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The mechanism of defibrotide in treating vascular injury

Defibrotide/Defibrotide/Defibrotide can increase the expression of tissue plasminogen activator (t-PA) and thrombomodulin, reduce the expression of von Willebrand factor (vWF) and plasminogen activator inhibitor-1 (PAI-1), thereby reducing EC activation and increasing EC-mediated fibrinolysis, and can protect endothelial cells from damage caused by chemotherapy, tumor necrosis factor-a (TNF-a), and serum perfusion.

Defibrinoside has a vascular protective effect, can repair damage to liver microvessels through various ways, promote blood circulation, and can treat vascular damage to a certain extent.

Indications for defibrination

It has antithrombotic and fibrinolytic activity and is indicated for the treatment of adult and pediatric patients with hepatic veno-occlusive disease (sinusoidal obstruction syndrome) and renal or pulmonary dysfunction after hematopoietic stem cell transplantation (HSCT).

Defibrotide is currently the only therapy approved in the United States for the treatment of hepatic VOD/SOS associated with pulmonary/renal dysfunction after HSCT, and in the EU for the treatment of severe hepatic VOD/SOS after HSCT.

Clinical practice of defibrotide

The safety and effectiveness of defibrotide in the treatment of VOD/SOS in adult and pediatric HCT patients have been confirmed in multiple trials. The complete response rate and +100-day overall survival rate were 25.5%-76% and 35%-64%, respectively.

Hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a potentially life-threatening complication of pretreatment during hematopoietic stem cell transplantation (HSCT) or HSCT-free chemotherapy. The average incidence rate after HSCT has been reported historically to be 13.7%. Typical symptoms of VOD/SOS may include hyperbilirubinemia, painful hepatomegaly, weight gain, and ascites.

Defibrinoside is a polydisperse mixture composed mainly of single-stranded polydeoxyribonucleotides. Defibrinoside has been shown to have fibrinolytic, antithrombotic, anti-inflammatory and vasoprotective effects, thereby promoting the anticoagulant phenotype of the endothelium and protecting and stabilizing endothelial cell function.

In a phase 3, historically controlled, multicenter trial of adults and children with VOD/SOS and MOD/MOF, defibrotide resulted in significantly higher +100-day survival after HSCT at 38.2% compared with controls (25.0%). In a Phase 3 prevention trial, defibrotide was found to reduce the incidence of VOD/SOS (off-approved indication) in children and reduce the incidence of graft-versus-host disease.

Defibrinoside usage and dosage

Defibrinoside is 6.25 mg/kg every 6 hours, administered by intravenous infusion over 2 hours, for at least 21 days. If signs and symptoms of hepatic VOD have not resolved after 21 days, continue medication until VOD resolves or for a maximum of 60 days.

References:

Richardson PG, Carreras E, Iacobelli M, Nejadnik B. The use of defibrotide in blood and marrow transplantation. Blood Adv. 2018 Jun 26;2(12):1495-1509. doi: 10.1182/bloodadvances.2017008375. Erratum in: Blood Adv. 2018 Aug 14;2(15):1853. PMID: 29945939; PMCID: PMC6020812.

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