Tissue factor pathway inhibitor in childhood nephrotic syndrome

Al-Mugeiren, M. M.; Gader, Abdel Galil M. Abdel; Al-Rasheed, S. A.; Al-Salloum, Abdullah A.

doi:10.1007/s00467-006-0061-2

Cited by 15 publications

(8 citation statements)

References 37 publications

(44 reference statements)

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“…Both total and free TFPI levels are increased in childhood NS, representing a natural anticoagulant mechanism of protection from hypercoagulability. 23…”

Section: Endogenous Antithrombotic Factorsmentioning

confidence: 99%

Thrombosis in Nephrotic Syndrome

Barbano

Gigante

Amoroso

et al. 2013

Semin Thromb Hemost

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Nephrotic syndrome (NS) is characterized by heavy proteinuria, edema, hypoalbuminemia, and hyperlipidemia and the most frequent causes are glomerular diseases. An uncommon presentation is iatrogenic NS, an adverse effect of some drugs administration. In the clinical course of NS, a typical feature is dysregulated coagulation state, promoted by the breakdown of permselectivity barrier of the glomerular capillary wall, resulting in the leakage of high-molecular-mass proteins, at least the size of albumin. This hypercoagulable condition is supported by several factors, such as abnormalities in platelet activation and an imbalance between anticoagulation/antithrombosis and procoagulant/prothrombotic mechanisms. Thus, NS and the risk of developing thromboses are strictly related. Thrombotic events affect the venous system rather than arterial vessels with different features and frequencies. Deep venous system of the lower extremities and renal veins are the most frequent source of pulmonary embolism, the most dangerous NS complication. Prophylactic anticoagulation and thrombosis treatment are not clearly established because large randomized trials and guidelines are lacking. The management of NS and the decision of when and how to anticoagulate the patient represent a teamwork challenge for physicians.

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“…Both total and free TFPI levels are increased in childhood NS, representing a natural anticoagulant mechanism of protection from hypercoagulability. 23…”

Section: Endogenous Antithrombotic Factorsmentioning

confidence: 99%

Thrombosis in Nephrotic Syndrome

Barbano

Gigante

Amoroso

et al. 2013

Semin Thromb Hemost

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“…These data are consistent with previous studies demonstrating improvement of both procoagulant and anticoagulant protein levels and enzymatic activities between active NS and NS in remission. [45][46][47][48] NS complications may occur due to the disease itself or as a consequence of adverse therapeutic events.…”

Section: Discussionmentioning

confidence: 99%

Nephrotic Syndrome-Associated Hypercoagulopathy is Alleviated by Nuclear Receptor Agonist Therapy with both Pioglitazone and Glucocorticoids

Waller

Agrawal

Wolfgang

et al. 2020

Preprint

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Manuscript Type: Original Article SIGNIFICANCE STATEMENTNephrotic syndrome (NS) is characterized by massive proteinuria and is complicated by a complex, acquired hypercoagulopathy that markedly increases the risk for potentially life-threatening venous thromboembolism (VTE). This study demonstrates a strong correlation between proteinuria reduction and improvement of an established VTE-risk biomarker, in both a well-established animal model and in childhood NS before and after steroid treatment. We show that nuclear receptor agonists with known disparate mechanisms of action successfully reduce proteinuria and simultaneously improve NS-associated hypercoagulopathy. These data suggest that complete or partial proteinuria reduction by any therapeutic modality may concurrently reduce NSassociated thrombotic risk. ABSTRACTBackground: Thrombosis is a potentially life-threatening nephrotic syndrome (NS) complication. We have previously demonstrated that hypercoagulopathy is proportional to NS severity in rat models and that pioglitazone (Pio) reduces proteinuria both independently and in combination with methylprednisolone (MP), a glucocorticoid (GC). However, the effect of these treatments on NS-associated hypercoagulopathy remains unknown. We thus sought to determine the ability of Pio and GC to alleviate NS-associated hypercoagulopathy. Methods:Puromycin aminonucleoside-induced rat NS was treated with sham, Low-or High-dose MP, Pio, or combination (Pio+Low-MP) and plasma was collected at day 11. Plasma samples were collected from children with steroid-sensitive NS (SSNS) and steroid-resistant NS (SRNS) upon presentation and after 7 weeks of GC therapy. Plasma endogenous thrombin potential (ETP), antithrombin (AT) activity, and albumin (Alb) were measured using thrombin generation, amidolytic, and colorimetric assays, respectively. Results:In a rat model of NS, both High-MP and Pio improved proteinuria and corrected hypoalbuminemia, ETP and AT activity (P<0.05). Proteinuria (P=0.005) and hypoalbuminemia (P<0.001) were correlated with ETP. In childhood NS, while ETP was not different at presentation, GC therapy improved proteinuria, hypoalbuminemia, and ETP in children with SSNS (P<0.001) but not SRNS (P=0.330). Conclusions:Both Pio and GC diminish proteinuria and significantly alleviate hypercoagulopathy. Both Pio and MP improved hypercoagulopathy in rats, and successful GC therapy (SSNS) also improved hypercoagulopathy in childhood NS. These data suggest that even a partial reduction in proteinuria may reduce NS-associated thrombotic risk. APPENDIX

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“…Concentration of TFPI in plasma is increased in patients with acute myocardial infarction 21,22. There are also reports on increased plasma levels of TFPI in relation to diabetes mellitus,23 renal diseases,24 and cancer 25,26. Recently we demonstrated that exogenous addition or over-expression of heparanase by transfected cells resulted in release of TFPI from the cell surface and its accumulation in the cell culture medium 27.…”

Section: Heparanase Releases Cell Surface Tissue Factor Pathway Inhibmentioning

confidence: 97%

Heparanase and Coagulation–New Insights

Nadir¹

2014

Rambam Maimonides Med J

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Heparanase, a β-D-endoglucuronidase abundant in platelets that was discovered 30 years ago, is an enzyme that cleaves heparan sulfate side chains on the cell surface and in the extracellular matrix. It was later recognized as being a pro-inflammatory and pro-metastatic protein. We had earlier demonstrated that heparanase may also affect the hemostatic system in a non-enzymatic manner. We had shown that heparanase up-regulated the expression of the blood coagulation initiator tissue factor (TF) and interacted with the tissue factor pathway inhibitor (TFPI) on the cell surface membrane of endothelial and tumor cells, leading to dissociation of TFPI and resulting in increased cell surface coagulation activity. Moreover, we have demonstrated that heparanase directly enhanced TF activity which led to increased factor Xa production and subsequent activation of the coagulation system. Recently, heparanase inhibitory peptides derived of TFPI-2 were demonstrated by us to inhibit heparanase procoagulant activity and attenuate sepsis in mouse models.

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Tissue factor pathway inhibitor in childhood nephrotic syndrome

Cited by 15 publications

References 37 publications

Thrombosis in Nephrotic Syndrome

Thrombosis in Nephrotic Syndrome

Nephrotic Syndrome-Associated Hypercoagulopathy is Alleviated by Nuclear Receptor Agonist Therapy with both Pioglitazone and Glucocorticoids

Heparanase and Coagulation–New Insights

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