title: Disease Severity Correlates with Thrombotic Capacity in Experimental Nephrotic Syndrome.
abstract: Thrombotic disease, a major life-threatening complication of nephrotic syndrome, has been associated with proteinuria and hypoalbuminemia severity. However, it is not fully understood how disease severity correlates with severity of the acquired hypercoagulopathy of nephrotic syndrome. Without this knowledge, the utility of proteinuria and/or hypoalbuminemia as biomarkers of thrombotic risk remains limited. Here, we show that two well established ex vivo hypercoagulopathy assays, thrombin generation and rotational thromboelastometry, are highly correlated with proteinuria and hypoalbuminemia in the puromycin aminonucleoside and adriamycin rat models of nephrotic syndrome. Notably, in the puromycin aminonucleoside model, hyperfibrinogenemia and antithrombin deficiency were also correlated with proteinuria severity, consistent with reports in human nephrotic syndrome. Importantly, although coagulation was not spontaneously activated in vivo with increasing proteinuria, vascular injury induced a more robust thrombotic response in nephrotic animals. In conclusion, hypercoagulopathy is highly correlated with nephrotic disease severity, but overt thrombosis may require an initiating insult, such as vascular injury. Our results suggest that proteinuria and/or hypoalbuminemia could be developed as clinically meaningful surrogate biomarkers of hypercoagulopathy to identify patients with nephrotic syndrome at highest risk for thrombotic disease and potentially target them for anticoagulant pharmacoprophylaxis.
authors: Center for Clinical and Translational Research, The Research Institute at Nationwide Children's, Columbus, Ohio; Divisions of Hematology/Oncology/Blood & Marrow Transplantation and Bryce.Kerlin@NationwideChildrens.org.
authors: Bryce A
authors: BA
authors: Kerlin
authors: Center for Clinical and Translational Research, The Research Institute at Nationwide Children's, Columbus, Ohio;
authors: Amanda P
authors: AP
authors: Waller
authors: Center for Clinical and Translational Research, The Research Institute at Nationwide Children's, Columbus, Ohio; Divisions of Hematology/Oncology/Blood & Marrow Transplantation and.
authors: Ruchika
authors: R
authors: Sharma
authors: Center for Clinical and Translational Research, The Research Institute at Nationwide Children's, Columbus, Ohio;
authors: Melinda A
authors: MA
authors: Chanley
authors: Department of Pharmacology, Case Western Reserve University, Cleveland, Ohio.
authors: Marvin T
authors: MT
authors: Nieman
authors: Center for Clinical and Translational Research, The Research Institute at Nationwide Children's, Columbus, Ohio; Nephrology, Department of Pediatrics, The Ohio State University College of Medicine, Columbus, Ohio; and.
authors: William E
authors: WE
authors: Smoyer
mesh_terms: D000818:Animals; D000991:Antithrombins / Q000097:blood; D015415:Biomarkers / Q000097:blood / Q000652:urine; D001777:Blood Coagulation / Q000502:physiology; D001778:Blood Coagulation Disorders / Q000097:blood* / Q000209:etiology / Q000652:urine*; D004195:Disease Models, Animal; D004317:Doxorubicin; D004548:Elasticity; D005340:Fibrinogen / Q000378:metabolism; D006487:Hemostasis; D034141:Hypoalbuminemia / Q000097:blood*; D008297:Male; D009404:Nephrotic Syndrome / Q000097:blood* / Q000139:chemically induced / Q000150:complications; D011507:Proteinuria / Q000097:blood*; D011692:Puromycin Aminonucleoside; D051381:Rats; D017208:Rats, Wistar; D012709:Serum Albumin / Q000378:metabolism; D012720:Severity of Illness Index; D013917:Thrombin / Q000096:biosynthesis; D013927:Thrombosis / Q000209:etiology*
chemical_list: D000991:Antithrombins; D015415:Biomarkers; D012709:Serum Albumin; D011692:Puromycin Aminonucleoside; D004317:Doxorubicin; D005340:Fibrinogen; D013917:Thrombin
keywords: cardiovascular disease; disease; hypoalbuminemia; nephrotic syndrome; proteinuria; thrombosis; vascular