Single Dose Of rFVIIa Research Articles

Use of Single Dose of rFVIIa in Congenital Hemophilia: Analysis of Data Capture from the Hemophilia and Thrombosis Research Society Registry (2004–2008)

The recommended dose of recombinant factor VIIa (rFVIIa, NovoSeven®) is 90 mcg/kg every 2–3 hours. The Home Treatment Study demonstrated an average of 2.2 doses of 90 mcg/kg were required to treat mild to moderate bleeds. Since it is recognized that a single dose administered shortly after a bleed, if equally effective, would be more convenient and possibly could reduce bleeding morbidity, this study examined the experience registered with the use of single rFVIIa doses in the United States.The HTRS database contains patient data relating to hemophilia treatment and related disorders, and in particular the treatment of acute bleeding episodes in individuals with hemophilia complicated by anti-factor VIII (FVIII) or IX (FIX) alloantibody inhibitors. Between January 2004 and March 2008, the database contained information on over 5,000 bleeding episodes. The data for patients receiving only a single bolus intravenous dose of rFVIIa and no additional treatment were evaluated. The parameters assessed included patient demographics, bleed location, bleed type (specifically joint and muscle bleeds), and dose.Of 2,532 patients who received rFVIIa, 70 with congenital hemophilia A (n=63) or B (n=7) and inhibitors experienced 508 bleeding episodes that were treated solely with a single dose of rFVIIa. The mean (median, range) age at the time of bleed was 12.7 years (8.2, 0.6–60.4). Mean titers for anti-FVIII and anti-FIX were 62.2 BU (15.0, 0–1408) and 6.8 BU (1.3, 0–31.7), respectively. The bleed sites recorded were joints (271 bleeds [53%], including 55 in target joints [20.2% of joint bleeds]), muscle (78, 15%), mucosal (45, 9%), intracranial (25, 5%), and subcutaneous (21, 4%). Joint bleeds occurred primarily in the ankles (124 bleeds), elbows (61 bleeds) and knees (53 bleeds).For 508 bleeds treated with a single dose of rFVIIa, the mean (median, range) dose was 119.5 mcg/kg (100, 25–500) with 20 of those doses ≥270 mcg/kg. Patients with joint bleeds were treated with 123.1 mcg/kg (100, 25–500), target joint bleeds with 155.3 (140, 50–393), and those with the muscle bleeds received 120.1 mcg/kg (100, 50–500). The most common single dose regimen overall and for the joint and muscle bleeds was 90 mcg/kg rFVIIa.The majority of bleeds (424, 82.7%) were treated at home, but bleeds were also treated at Hemophilia Treatment Centers (61, 12.0%) and in the emergency room (15, 3.0%). Overall, physician reported “bleeding stopped” in 97% of the 494 bleeds, 97% of hemarthroses, 96% of target joint hemarthroses and 96% of muscle bleeds. For the remaining 14 episodes, although documentation did not indicate “bleeding stopped”, no other medications were recorded.There were no serious adverse drug reactions.Registry data can only demonstrate the treatment reported in selected bleeds captured, and the analysis here specifically examined bleeds treated with only a single dose either because of bleed resolution or by physician/patient choice. The data analyzed here demonstrate single doses of rFVIIa of up to 500 mcg/kg (mean 119 mcg/kg) for mild to moderate bleeds effectively resolved bleeds in 97%, including hemarthrosis, target joints hemarthrosis, and muscle bleeds. These data support the possibility that rFVIIa can be administered in a single bolus dose with equivalent or superior efficacy as multiple lower doses for bleeding episodes treated as part of a home therapy regimen. While 3 randomized trials have examined the equivalence of a single dose of 270 mcg/kg with 3 doses of 90 mcg/kg, these data suggest that single doses of rFVIIa therapy in the real world often were empirically titrated on a patient specific basis, according to the severity and site of the bleeding episode. These registry data provide justification for prospective, randomized, single dose titration trials of rFVIIa or future analogues.

