Safety and efficacy of a single bolus administration of recombinant factor VIIa in liver transplantation due to chronic liver disease.

Orthotopic liver transplantation (OLT) can be associated with excessive blood loss. As a result, there may be increased risk of adverse outcomes. Activated recombinant factor VII (rFVIIa) has demonstrated the ability to improve hemostasis in a variety of disorders; however, there has been a limited amount of research into its use in OLT. The purpose of this dose-finding study was to examine the efficacy and safety of rFVIIa in the reduction of bleeding in patients undergoing OLT. In this double-blind trial, patients with end-stage liver disease scheduled for OLT were randomized to 1 of 4 parallel study groups. They received a single intravenous bolus of rFVIIa (20, 40, or 80 microg/kg) or placebo prior to surgery. The primary assessment endpoint was the total number of red blood cell (RBC) units transfused perioperatively. Safety was evaluated by adverse events reported. Eighty-three comparable patients were randomized to receive study product, with 82 ultimately undergoing OLT. There were no significant differences in required RBC units between the placebo and rFVIIa study groups. The number of adverse events was comparable between study groups. In conclusion, rFVIIa has a good safety profile in patients undergoing OLT. However, the doses studied did not have any effect on the number of RBC transfusions required.     

Reduced transfusion requirements by recombinant factor VIIa in orthotopic liver transplantation: a pilot study

BACKGROUND: Large transfusion requirements, i.e., excessive blood loss, during orthotopic liver transplantation (OLT) are correlated with increased morbidity and mortality. Recombinant factor VIIa (rF-VIIa) has been shown to improve hemostasis in a variety of conditions, but has never been studied in liver transplantation. METHODS: We performed a single-center, open-label, pilot study in adult patients undergoing OLT for cirrhosis Child-Pugh B or C, to assess efficacy and safety of rFVIIa. rFVIIa (80 microg/kg) was administered at the start of the operation, to be repeated according to predefined criteria. Packed red blood cells (RBC), fresh-frozen plasma, and platelet concentrates were administered according to predefined criteria. Perioperative transfusion requirements in study patients were compared with matched controls. RESULTS: Six patients were enrolled in the study. All received a single dose of rFVIIa. Transfusion requirements (given as median, with range in parentheses) were lower in the study group than in matched controls: 1.5 (0-5) vs. 7 (2-18) units of allogeneic RBC (P=0.006), 0 (0-2) vs. 3.5 (0-23) units of autologous RBC (P=0.043), total amount of RBC 3 (0-5) vs. 9 (4-40) units (P=0.002). Transfused fresh-frozen plasma was 1 (0-7) vs. 8 (2-35) units (P=0.011). Blood loss was 3.5 L (1.4-5.3) vs. 9.8 L (3.7-35.0) (P=0.004). One study patient developed a hepatic artery thrombosis at day 1 postoperatively. CONCLUSIONS: A single dose of 80 microg/kg rFVIIa significantly reduced transfusion requirements during OLT. Further study is needed to establish the optimally effective and safe dose of rFVIIa in orthotopic liver transplantation.     

Recombinant factor VIIa in major abdominal surgery and liver transplantation

The author reviewed the literature regarding recombinant activated Factor VII (rFVIIa) in major abdominal surgery and liver transplantation and concluded that, on the basis of evidence-based medicine, there is no evidence to support an extensive use of rFVIIa. Nevertheless, various case reports suggest the usefulness of rFVIIa to treat life-threatening bleeding after failure of conventional therapies. It appears that there is a consensus that rFVIIa can be used with good results as a rescue therapy in extremely severe situations. Economic cost and potential thrombosis risk remain arguments against more widespread use of rFVIIa. Doses from 5 to 120 kg/kg in each administration have been reported without clear evidence to support a specific protocol. Efficacy of 15 to 20 kg/kg in surgical settings has been reported, but higher doses are more frequently used. The majority of the reviewed investigators accepted the use of rFVIIa after or simultaneously with the use of aprotinin; no data refute the safety of this association.     

