defibrotide and Thrombosis

The catastrophic variant of the antiphospholipid syndrome (APS) is the most severe form of APS with acute multiple organ involvement and small vessel thrombosis. Refractory catastrophic APS may be defined as patients who did not respond to first-line therapies (anticoagulation, glucocorticoids and plasma exchange and/or intravenous immunoglobulins) and died in the acute phase of the episode or patients with recurrent episodes of catastrophic APS. The purpose of this review is to focus on the current management of these refractory patients and some of the potential new therapeutic approaches.

Topics: Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal, Murine-Derived; Anticoagulants; Antiphospholipid Syndrome; Catastrophic Illness; Glucocorticoids; Humans; Immunoglobulins, Intravenous; Immunotherapy; Multiple Organ Failure; Plasma Exchange; Polydeoxyribonucleotides; Recurrence; Rituximab; Thrombosis; Treatment Outcome

Each year in the US, more than 10 000 patients benefit from allogeneic haematopoietic stem cell transplantation (HSCT), a modality that offers an excellent chance of eradicating malignancy but confers a higher risk of treatment-related mortality. An uncommon but devastating consequence of HSCT is transplantation-associated thrombotic microangiopathy (TA-TMA). The incidence of TA-TMA ranges from 0.5% to 76%, with a mortality rate of 60-90% despite treatment. Although there appears to be a consistent treatment approach to idiopathic thrombotic thrombocytopenic purpura (TTP) using plasma exchange, corticosteroids and rituximab, the treatment strategies for TA-TMA are perplexing, in part, because the literature regarding this complex condition does not provide true consensus for incidence, aetiology, diagnostic criteria, classification and optimal therapy. The classic definition of idiopathic TTP includes schistocytes on the peripheral blood smear, thrombocytopenia and increased serum lactate dehydrogenase. Classic idiopathic TTP has been attributed to deficient activity of the metalloproteinase responsible for cleaving ultra-large von Willebrand factor multimers. This protease is a member of the 'a disintegrin and metalloprotease with thrombospondin type 1 motif' family and is subsequently named ADAMTS-13. Severely deficient ADAMTS-13 activity (<5% of normal) is associated with idiopathic TTP in 33-100% of patients. In constrast to the pathophysiology of idiopathic TTP, patients with TA-TMA have >5% ADAMTS-13 serum activity. These data may explain why plasma exchange, a standard treatment modality for idiopathic TTP that restores ADAMTS-13 activity, is not effective in TA-TMA. TA-TMA has a multifactorial aetiology of endothelial damage induced by intensive conditioning therapy, irradiation, immunosuppressants, infection and graft-versus-host disease. Treatment consists of substituting calcineurin inhibitors with an alternative immunosuppressive agent that possesses another mode of action. One candidate may be daclizumab, especially in those with mild to moderate TMA. Rituximab therapy or the addition of defibrotide may also be beneficial. In general, plasma exchange is not recommended.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal, Murine-Derived; Daclizumab; Hematopoietic Stem Cell Transplantation; Humans; Immunoglobulin G; Microcirculation; Plasma Exchange; Polydeoxyribonucleotides; Prognosis; Risk Factors; Rituximab; Syndrome; Thrombosis

Defibrotide is a deoxyribonucleic acid derivative extracted from mammalian organs, which has been developed for the treatment of a number of vascular disorders. It appears to increase fibrinolysis and may possess antithrombotic, antiatherosclerotic and anti-ischaemic actions, probably due to its ability to selectively increase prostaglandin I2 and E2 levels and to increase tissue plasminogen activator and decrease plasminogen activator inhibitor function. Defibrotide is available as an intravenous and intramuscular preparation, and also as an oral formulation for long term use. Trials performed to date have provided initial evidence that defibrotide is effective in the treatment of peripheral obliterative arterial disease and acute thrombophlebitis, while preliminary data suggest possible use in preventing fibrin deposition in the circuitry of renal haemodialysis equipment. Efficacy in preventing deep vein thrombosis after surgery has been demonstrated but defibrotide does not appear to offer any therapeutic advantage over heparin. Further clinical experience is required in other disorders, including acute myocardial infarction, Raynaud's phenomenon, renal thrombotic microangiopathy and renal transplant rejection, before adequate assessment of efficacy in these areas can be made. Defibrotide is well tolerated, as assessed in trials of up to 6 months duration, with a low global incidence of adverse events (< 1 to 9%). Mild allergic reactions and gastrointestinal disturbances have occasionally been described, and a hypotensive effect has also infrequently been observed. Thus, available data suggest that defibrotide is a well tolerated agent with little or no anticoagulant activity, which is conveniently available in both parenteral and oral formulations. Initial data indicate that the drug may be a useful alternative in the treatment of peripheral obliterative arterial disease and thrombophlebitis, while its therapeutic potential in other vascular disorders and efficacy relative to established agents remains to be fully determined.

