Acute coagulopathy after reperfusion of the liver graft in children correction with recombinant activated factor VII

BACKGROUND: Several studies have proven that massive blood loss increases postoperative morbidity and mortality in liver graft recipients. Since we have successfully corrected coagulopathy preoperatively using an intravenous (IV) bolus of recombinant activated factor VII (rFVIIa) in 2 patients with fulminant liver failure, we observed that there was rapid reversal of preexisting advanced coagulopathy in another 40 patients with high risk for intraoperative bleeding by this treatment immediately before transplantation. Recently to control hemostasis we have administered rFVIIa also to patients presenting with acute coagulopathy and nonsurgical bleeding after graft reperfusion as described herein. MATERIALS AND METHODS: We have used rFVIIa in 7 children presenting with severe coagulopathy and nonsurgical bleeding after liver graft reperfusion. The dosage of rFVIIa ranged between 37 and 148 mcg/kg. An antifibrinolytic agent (aprotinin, tranexamic acid) was administered simultaneously. RESULTS: APTT before rFVIIa was 86.10 to 183 seconds, (mean, 132.1 +/- 39.88), after the bolus of rFVIIa 49.4 to 206.1 (mean, 112.7 +/- 58.53), and at the end of surgery 71.70 to 180 (mean, 110.3 +/- 40.98). INR after reperfusion was 1.82 to 3.91 (mean, 2.56 +/- 0.67), 1.03 to 1.92 (mean, 1.54 +/- 0.35) after rFVIIa, and 1.74 to 5.58 (mean, 2.64 +/- 1.35) at the end of surgery. Before rFVIIa administration intraoperative blood transfusions after graft reperfusion were 900 to 4200 mL of red blood cells (RBC) (0.82-5.4 total blood volume) and after reperfusion 0 to 1800 mL of RBC (0-2.5 TBV). No postoperative vascular complications were observed. CONCLUSIONS: A single dose of rFVIIa effectively reverses the severe coagulopathy developing after graft reperfusion, establishing effective hemostasis in liver transplant recipients without an increased risk of thrombotic complications.     

The effect of in vitro recombinant factor VIIA on coagulation parameters for blood taken during liver transplantation

Recombinant factor VIIa (rFVIIa) has been utilized in pilot studies in orthotopic liver transplantation (OLT) when administered to patients at doses of 68.37 microg/kg and 80 microg/kg. Although some effectiveness in normalizing measurements of coagulation has been demonstrated, the optimal dose for patients undergoing OLT has not been established. This study evaluated the effects of an in vitro equivalent dose of 120 microg/kg of rFVIIa on coagulation parameters when applied to the blood drawn from patients undergoing OLT. Coagulation function was assessed in 10 patients at four points during OLT. These time points were baseline, 5 minutes prior to reperfusion, 10 minutes after reperfusion, and 70 minutes after reperfusion. These patients did not receive rFVIIa perioperatively. At each of these four time points, a native sample was analyzed for prothrombin time (PT) and thromboelastogram. The rFVIIa (6.1 microg/kg or the approximate equivalent dose of 120 microg/kg for a 70 kg patient) was added to a second sample from the same patient. This second sample was also analyzed for PT and thromboelastogram. There was a statistically significant difference in baseline PT between native versus rFVIIa supplemented samples (15.8 +/- 3.21 vs 13.6 +/- 2.36 seconds, P < .02). The maximum amplitude of the thromboelastogram was larger in the native samples at 5 minutes prior to reperfusion (53.5 mm vs 39 mm, P < .02). No significant differences existed in the variables at any of the other sampling times. This study failed to demonstrate a consistent in vitro effect of rFVIIa on the blood taken from patients during OLT.     

Administration of a Recombinant Factor Vlla in Patients Undergoing Liver Transplantation for Fulminant Hepatic Failure

Background

Fulminant hepatic failure (FHF) is associated with profound clotting disturbances leading to the risk of a major blood loss during orthotopic liver transplantation (OLT). Application of a recombinant factor VIIa (rVIIa) that promptly corrects clotting abnormalities remains controversial in the OLT setting. We conducted a retrospective analysis of the effect of rVIIa on the prothrombin time (PT) and other perioperative parameters in patients transplanted for FHF in our center.