Perioperative Use of Recombinant Factor VII to Prevent Intraoperative Aneurysm Rupture in High Risk Patients: A Preliminary Safety Evaluation

The authors present a safety evaluation of the perioperative use of recombinant activated factor VII (rFVIIa) in a series of subarachnoid hemorrhage patients undergoing microsurgical aneurysm clipping. We performed a retrospective chart review of the records of 18 consecutive subarachnoid hemorrhage patients who underwent craniotomy for aneurysm clipping and received an intraoperative dose of rFVIIa. In each case, the aneurysm was felt to be a "high risk" lesion for intraoperative rupture either because it had bled multiple times prior to surgery or based on anatomical considerations. All complications were recorded whether or not they were attributed to the use of rFVIIa. Eighteen patients, 7 men and 11 women, ranging in age from 42 to 85 years were included in this review. Nine patients (50%) were either Hunt/Hess Grades IV or V. Six patients developed clinically significant cerebral vasospasm. Fifteen patients required ventricular drainage on admission, and seven patients ultimately required a ventriculoperitoneal shunt. One lower extremity deep venous thrombosis and seven upper extremity venous thromboses in association with peripherally inserted central catheter (PICC) lines were identified on screening Doppler evaluations. There were no associated pulmonary emboli. No aneurysm ruptured intraoperatively. We describe our experience with the use of a single dose of rFVIIa administered perioperatively in an attempt to decrease the rate of intraoperative aneurysm rupture in patients undergoing microsurgical aneurysm clipping. There were no significant immediate or long-term adverse effects attributable to the use of rFVIIa in this group, and we encountered no intraoperative ruptures in this relatively small series.

Recombinant Activated Factor VII in Cardiac Surgery: Experience From the Australian and New Zealand Haemostasis Registry

Data from the Australian and New Zealand Haemostasis Registry (ANZHR) were used to report on the efficacy, mortality, and outcomes of a cohort of cardiac surgical cases receiving recombinant activated factor VII (rFVIIa). The ANZHR collects retrospective and contemporaneous data on the use of rFVIIa in patients with critical bleeding from hospitals throughout Australia and New Zealand. Participating centers commit to the collection of data on all patients without hemophilia treated with rFVIIa, which limits bias and prevents the reporting of only positive or anecdotal experiences. At September 2006, the cardiac surgical cohort comprised 304 patients (43%) of a total of 695 cases reported to the ANZHR from 46 hospitals. The 304 cases date from January 2001. The median patient age was 66 years (interquartile range [IQR], 53 to 75 years), and 73% were men. After administration of rFVIIa, all blood product usage was significantly reduced. Patients received a median dose of 93 mug/kg (IQR, 82 to 102), and 85% of patients received a single dose. The documented response rate to a single dose of rFVIIa was 84%, of which 23% reported cessation of bleeding and 61% reported a reduction in bleeding. Patients received a median volume of 6 U of red blood cells before rFVIIa treatment. The median reduction in red blood cells after the rFVIIa dose compared with before was 4 U. Response was reduced in patients with a lower baseline hemoglobin, coagulopathy (determined by international normalized ratio, fibrinogen, and platelets), the number of red blood cell units transfused before rFVIIa, advanced age, more complex operations, hypothermia, and acidosis. Responders had a significantly reduced mortality (p < 0.001). The percentage of patients alive at 28 days was 95% if bleeding ceased after rFVIIa, 86% if bleeding reduced, and 60% for nonresponders. A 7% adverse event rate attributed as "probably" or "possibly" associated with rFVIIa was reported with a 4% reported thromboembolic event rate. Recombinant FVIIa is a potential rescue therapy in severe uncontrollable critical bleeding after cardiac operations. The observed response rate was high, and response was associated with improved mortality. There was an observed reduction in blood product usage after rFVIIa. The adverse event rate reported was similar to documented adverse event rates in complex cardiac surgical patients. In the absence of randomized controlled trials, this registry provides a basis for understanding current clinical practice with rFVIIa in cardiac surgical procedures.

Risk of Thromboembolic Events in Controlled Trials of rFVIIa in Spontaneous Intracerebral Hemorrhage

Recombinant activated factor VII (rFVIIa) reduces hematoma expansion and improves outcome after intracerebral hemorrhage (ICH), with an apparent increase in nonfatal thromboembolic events (TEs) with higher doses. Despite low incidences of such events in rFVIIa-treated hemophiliacs, the frequency in older patients with more atherosclerosis and immobility has yet to be defined. Data were pooled from 3 randomized placebo-controlled studies in patients diagnosed within 3 hours of spontaneous ICH who received a single dose of rFVIIa (5 to 160 microg/kg; n=371) or placebo (n=115). Clinical/laboratory evaluations, lower extremity Doppler studies, and 72-hour CT scans were used to monitor for TEs. Adverse events occurring while hospitalized and serious events occurring through day 90 were carefully reviewed. There was no overall increase in risk of total TEs in rFVIIa-treated patents; however, there were more arterial, but not venous, TEs in the high dose group (120 to 160 microg/kg) compared with placebo (5.4% versus 1.7%; P=0.13). Arterial events occurring within 7 days of drug administration classified as possibly or probably associated with study drug included myocardial ischemia (n=9, 8 were non-ST-segment elevation and non-Q-wave events; 2 of the 9 had sequelae) and ischemic stroke (n=9, 4 of which had likely causes other than rFVIIa). Regression analysis identified high doses (120 to 160 microg/kg) of rFVIIa as the only factor associated with arterial TEs (odds ratio=6.75; P=0.02). There appears to be a increased risk of arterial TEs associated with higher doses of rFVIIa in ICH patients as compared with placebo. Further studies are underway to identify specific factors associated with these events and to define the dose that maximizes benefit and minimizes risk.