Topics: Animals; Arachidonic Acid; Fibrinolytic Agents; Hemostasis; Humans; Myocardial Infarction; Polydeoxyribonucleotides; Thrombosis; Vascular Diseases

Total intraparenteral nutrition therapy using an endocaval catheter is subject to complications due to the catheter itself and to the onset of phlebothrombosis of the venous district involved. Two groups of patients suffering from abdominal surgical pathologies requiring prolonged postoperative parenteral treatment were subjected to antithrombotic prophylaxis. In the first group of 20 patients, calciheparin u.s. was used and in the second defibrotide in the doses recommended in the literature. Serial lab screening of certain clotting parameters was carried of the brachio-subclavio-caval district. In the calciheparin group, the trend of certain examinations shows, as usual, a change in parameters in agreement with the drug's anticlotting action; in the group treated with defibrotide, the haemostatic balance is respected: the angiographies never showed intimal lesion or phlebothrombosis in either group. The usefulness of correct antithrombotic prophylaxis in these patients is confirmed and it is pointed out that defibrotide is more flexible and handy and that it can be used in patients in whom calciheparin is potentially risk.

Topics: Aged; Catheterization, Central Venous; Clinical Trials as Topic; Drug Evaluation; Female; Fibrinolytic Agents; Heparin; Humans; Male; Middle Aged; Polydeoxyribonucleotides; Thrombosis; Vena Cava, Superior

In an open multicenter comparative study aimed at the evaluation of the efficacy of defibrotide in the prophylaxis of postsurgical deep vein thromboses (DVT) an ad interim evaluation has been made on 2626 patients thus far enrolled. 1323 had received defibrotide (200 mg q.i.d. by IV route from day -1 to day +7th postoperative), 941 calcium heparin (5000 IU b.i.d. or t.i.d. by SC route from day 0 to day +7 postoperative) and 362 other treatments (antiaggregating agents, placebo or no therapy). This group has not been included in the final evaluation, due to its limited size. The diagnosis of DVT or pulmonary embolism (PE) was made according to clinical routinary criteria. The incidence of DTV has been 15/1323 (1.13%) in the defibrotide group and 21/941 (2.23%) in the heparin group (chi-square, p = 0.056) while the cases of suspected or ascertained PE have been respectively 3/1323 (0.22%) and 10/941 (1.06%) (p = 0.02). The incidence of adverse effects with defibrotide was less than 1%; occasional cases of increased serum transaminase levels were seen with heparin. These preliminary results supports the effectiveness of defibrotide in the prevention of post-surgery DVT, its effects being similar or more prominent than those of calcium heparin, currently regarded as the standard medication.

Topics: Adult; Aged; Clinical Trials as Topic; Female; Fibrinolytic Agents; Heparin; Humans; Male; Middle Aged; Polydeoxyribonucleotides; Postoperative Complications; Pulmonary Embolism; Thrombosis

In transplanted patients graft rejection is the most frequent complication in the first year after surgery. Vascular lesions (necrosis, intimal proliferation, thrombosis) are signs of poor prognosis and lead to irreversible loss of renal function and graft removal in most cases. The problem of vascular rejection is still not solved and the results of therapy unsatisfactory, both because of inadequacy of diagnosis and/or inadequacy of available therapy. The role of prevention, very likely the best approach, is still sub judice. In an attempt to explore the validity of prevention, 22 transplanted patients (group A) were given a new antithrombotic agent (defibrotide) immediately after surgery, and the results were compared with those of a well-matched group of 30 patients on dipyridamole (group B). Follow-up lasted 6-19 months (mean 9.9) for group A; 5-21 months (mean 12) for group B. In group A, 8 patients (36%) had rejection episodes. Antirejection therapy was followed by recovery of renal function in all cases. In group B, 9 patients (29%) had rejection crises and graft removal was necessary in 7 instances due to severe vascular lesions. At the end of follow-up, all patients treated with defibrotide had normally functioning grafts: among the 30 patients on dipyridamole, 22 (73%) had satisfactory graft function.