Materials and Methods

Nineteen consecutive patients (9 males/10 females) of overall mean age of 33 ± 13 years underwent the procedure due to: Wilson's (n = 8), non-A-non-B hepatitis (n = 6) or Amanita phalloides toxicity (n = 5). All subjects received rVIIa at a mean dose of 54 ± 16 μg/kg body weight at 10 minutes before the skin incision. The PT was measured at 15 minutes and 12 hours after injection. Data were analyzed with StatView program with P < .05 considered significant.

Results

Rapid correction of PT was observed in all patients: the mean PT before injection was 37 ± 14 versus 14 ± 3 after 15 minutes (P < .0001). Twelve hours after the injection the PT was 19 ± 5 (P < .0001 vs before injection and P < .0007 vs 15 minutes after injection). Two patients died at 1 and 4 days after OLT. Mean red blood cell requirement was 5 ± 4 U and fresh frozen plasma was 11 ± 5 U. The mean operative time was 527 ± 126 minutes and intensive care unit stay 8 ± 9 days. None of the patients developed thromboembolic complications.

Conclusion

Administration of rVIIa caused a rapid improvement in the PT shortly after injection. It was safe and not associated with any thromboembolic events in our series.     

Intravenous rFVIIa administered for hemorrhage control in hypothermic coagulopathic swine with grade V liver injuries

BACKGROUND: Intravenous administration of recombinant activated human clotting factor VII (rFVIIa) has been used successfully to prevent bleeding in hemophilia patients undergoing elective surgery, but not in previously normal trauma patients. This study was conducted to determine whether rFVIIa was a useful adjunct to gauze packing for decreasing blood loss from grade V liver injuries in hypothermic and coagulopathic swine. METHODS: All animals (n = 10, 35 +/- 2 kg) underwent a 60% isovolemic exchange transfusion with 6% hydroxyethyl starch and were cooled to 33 degrees C core temperature. The swine then received a grade V liver injury and 30 seconds later, either 180 microg/kg rFVIIa, or saline control. All animals were gauze packed 30 seconds after injury and resuscitated 5.5 minutes after injury with lactated Ringer's solution to their preinjury mean arterial pressure. Posttreatment blood loss, mean arterial pressure, resuscitation volume, and clotting studies were monitored for 1 hour. Histology of lung, kidney, and small bowel were obtained to evaluate for the presence of microvascular thrombi. RESULTS: At the time of injury, core temperature was 33.3 degrees +/- 0.4 degrees C, hemoglobin was 6 +/- 0.7 g/dL, prothrombin time was 19.1 +/- 1.0 seconds, activated partial thromboplastin time was 29.0 +/- 4.8 seconds, fibrinogen was 91 +/- 20 mg/dL, and platelets were 221 +/- 57 x 105/mL, with no differences between groups (p > 0.05). Clotting factor levels confirmed a coagulopathy at the preinjury point. The posttreatment blood loss was less (p < 0.05) in group 1 (527 +/- 323 mL), than in group 2 (976 +/- 573 mL). The resuscitation volume was not different (p > 0.05). One-hour survival in both groups was 100%. Compared with the control group, rFVIIa increased the circulating levels of VIIa and, despite hypothermia, shortened the prothrombin time 5 minutes after injection (p < 0.05). Laboratory evaluation revealed no systemic activation of the clotting cascade. Postmortem evaluation revealed no evidence of large clots in the hepatic veins or inferior vena cava, or microscopic thrombi in lung, kidney, or small intestine. CONCLUSION: rFVIIa reduced blood loss and restored abnormal coagulation function when used in conjunction with liver packing in hypothermic and coagulopathic swine. No adverse effects were identified.     

