OC 37.1 - Hypoalbuminemia increases clot fibrin network density and impairs fibrinolysis during glomerular proteinuria

Background: Hypercoagulopathy and hypofibrinolysis are both described contributors to glomerular disease-related thrombotic risk, however the factors contributing to the latter are poorly understood.

Aims: The aim of this study was to investigate the pathogenic mechanisms underlying the purported hypofibrinolytic defect, using two well-established rodent models and a cohort of adult and pediatric patients. We hypothesized that hypofibrinolysis arises from derangements in clot architecture that lead to increased fibrin density and altered incorporation of pro-/anti-fibrinolytic proteins into clots.

Methods: In vitro experiments were performed on plasma from two pathologically distinct rat models of glomerular disease exhibiting a wide range of proteinuria severity (n=5-8/group), and a local cohort of pediatric and adult patients with glomerular proteinuria (n=23). Albumin effects on clot lysis were further confirmed using our congenitally analbuminemic rat model (n=5/group)

Results: Clot fibrin network density and resistance to fibrinolysis were directly proportional to markers of glomerular disease severity (proteinuria and hypoalbuminemia; R≥0.462, P≤0.01) and hypercoagulopathy (fibrinogen concentration and thrombin generation (R≥0.637, P≤0.001). There was no correlation with uPA, PAI-1, α2AP, tPA, TAFI, or plasminogen, whereas plasmin generation was paradoxically increased in relation to disease severity. Incorporation of TAFI, PAI-1, α2AP, and α2-macroglobulin into clots was enhanced with increasing disease severity (P≤0.01), however depletion of these antifibrinolytic proteins to < 10% of normal did not significantly improve clot lysis. Addition of recombinant albumin to upper normal levels restored fibrin network density and ameliorated the hypofibrinolytic defect (Figure 1). Results from congenitally analbuminemic rats further confirmed that albumin enhances fibrinolysis (Figure 2).

Conclusion(s): These data represent a comprehensive examination of the fibrinolytic system in the setting of glomerular proteinuria, revealing for the first time that albumin plays a significant regulatory role in fibrinolysis. Taken together these data strongly suggest that hypoalbuminemia is not just a biomarker of thrombotic risk but also contributes mechanistically to hypofibrinolytic pathology.