The use of recombinant activated factor VII to control haemorrhage following exentheresis and massive transfusion in coagulopathic patients

Exentheresis pelvis totalis due to locally advanced pelvic malignancies is an extensive surgical procedure. The operation is commonly associated with anticipated perioperative haemorrhage requiring a large volume of haemoproducts. Sometimes, the intervention can result in unexpected massive and uncontrolled haemorrhage that is frequently a combination of surgical and coagulopathic bleeding. Attempts to arrest massive bleeding by conventional means may fail. We describe our experience in the use of recombinant activated factor VII (rFVIIa) in three previously hemostatically competent patients who underwent exentheresis in order to control massive bleeding resulting from dilution coagulopathy in the operating theatre, as well as in the treatment of postoperative bleeding associated with consumptive coagulopathy. Of these, two massively transfused patients developed dilution coagulopathy in the operative theatre, which was poorly responsive to conventional management. In both cases, a single dose of rFVIIa (70 microg/kg and 60 microg/kg respectively) was given. Prompt clinical response was achieved and operations were successfully finished. In the third case, the patient developed consumptive coagulopathy on the first day after surgical procedure that was treated with conventional therapy. On the second postoperative day the patient became anuric and experienced severe intraabdominal bleeding. The bleeding was successfully controlled with rFVIIa in a single dose of 70 microg/kg. RFVIIa can be a treatment option in patients suffering from intractable coagulopathic bleeding when standard therapy has failed.

Recombinant factor VIIa as an adjunct in nonoperative management of solid organ injuries in children

Ongoing bleeding after blunt solid organ injury in children may require invasive therapy in the form of either angiographic or operative control. We report our experience in the use of a procoagulant, recombinant activated factor VII (rFVIIa), for controlling persistent bleeding in blunt abdominal trauma in children. After institutional review board approval, the records of 8 children with blunt abdominal trauma, persistent bleeding, and managed nonoperatively with rFVIIa were reviewed. All 8 patients presented to our institution after sustaining blunt abdominal trauma and solid organ injury. All children had evidence of persistent bleeding with a drop in hematocrit and elevation in heart rate. Patients received a single dose of rFVIIa at 75 to 90 microg/kg (1 patient had 24 microg/kg) and had successful control of their bleeding without any further therapeutic intervention. Only 3 patients required a blood transfusion after rFVIIa administration--2 who had subarachnoid hemorrhages and the third during pelvic fixation. There were no cases of thromboembolic events after treatment with rFVIIa. Recombinant factor VIIa is a useful adjunctive therapy in pediatric patients with evidence of ongoing hemorrhage from blunt abdominal injury and may reduce the need for invasive therapeutic procedures and transfusions.

Single 270 μg kg−1‐dose rFVIIa vs. standard 90 μg kg−1‐dose rFVIIa and APCC for home treatment of joint bleeds in haemophilia patients with inhibitors: a randomized comparison