Topics: Clinical Trials as Topic; Dipyridamole; Fibrinolytic Agents; Graft Rejection; HLA Antigens; Humans; Kidney; Kidney Diseases; Kidney Transplantation; Polydeoxyribonucleotides; Postoperative Complications; Random Allocation; Thrombosis

Topics: Humans; Polydeoxyribonucleotides; Thrombosis

Neutrophil-mediated activation and injury of the endothelium play roles in the pathogenesis of diverse disease states ranging from autoimmunity to cancer to COVID-19. Neutralization of cationic proteins (such as neutrophil extracellular trap-derived [NET-derived] histones) with polyanionic compounds has been suggested as a potential strategy for protecting the endothelium from such insults. Here, we report that the US Food and Drug Administration-approved polyanionic agent defibrotide (a pleiotropic mixture of oligonucleotides) directly engages histones and thereby blocks their pathological effects on endothelium. In vitro, defibrotide counteracted endothelial cell activation and pyroptosis-mediated cell death, whether triggered by purified NETs or recombinant histone H4. In vivo, defibrotide stabilized the endothelium and protected against histone-accelerated inferior vena cava thrombosis in mice. Mechanistically, defibrotide demonstrated direct and tight binding to histone H4 as detected by both electrophoretic mobility shift assay and surface plasmon resonance. Taken together, these data provide insights into the potential role of polyanionic compounds in protecting the endothelium from thromboinflammation with potential implications for myriad NET- and histone-accelerated disease states.

Topics: Animals; Extracellular Traps; Fibrinolytic Agents; Histones; Human Umbilical Vein Endothelial Cells; Humans; Male; Mice; Mice, Inbred C57BL; Polydeoxyribonucleotides; Pyroptosis; Thrombosis

Topics: Aged; Anticoagulants; Body Mass Index; Case-Control Studies; COVID-19; Enoxaparin; Female; Heparin, Low-Molecular-Weight; Home Care Services; Humans; Male; Middle Aged; Polydeoxyribonucleotides; Preliminary Data; Registries; Thrombosis

In this study, we aimed to investigate the additive effect of mesenchymal stem cells (MSC) and defibrotide (DFT) in a rat model of femoral arterial thrombosis.. Thirty Sprague Dawley rats were included. An arterial thrombosis model by ferric chloride (FeCl3) was developed in the left femoral artery. The rats were equally assigned to 5 groups: Group 1-Sham-operated (without arterial injury); Group 2-Phosphate buffered saline (PBS) injected; Group 3-MSC; Group 4-DFT; Group 5-MSC + DFT. All had two intraperitoneal injections of 0.5 ml: the 1st injection was 4 h after the procedure and the 2nd one 48 h after the 1st injection. The rats were sacrificed 7 days after the 2nd injection.. Although the use of human bone marrow-derived (hBM) hBM-MSC or DFT alone enabled partial resolution of the thrombus, combining them resulted in near-complete resolution. Neovascularization was two-fold better in hBM-MSC + DFT treated rats (11.6 ± 2.4 channels) compared with the hBM-MSC (3.8 ± 2.7 channels) and DFT groups (5.5 ± 1.8 channels) (P < 0.0001 and P= 0.002, respectively).. The combined use of hBM-MSC and DFT in a rat model of arterial thrombosis showed additive effect resulting in near-complete resolution of the thrombus.. El objetivo de este estudio consistió en investigar el efecto aditivo de las células madre mesenquimales (MSC, por sus siglas en inglés) y del defibrótido (DFT) en un modelo de trombosis arterial femoral en ratas.. Se incluyeron 30 ratas Sprague Dawley. Se desarrolló un modelo de trombosis arterial mediante cloruro de hierro (FeCl3) en la arteria femoral izquierda. Las ratas se asignaron equitativamente en cinco grupos: grupo 1, intervención quirúrgica simulada (sin lesión arterial); grupo 2, inyección de solución salina tamponada con fosfato (PBS); grupo 3, MSC; grupo 4, DFT; grupo 5, MSC + DFT. Todas las ratas recibieron dos inyecciones intraperitoneales de 0,5 ml: la primera se administró 4 horas después del procedimiento y la segunda 48 horas después de la primera. Se sacrificó a las ratas siete días después de la segunda inyección.. Aunque el uso por separado de MSC derivadas de médula ósea humana (hBM-MSC) o de DFT permitió una resolución parcial del trombo, la combinación de ambos tuvo como resultado la resolución casi completa. La neovascularización fue doblemente mejor en las ratas tratadas con hBM-MSC + DFT (11,6 ± 2,4 canales) en comparación con los grupos asignados por separado a hBM-MSC (3,8 ± 2,7 canales) y DFT (5,5 ± 1,8 canales) (P < 0,0001 y P= 0,002, respectivamente).. El uso combinado de hBM-MSC y DFT en un modelo de trombosis arterial en ratas mostró que el efecto aditivo tuvo como resultado la resolución casi completa del trombo.