Use of recombinant factor VIIa in pediatric patients with liver failure and severe coagulopathy

BACKGROUND: Several reports have suggested a benefit for recombinant Factor VIIa (rFVIIa) in nonhematological conditions, including liver disease and transplantation. However, there are few reports of its use in children with liver failure. Recently, we used rFVIIa in four patients with liver failure and severe coagulopathy with bleeding who demonstrated significant laboratory and clinical improvement following its use with no side effects. PATIENTS AND METHODS: All four patients were hospitalized with liver failure, coagulopathy, and bleeding that was controlled with fresh frozen plasma, platelets, and other therapies, as indicated. Their international normalization ratios (INR) ranged from 1.7 to 5.8 (normal 0.9-1.1). All four patients received rFVIIa for bleeding episodes that were not responding to their usual therapy, for procedures with a high risk of bleeding, or both. The dose of rFVIIa ranged from 0.067 to 0.3 mg/kg. The INR improved to normal or near normal in all four patients. In all cases, bleeding stopped within 10 minutes of receiving the rFVIIa, and there were no complications observed. CONCLUSIONS: rFVIIa provided significant benefit in these children with liver failure and severe coagulopathy, in terms of clinical and laboratory improvement in their bleeding and coagulation profiles. There were no obvious side effects from the rFVIIa. This drug may be an important tool in the treatment of children with liver failure and more study is needed to define the optimal dosing for children.     

Activated recombinant factor VII in orthotopic liver transplantation

Orthotopic liver transplantation (OLT) is affected by important alterations of hemostasis. The aim of this study was to evaluate the efficacy of recombinant factor VII activated (rFVIIa) to reduce intraoperative bleeding during OLT. METHODS: Twenty OLT patients were assigned in double-blind way to a rFVIIa group or a control group. Inclusion criteria were hemoglobin > 8 g/dL: INR > 1,5 and fibrinogen > 100 mg/dL. We administered a single bouls of rFVIIa (40 microg/kg) or placebo. We determined INR, partial thromboplastin time, fibrinogen, ATIII, and blood cell counts. Blood products were administered as follows: 4 units of fresh frozen plasma when INR > 1.5, and 1 unit of RBC for Hb < 10 g/dL. The study ended 6 hours after the bolus. RESULTS: No thromboembolic events occurred. The INR was different between rFVIIa group and the controls at T0 (1.9 vs 1.6 P < .021) and during T1 (1.2 vs 1.6 P < .004). The total transfused red blood cells was 300 mL +/- 133 in rFVIIa group and 570 mL +/- 111 in control group (P < .017). The total fresh frozen plasma was 600 mL +/- 154 in rFVIIa group and 1400 mL +/- 187 in control group (P < .001). Total blood loss was greater in the control group than the rFVIIa group: 1140 mL +/- 112 vs 740 mL +/- 131 (P < .049). DISCUSSION: The use of rFVIIa during OLT can reduce the risk of bleeding during surgery. The literature has described cases who did not benefit from the treatment. An adequate cut-off of INR, allowed us to treat only patients at greater bleeding risk.     

Recombinant human coagulation factor VIIa in Jehovah's Witness patients undergoing liver transplantation

Indisputably, liver transplantation is among the most technically challenging operations in current practice and is compounded by significant coagulopathy and portal hypertension. Recombinant human coagulation factor VIIa (rFVIIa) is a new product that was initially described to treat bleeding in hemophilia patients. We present in this paper 10 liver transplants in Jehovah's Witness patients using this novel product at University of Southern California-University Hospital. The subject population included nine males and one female with an average age of 50 years. Six patients underwent cadaveric and four live donor liver transplantation. Surgeries were conducted following our established protocol for transfusion-free liver transplantation, which includes preoperative blood augmentation, intraoperative blood salvage, acute normovolemic hemodilution, and postoperative blood conservation. Factor rFVIIa was used at a dose of 80 microg/kg intravenously just prior to the incision in all patients, and a second intraoperative dose was used in 3 patients. All living donor liver transplantation (LDLT) recipients did well and were discharged uneventfully with normal liver functions. Two of the six cadaveric recipients died. One patient died intraoperatively from acute primary graft nonfunction, and the other died 38 hours postoperatively from severe anemia. This report suggests factor rFVIIa might have a much broader application in surgery in the control of bleeding associated with coagulopathy.     