Evidence suggests greater doses of recombinant activated factor VII (rFVIIa; NovoSeven, Novo Nordisk A/S, Bagsvaerd, Denmark) than currently administered may result in enhanced haemostasis and convenience for patients with haemophilia A and B with inhibitors. This study evaluated efficacy and safety of rFVIIa and an activated prothrombin complex concentrate (APCC; Factor Eight Inhibitor Bypassing Activity [FEIBA], Baxter AG, Vienna, Austria) for controlling joint bleeds in a home-treatment setting. Patients received each of three treatments in one of six possible sequences: 270 microg kg(-1) rFVIIa at hour 0 + placebo at hours 3 and 6, 90 microg kg(-1) rFVIIa at hours 0, 3 and 6, and 75 U kg(-1) APCC at hour 0. Efficacy was assessed by the requirement for additional haemostatics within 9 h and by a novel global response algorithm. The percentage of rFVIIa 270 microg kg(-1) group patients requiring additional haemostatics within 9 h (8.3%) was significantly lower than that for the APCC group (36.4%, P = 0.032). The percentage of rFVIIa 90 x 3 microg kg(-1) group patients requiring such rescue medication (9.1%) was also lower compared to the APCC group. This result approached, but did not reach statistical significance (P = 0.069). Both rFVIIa treatment groups showed similar use of rescue medication (8.3% and 9.1% of episodes for rFVIIa 270 microg kg(-1) and rFVIIa 90 x 3 microg kg(-1) groups respectively). No significant differences in treatment response were observed with the global response algorithm (P = 0.173). No safety issues were identified. A single dose of rFVIIa 270 microg kg(-1) is as safe and effective as rFVIIa 90 x 3 microg kg(-1) dosing, and may be considered a potentially more effective alternative to APCCs for the management of joint bleeding in this population.

Recombinant activated factor VII in critical bleeding: experience from the Australian and New Zealand Haemostasis Register

There has been increasing off-label use of recombinant activated factor VII (rFVIIa/NovoSeven; Novo Nordisk, Bagsvaerd, Denmark) for patients with critical bleeding. Given the lack of high-level evidence, the clinical indications, observed response and adverse events are important to capture. The Haemostasis Registry collects retrospective and contemporaneous data on all use of rFVIIa at participating institutions for non-haemophiliac patients with critical bleeding (i.e. off-label use). As of October 2006, 694 cases had been reported into the register from 37 hospitals across Australia and New Zealand. These comprise an array of therapeutic categories, including salvage use in: perioperative cardiothoracic surgery (44%), trauma (16%), medical bleeding (9%), obstetric bleeding (4%) and other types of critical bleeding (28%). Patients received a median (interquartile range) dose of 91 mug/kg (75-103) and 83% of patients received a single dose of rFVIIa. The documented response rate to a single dose of rFVIIa was 69%. The 28-day survival was 68%, but varied with clinical category. The rate of adverse events probably or possibly linked to the use of rFVIIa was 6%, with most of the thromboembolic adverse events occurring in the cardiac surgery group. The Haemostasis Registry cannot replace well-designed prospective randomized controlled trials, but in their absence this registry provides a basis for understanding current clinical experience of rFVIIa. Registries continue to be vital in monitoring off-label uses of medications.

Experience of recombinant-activated factor VII to control bleeding in children with Glanzmann’s thrombasthenia

Patients with Glanzmann’s thrombasthenia (GT) are at an increased risk of haemorrhage. Recombinant-activated factor VII (rFVIIa) is a new therapeutic option, but experience of its use in GT is limited. We present an analysis of patients ≤16 years with GT receiving rFVIIa, whose details were submitted to an independent, peer-reviewed registry http://www.haemostasis.com. Thirty-five reports of rFVIIa use in ten patients (age range, 2–16 years) with GT were identified. In seven out of ten patients, rFVIIa was administered for the treatment of active bleeding, and in three out of ten, the agent was given prophylactically before an intervention. A median total rFVIIa dose of 270 μg/kg body weight (range, 89.7–635.4 μg/kg) was associated with cessation of bleeding in 23/32 episodes (72%) and absence of significant bleeding in the three patients undergoing invasive procedures. In 14 successful treatment episodes (60.9%), bleeding ceased within 2 h of rFVIIa administration. Fifteen bleeds/potential bleeds were stopped/prevented with a single dose of rFVIIa. No adverse events were reported. These results indicate that rFVIIa is safe and may be effective for the prophylaxis or treatment of bleeding in patients with GT.

Clinical Outcomes of Off-Label Use of Recombinant Activated Factor VII (rFVIIa) at Teaching Hospitals Affiliated with a Medical School.

