High Absolute Risk and Predictors of Venous and Arterial Thromboembolic Events in Patients With Nephrotic Syndrome: Results from a Large Retrospective Cohort Study

Abstract

Fishbein I, Alferiev I, Bakay M, et al. Circulation 2008;117:2096-103. Conclusion: Sustained release of gene vectors is possible through reversible immobilization of adenovirus vectors on bare-metal surfaces of vascular stents.Summary: Polymer-coated stents facilitate local drug delivery to the vasculature and have proven efficacious in preventing in-stent restenosis. There are, however, concerns about the inflammatory effects of polymer coatings and late outcomes of drug-eluting stents. The authors investigated whether adenoviral vectors could be delivered from bare metal surfaces of stents using a synthetic complex for reversible vector binding. Three components of a gene vector-binding complex were synthesized: (1) a polyallylamine bisphosphonate with latent thiol groups (PABT), (2) a polyethylenimine (PEI) with pyridyldithio groups for amplification of attachments sites [PEI (PVT)], and (3) a bifunctional amine-reactive and thiol-reactive cross-linker with labile ester bond (HL).The HL-modified adenovirus attached to PABT/PEI(PDT)-treated steel surfaces and demonstrated in vitro sustained release for 30 days. They also demonstrated localized green fluorescent protein expression in rat arterial smooth muscle cell cultures. This expression was not sensitive to inhibition by neutralizing antiadenovirus antibodies or inactivation after storage at 37°C. In rat carotid studies, steel stents configured with PABT/PEI(PDT)/HL-tethered adenoviral vectors demonstrated site-specific arterial adenovirus green fluorescent protein expression and adenovirus-luciferase transgene activity by optical imaging. Adenovirus encoding inducible nitric oxide synthase delivered by a carotid stent resulted in significant inhibition of restenosis.Comment: This study investigated local delivery of gene therapy from bare-metal stent surfaces using reversible chemical attachment of vectors to the bare-metal stents. Adenovirus vectors on the surfaces of the stents demonstrated Ͼ1-month release kinetics and site-specific transduction of target cell types in vitro and in vivo in this rat model. Deployment of stents configured with 10 9 adenovirus vectors encoded for inducible nitric oxide synthase resulted in significant reduction of in-stent restenosis. It appears that the concept of gene-eluting stents is valid and may provide a mechanism of local and systemic delivery of gene products by the vasculature.

Platelet abnormalities in nephrotic syndrome

“…Even though cerebral arterial thrombotic events were not included in this study, based on these data, pediatric patients with NS seem to have a very high relative risk of this potentially life-threatening complication compared to the general pediatric population. This risk is even higher than the eightfold increase in relative risk seen in adult NS patients [21]. These data suggest that NS has a strong influence on the risk of both arterial and venous thrombosis.…”

“…Disturbances of coagulation or fibrinolytic factors, and abnormalities of blood vessels and blood flow are important in the pathogenesis of venous thrombosis. As described above, alterations in plasma levels of pro-and anticoagulant factors were observed in patients with NS, explaining the increased risk of venous thrombosis [21,59]. Arterial thrombosis on the other hand, depends on platelets and vessel wall defects [60].…”

“…Patients with NS have an increased risk of thromboembolic disease, including both deep venous and arterial thrombosis, which significantly increases morbidity and mortality rates. It occurs in 20-37 % of adults, and 1-27 % of children, depending on etiology and severity of the NS and on whether imaging to diagnose thromboembolism is performed in all patients or only in patients with clinical symptoms [20][21][22]. Underlying mechanisms of thromboembolism in NS are considered to be multifactorial.…”

“…The epidemiology of venous thrombosis has recently been reviewed in detail [66]. The incidence of arterial thrombosis in adult patients with NS was found to be eight times higher than that in the control population [21]. Few recent epidemiologic data regarding the incidence of arterial thrombosis in childhood idiopathic NS are available, but a 2009 study of Kerlin et al [59] observed 25.8 thromboembolic events per 1000 patient-years in pediatric patients with NS, with 0.68 arterial thrombotic events per 1000 patient-years.…”

Acute Cardiorespiratory Decompensation in a Child with Nephrotic Syndrome with Bronchial Asthma: Is it Exaggeration of Bronchial Asthma?

“…The most frequent site of thrombosis is the deep vein and renal vein [1,2]. Incidence of Arterial thrombosis though less common than venous thrombosis but occurs with higher frequency then general population [3]. The pulmonary embolism (PE) is seldom reported in children, and many pulmonary embolisms remain undiagnosed until postmortem examinations are performed.…”