Topics: Animals; Combined Modality Therapy; Disease Models, Animal; Fibrinolytic Agents; Male; Mesenchymal Stem Cell Transplantation; Polydeoxyribonucleotides; Rats; Rats, Sprague-Dawley; Thrombosis

Topics: Adult; Female; Fibrinolytic Agents; Hematopoietic Stem Cell Transplantation; Humans; Hypereosinophilic Syndrome; Lymphoma, T-Cell, Peripheral; Polydeoxyribonucleotides; Thrombosis; Transplantation Conditioning; Transplantation, Homologous; Ventricular Dysfunction, Left; Ventricular Dysfunction, Right

Defibrotide, acetylsalicylic acid, low molecular weight heparin (CY 216), sodium heparin, Molsidomin and a thromboxane receptor antagonist have been investigated separately and in combinations in an animal thrombosis model in which rat mesenteric venules are damaged by defined laser energy. Furthermore, the ex vivo anticoagulant activity of Defibrotide and heparin were studied in rat plasma. All investigated agents showed a significant and dose-dependent antithrombotic effect when venules were damaged. A strong additive effect was observed when Defibrotide was administered together with heparins. The combinations of Defibrotide with other antithrombotic agents did not have significant additive effects. In the present study the combination of Defibrotide and heparins showed a prolongation of aPTT and Heptest in comparison with heparin given exclusively.

Topics: Animals; Anticoagulants; Aspirin; Blood Coagulation; Drug Interactions; Fibrinolytic Agents; Heparin; In Vitro Techniques; Male; Molsidomine; Polydeoxyribonucleotides; Rats; Rats, Inbred Strains; Thrombolytic Therapy; Thrombosis

Defibrotide (DEF) is a product of the controlled hydrolysis of DNA from mammalian lungs. In vitro DEF (1-2000 micrograms/ml) neither inhibited the aggregation of human, rabbit and cat platelets nor released PGI2 from cultured porcine aortic endothelial cells. Preincubated with platelet preparations, DEF (10 micrograms/ml) lowered the IC50 for the anti-aggregatory action of PGI2 from 2.1-6.5 nM to 0.6-2.4 nM. In vivo DEF (2-20 mg/kg i.v. or 0.1-10 micrograms/ml locally o.t.) dispersed platelet thrombi in the extracorporeal circulation of anaesthetized heparinized cats. In contrast to an immediate and reversible action of PGI2 (0.3-3 micrograms/kg i.v. or 1-3 ng/ml locally o.t.), the delayed and irreversible dispersion of thrombi by DEF in vivo was inhibited by aspirin (50 mg/kg i.v.), indomethacin (10 mg/kg i.v.) or dexamethasone (2 mg/kg i.v.). After pretreatment with these drugs DEF, although deprived of its own effect on thrombi, still enhanced their dispersion by exogenous and endogenous PGI2. Similarly, at its subthreshold effective concentration (10 ng/ml, o.t.) DEF potentiated the thrombolytic action of PGI2 (1 microgram/kg, i.v.), dazoxiben (1 mg/kg, i.v.) and nicotinamide (100 mg/kg i.v.). It is concluded that DEF potentiates the action of PGI2 on platelets. In vivo DEF may facilitate an interaction between platelets and endothelium, leading to augmented generation of PGI2 or of its biologically active products, which are endowed with fibrinolytic properties.