BACKGROUND: Recombinant factor VIIa (rFVIIa), NovoSeven®, is currently licensed in the United States for treatment of bleeding in hemophilia patients with acquired coagulation factor inhibitors. The off-label uses of this medication have expanded dramatically in past few years. Here we report our experience with the off-label use of rFVIIa at University at Buffalo affiliated teaching hospitals which include a level III trauma and major cardiothoracic centers.PATIENTS AND METHODS: We reviewed the clinical, laboratory, and radiographic data of a consecutive series of 43 patients who received off-label rFVIIa between December 2001 and September 2005.RESULTS: The indications for off-label rFVIIa use included CNS bleeding (17 patients), cardiothoracic and vascular surgery (9 patients), trauma (7 patients), GI bleeding (4 patients), coagulopathy (2 patients) and prophylaxis for surgery (4 patients). The dosage ranged from 32 to 150 mcg/kg with most patients receiving 90 mcg/kg. While a majority of patients received a single dose of rFVIIa (29 patients), one received a total of 22 doses. Overall 21 patients (49%) were alive at discharge. Those patients who received rFVIIa to stop severe bleeding from trauma or surgery appeared to have the worst outcome. The patient who received 22 doses of rFVIIa appeared to derive some clinical benefit after his initial doses, but became non-responsive to additional therapies. Successful hemostasis with rFVIIa was achieved in 100% of patients with preoperative prophylactic use. There were no thromboembolic events attributed to rFVIIa treatment.CONCLUSIONS: The outcome of off-label use of rFVIIa appears to correlate with clinical indications, with prophylactic use having greatest benefit and surgical hemorrhage, the worst. Our findings were used to revise guidelines to allow for more efficacious use of off-label rFVIIa.

Effects of Recombinant Activated Factor VII in Traumatic Nonsurgical Intracranial Hemorrhage

To determine whether treatment with recombinant activated factor VII (rFVIIa) will prevent progression of bleeding in nonsurgical hemorrhagic traumatic brain injury (TBI). Chart review from the trauma registry of a level 1 trauma center between January 1, 2002 and December 31, 2004 identified 2 patients who received rFVIIa for progressive hemorrhagic TBI. These patients were given a single dose of rFVIIa (120 mcg/kg) after a repeat head computed tomography (CT) scan showed worsening of intracranial bleeding. Pre-rFVIIa and post-rFVIIa coagulation parameters and postintervention CT scans were performed. A matched convenience sample was drawn from the institution's trauma registry reflecting similar injury patterns. The 2 patients who received rFVIIa were ages 61 and 79 years; the patients in the matched convenience sample were 57 and 63 years. Both sets of patients comprised 1 man and 1 woman who had suffered blunt trauma, including hemorrhagic TBI, and were matched according to age, gender, and injury severity score (ISS). During their hospital course, repeat CT scans documented worsening of intracranial hemorrhage in both cohorts. In the rFVIIa patients, follow-up CT showed overall improvement of head injury compared with the convenience sample. The rFVIIa patients also saw an appreciable decrease in both prothrombin time (PT) and international normalized ratio (INR). In hemorrhagic TBI, rFVIIa has the potential to limit or even halt the progression of bleeding that would otherwise place growing pressure on the brain. A prospective, randomized multicenter trial is planned to elucidate this hypothesis.

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.

Successful Use of Recombinant Factor VIIa for Treatment of Severe Postpartum Hemorrhage

1postpartum blood loss still results in severe maternal morbidity, 2 such as hypovolemic shock, renal failure, adult respiratory distress syndrome, hepatic failure, and disseminated intravascular coagulopathy. 3 Early, effective, and preferably noninvasive treatment is therefore essential. Primary postpartum hemorrhage is initially managed by restoration of blood volume, administration of oxytocin and prostaglandins, and the correction of coagulation. 2 If these initial conservative therapeutic measures do not control the bleeding, more drastic and invasive interventions such as bilateral artery ligation, angiography with selective embolization, or, as a last resort, hysterectomy can be performed. Recombinant factor VIIa (rFVIIa; NovoSeven) is a safe and effective drug for the treatment of bleeding episodes in patients with inherited or acquired hemophilia A or B and antibodies to the relevant coagulation factor (VIII or IX, respectively). Recently rFVIIa has been used successfully in patients with congenital or acquired platelet disorders, thrombocytopenia, and severe von Willebrand’s disease (type 3). The use of rFVIIa in patients with severe bleeding without known coagulation factor deficiencies or (preexisting) bleeding disorders has been reported in several case reports. 4-7 We describe a case of severe postpartum hemorrhage due to uterine atony resistant to conservative treatment in which use of a single dose of rFVIIa successfully controlled the bleeding and thereby obviated invasive procedures.

