Limited Role of Antithrombin Deficiency in Nephrotic Syndrome-Associated Hypercoagulopathy

BackgroundNephrotic syndrome is associated with an acquired hypercoagulopathy thought to drive its predisposition for venous thromboembolism. Previous studies have suggested that urinary antithrombin loss leading to acquired antithrombin deficiency is the primary mechanism underlying this hypercoagulopathy, but this hypothesis has not been directly tested. The objectives of this study were to test the influence of antithrombin levels on hypercoagulopathy in nephrotic syndrome patient samples and perform meta-analyses to evaluate the likelihood of antithrombin deficiency in nephrotic syndrome patients. DesignSamples from 3 independent nephrotic syndrome cohorts were analyzed. Antithrombin antigen and activity assays were performed using ELISA and amidolytic assays, respectively. Plasma thrombin generation, albumin, and urine protein-to-creatinine ratios were determined using established methods. Meta-analyses were performed by combining these new data with previously published data. ResultsAntithrombin levels were not consistently related to either plasma albumin or proteinuria. Antithrombin was quantitatively related to hypercoagulopathy in adult nephrotic syndrome. Whereas antithrombin activity was inconsistently associated with hypercoagulopathy in childhood nephrotic syndrome. Notably, hypercoagulopathy did not differ between patients with normal antithrombin levels and those with levels below the threshold used to define clinical antithrombin deficiency (<70%). Moreover, ex vivo antithrombin supplementation did not significantly alter hypercoagulopathy in antithrombin deficient plasma samples. Moreover, the meta-analyses demonstrated that antithrombin deficiency is not a uniform feature of nephrotic syndrome but may be more common in children than adults. ConclusionsThese data suggest that antithrombin deficiency plays only a limited role in the mechanisms underlying the acquired hypercoagulopathy of nephrotic syndrome. Moreover, antithrombin deficiency is not present in all nephrotic syndrome patients and is more likely in children than adults despite the higher risk for venous thromboembolism in adults than children. Future studies should focus on identifying antithrombin-independent mechanisms that better explain the pathophysiology of hypercoagulopathy in nephrotic syndrome.