The use of recombinant activated factor VII to reverse warfarin-induced anticoagulation in patients with hemorrhages in the central nervous system: preliminary findings

OBJECT: In this report the authors describe the use of the hemostatic agent recombinant activated factor VII (rFVIIa) in the perioperative treatment of hemorrhages in the central nervous system that are associated with warfarin therapy. METHODS: Two patients sustained hemorrhages within the spinal canal, and the other two had acute intracranial subdural hematomas. All patients had normal platelet counts, activated partial thromboplastin times, and fibrinogen levels, and all received fresh frozen plasma in conjunction with rFVIIa. The initial international normalized ratios (INRs) ranged from 1.9 to 5.6. Each dose of rFVIIa was 1200 microg, ranging from 16 to 22 microg/kg of body weight. Two patients received two perioperative doses of rFVIIa; the others required just one dose before surgery. The INR normalized within 2 hours of administration of rFVIIa in all patients. There were no thromboembolic complications, and surgical blood loss was less than 100 ml for all operations. CONCLUSIONS: This clinical experience indicates that rFVIIa may be safe and effective as the initial hemostatic agent for rapid reversal of orally administered anticoagulation medications in patients who require urgent neurosurgical intervention.     

Recombinant activated factor VII for the rapid correction of coagulopathy in nonhemophilic neurosurgical patients

OBJECTIVE: Coagulopathy is a significant contraindication for neurosurgery. Unfortunately, many coagulopathic patients require urgent neurosurgical intervention. Standard use of blood products, including fresh-frozen plasma or prothrombin complexes, to correct the coagulopathy often leads to significant delays in treatment. Recombinant activated factor VII (rFVIIa) is a medication originally designed to treat bleeding in hemophiliacs but also seems to correct a wide variety of coagulopathies rapidly and safely in nonhemophilic patients. METHODS: The medical records of nine patients with coagulopathy requiring urgent neurosurgical intervention were reviewed retrospectively. Each patient was given a dose ranging from 40 to 90 microg/kg of rFVIIa before undergoing surgery. Pre-rFVIIa coagulation and post-rFVIIa coagulation parameters were obtained. Once correction of the coagulopathy was verified, each patient underwent the appropriate neurosurgical procedure. RESULTS: The average age of the patients was 40.9 years; six were women. The causes of the coagulopathy included anticoagulant medication, liver dysfunction, and dilutional coagulopathy after traumatic hemorrhage. Neurosurgical indications included intraparenchymal/intraventricular hemorrhage, hydrocephalus, diffuse cerebral edema, and epidural hematoma. Post-rFVIIa coagulation parameters obtained as early as 20 minutes after infusion of the medication showed normalization of values. There were no procedural or operative complications and no postoperative hemorrhagic complications. No associated thromboembolic or other complications with the use of rFVIIa were observed. CONCLUSION: The use of rFVIIa for the urgent surgical treatment of coagulopathic patients is quite promising. Further studies, including randomized, prospective trials using rFVIIa to address issues such as optimal dosing, efficacy, surgical indications, cost-effectiveness, morbidity, and mortality are needed.     

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.     

肝移植围手术期出凝血功能的变化

目的探讨原位肝移植围手术期出凝血功能变化的规律。方法 2000年6月至2009年6月实施34例原位肝移植。对术前、术中开腹后10 min、无肝期30 min和新肝植入后30 min(新肝植入早期),关腹前10 min和术后48 h的血小板、凝血酶原时间(PT)、凝血酶原时间的国际标准化比值(INR)、活化部分凝血活酶时间(APTT)和血浆纤维蛋白原(Fg)进行分析。结果与术前相比,本组受体在无肝期30 min出现血小板明显减少(P0.05),PT、APTT、INR延长(P0.05),Fg增加(P0.05),于新肝植入早期变化最显著。随着新肝植入,在术后48 h时PT、APTT、Fg及INR接近正常范围。结论肝移植术中出凝血功能变化幅度较大,无肝期凝血功能障碍明显,术后凝血功能恢复较快,可接近正常范围。     

The clinical and laboratory response to recombinant factor VIIA in trauma and surgical patients with acquired coagulopathy

