Low-dose Recombinant Factor VIIa Research Articles

Enhancing hemophilia A management: emicizumab as a cost-effective adjunct to standard therapy for inhibitor patients

This case report discusses the cost-effectiveness of emicizumab + low dose recombinant factor VIIa (rFVIIa) therapy in management of mild hemophilia A with inhibitors. Initial treatment with recombinant factor VIII was complicated by inhibitor development, leading to recurrent bleeding and hematoma formation. After administering full dose rFVIIa to patient for controlling bleeding episodes initially, patient was transitioned to emicizumab alongside low-dose recombinant factor VIIa, which proved efficacious and cost-effective. This case highlights the potential of emicizumab to alleviate the financial burden on patients and healthcare systems, improving treatment access and outcomes for a broader hemophilia patient population.

Comparison of Low Dose Recombinant Factor VIIa and 4-Factor Prothrombin Complex Concentrate for Treatment of Bleeding Related to Cardiac Surgery.

Background: Recombinant factor VIIa (rFVIIa) and prothrombin concentrate complex (PCC) are used for uncontrolled bleeding in cardiac surgery (CS), however, there are limited direct comparisons of these agents. Objective: To evaluate the efficacy and safety of rFVIIa and PCC in CS related bleeding. Methods: This retrospective study included adult CS patients who received either low dose rFVIIa (<30mcg/kg) or 4-factor PCC. The primary outcome was transfusion requirements of packed red blood cells (pRBC) within 6 hours of factor administration. Secondary efficacy outcomes included transfusion requirements 0-18hours, doses of additional factor product, thrombotic events, and acute kidney injury (AKI). Results: A total of 179 patients were included (n = 78 rFVIIa; n = 101 PCC). Of patients who received blood products, there was no difference in the requirement of pRBCs within 6 hours (73.8 vs 68.9%, P = .5359) or in the median amount of pRBC transfused (500mL vs 640mL, P = .0723) in the rFVIIa and PCC groups respectively. Patients in the PCC group were more likely to require additional factor products (24.4% vs 47.5%, P = .0015), develop AKI (12.8% vs 25.7%, P = .0325), have longer ICU lengths of stay [2 (IQR 1-5) vs 4 (IQR 2-6), P = .0487] and greater in-hospital mortality (2.6% vs 10.9%, P = .033). There was no difference in thrombotic events. Conclusion: Although, there was no difference in pRBC transfusion requirements between PCC and rFVIIa, more patients in the PCC group required additional factor products and had increased adverse effects. Further comparisons of PCC and rFVIIa are warranted.

Characteristics Associated With Mortality in 372 Patients Receiving Low-Dose Recombinant Factor VIIa (rFVIIa) for Cardiac Surgical Bleeding

Activated recombinant factor VII (rFVIIa) has been used to treat cardiac surgical bleeding in an off-label manner. This observational report analyzes the outcomes with use of a low dose and early administration of rFVIIa for cardiac surgical bleeding. A retrospective, observational study. Single-center, tertiary care cardiothoracic surgical setting. A total of 6,862 patients underwent cardiac surgery from January 2012 to January 2018. Of those, 372 patients received rFVIIa perioperatively. An institutional policy directed low-dose, incremental aliquots of intravenous rFVIIa (0.5-1 mg). Characteristics and outcomes were compared among patients who survived (n = 328) and patients who died (n = 44). The median dose of rFVIIa was low at 13.29 μg/kg. Higher doses were given to patients who died (15.79 μg/kg v 12.99 μg/kg; p = 0.0133). Patients who died received more blood and component transfusions (median 9 products in those who died v 6 products in survivors; p = 0.0022), although the median transfusion requirement for all patients was 6 units per patient. The rate of reoperation was not different in the 2 groups. Mortality was associated with emergent/urgent surgical procedures (p = 0.0282), type of surgical procedure with aortic procedures being highest risk (p = 0.0014), cardiogenic shock (p = 0.0028), postoperative renal failure (p = 0.0035), postoperative cardiac arrest (p = 0.0006), and ischemic stroke (p = 0.0084). Mortality after life-threatening cardiac surgical bleeding treated with rFVIIa was more common in aortic procedures and emergent and urgent surgeries. Lower doses of rFVIIa than previously reported may achieve bleeding cessation because overall blood component transfusions were low in this cohort.