Use of recombinant activated factor VII to control bleeding in a young child with qualitative platelet disorder: a case report

Defects of platelet adhesion, aggregation, secretion, or procoagulant activities can lead to bleeding diathesis of variable severity. We used recombinant activated factor VII (rFVIIa) in the treatment of uncontrolled epistaxis in a patient with a qualitative platelet disorder. We aimed to assess the efficacy of a single rFVIIa dose (100 microg/kg) in the control of mild and severe refractory epistaxis, and evaluate the influence of rFVIIa on markers of platelet adhesion and aggregation during a period of hematological stability (i.e. non-bleeding, no medication). The efficacy study showed mild episodes of epistaxis could be successfully managed using a single rFVIIa (100 microg/kg) dose; however, severe bleedings were not well controlled, and platelet transfusion was required to achieve hemostasis. Hematological investigations showed ADP-induced and collagen-induced platelet aggregation increases from 20 to 34% and 16 to 30%, respectively, following rFVIIa administration. There were no differences between pre-dose and post-dose concentrations of membrane glycoproteins. rFVIIa may therefore induce platelet aggregation by activating a glycoprotein-independent aggregation pathway. rFVIIa may have a role in managing mild bleeding episodes not controlled using conventional measures in patients with a qualitative platelet disorder. Further research is needed to determine the mechanism of action, efficacy, and safety of rFVIIa in this population.

Recombinant factor VIIa reduces transfusion requirements in liver transplant patients with high MELD scores

Patients undergoing orthotopic liver transplantation (OLT) often experience significant coagulopathy and remain at risk for excessive blood loss and massive transfusion. The ability of recombinant factor VIIa (rFVIIa) to reduce transfusion requirements during OLT has not been well established. This retrospective study investigates whether rFVIIa reduces transfusion requirements in liver transplant patients with a significantly prolonged prothrombin time (PT) and a model of end-stage liver disease (MELD) score of > 20. Eleven patients received a single dose of rFVIIa (58 +/- 18 microg kg(-1)) at the time of incision. This group was matched with a selected control group that fulfilled all of the inclusion/exclusion criteria. Patient characteristics, pre-operative PT, HCT, PLT and MELD were identical between groups. Prophylactic application of rFVIIA reduced packed red blood cells (3.9 +/- 2.6 versus 6.9 +/- 2.3 U, P = 0.01) and fresh-frozen plasma (FFP) (12.6 +/- 6 versus 19.8 +/- 7 U, P = 0.018) transfusion requirements when compared with the control group. FFP administration in the first 24 h after surgery was also significantly less in the rVIIa group when compared with the control group (388 +/- 385 versus 1225 +/- 701 mL, P = 0.003). Hospital stay following transplantation tended to be shorter in the rFVIIa group, albeit statistical significance was not achieved (11 +/- 7.3 versus 7.9 +/- 2.7, P = 0.2). All but one patient in the control group survived for 30 days after transplantation. In a selected group of patients with prolonged PT and high MELD score, the prophylactic application of rFVIIa at the start of the OLT may reduce perioperative transfusion requirements.

Successful pulmonary administration of activated recombinant factor VII in diffuse alveolar hemorrhage

IntroductionDiffuse alveolar hemorrhage (DAH) is a serious pulmonary complication seen in patients with autoimmune disorders and patients treated with chemotherapy or after hematopoietic stem cell transplantation. The clinical management of DAH is complex and the condition has a high mortality rate. Tissue factor is expressed in the lung alveoli during inflammation and therefore pulmonary administration of human recombinant activated factor VIIa (rFVIIa) could be a rational treatment option.MethodsSix patients with acute, bronchoscopically confirmed DAH from a single intensive care unit university hospital center were included in the study of acute DAH in critically ill patients. The patients were treated with intrapulmonary administration of 50 μg/kg rFVIIa in 50 ml of sodium chloride by bronchoalveolar lavage (BAL) with 25 ml in each of the main bronchi, which was repeated after 24 hours in case of treatment failure.ResultsAn excellent response, defined as complete and sustained hemostasis after a single dose of rFVIIa, was seen in three patients. A good response, meaning that sustained hemostasis was achieved by a repeated rFVIIa administration, was seen in the remaining three patients. In one of these patients, the BAL treatment was repeated twice; in another patient, the second dose of rFVIIa was administered by nebulizer after extubation after the initial BAL. The hemostatic effect was statistically significant (p = 0.031). The oxygenation capacity, as reflected by the PaO2/FiO2 (arterial oxygen pressure/inspiratory fractional oxygen content) ratio, increased significantly (p = 0.024) in all six patients following the local rFVIIa therapy.ConclusionSymptomatic therapy of DAH after intrapulmonary administration of one or more doses of rFVIIa was found to have a good to excellent hemostatic effect in six consecutive patients with DAH. The intrapulmonary administration of rFVIIa seemed to have a high benefit-to-risk ratio. Larger series should confirm the safety of this approach.

