Nephrotic syndrome disease activity is proportional to its associated hypercoagulopathy

Waller, Amanda P.; Troost, Jonathan P.; Parikh, Samir; Wolfgang, Katelyn J; Rovin, Brad H.; Nieman, Marvin T.; Smoyer, William E.; Kretzler, Matthias; Kerlin, Bryce A.; Investigators, Neptune

doi:10.1016/j.thromres.2021.02.007

Cited by 13 publications

(41 citation statements)

References 74 publications

(108 reference statements)

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“…Key NS patient demographic features in the NEPTUNE, PNRC, and Columbus cohorts are summarized in Table 2, additional details were previously published. 10,11 AT deficiency was observed in all 3 cohorts such that AT antigen and/or activity <70% (<0.7 IU/mL) was observed in 71%, 95%, and 52% of the NEPTUNE, PNRC, and Columbus patients, respectively. AT relationships with plasma albumin, UPCR, and ETP are shown for the NEPTUNE, PNRC, and Columbus cohorts in Figures 1, 2, and S3, respectively.…”

Section: Nephrotic Syndrome Patientsmentioning

confidence: 95%

“…Plasma albumin was quantified using a bromocresol purple assay kit according to the manufacturer's instructions (BioAssay Systems, Hayward, CA), as previously described. 10,39 Coagulation Parameters Thrombin generation assays were performed using Technothrombin TGA kits (Technoclone, Vienna, Austria) and TGA RC Low reagent, read on a Spectramax M2 fluorescent plate reader (Molecular Devices, Sunnyvale, California), as previously described. 10,11,15 TGA generates several hemostasis parameters, including endogenous thrombin potential (ETP), that may be indicative of hypercoagulopathy.…”

Section: Study Subjectsmentioning

confidence: 99%

“…8,9 NS is associated with an acquired hypercoagulopathy that is thought to be a key pathophysiologic driver of VTE risk and historical data suggest that VTE complicates 25% of adult and 3% of childhood NS cases. 3,[10][11][12][13] The mechanisms underlying NS-associated hypercoagulopathy include urinary loss of anticoagulant and profibrinolytic proteins, accumulation of procoagulant proteins, thrombocytosis, and platelet hyper-reactivity. 3,14 We and others have thus utilized global hemostasis assays, such as thrombin generation and thromboelastography, to better understand the summative effects of these complex derangements on coagulation activity and thus quantify NS-hypercoagulopathy.…”

Section: Introductionmentioning

confidence: 99%

“…[27][28][29] We thus reanalyzed our thrombin generation data from three independent NS cohorts to evaluate the influence of AT levels on NS-hypercoagulopathy. 10,11 Previous studies have shown conflicting data on the prevalence of AT deficiency during NS. While some studies observed significantly diminished AT levels in NS patients, others have demonstrated normal or even increased AT levels.…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Limited Role of Antithrombin Deficiency in Nephrotic Syndrome-Associated Hypercoagulopathy

Abdelghani

Waller

Wolfgang

et al. 2022

Preprint

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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.

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Section: Nephrotic Syndrome Patientsmentioning

confidence: 95%