OBJECTIVE: In bleeding patients who are coagulopathic, the clinical response to administration of recombinant factor VIIa (rFVIIa) relates to the changes in prothrombin time (PT). DESIGN: Retrospective review of all surgical and trauma patients who were coagulopathic and received factor VIIa at the authors' institution over the past 27 months. SETTING: Academic tertiary referral facility and level I trauma center. PARTICIPANTS: Eighteen patients met inclusion criteria, 10 trauma and 8 surgical. Mean age 50 years (range, 17-84). RESULTS: Overall mortality was 39%. All but 1 patient (17/18) had resolution of coagulopathic bleeding with rFVIIa, and all clinical responders (n = 17) (defined as clinical cessation of bleeding within 24 hours determined by either attending surgeon or chief resident progress note) had a decrease in PT to normal range. In contrast, the single clinical nonresponder had an insignificant PT decrease (19 to 18 seconds). Prothrombin time decreased from 20 +/- 4 seconds to 12 +/- 2 seconds, p < 0.05 (n = 17). International Normalized Ratio (INR) decreased from 1.59 to 0.86, p < 0.05 (n = 17). Fibrinogen before administration was 299.73 (range, 105-564) (n = 15). pH before administration was 7.25 (+/-0.18) (n = 10). Patient temperature was 98.64 (+/-2.06). Effect in partial thromboplastin time (PTT) was inconsistent (50 +/- 49 seconds to 34 +/- 6 seconds, p > 0.05). Transfusion requirements for red blood cells (14 to 3 units) and plasma (12 to 3 units) were significantly reduced after rFVIIa. There were no significant differences in percentage PT decrease between dose > or =100 mcg/kg vs <100 mcg/kg, surgical vs trauma patients, survivors vs nonsurvivors, and those with pretreatment platelet count > or =100 K vs <100 K. CONCLUSIONS: The administration of rFVIIa caused a decrease in the PT in nearly all patients. There were an insufficient number of patients to support the use of PT as a clinical predictor of response; however, the data are suggestive of such utility. If the PT does not correct, then it is likely that there is a deficiency of other factors of the coagulation cascade.     

重组活化凝血因子Ⅶ和抑肽酶在肝移植术中的应用

目的 前瞻性地观察使用重组活化凝血因子Ⅶ（rFⅦa）和抑肽酶对减少肝移植术中出血的有效性和安全性。方法 将中山大学附属第三医院2003—2004年欲行肝移植60例病人术前随机分为3组，第1组为rFⅦa组，第2组为抑肽酶组，第3组为对照组。对3组病人各个时间点的凝血指标、凝血弹性图（TEG）指标进行观察，比较3组术中出血量、输血量、住院时间、住院费用和血管并发症。结果 使用rFⅦa后凝血酶原时间（PT）、TEG中的反应时间（R）和最大幅度（MA）与对照组差异有显著性（P〈0.05）。而部分凝血酶原时间（APTT）、纤维蛋白原水平（FIB）、血小板计数（PLT）和TEG中的血凝块减少速率（LY30）与对照组的差异无显著性（P〉0.05）。抑肽酶组与对照组MA和LY30的差异有显著性（P〈0.05），其他指标无明显改善。rFⅦa组和抑肽酶组术中出血量、输血量均较对照组明显减少（P〈0．05）。结论 rFⅦa能迅速改善外源性凝血系统功能，抑肽酶能改善新肝期的纤溶亢进，未见增加术后血管并发症。     

Efficacy and safety of repeated perioperative doses of recombinant factor VIIa in liver transplantation.

Patients undergoing orthotopic liver transplantation (OLT) have excessive blood loss during surgery that requires blood transfusions, leading to increased postoperative morbidity and mortality. We studied the efficacy and safety of activated recombinant factor VII (rFVIIa) in reducing transfusion requirements in OLT. This multicenter, randomized, double-blind, placebo-controlled trial enrolled patients undergoing OLT because of cirrhosis (Child-Turcotte-Pugh class B or C). Patients received a repeated intravenous bolus regimen of rFVIIa 60 or 120 microg/kg or placebo. The primary efficacy endpoint was the total number of red blood cell (RBC) units transfused during the perioperative period. A total of 182 patients were analyzed for efficacy and 183 for safety. No significant effect of rFVIIa was observed on the number of RBC units transfused or intraoperative blood loss compared with the placebo group. A significantly higher number of patients in the rFVIIa study groups avoided RBC transfusion. Administration of rFVIIa but not placebo restored the preoperative prolonged prothrombin time to normal value during surgery. Patients receiving rFVIIa and placebo did not experience a significant difference in rate of thromboembolic events. Additionally, there was no statistically significant effect of rFVIIa treatment on hospitalization rate, total surgery time, and the proportion of patients undergoing retransplantation. In conclusion, use of rFVIIa during OLT significantly reduced the number of patients requiring RBC transfusion. There was no increase in thromboembolic events with rFVIIa administration compared with placebo.     