Evaluation of Recombinant Factor VIIa Utilization and Development of a Cost-Effective Dose Minimization Protocol in Adult Cardiac Surgery Patients at an Academic Medical Center

Background: Although recombinant factor VIIa is often utilized to mitigate critical bleeding following cardiac surgery, the optimal dosing strategy in this population is not well-established. At our institution, hospital guidelines recommend administration of recombinant factor VIIa 60 mcg/kg for all off-label indications. However, available data suggest doses as low as 17 mcg/kg have been efficacious in cardiac surgery patients with critical bleeding. Additionally, although low-dose recombinant factor VIIa (< 40 mcg/kg) and high-dose (50-109 mcg/kg) dosing strategies have been reported equally efficacious according to retrospective, observational studies, higher doses may be associated with increased incidence of adverse events. Therefore, we aimed to evaluate the safety of recombinant factor VIIa in cardiac surgery patients with critical bleeding, and estimate potential cost-savings associated with implementation of a low-dose recombinant factor VIIa protocol in this population.Methods: All adult cardiac surgery patients who received one or more doses of recombinant factor VIIa during a 1-year period (July 1, 2016 to June 30, 2017) were included. Thromboembolic event rates documented within 14 days following recombinant factor VIIa administration were evaluated in patients alive at discharge. An average wholesale price of 2.59 USD per mcg was utilized for recombinant factor VIIa cost calculations.Results: A total of 16 patients received 24 doses of recombinant factor VIIa during the study period. The median weight-based dose administered was 55 mcg/kg (utilizing actual body weight), and the median dose was 5 mg. The median cost per recombinant factor VIIa dose was 12,950 USD, resulting in a total expenditure of 277,174 USD. Nine of sixteen patients (56%) survived to hospital discharge. Five of nine (56%) patients alive at discharge experienced thromboembolic complications following recombinant factor VIIa administration, three (60%) of which were central nervous system (CNS) thromboembolic events. Based on data supporting low-dose strategies, a proposed weight-based recombinant factor VIIa dose-minimization protocol was developed by leadership in the departments of pharmacy, hematology, cardiac surgery, and cardiac anesthesia (Table 1). Implementation of this protocol would result in an estimated annual cost-avoidance of 168,376 USD.Conclusions: Recombinant factor VIIa administration at a dose of 55 mcg/kg in adult cardiac surgery patients with critical bleeding is associated with a high rate of thromboembolic events, including CNS thromboembolism. Additionally, this recombinant factor VIIa dosing strategy is associated with significant cost, which can be substantially reduced with implementation of a low-dose recombinant factor VIIa protocol in the cardiac surgery population. DisclosuresNo relevant conflicts of interest to declare.

Use of low-dose recombinant factor VIIa in a pregnant patient with factor VII deficiency undergoing a minor surgery

Use of low-dose recombinant factor VIIa in a pregnant patient with factor VII deficiency undergoing a minor surgery

Low-dose recombinant factor VIIa for reversing coagulopathy in patients with isolated traumatic brain injury

PurposeThe purpose of this study was to investigate the role of low-dose recombinant factor VIIa (rFVIIa) (20 μg/kg) in reversing coagulopathy in patients with isolated traumatic brain injury (TBI). Materials and methodsPatients with isolated TBI and coagulopathy at admission were enrolled prospectively from January 2010 to December 2011. The patients were divided into 2 groups: the rFVIIa and the no-rFVIIa groups. In the rFVIIa group, patients received a single dose of 20 μg/kg rFVIIa intravenously to reverse their coagulopathy in addition to blood products. Patients in the no-rFVIIa group received only blood products to correct the coagulopathy. The clinical outcome variables evaluated included changes in coagulation parameters after administration for reversing coagulopathy, the occurrence of progressive hemorrhagic injury (PHI), intensive care unit length of stay, the incidence of thromboembolic complications, inhospital mortality, and 90-day Glasgow Outcome Scale. ResultsEighty-seven patients were ultimately included in this study. Of them, 49 patients were treated with blood products alone, whereas 38 patients also received rFVIIa to reverse their coagulopathy. The improvement in international normalized ratio was greater in the rFVIIa group (0.26 [0.18-0.39]) than in the no-rFVIIa group (0.06 [−0.11 to 0.30]) (P = .001). In addition, the improvement in lactate was also greater in the rFVIIa group (0.33 [−0.18 to 0.54]) than in the no-rFVIIa group (0.04 [−0.25 to 0.20]) (P = .029). During the period after we began to correct the coagulopathy, PHI occurred in 19 patients (38.8%) in the no-rFVIIa group, which was significantly higher than that in the rFVIIa group (7, 18.4%; P = .040). The rate of cerebral infarction was similar in both groups (10.2% vs 5.3%). There was a trend indicating that low-dose rFVIIa therapy was associated with a lower mortality, but the association was not statistically significant (P = .266). ConclusionsThe use of low-dose rFVIIa (20 μg/kg) is effective for correcting coagulopathy in patients with TBI without an increase in thromboembolic events. Moreover, it is more effective for preventing the occurrence of PHI.

