Hypoalbuminemia increases fibrin clot density and impairs fibrinolysis.

Abstract

BACKGROUND: Hypoalbuminemia is a thrombotic disease risk biomarker. Albumin is a negative acute-phase reactant and may thus be an indirect biomarker of thromboinflammation. However, nephrotic syndrome (resulting from noninflammatory proteinuric glomerular disease) causes both hypoalbuminemia and an elevated thrombotic risk. Hypofibrinolysis has been observed in nephrotic syndrome, and published data suggest that albumin may directly enhance fibrinolysis. These observations suggest that albumin may directly influence thrombotic risk. OBJECTIVES: To test the hypothesis that hypoalbuminemia impairs fibrinolysis. METHODS: Hypoalbuminemic blood and plasma from nephrotic syndrome rat models and nephrotic patients were analyzed by thromboelastometry, clot lysis assays, fibrin clot turbidity, confocal microscopy, and immunoblotting. Some studies were conducted without vs with albumin repletion. Plasma from an analbuminemic mutant rat model was used to confirm albumin-dependent observations. RESULTS: Hypoalbuminemia was associated with hypofibrinolysis in nephrotic whole blood. Albumin levels were positively associated with fibrinolysis in both nephrotic rats and patient plasma. Albumin altered both fibrin clot formation and fiber diameter. Dense fibrin clots are known to be resistant to fibrinolysis, and fibrin clot network density was increased in hypoalbuminemic plasma clots from both nephrotic rats and patients. Clots formed from hypoalbuminemic plasma contained less albumin than controls, and repletion with recombinant albumin to healthy control levels corrected both fibrin network density and fibrinolysis in nephrotic and analbuminemic rat plasma. CONCLUSION: These data show that albumin directly increases fibrin network porosity and enhances fibrinolysis. Hypoalbuminemia may mechanistically contribute to nephrotic syndrome thrombotic complications, and may similarly increase thrombotic risk in other hypoalbuminemic conditions.