重组活化人凝血因子VII在肝脏移植术中应用

重组活化人凝血因子VII(recombinant factorVIIa,rFVIIa),是一种新型止血药,最初用于治疗存在有因子VIII(FVIII)和因子IX(FIX)抗体(抑制物)的先天性血友病和继发性血友病患者的自发性或手术性出血。目前,已证实该药对控制多种临床出血情况是有益的[1]。1分子结构活化人凝血因子     

Efficacy and safety of oral low-dose tacrolimus treatment in liver transplantation

Abstract Eighty-four adult patients were recruited from four centres in Spain to evaluate the efficacy and safety of low-dose (0.1 mg/kg per day) oral tacrolimus plus corticosteroid immunosuppression in liver transplantation. The median daily dose of tacrolimus was increased during the first 3 weeks of therapy from an initial dose of 0.1 mg/kg per day to a maximum of 0.145 mg/kg per day and was subsequently decreased gradually to a minimum of 0.076 mg/kg per day at 1 year. At 7 days posttransplantation, 87.7 % of patients had trough whole blood levels of tacrolimus within the therapeutic range (5–20 ng/ml), and the median levels remained fairly constant during the rest of the year (10.1–11.8 ng/ml). None of the patients required intravenous administration of tacrolimus. At 1 year, Kaplan-Meier estimates showed that 73.8 % of the patients were receiving tacrolimus monotherapy without the need for corticosteroids. One-year patient and graft survival were 75.9 % and 72.3 %, respectively. The incidence of acute rejection was 51.2 %; 9.5 % of cases resolved spontaneously without antirejection therapy and 10.7 % were corticosteroid resistant. Only 1 patient (1.2 %) developed chronic rejection. The most important adverse events were hypertension (45.2%), tremor (44.0%), diabetes mellitus (33.3%), diarrhoea (31 %) and nephrotoxicity (29.8%). Severe neurotoxicity-like convulsions (4.8%), dysarthria (9.5 %), delirium (1.2%), coma (1.2 %) and the need for haemodialysis (3 patients) were uncommon. In conclusion, low-dose oral tacrolimus immunosuppression is associated with low toxicity without compromising efficacy.     

Efficacy and safety of monotherapy with mycophenolate mofetil in liver transplantation

AIM: To analyze the efficacy and safety of mycophenolate mofetil (MMF) as monotherapy in liver transplant patients who have adverse effects associated with calcineurin inhibitors (CNIs). PATIENTS AND METHODS: Seventeen patients, 13 men and four women, mean age 62 years, who received a liver transplant between 1998 and 2003 and initial immunosuppressive therapy with CNIs (10 tacrolimus and seven cyclosporine), were converted to monotherapy with MMF due to adverse events associated with CNIs: chronic renal failure in 16 patients (four with diabetes mellitus and seven with hypertension) and neurotoxicity in one patient. The mean time between transplant and starting monotherapy was 32 months (range: 18 to 70) and the mean follow-up time on monotherapy was 20 months (range: 8 to 39). MMF was introduced gradually at the same time as the CNIs were reduced. RESULTS: There was a progressive decrease in creatinine during the initial months. Compared with baseline levels, the differences at 3 and 6 months of monotherapy were significant (P < .001), remaining so throughout the follow-up period. Renal function improved in 15 of 17 patients (88%) and normalized in 10 of 17 (60%). The patient with neurotoxicity due to CNI improved. One patient (6%) had moderate rejection that was corrected after reintroducing tacrolimus. In two patients it was necessary to suspend MMF, one due to gastrointestinal intolerance and the other due to severe myelotoxicity and Pneumocystis jiroveci infection. Other, minor adverse events were corrected by adjusting the dose: one herpes zoster, two diarrhea, and two anemia. CONCLUSIONS: Monotherapy with MMF efficiently and safely corrected renal dysfunction associated with CNIs, with few side effects and a low incidence of rejection.     