Safety and hemostatic effect of recombinant activated factor VII in cirrhotic patients undergoing partial hepatectomy: a multicenter, randomized, double-blind, placebo-controlled trial

BACKGROUND: Coagulopathy caused by cirrhosis may contribute to excessive bleeding during hepatectomy. We evaluated the hemostatic effect and safety of recombinant factor VIIa (rFVIIa) in cirrhotic patients undergoing partial hepatectomy. METHODS: Patients were randomized to rFVIIa 50 or 100 mug/kg or placebo, administered intravenously 10 minutes before surgery and every second hour during surgery. The primary efficacy end points were the proportion of patients receiving red blood cell (RBC) transfusions and the amount of RBCs transfused. The RBC transfusion trigger was blood loss of 500 mL. Safety end points included thromboembolic and adverse events. RESULTS: No statistically significant effect of rFVIIa treatment on efficacy end points was observed. Serious and thromboembolic adverse events occurred at similar incidences in the study groups. CONCLUSIONS: Using blood loss as a transfusion trigger, the efficacy of rFVIIa in reducing the requirement for RBC transfusion was not established in this study. No safety concerns were identified.     

Anticoagulant efficacy of PEG-Hirudin in patients on maintenance hemodialysis

BACKGROUND: Heparins are currently the anticoagulants of choice in long-term hemodialysis (HD). Because of their shortcomings, including the increasing incidence of heparin-induced thrombocytopenia (HIT II), alternative anticoagulation is necessary. The study objectives were to provide safe and effective HD by investigating an appropriate PEG (polyethylene glycol)-Hirudin dosage regimen in patients on HD, as well as to compare the safety, tolerability, and efficacy of PEG-Hirudin with that of unfractionated heparin (UFH). METHODS: Twenty patients (12 males, 8 females, mean age 57.8 years) with end-stage renal disease (ESRD) took part in the study. Dialysis sessions lasting a mean of 4.3 hours (QB 250 to 300 mL/min, QD 500 mL/min) were performed 3 times a week with a Gambro GFS plus 16 dialyzer. Ten patients (group I) received UFH at 3 regular dialysis sessions (HD1-3) followed by 5 dialysis sessions using PEG-Hirudin (HD4-8). Another 10 patients (group II) received UFH at 3 regular dialysis sessions (HD1-3) followed by 10 sessions on PEG-Hirudin (HD4-13). The starting dose of PEG-Hirudin was a single bolus injection of 80 microg/kg BW (HD4), except for the first patient, who received 50 microg/kg BW followed by a 12 microg/kg bolus. Before each of the following sessions (HD5-13), an individualized PEG-Hirudin dose of between 26 to 65 microg/kg body weight (BW) (mean dose 41 microg/kg BW) was injected. PEG-Hirudin plasma and blood concentrations derived from anti-Iia activity and ecarin clotting time (ECT), respectively, activated partial thromboplastin time (aPTT), bleeding time, and arteriovenous (AV) fistula compression time were investigated to calculate the pharmacokinetic parameters or to assess anticoagulant efficacy. RESULTS: Mean predialysis PEG-Hirudin plasma concentrations increased up to a maximum of 488 ng/mL in group I (HD8) and up to 536 ng/mL in group II (HD8). Mean plasma concentrations measured at 5 minutes after the 1st (HD4), 5th (HD8), and 10th (HD13) PEG-Hirudin injection ranged from 1076 to 1298 ng/mL. Mean post-dialysis plasma levels ranged from 818 to 995 ng/mL. Mean predialysis aPTT was not affected by UFH, but was prolonged by 46 to 56 seconds by PEG-Hirudin. Five minutes after injecting PEG-Hirudin or UFH, mean aPTT was prolonged to a maximum of 85 and 188 seconds, respectively. Mean post-dialysis aPTT values ranged from 60 to 68 seconds after PEG-Hirudin and 34 to 46 seconds after UFH. PEG-Hirudin was well tolerated; no serious adverse events or bleeding complications were observed. Safety assessments yielded no significant difference between the two anticoagulants. CONCLUSION: This pilot study confirmed the usefulness and tolerability of a PEG-Hirudin dose regimen consisting of a single, fixed bolus dose of 80 microg/kg BW injected before starting the first dialysis session (HD4) and followed by a dose titration period over at least 4 sessions (HD5-8), which again was followed by a fixed maintenance dose period (HD9-13). On the basis of PEG-Hirudin data from patients with various degrees of renal insufficiency but not undergoing hemodialysis and prior recombinant-hirudin (r-hirudin) experience, patients were titrated into an EC-controlled dose range that proved to be efficacious enough to prevent clotting and safe enough to prevent bleeding. Due to the favorable pharmacokinetic properties of PEG-Hirudin, a residual anticoagulant effect is maintained in the intervals between dialysis sessions, and this permanent state of anticoagulation may prevent vascular access complications as well as other vascular events.     

