defibrotide and Hemorrhage

For patients with untreated hepatic veno-occlusive disease (VOD)/sinusoidal obstruction syndrome (SOS) with multi-organ dysfunction (MOD), mortality is >80%. We conducted a pooled analysis of three studies that assessed Day 100 survival in relationship to MOD severity, with dialysis and/or ventilator dependence representing the most severe organ dysfunction. All patients in the analysis were diagnosed using Baltimore criteria/biopsy. This analysis of patients with VOD/SOS and MOD after haematopoietic cell transplantation (HCT; n = 651) demonstrated higher Day 100 survival rates amongst defibrotide-treated patients with VOD/SOS with less versus more severe forms of MOD. Even patients with severe forms of MOD post-HCT benefitted from defibrotide.

Topics: Acute Kidney Injury; Adolescent; Adult; Aged; Child; Child, Preschool; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Confidence Intervals; Female; Fibrinolytic Agents; Hematopoietic Stem Cell Transplantation; Hemorrhage; Hepatic Veno-Occlusive Disease; Humans; Infant; Infant, Newborn; Male; Middle Aged; Multicenter Studies as Topic; Multiple Organ Failure; Odds Ratio; Polydeoxyribonucleotides; Renal Dialysis; Respiration Disorders; Respiration, Artificial; Retrospective Studies; Transplantation Conditioning; Young Adult

Hepatic veno-occlusive disease (VOD) is the most common of the regimen-related toxicities accompanying stem cell transplantation (SCT). Despite aggressive therapies, including the combination of tissue plasminogen activator (t-PA) and heparin, severe VOD is almost uniformly fatal. Defibrotide (DF) is a polydeoxyribonucleotide with activity in several vascular disorders and, unlike t-PA and heparin, produces no systemic anticoagulant effects. Nineteen patients who developed severe VOD after SCT were treated with DF on a compassionate-use basis. Patients had clinically established VOD and met risk criteria predicting progression and fatality. At the initiation of DF, all 19 patients had evidence of multiorgan dysfunction; median bilirubin was 22.3 mg/dL, 12 patients had renal insufficiency (5 dialysis dependent), 14 required oxygen supplementation, and encephalopathy was present in 8 patients. Beginning a median of 6 days after diagnosis of VOD, DF was administered intravenously in doses ranging from 5 to 60 mg/kg/d for a planned minimum course of 14 days. In no case was DF discontinued for attributable toxicity. No severe hemorrhage related to DF administration was observed. Resolution of VOD (bilirubin <2 mg/dL with improvement in other symptoms and signs) was seen in 8 patients (42%). Six of 8 responders survived past day +100, contrasted with the 2% predicted survival reported in comparable patients. The observed response rate, survival to day +100, and absence of significant DF treatment-associated toxicity are compelling and warrant further evaluation.

Topics: Adolescent; Adult; Bilirubin; Child; Child, Preschool; Drug Evaluation; Feasibility Studies; Female; Fibrinolytic Agents; Hematopoietic Stem Cell Transplantation; Hemorrhage; Heparin; Hepatic Veno-Occlusive Disease; Humans; Male; Multiple Organ Failure; Neoplasms; Palliative Care; Polydeoxyribonucleotides; Receptors, Purinergic P1; Retrospective Studies; Risk; Thalassemia; Tissue Plasminogen Activator; Treatment Outcome

Hepatic veno-occlusive disease (VOD) is a serious complication of high-dose chemotherapy regimens, such as those used in hematopoietic cell transplantation recipients. Defibrotide is considered a safe and effective treatment when dosed at 25 mg/kg/day. However, patients who develop VOD still have increased mortality despite the use of defibrotide. Data are limited on the use of doses above 60 mg/kg/day for persistent VOD. In this prospective clinical trial 34 patients received escalating doses of defibrotide. For patients with persistent VOD despite doses of 60 mg/kg/day, doses were increased to a maximum of 110 mg/kg/day. Increased toxicity was not observed until doses rose beyond 100 mg/kg/day. Patients receiving doses between 10 and 100 mg/kg/day experienced an average of 3 bleeding episodes per 100 days of treatment, whereas those receiving doses >100 mg/kg/day experienced 13.2 bleeding episodes per 100 days (P = .008). Moreover, dose reductions due to toxicity were needed at doses of 110 mg/kg/day more often than at lower doses. Defibrotide may be safely escalated to doses well above the current standard without an increase in bleeding risk. However, the efficacy of this dose-escalation strategy remains unclear, because outcomes were similar to published cohorts of patients receiving standard doses of defibrotide for VOD.

