Thursday, March 3, 2011

Thrombosis and the nephrotic syndrome

Should patients with nephrotic syndrome (NS) be anticoagulated? Is there any level of proteinuria or albumin at which we should be especially concerned?

The rates of venous thromboembolism (VTE) have ranged from 8-44% in observational studies and it is estimated that patients with NS are 8 times more likely to develop a clot than the general population and that this risk is highest in the first 6 months after diagnosis (140 times the general population or 9.8%). The risk appears to be higher in patients with severe NS; in one study of 89 patients with NS and an albumin of less than 2.0, 31% of patients were found to have PE on pulmonary angiogram.

There are a number of potential mechanisms for the hypercoagulable state seen in patients with NS:

- Increased platelet aggregation: There are a number of potential mechanisms for this including increased production of thromboxane A2 (arachidonic acid is normally albumin-bound and hypoalbuminemia leads to increased availability) and high LDL levels (which appears to independently increase platelet aggregation). There also seems to be an increase in interactions between platelets and the vascular endothelium with increased levels of circulating markers of platelet activation

- Defects in the clotting system: Loss of antithrombin in the urine (serum antithrombin levels correlate with albumin levels in patients with NS). Elevated protein C and protein S have also been noted in patients with NS

- Impaired fibrinolysis: Plasminogen levels are decreased in NS and correlate with proteinuria. Albumin is itself is a cofactor for plasminogen binding to fibrin and thus its lack may contribute to impaired fibrinolysis.

- Etiology of the Nephrotic Syndrome: It appears that patients with membranous nephropathy, MPGN and minimal change disease are more at risk of VTE than patients with other causes of NS. The reason for this is uncertain and the risk is particularly high with membranous nephropathy.

Click to enlarge

Unfortunately, there are no tests that can accurately predict the risk for VTE in patients with NS. It has been suggested prophylactic anticoagulation should be considered in patients with an albumin of 2.0 although this is based on opinion rather than evidence. There is some suggestion that treatment of the hyperlipidemia associated with NS can reduce platelet aggregation and similarly, prophylactic aspirin should be considered although, again, there are no trials proving its efficacy. Overall, although the risk of of VTE in patients with NS is 8 times the general population, this is still less than 1% per year and given that the risk of major bleeding with warfarin is greater than this, it is hard to justify routinely anticoagulating all patients. Perhaps if we had a better measure of risk we could better stratify these patients and select those who would benefit most from anticoagulation early.

Here is a recent review of the topic the picture above is from this review

1 comment:

Sameer said...

Elevated protein C and S levels should decrease the risk of thrombosis in nephrotic syndrome.