic synthesis of procoagulant factors and alterations in platelet function. 1
Primary Pathophysiologic Mechanisms
Loss of Natural Anticoagulants
- Urinary loss of antithrombin III, protein C, and protein S reduces the body's natural anticoagulant defenses, creating the fundamental prothrombotic imbalance 1
- Higher than usual heparin dosing is required in nephrotic syndrome specifically due to antithrombin III urinary loss 2
- The severity of proteinuria directly correlates with the degree of anticoagulant protein loss 3
Hepatic Overproduction of Procoagulant Factors
- The liver compensates for hypoalbuminemia by increasing protein synthesis, which disproportionately increases production of procoagulant factors including fibrinogen, factor V, factor VIII, and von Willebrand factor 4
- This creates an imbalance favoring thrombosis over natural anticoagulation 3
Hypoalbuminemia as the Critical Risk Factor
- Serum albumin <20-25 g/L is the most significant independent predictor of thrombotic risk, particularly when <20 g/dL 1, 3
- Hypoalbuminemia affects the balance between pro-coagulant and anti-coagulant factors 3
Secondary Contributing Factors
Disease-Specific Risk
- Membranous glomerulonephritis carries a particularly high risk of thromboembolic events compared to other causes of nephrotic syndrome 2, 5
- The type of underlying glomerulonephritis significantly influences thrombotic risk 3, 5
Severity of Proteinuria
- Proteinuria >10 g/day substantially increases thrombotic risk independent of albumin levels 1
- Severe proteinuria indicates greater urinary loss of protective anticoagulant proteins 6
Additional Clinical Risk Factors
The following factors compound the baseline hypercoagulable state 1:
- Body mass index >35 kg/m² 1
- Heart failure (NYHA class III or IV) 1
- Recent orthopedic or abdominal surgery 1
- Prolonged immobilization 1
- Previous thromboembolic episodes 5
Inherited Thrombophilia
- Congenital protein S deficiency or other inherited thrombophilic conditions can act as critical additional risk factors when combined with nephrotic syndrome 7
- Genetic predisposition to thrombosis may amplify the acquired hypercoagulable state 5
Alterations in Platelet Function
- Platelet hyperaggregability and increased platelet counts contribute to the prothrombotic state 4
- Changes in platelet function occur secondary to the metabolic derangements of nephrotic syndrome 4
Clinical Implications
Risk Stratification Algorithm
High-risk patients requiring prophylactic anticoagulation include those with 1:
- Serum albumin <20-25 g/L PLUS any of the following:
- Proteinuria >10 g/day
- BMI >35 kg/m²
- NYHA class III-IV heart failure
- Recent major surgery
- Prolonged immobilization
- Membranous glomerulonephritis
Common Pitfall
- Do not wait for a thrombotic event to occur before considering anticoagulation in patients meeting high-risk criteria 1
- The decision to anticoagulate prophylactically must balance thrombotic risk against bleeding risk on a case-by-case basis, but when albumin is <20-25 g/L with additional risk factors and no absolute bleeding contraindications, the decision favors anticoagulation 1, 5