Topics: Adolescent; Adult; Child; Child, Preschool; Drug Administration Schedule; Drug Dosage Calculations; Female; Fibrinolytic Agents; Graft vs Host Disease; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Hemorrhage; Hepatic Veno-Occlusive Disease; Humans; Infant; Male; Myeloablative Agonists; Polydeoxyribonucleotides; Prospective Studies; Survival Analysis; Transplantation Conditioning; Transplantation, Homologous; Treatment Outcome

The latest research into the prevention of peri- and postoperative thromboembolic disease has found orthopaedic surgery patients to be most at risk. As the genesis of deep venous thrombosis (DVT) is due to haemodynamic, hemorheologic and parietal factors, various prophylactic measures have been considered in the past, measures which have not proved able to provide satisfactory protection in orthopaedics. The results obtained with Defibrotide in a random and controlled clinical study versus calcium heparin involving 211 patients of both sexes candidates to receive total hip arthroplasty and presenting at least one major thromboembolic risk factor are reported. The patients were assigned at random to one of the following treatments: 1) Defibrotide at a dose of 400 mg b.i.d. i.v. in 50 ml phleboclysis in 5 minutes (n = 108); 2) calcium heparin at a dose of 5000 IU t.i.d. subcutaneously (n = 103). The treatment began the day before operation and continued on average up to the eighth day for the Defibrotide group. With the control group it continued until discharge (usually on the 15th day) and at home for about three weeks until the completion of the physiotherapy cycle. In the 108 patients treated with Defibrotide only one case of DVT was reported and in none of these patients were symptoms or signs of pulmonary embolism encountered. In the group treated with calcium heparin 2 cases of clinically and radiologically diagnosed pulmonary embolism and 4 cases of DVT were observed. Although the differences were not statistically significant, the tendency favours Defibrotide. Statistically significant (p less than 0.01) was the difference in postoperative bleeding evaluated with particular attention in patients of advanced age. Further, in the Defibrotide group, scarring was considered excellent in 96% of cases while in the heparin group scarring was excellent in 85% (p less than 0.05). To conclude, the sure clinical effectiveness, tolerance, handiness and lack of interference with clotting functions make Defibrotide a really useful drug for the prevention of thromboembolic episodes in patients undergoing major orthopaedic surgery.

Topics: Adult; Aged; Aged, 80 and over; Clinical Trials as Topic; Female; Fibrinolytic Agents; Hemorrhage; Heparin; Hip Prosthesis; Humans; Male; Middle Aged; Polydeoxyribonucleotides; Postoperative Complications; Premedication; Random Allocation; Thromboembolism; Wound Healing

Topics: Hemorrhage; Hepatic Veno-Occlusive Disease; Humans; Male; Middle Aged; Platelet Aggregation Inhibitors; Polydeoxyribonucleotides; Severity of Illness Index

The authors report on the pharmacological employment of defibrotide in the treatment of a case of deep vein thrombosis (DVT) of the left iliac-femoral veins in a patient with a high-risk of hemorrhage (haematuria from kidney neoplasm, rupture of basilar artery aneurysm, urethral bleeding from catheter trauma). Alternatively to the traditional thrombolytic and anticoagulants, not indicated here for their haemorrhagic risk potential, defibrotide promptly resolved the DVT without any major effect on blood coagulation parameters. Initially, 1 gr of defibrotide in 250 ml of glucose-1-phosphate solution was administered twice-daily for the first two days when improvement had been observed. An additional 5 days of therapy was continued under the same regimen, then 400 mg intravenously every 2 hours for 14 days, and 400 mg intramuscularly every 24 hours until the 30th day. The patient was dismissed from the hospital on therapy with indobufen 200 mg orally, and elastic support stocking. After 6 months the patient is well. An echo color Doppler evaluation showed a normal venous blood flow through the femoral, iliac and caval veins, and venous blood reflux in the iliac-femoral and femoral saphenous veins due to valvular insufficiency. Caval filters, although recognized by many institutions as a preferred method of protection against pulmonary thromboembolism especially in patients with a contraindication to anticoagulation therapy or recurrent pulmonary embolism, was not used in this case, since the patient was critically ill. From this case report and the review of the literature it seems that defibrotide may represent a valid alternative therapy in the treatment of DVT, especially in high risk haemorrhagic patients.

Topics: Aged; Bandages; Fibrinolytic Agents; Hemorrhage; Humans; Isoindoles; Male; Phenylbutyrates; Polydeoxyribonucleotides; Risk Factors; Thrombophlebitis; Ultrasonography