Benefits of recombinant activated factor VII in complicated liver transplantation

INTRODUCTION: Recombinant activated factor VII (rFVIIa, NovoSeven, NovoNordiskA/S, Bagsvaerd, Denmark) has shown benefits in hemophilic patients and recently in transplant recipients. This study presents our experiences with rFVIIa in complicated liver transplant recipients. METHODS: From May 2001 to August 2004, rFVIIa was administered to 7 patients undergoing liver transplantation. All treatments were made on emergency bases, except for 1 case with hemophilia A, who received prophylactic treatment. The drug was delivered when severe bleeding with coagulopathy persisted despite the usual treatment with blood products. The drug doses were 60-90 mug/kg; the results were evaluated clinically and analytically. RESULTS: Seven patients undergoing liver transplantation were treated with FVIIa. Mean prothrombin times before and after treatment were 17.5 and 10.9 seconds, respectively, with a mean reduction of 7.2 seconds (P = .03). Mean thromboplastin times before and after treatment were 38.1 and 29.4 seconds, respectively, with a mean reduction of 8.7 seconds (P = .034). The average dose was 83.6 mug/kg, leading to decreased consumption of blood products (P < .01). In all cases, rFVIIa allowed sufficient hemostasis to carry on definitive treatment. There was no mortality in this series. CONCLUSIONS: These results provide new evidence on the potential benefits of rFVIIa in liver transplantation, especially for rescue therapy in cases of severe bleeding.     

The effect of recombinant factor VIIa on noncoagulopathic pigs with grade V liver injuries

BACKGROUND:Recombinant Factor VIIa (rFVIIa) has been used to decrease bleeding in a number of settings, including hemophilia, liver transplantation, intractable bleeding, and cirrhosis. It has also been shown to reduce bleeding in coagulopathic pigs with Grade V liver injuries when used as an adjunct to packing. This study was performed to determine if rFVIIa would reduce blood loss after a Grade V liver injury in noncoagulopathic pigs when used as sole therapy. STUDY DESIGN: Thirty normothermic animals were randomized to receive either 150 microg/kg of rFVIIa or normal saline intravenously. After laparotomy and splenectomy, a standardized Grade V liver injury was made with a liver clamp. Thirty seconds after injury, blinded therapy was given. Blood loss was measured 15 minutes after injury and the abdomen was closed. Animals were resuscitated to their baseline blood pressure and the study was continued for 2 hours. Serial coagulation parameters were obtained. Following the study period, blood loss was measured and an autopsy was performed. Grossly normal areas of lung were examined for evidence of intravascular thrombosis. RESULTS: Mean Factor VII:C levels increased 155-fold in the treatment group after infusion of rFVIIa. The mean prothrombin time in the treatment group decreased from 9.8 +/- 0.4 seconds to 7.3 +/- 0.2 seconds and remained significantly different from the control group throughout the study (p < 0.01). There were no differences in other coagulation parameters. Mean initial blood loss was 822 +/- 266 mL in the treatment group and 768 +/- 215 mL in the control group (p = 0.6). Rebleeding blood volume was 397 +/- 191 mL in the treatment group and 437 +/- 274 mL (p = 0.6) in the control group. Lung histology revealed no evidence of abnormal microvascular thrombosis. CONCLUSIONS:rFVIIa does not reduce blood loss after Grade V liver injury when it is used as sole therapy in warm noncoagulopathic pigs.     

