Role of Plasminogen Activator Inhibitor-1 (PAI-1) Levels in the Diagnosis of BMT-associated Hepatic Veno-occlusive Disease and Monitoring of Subsequent Therapy with Defibrotide (DF)

Kaleelrahman, M.; Eaton, Jonathan; Leeming, D.; Bowyer, Kimberly; Taberner, D A; Chang, Jeff; Scarffe, J. H.; Chopra, Rajesh

doi:10.1080/1024533031000084231

Cited by 35 publications

(29 citation statements)

References 9 publications

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“…VOD severity varies, but it is widely recognized that severe cases of VOD characterized by multiorgan failure (MOF) have an extremely poor prognosis, with mortality at day 100 after SCT in excess of 80% [5,6]. Decreased fibrinolytic activity with endothelial injury following SCT has been shown to be associated with hepatic VOD, as demonstrated by: elevated levels of plasminogen activator inhibitor-1 (PAI-1) and low levels of protein C [4,7,8]; fibrin, fibrinogen, and factor VII-vWF deposition at the interface between sinusoids and terminal venules [4]; reduction of antithrombin levels [4]; occurrence of VOD after SCT following administration of antifibrinolytic agents [9]. Although systemic therapy with thrombolytics has been tested extensively in this disease, this approach has been hampered by a high incidence of severe bleeding and poor survival [10].…”

Section: Introductionmentioning

confidence: 98%

The fibrinolytic mechanism of defibrotide: effect of defibrotide on plasmin activity

Echart¹,

Graziadio²,

Somaini³

et al. 2009

Blood Coagulation &Amp; Fibrinolysis

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Fibrinolytic activity has been shown to be reduced in many vascular diseases, including hepatic veno-occlusive disease after stem cell transplantation, a microangiopathy characterized by sinusoidal endothelial cell injury. Defibrotide is a polydisperse oligonucleotide with antithrombotic, profibrinolytic, anti-ischemic, and antiadhesive properties. Numerous clinical studies have shown promising activity of defibrotide in the treatment and prevention of veno-occlusive disease, with minimal toxicity. In corollary laboratory studies, defibrotide has been shown to decrease plasminogen activator inhibitor-1, increase tissue plasminogen activator levels, and increase overall plasma fibrinolytic activity in patients. Plasmin, a potent and nonspecific serine protease, plays a pivotal role in fibrinolysis by virtue of its ability to effectively degrade fibrin clots. In this study, defibrotide increases the activity of plasmin in hydrolyzing its substrate in a dose-dependent and length-dependent manner. Similar concentration-dependent effects of defibrotide were observed when plasmin was generated by tissue plasminogen activator or urokinase activation of plasminogen. In contrast, defibrotide had no direct effect on the activation of plasminogen to plasmin. Defibrotide was also able to enhance the activity of plasmin in degrading fibrin clot formed from fibrinogen, plasminogen, and thrombin. This effect was also concentration-dependent and directly correlated with the enzymatic activity of plasmin. This study therefore demonstrates that defibrotide is capable of enhancing the activity of plasmin and so contributes to its fibrinolytic activity. Taken together, these results support the effect of defibrotide in restoring the fibrinolytic vascular phenotype, in microangiopathic conditions such as veno-occlusive disease.

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Section: Introductionmentioning

confidence: 98%

The fibrinolytic mechanism of defibrotide: effect of defibrotide on plasmin activity

Echart¹,

Graziadio²,

Somaini³

et al. 2009

Blood Coagulation &Amp; Fibrinolysis

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show abstract

“…As PAI-1 is strongly suppressed by nitric oxide, endothelial damage and decreased production of NO favors both vasoconstriction and thrombosis. 66 This vasoconstriction and thrombosis leads to eventual vascular fibrosis, which are features that characterize the pathogenesis of HVOD. A similar dysregulation of NO production and increased PAI-1 may characterize the pathogenesis of PVOD, as a similar thrombotic and fibrotic process is observed in the postcapillary venule of this condition.…”