肝移植围手术期凝血功能的变化及调控措施

目的探讨同种异体原位肝移植围麻醉期预处理对凝血功能的影响。方法18例ASAⅢ—Ⅳ级因终末期肝病而行原位肝移植的患者,术前及麻醉诱导后进行预处理,并在不同时期采血检测凝血酶原时间（PT）、活化的部分凝血酶原时间（APTT）、纤维蛋白原（FIB）、D-二聚体（D—dimer）、血小板（PLT）及血清钙离子浓度并进行动态观察。同时应用SONOCLOT凝血及血小板功能分析仪对凝血与血小板功能进行定性分析,记录术中出血量及输血量。结果术中PT、APTT逐渐延长,门脉开放初期达到高峰,新肝再灌注后PT、APTT又逐渐缩短;D—dimer总体上呈现逐渐增加的趋势,再灌注后逐渐下降,但始终高于术前水平。大多数病人全血凝固时间（ACT）在手术开始前即开始延长,新肝期最为突出,新肝后期逐渐缩短。凝结速率（CR）新肝期明显减慢,以后逐渐恢复。血小板功能（PF）在新肝初期最差,到术毕明显恢复。结论肝移植术中的早期预处理,并适时个体化调整有利于改善凝血功能障碍,维持术中的相对稳定,减少术中术后出血和输血。     

Is recombinant activated factor VII effective in the treatment of excessive bleeding after paediatric cardiac surgery?

A best evidence topic in paediatric cardiac surgery was written according to a structured protocol. The question addressed was whether recombinant activated factor VII was effective for the treatment of excessive bleeding after paediatric cardiac surgery. Altogether 150 papers were found using the reported search; 13 papers were identified that provided the best evidence to answer the question. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these studies were tabulated. A total of 311 children experienced excessive bleeding following cardiac surgery that was refractory to the conventional methods of achieving haemostasis. One hundred and ninety-two patients received the rFVIIa while 116 were in control arm from five studies. The primary end-point was on chest tube drainage, the plasma prothrombin time, the activated partial thromboplastin time after the administration of rFVIIa and the secondary end-point was reduction of blood products transfusion. Thrombosis was a complication in 8 patients (4.2%); three deaths (1.6%) but not attributable to thromboembolic events following the use of rFVIIa. Most of the studies failed to clearly state the doses but the extracted doses ranged between 30 and 180?μg/kg/dose, the interval between doses ranged between 15 and 120?min with a maximum of four doses. However, most of the patients had 180?μg/kg/dose with interval between dose of 2?h and maximum of two doses with dosage moderated with respect to weight, prior coagulopathy and responsiveness. There were two randomized studies with good sample size. One showed no significant differences in the secondary end points between the two arms and noted no adverse complications. However, the rFVIIa was used prophylactically. The other observed that there were no increase in thromboembolic events rather rFVIIa was effective in decreasing excessive bleeding that may complicate cardiac surgery in children. In conclusion, the studies were in support of the notion that the use of rFVIIa was effective in decreasing excessive bleeding which may complicate paediatric cardiac surgery, and care should be exercised when using it in the children on ECMO circuit.     