Successful Use of Recombinant Factor VIIa in Reversal of Life Threatening Bleeding Caused by Coagulopathy.

A 78-year old female with a history of atrial fibrillation (AF) presented to our institution with complaints of hematuria, epistaxis, hematochezia, hematemesis and fever. She was on anticoagulation with coumadin therapy for AF and had been recently started on levofloxacin for a urinary tract infection. On examination her pulse rate was 110/minute and blood pressure was 80/40 mm Hg. Investigations revealed hemoglobin of 9.4 g/dl, a hematocrit of 27.8 %, prothrombin time (PT) > 40 and international normalized ratio (INR) >10. She was given intravenous fluids to correct hypotension, fresh frozen plasma (FFP) and vitamin K to correct the coagulopathy. She developed acute renal failure and respiratory failure requiring intubation. Over the period of first week, patient had received a total of 26 units of FFPs, 5 units of cryoprecipitate, 17 units of packed red blood cells and multiple doses of Vitamin K without any improvement of her coagulopathy. She developed disseminated intravascular coagulation (Platelet 42,000/nl, D-Dimer 4032ng/l, fibrinogen degradation products >40 mg/l, fibrinogen 157 mg/dl) and her prognosis appeared poor. She also received 18 units of platelets and 2500 units of Autoplex T (anti-inhibitor coagulant complex), however her INR was persistently >10 and she continued to bleed. Then patient was given recombinant factor VIIa (RF VIIa) at dose of 90 mg/kg and she responded well to single dose of RF VIIa and cessation of her bleeding was noticed within two hours. Repeat coagulation studies showed PT of 13.1 and INR of 1.2. Subsequently patient was extubated, her renal failure reversed and she was discharged home in a stable condition. Originally used for treatment of bleeding in patients with hemophila, rF VIIa, a single chain protease has been used in patients with serious and complicated coagulation defects to arrest or to prevent bleeding. The mechanism of action of rF VIIa remains unclear. It has been suggested that rF VIIa, when administered leads to saturation of tissue factor and this leads to generation of thrombin via the factor Xa. There is evidence that rFVIIa can generate thrombin independently of above pathway. In view of its potent prohemostatic effect, rF VIIa appears to be a promising agent that can be used for application in patients with life-threatening bleeding, in whom all other hemostatic treatments have failed as seen in our patient. However at present time it is not completely clear at what stage recombinant factor VIIa should be administered. Since the efficacy and safety of recombinant factor VIIa have not been established in randomized controlled studies, it may be argued that the safest approach is to administer the agent only if all other treatment has failed. However, if the agent is given too late, ongoing bleeding and transfusion may have resulted in such a derangement of the coagulation system that the drug is less effective. Further studies comparing early versus late administration of rF VIIa are needed. While we await the result of these studies and until more information is available on the safety of rFVIIa, its use in our view should be restricted to life-threatening situations.

Ex-Vivo Assessments in the Evaluation of Dose Response to Recombinant Factor VIIa When Administered for Bleeding Following Punch Biopsies in Healthy Volunteers.