Successful treatment of gastrointestinal bleeding with recombinant factor VIIa after kidney transplantation in patients with pancytopenia

Hemostatic disorders can often complicate transplantation procedures. Moreover, antihemmorhagic drugs may not efficiently control bleeding that occurs in such cases. We report on a patient who underwent kidney transplantation complicated by bone marrow aplasia and gastric bleeding who was successfully treated with recombinant activated FVII (Novoseven). In May 2005, a 53-year-old man affected by chronic renal insufficiency underwent kidney transplantation. At the beginning of June, laboratory tests showed progressive reduction in the blood cell count with anemia, granulocytopenia, and thrombocytopenia related to the development of marrow insufficiency. We commenced transfusion therapy and administered hematologic growth factors. On June 3, 2005, the patient underwent surgical procedure to repair the abdominal wall. Two days thereafter, the postsurgical period was complicated by an episode of melena. The patient received additional treatment with packed red cells, platelets, and fresh-frozen plasma. The gastrointestinal bleeding continued until June 9, 2005, when therapy with recombinant activated FVII (Novoseven) was commenced at an initial dose of 90 microgr/kg. The first bolus did not significantly reduce the blood loss; it was therefore administered as a successive bolus at the same dosage that was able to stop bleeding. Endoscopic examination performed the day after showed the absence of the hemorrhagic lesion in the gastric mucosa. In the subsequent days, the need for transfusion was dramatically reduced with no episode of bleeding. At the same time, the laboratory and clinical findings of marrow insufficiency disappeared. Our case report showed that the use of a global antihemorrhagic factor, such as Novoseven, can successfully control gastrointestinal bleeding even in complicated patients despite failure of traditional antihemostatic therapy.     

The effect of recombinant factor VIIa on coagulopathic pigs with grade V liver injuries

BACKGROUND: Recombinant factor VIIa (rFVIIa) has been used to decrease bleeding in a number of settings including hemophilia, liver transplantation, intractable bleeding, and cirrhosis. Experience in the trauma setting is limited. This study was performed to determine whether rFVIIa would reduce bleeding after a grade V liver injury in hypothermic, dilutionally coagulopathic pigs when used as an adjunct to abdominal packing and to determine whether increasing the dose of the drug increased its hemostatic efficacy. METHODS: Thirty animals were randomized to receive 180 microg/kg of rFVIIa, 720 microg/kg of rFVIIa, or vehicle buffer control. After laparotomy and splenectomy, animals underwent a 60% blood volume isovolemic exchange transfusion with 5% human albumin. The animals' temperature was maintained at 33 degrees C and a standardized grade V liver injury was made with a liver clamp. Thirty seconds after injury, the abdomen was packed with laparotomy sponges, resuscitation was initiated, and blinded therapy was given. Animals were resuscitated to their baseline mean arterial pressure and the study was continued for 2 hours. Serial coagulation parameters were measured at the temperature they were drawn. After the study period, surviving animals were killed, posttreatment blood loss was measured, and an autopsy was performed. RESULTS: Ten animals were randomized to each group. After administration of study drug, factor VII clotting activity (FVII:C) was higher in the 720 microg/kg group than in the 180 microg/kg group (p < 0.01). FVII:C was higher in both treatment groups than in the control group (p < 0.01). The mean prothrombin time was shorter in the treatment groups than in the control group (p < 0.05). Mean arterial pressure was lower in the control group than in the treatment groups throughout the study (p < 0.01). Mean blood loss was less in the treatment groups than in the control group (p = 0.03). Mortality was not different between groups. There were no differences between the groups that received rFVIIa in any measured parameters except for FVII:C. Liver injuries were similar between groups and there was no evidence of microthrombosis on lung histology. CONCLUSION: rFVIIa reduces blood loss in hypothermic, dilutionally coagulopathic pigs with grade V injuries when used as an adjunct to packing. Increasing the dose does not enhance the hemostatic effect.