Einsatz von rekombinantem aktiviertem Faktor VIIa zur Behandlung der traumatischen Leberruptur

Hepatic rupture after blunt abdominal trauma may lead to severe bleeding, depletion and consumption of clotting factors, with the risk of packing to defer the definitive operation. We report two cases of hepatic rupture after blunt trauma with intrahepatic hematoma and severe intraabdominal bleeding. In both cases the bleeding could be stopped by early intervention with recombinant activated factor VIIa (rFVIIa). In neither case was surgical intervention necessary and after 3 weeks both patients were released without complications. These cases demonstrate that the early therapy with a single dose of rFVIIa before the development of a hemostatic crisis is a therapeutic option in selected cases where surgical therapy of the bleeding is difficult and risky.     

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.     

Recombinant activated factor VIIa use in massive transfusion and coagulopathy unresponsive to conventional therapy

We report a retrospective analysis of patients admitted to a tertiary intensive care unit who received recombinant activated factor VIIa (rFVIIa) in an effort to control life-threatening haemorrhage and coagulopathy. Data extracted included: demographics, diagnoses and clinical course, dosage of rFVIIa, blood product requirements and coagulation tests prior to and after rFVIIa, pH, base deficit and temperature. During the study period rFVIIa was given to nine patients with refractory coagulopathy in imminent danger of death. Three patients were post cardiac surgery, three patients had multiple blunt trauma, one patient had a close range shotgun wound to the abdomen, one patient had a ruptured iliac artery aneurysm and one patient was post caesarean section with acute fatty liver of pregnancy. Improvements in prothrombin time (PT) (median 17s pre vs 10.6s post rFVIIa (P < 0.05)) were seen in all nine cases. Reduced requirements for red blood cells, fresh frozen plasma, platelets and cryoprecipitate followed rFVIIa administration in eight cases. One patient died after 48 hours of complications unrelated to the initial pathology. Seven patients were discharged from hospital; one remains in hospital. rFVIIa provided improvement in coagulopathy unresponsive to conventional therapy.     

Elevated partial thromboplastin time as an indicator of hemorrhagic risk in postoperative patients on warfarin prophylaxis

Warfarin provides effective prophylaxis against postoperative venous thromboembolic complications in adults undergoing elective hip surgery, but at the risk of increased bleeding complications. Although patients on this drug are routinely monitored by prothrombin time (PT), mild elevations of the partial thromboplastin time (PTT) have been reported with warfarin therapy. In a prospective study of 194 patients undergoing elective hip surgery, the authors assessed the incidence of elevation of the PTT above 50 seconds while the patient was receiving warfarin prophylaxis and the effect of this elevation on bleeding complications. The prophylactic warfarin was begun the night prior to surgery. Thirty-eight patients (19.6%) had a PTT greater than 50 seconds (group 1) and 156 had milder or no elevation of the PTT (group 2). The mean maximum PTT in group 1 was 61.2 ( +/- 12.9), versus 39.9 ( +/- 5.0) seconds in group 2. Major postoperative bleeding complications occurred in 26.3% of group 1 patients, versus 4.5% of group 2 (P less than .01). This subset of patients with an abnormal PTT elevation despite appropriate control of the PT is at a significantly increased risk of major postoperative bleeding. This observation may also prove valuable in reducing bleeding complications from warfarin use in nonsurgical patients.     

Recombinant activated factor VII in the postanesthetic recovery unit: review of 16 cases

We describe a series of 16 cases in which recombinant activated factor VII (rFVIIa) was used in our postanesthetic recovery unit. The mean age of the patients was 53.5 years (range, 30-84 years). Eleven were men and 5 women. The mean dose of rFVIIa used was 75 microg x kg(-1) (range, 60-90 microg x kg(-1)) and 25% of the patients needed a second dose. All the patients had postoperative bleeding, 62.5% after general surgery, 25% after a liver transplant, and 12.5% after a lung transplant. rFVIIa therapy was effective in 66% of the patients and no adverse thrombotic events related to treatment were observed. rFVIIa can be an efficacious therapeutic option for bleeding and coagulation disorders that are refractory to conventional replacement therapy. Approval to use rFVIIa in this setting and the establishment of indications should be based on further research.