The utility of existing methods for the evaluation of hemostatic agents has been limited. The purpose of this study was to evaluate and optimize the use of a standardized punch biopsy to investigate the effects of hemostatic agents in healthy subjects. Recombinant FVIIa (rFVIIa) is licensed for the treatment of bleeding episodes in patients with hemophilia A or B with inhibitors. Recent reports (anecdotal and from randomized clinical trials) have described the successful use of rFVIIa in patients with liver disease, intracerebral hemorrhage, congenital and acquired coagulation factor deficiency, warfarin-induced bleeding, thrombocytopenia, traumatic brain injury, spinal cord surgery, and platelet disorders using a wide range of doses and dosing regimens. This variety of clinical situations, suggests a need to determine the optimal dose and dosing regime of rFVIIa for use in these potentially new therapeutic areas. A study was designed to evaluate the dose-response of rFVIIa in a controlled manner using a punch biopsy procedure in healthy volunteers that consented to participate in an IRB approved protocol. The study was designed as a three-part trial. Part A (6 subjects) optimized the size of the biopsy needed to create bleeding times and durations appropriate for study purposes. Part B (10 subjects) determined the feasibility of evaluating rFVIIa efficacy and safety in this bleeding model. Part C (48 subjects) examined, in an ascending dose escalation paradigm, the effect of a single dose of rFVIIa on bleeding time, blood loss volume, coagulation parameters and coagulation status in healthy volunteers. In Part C, all patients underwent three punch biopsies: the first (baseline biopsy) with no treatment, the second with either a low or high rFVIIa dose administered prior to biopsy, the third with either a low or high dose of rFVIIa administered prior to biopsy. The treatment pair sequences were placebo/10, 10/20, 20/40, 40/80, 80/120, and 120/160 μg/kg. Blood samples were drawn 15 minutes pre-, 15 minutes post-, and 1 hour post-biopsy to monitor coagulation and conduct ex-vivo assessments of hemostasis [Hemodyne Hemostasis Analyzer (HHA)]. Safety evaluations were conducted by an Independent Safety Officer after each dose tier, and subjects were permitted to enroll in the next higher dose tier only if no significant safety issues were observed. In healthy subjects with no pre-existing coagulopathies, regression analyses indicated that increasing doses of rFVIIa did not have a dose-related linear effect on blood loss volume or duration of bleeding. However, it is of interest that with HHA, a statistically significant impact was noted on the time to 20 mm clot strength, platelet contractile force, and clot elastic modulus, suggesting that rFVIIa does have a measureable and perhaps meaningful effect in individuals with normal coagulation systems. No safety issues were detected during this study. Thus in this model system, designed to evaluate hemostasis, interesting effects were seen with the HHA instrument which suggest that increasing doses of rFVIIa may impact clot stability, but these observations are limited by the significant hetereogeneity which may benefit from improved experimental controls.

Use of Recombinant Activated Factor VII for Bleeding Following Operations Requiring Cardiopulmonary Bypass

Postoperative bleeding is a common complication following cardiothoracic surgical procedures requiring cardiopulmonary bypass (CPB). Serious bleeding complications requiring the administration of blood products, hemostatic drugs, and even repeat surgery are associated with considerable morbidity, mortality, and resource consumption. Therapy with recombinant activated factor VII (rFVIIa) may be an effective treatment strategy for patients with refractory bleeding. We report the successful use of rFVIIa for the treatment of intractable postoperative bleeding following aortic aneurysm repair in two patients with Marfan syndrome. In both patients, surgical reexploration was avoided, and the patients' clinical status was stabilized after the administration of rFVIIa. In one patient, hemostasis was rapidly achieved within minutes, whereas hemostasis occurred gradually over several hours in the second patient. Including our personal experience with the two cases, the use of rFVIIa has been reported in 20 patients who required CPB for cardiothoracic surgical procedures. Hemostasis was achieved in all patients. In 14 patients (70%), rapid hemostasis was achieved following a single dose of rFVIIa (mean dose, 57 microg/kg). In the remaining six patients, gradual hemostasis was achieved after a mean of 3.4 doses (mean cumulative dose, 225 microg/kg). Two patients (10%) were believed to have experienced thromboembolic complications after the administration of rFVIIa (one was fatal), and, in another patient, intracoronary thrombosis was suspected but was not confirmed. In patients experiencing postoperative bleeding complications that are refractory to treatment with blood products, hemostatic agents, and/or repeat surgery, the use of rFVIIa may be considered.

Recombinant Activated Factor VII (rFVIIa) Effectively Controls Bleeding in Gynecologic Surgery: A Report on Four Cases

Peri- and early postoperative bleeding is a common complication of gynecologic surgery. We report four postmenopausal patients (age range, 58–72 years) who each received recombinant activated factor VII (rFVIIa; dose range, 17–70 μg/kg) to control severe postoperative hemorrhage associated with elective hysterectomy for benign uterine fibroids, carcinoma of the endometrium, cervical and uterine cancer, or metastatic carcinoma of the genital tract. Bleeding resolved within 12 hours in three patients after a single dose of rFVIIa. In the patient with metastatic disease, bleeding was markedly reduced after each of two doses of rFVIIa and resolved completely within 12 hours of the second dose. Supplemental blood product requirements (measured by units of packed red blood cells and fresh frozen plasma) were reduced, and coagulation status (prothrombin time, activated partial thromboplastin time) was generally improved postadministration. No thromboembolic complications occurred. Our findings suggest that recombinant FVIIa may offer an effective means of controlling bleeding associated with gynecologic surgery when conventional surgical and pharmacologic measures are unsuccessful; however, further investigation of the use of rFVIIa in this indication, preferably in the form of large, randomized clinical trials, is clearly needed. (J GYNECOL SURG 21:13)