Background: Nephrotic syndrome is associated with an acquired hypercoagulopathy thought to drive its predisposition for venous thromboembolism. Previous studies have suggested that urinary antithrombin losses leading to acquired antithrombin deficiency are the primary mechanism underlying 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. Design: Samples 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. Results: Antithrombin levels were not consistently related to 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. However, hypercoagulopathy did not differ between patients with normal antithrombin levels and those with antithrombin levels below the threshold used to define clinical antithrombin deficiency (<70%). Moreover, ex vivo antithrombin supplementation did not significantly alter hypercoagulopathy in antithrombin deficient samples. The meta-analyses demonstrate that antithrombin deficiency is not a uniform feature of nephrotic syndrome but may be more common in children than adults. Conclusions: Antithrombin deficiency plays 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.

The authors have declared no competing interest.

BAK was supported by grants U54DK083912-05S1, U54DK083912-07S1, K08DK103982, R03DK118315, and R01DK124549 from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health (NIH). The Nephrotic Syndrome Study Network (NEPTUNE) is part of the Rare Diseases Clinical Research Network (RDCRN), which is funded by the NIH and led by the National Center for Advancing Translational Sciences (NCATS) through its Division of Rare Diseases Research Innovation (DRDRI). NEPTUNE is funded under grant number U54DK083912 as a collaboration between NCATS and the NIDDK. Additional funding and/or programmatic support is provided by the University of Michigan, NephCure Kidney International and the Halpin Foundation. RDCRN consortia are supported by the RDCRN Data Management and Coordinating Center (DMCC), funded by NCATS and the National Institute of Neurological Disorders and Stroke (NINDS) under U2CTR002818.

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