Low-dose recombinant factor VIIa for massive bleeding: A single centre observational cohort study with 73 patients

recombinant activated factor VII (rFVIIa) is used off-label for massive bleeding. There is no convincing evidence of the benefits of this practice and the minimal effective dose is unknown. The aim of the study was to evaluate our in-house guideline recommending a low dose of 60 μg/kg for off-label use of rFVIIa. observational cohort study at the Inselspital Bern, a tertiary care University Hospital in Switzerland. All patients with massive bleeding treated off-label with rFVIIa between January 2005 and December 2007 were included. Survival, change of bleeding and transfusion rates, coagulation parameters and complications were analysed. seventy-three patients received rFVIIa. Severe haemorrhage was documented by a bleeding rate of 1000 mL/h (median; interquartile range 350-3000) and total volume replacement of 11.9 L (6.6-15.2) before administration of rFVIIa. The median rFVIIa-dose was 64 μg/kg (56-71). rFVIIa was administered once in 79% patients, twice in 18%. The bleeding rate was reduced in 82% of the patients. Transfused packed red blood cells decreased from 14 units (8-22) over 4.9 h (2.5-8.8) before rFVIIa to 2 (0-6) in 24 h thereafter, platelet concentrates from 2 units (1-3) to 1 (0-2) and FFP from 11 units (6-16) to 2 (0-9). In-hospital mortality was 14% within 24 h and 32% at day 30. There were two arterial thromboembolic complications possibly related to rFVIIa. a single injection of 60 μg/kg rFVIIa, a lower dose than usually recommended, appears to be efficacious in controlling massive bleeding with a very low complication rate.

The role of recombinant factor VIIa for obstetric block in women with severe factor XI deficiency

Regional blocks like spinal, epidural and combined spinal epidural (CSE) are relatively contraindicated in individuals with bleeding disorders. Consequently pregnant women with severe factor XI (FXI) deficiency are often denied this option during labour and caesarean section. We describe three women with severe FXI deficiency in whom regional block was performed with low-dose recombinant factor VIIa (rFVIIa) for their operative procedures during delivery. All women achieved haemostasis and had uncomplicated regional block, delivery and surgical procedures. The point of care device--rotational thromboelastometry (ROTEM) was used to monitor the patients' coagulation and determine the dose of rFVIIa to achieve in vitro haemostasis in these women that was then subsequently used in vivo. Low-dose rFVIIa seems to be effective and safe in the management of delivery and enables provision of regional blocks in women with severe FXI deficiency.

Monitoring low dose recombinant factor VIIa therapy in patients with severe factor XI deficiency undergoing surgery

Although factor XI (FXI) concentrate is an effective replacement therapy in severe FXI deficiency without inhibitors, some patients are unwilling to receive it because it is plasma-derived. We report on the use and monitoring of low dose, recombinant factor VIIa (rFVIIa, NovoSeven®), to cover surgery (caesarean section, cholecystectomy and abdominoplasty) in four female patients (FXI:C 2-4 IU/dl, aged 32-51 years) who wished to avoid exposure to plasma. None of our patients had inhibitors to FXI. Our aim was to find the optimal dose of rFVIIa by in vitro spiking of patient samples and to correlate this with the response to rFVIIa in vivo . Prior to surgery, venous blood was collected into sodium citrate with corn trypsin inhibitor and spiked with 0.25-1.0 μg/ml rFVIIa in vitro , equivalent to a 15-70 μg/kg dose of rFVIIa in vivo . Analysis using thromboelastometry and thrombin generation assays, triggered with tissue factor, showed that the thrombin generation assay was insufficiently sensitive to the haemostatic defect in these patients. A concentration of 0.5 μg/ml was as effective as 1.0 μg/ml FVIIa in normalising thromboelastometry in vitro in all four patients. Therefore, patients received 15-30 μg/kg rFVIIa at 2-4 hourly intervals with tranexamic acid 1g every six hours. Post treatment samples were taken at 10-240 minutes and showed initial normalisation of thromboelastometry with gradual return to baseline after 2-4 hours. In conclusion, low-dose rFVIIa therapy was successfully used in four patients with severe FXI deficiency undergoing surgery to prevent bleeding and can be monitored using thromboelastometry.