Section: Radiographic Findingsmentioning

confidence: 99%

Pulmonary veno-occlusive disease following hematopoietic stem cell transplantation: a rare model of endothelial dysfunction

Bunte

Patnaik

Pritzker

et al. 2008

Bone Marrow Transplant

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“…Increased levels of PAI-1 and tissue plasminogen activator and decreased levels of plasminogen in patients' plasma were shown to distinguish patients with HVOD from those without HVOD, days before clinical onset [4,6,9,41]. Furthermore, PAI-1 levels could be used to distinguish HVOD from graft-versus-host disease (GvHD) or other hepatic injuries, as well as from jaundice caused by diseases other than HVOD [42][43][44][45], and the levels served as an independent predictive marker for the occurrence and severity of HVOD [10]. Interestingly, it is mostly unknown whether PAI-1 is directly involved in the initiation of HVOD or increases in the course of HVOD development.…”

Section: Induction Of Pai-1 and Tissue Factor By Busulfan Is Abrogatementioning

confidence: 96%

Antineoplastic agent busulfan regulates a network of genes related to coagulation and fibrinolysis

Reimer

Bien

Ameling

et al. 2012

Eur J Clin Pharmacol

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Purpose Hepatic veno-occlusive disease (HVOD) is one of the major complications following hematopoietic stem cell transplantation (HSCT). Although high-dose busulfan is associated with the development of HVOD, the underlying molecular mechanisms are still unknown.Methods Transcriptional gene regulation by busulfan was profiled using Affymetrix GeneChip® Human Genome U133 Plus 2.0 arrays. Messenger RNA (mRNA) expression of regulated genes was assessed by TaqMan real-time polymerase chain reaction (PCR), and protein expression and secretion was determined by enzyme-linked immunosorbent assay (ELISA)in cell supernatants, lysates, and patient plasma.Results Plasma levels of plasminogen activator inhibitor(PAI)-1 significantly increased 48 h after starting busulfan treatment IV in children preconditioned for HSCT. In vitro,busulfan significantly induced plasminogen activator inhibitor-1 (PAI-1) expression in endothelium-like ECV304 cells in a concentration- and time-dependent manner. Comparative transcriptional profiling of busulfan-treated and control ECV304 cells identified differential expression of genes related to coagulation and fibrinolysis, including tissue factor, tissue factor pathway inhibitor-1, protein S, thrombospondin-1, urokinase receptor, and PAI-1, as well as activin A and transforming growth factor beta 1 (TGF-β1). Ingenuity pathway analysis (IPA) suggested TGF-β1 as a central modulator of gene regulation by busulfan. Consequently, expression of tissue factor, urokinase receptor, and PAI-1 mRNA and PAI-1 protein secretion induced by busulfan were significantly reduced by the activin A/TGF-β1 inhibitor SB 431542 in ECV304 and primary endothelial cells.Conclusions This is the first report that directly relates busulfan exposure to antifibrinolytic activity by PAI-1 and hypercoagulation possibly mediated by members of the TGF-β1 family. This suggests further research to evaluate activin A and TGF-β1 as potential targets for HVOD treatment.

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Role of Plasminogen Activator Inhibitor-1 (PAI-1) Levels in the Diagnosis of BMT-associated Hepatic Veno-occlusive Disease and Monitoring of Subsequent Therapy with Defibrotide (DF)

Abstract: Raised PAI-1 levels post stem cell transplant are specific for VOD and a subsequent decrease in levels following treatment with DF may be associated with response to treatment.

Cited by 35 publications

References 9 publications

The fibrinolytic mechanism of defibrotide: effect of defibrotide on plasmin activity

The fibrinolytic mechanism of defibrotide: effect of defibrotide on plasmin activity

Pulmonary veno-occlusive disease following hematopoietic stem cell transplantation: a rare model of endothelial dysfunction

Antineoplastic agent busulfan regulates a network of genes related to coagulation and fibrinolysis

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