Topics: Animals; Cats; Cells, Cultured; Endothelium, Vascular; Epoprostenol; Female; Fibrinolytic Agents; Humans; In Vitro Techniques; Male; Platelet Aggregation; Polydeoxyribonucleotides; Rabbits; Thrombosis

Topics: alpha-2-Antiplasmin; Animals; Fibrinogen; Fibrinolytic Agents; Humans; Polydeoxyribonucleotides; Primates; Rabbits; Thrombosis; Tissue Plasminogen Activator

Topics: Aged; Blood Flow Velocity; Female; Femoral Vein; Fibrinolytic Agents; Humans; Iliac Vein; Male; Middle Aged; Pilot Projects; Polydeoxyribonucleotides; Rheology; Thrombosis

Topics: Animals; Endothelium, Vascular; Fibrinolytic Agents; Humans; Polydeoxyribonucleotides; Thrombosis; Vascular Diseases

The action of iv. defibrotide (100 mg/kg bolus injection, followed by 30 mg/kg x h) on arterial and venous thrombus formation was studied in rabbits and compared with iv. urokinase (4,000 IU/kg bolus injection, followed by 1,500 IU/kg x h). In comparison with saline treated controls, defibrotide reduced the thrombus weight by 43% in veins and 76% in arteries (P less than 0.01), while urokinase reduced the thrombus weight by 50% in veins and 71% in arteries. The data suggest a potent thrombolytic activity of defibrotide which is comparable to that of urokinase.

Topics: Animals; Blood Pressure; Fibrinolytic Agents; Male; Polydeoxyribonucleotides; Rabbits; Thrombosis; Urokinase-Type Plasminogen Activator

Topics: Animals; Fibrinolytic Agents; Humans; Polydeoxyribonucleotides; Thrombophlebitis; Thrombosis

Thrombotic microangiopathy (TMA) can occur whenever pathogenetic events lead to fibrin deposition in the microcirculation. It has been suggested that intravascular coagulation is important in the development of renal as well as cerebral lesions. The mortality rate in adults varies from 50 to 70%; chronic or progressive renal failure occurs in approximately two thirds of children over 2 years of age. Poor success may be due to therapy being initiated too late or to inappropriate use of antagonistic drugs, or both. In the last 2 years we have treated 8 patients with TMA (5 with thrombotic thrombocytopenic purpura; 3 with hemolytic uremic syndrome) with defibrotide, a new antithrombotic agent extracted from mammalian lungs. At admission all patients had severe renal involvement (serum creatinine 5.3-14.9 mg/dl) and coagulation abnormalities (low platelet count; high levels of circulating fibrin degradation products). There were neurological manifestations in 6 patients. Defibrotide administration was followed in 6 patients by recovery of renal function. In all patients, defibrotide therapy induced the disappearance of neurological manifestations and normalization of coagulation abnormalities. Defibrotide caused no side effects. All patients are alive after 7-22 months of follow-up.

Topics: Acute Kidney Injury; Adult; Blood Coagulation Tests; Child; Child, Preschool; Female; Fibrin Fibrinogen Degradation Products; Fibrinolytic Agents; Hemolytic-Uremic Syndrome; Humans; Male; Middle Aged; Polydeoxyribonucleotides; Purpura, Thrombotic Thrombocytopenic; Thrombosis

8 patients with thrombotic microangiopathy were treated with a new antithrombotic agent, defibrotide. This drug displays considerable fibrinolytic and antithrombotic activity, and induces generation and release of a prostacyclin-like substance from vascular tissue. At admission all patients presented severe renal involvement and coagulation abnormalities. Neurological manifestations were present in 6. Defibrotide administration was followed by recovery of renal function in 6, disappearance of neurological symptoms and coagulation abnormalities in all patients. The use of defibrotide was not associated with side effects. On the basis of the results obtained in these patients, we suggest that defibrotide might be considered as a valuable drug in the management of patients with thrombotic microangiopathy.

Topics: Acute Kidney Injury; Adolescent; Adult; Biopsy; Child; Creatinine; Diuresis; Female; Fibrin Fibrinogen Degradation Products; Fibrinolytic Agents; Humans; Hypertension, Renal; Kidney; Male; Microcirculation; Middle Aged; Platelet Count; Polydeoxyribonucleotides; Thrombosis