Tissue Factor in Brain Is Not Saturated With Factor VIIa

The recent commentary by Dr Torbey on “Intracerebral Hemorrhage: What’s Next?”1 has prompted us to share some data and thoughts on the use of activated factor VII (FVIIa, NovoSeven, Novo Nordisk A/S) in the management of intracerebral hemorrhage. FVIIa is approved to promote hemostasis in hemophiliacs with inhibitors. Studies have also suggested that it promotes hemostasis in nonhemophilic patients with bleeding attributable to trauma2 or with intracranial hemorrhage.3 The commercial FVIIa product is the activated form of the naturally occurring human protein. The precursor, FVII, is readily activated by a number of coagulation and noncoagulation proteases once it has bound to its cofactor, tissue factor (TF). FVIIa has little proteolytic activity in solution. Binding to a suitable phospholipid surface enhances its activity somewhat, but binding to TF greatly enhances proteolytic activity toward its substrates, FIX and FX. Plasma levels of FVIIa are normally around 100 pmol/L.4 Because of the very low activity exhibited by FVIIa in the absence of TF and the very high affinity of TF for FVII, it is thought that FVIIa only exhibits significant activity in vivo when complexed to TF. Exogenous FVIIa was originally thought to enhance hemostasis by increasing activation of FX by the TF pathway. However, very high levels of FVIIa are required to promote hemostasis in hemophilia: up to 1000× the normal …

Management of Warfarin Associated Intracranial Hemorrhage with a 3-Factor Prothrombin Complex Concentrate and Low Dose Recombinant Factor VIIa.

Background: Intracranial hemorrhage (ICH) is a serious complication of warfarin therapy. Plasma infusion is the current standard of care in the US, even though most guidelines recommend prothrombin complex concentrate (PCC) as the preferred therapy; PCC has several advantages over plasma including no ABO blood type requirement, no lengthy thawing and infusion process, and a very small volume of virally inactivated pure vitamin K-dependent factors (VKDF) content that causes neither volume overload nor TRALI. Ideal PCC should contain adequate amounts of all VKDF (4-factor). As our group reported at the 2006 ASH meeting, PCC currently available in the USA have a very low FVII content (hence called a 3-factor PCC), often resulting in an incomplete correction of supratherapeutic INR. PCC is, therefore, often supplemented with 1–2 units of plasma to provide FVII; however, many elderly patients on warfarin do not tolerate an additional fluid volume and there is an urgency to correct coagulopathy in ICH. Recombinant FVIIa (rFVIIa) has been used to reverse warfarin effect with variable success. An experimental model has shown that rFVIIa corrects PT/INR in vitro but fails to correct bleeding because it does not address FII and X deficiencies critical for thrombin generation in vivo when compared with PCC. Therefore, we developed a trauma coumadin protocol (TCP) for urgent warfarin reversal for ICH, which includes both PCC and a low dose rFVIIa.Methods: TCP was approved by the Blood Utilization Review Committee of the Parkland Memorial Hospital and consists of administration of 4000 IU PCC (Profilnine, Grifols) and 1.2 mg rFVIIa; 5 mg intravenous Vit K1 is also administered daily for 3 days. PCC contains FII no more than 150 units, FX no more than100 units, and FVII no more than 35 units for each 100 units of FIX. Pre- and post-TCP VKDF were measured when possible (Table 2). We compared 19 patients treated with TCP with a 12 patient-non-TCP control group (warfarin-ICH) treated either with plasma alone (n=3) or plasma plus PCC (n=9). We will also compare (software delay) the 2 groups for extension of hematoma volume; the radiologist will be blinded to the therapy.Results: The TCP group included 12 females and 7 males aged 46–87 years (median 64). The control group included 4 females and 8 males aged 53–89 years (median 73). TCP patients had significantly faster as well as complete correction of PT/INR as compared to the controls. (Table-1). Post-TCP CT scans showed stable hematomas. 1/19 TCP patients with pituitary adenoma had pre-TCP INR of 7.2 and post-TCP INR of 0.9. He developed thrombotic stroke and acute myocardial infarction 2 days later; he was discharged home. The patient received 2.4 mg of rFVIIa because initially the dose of rVIIa was stratified based on INR (1.2 mg for INR 5.0 or less and 2.4 mg for INR greater than 5.0). . Examination of post-treatment FVII levels (Table-2) led us to modify TCP rFVIIa dose to a 1.2 mg, irrespective of INR.Conclusion: TCP rapidly and effectively corrects warfarin-associated coagulopathy in patients with ICH. Because thrombotic complications remain a concern, 4-factor PCC should further be evaluated.Table 1.Test resultsTime relative to TCP treatmentTCP group n=19Control group n=12p valueINR Mean ± SD (range)Pre3.1±2.0 (1.4–5.1)3.2 ±1.6 (1.4–7.2)0.991Post1.1±0.3 (0.9–2.0)1.4 ±0.3 (0.9–2.0)0.003PT Mean ± SD (range)Pre28.1±17.3 (13.5–65.1)28.9±14.0 (13.7–62.6)0.887Post10.7±2.2 (9.3–18.1)13.8±2.8 (9.3–18.3)0.002PTT Mean ± SD (range)Pre36.0±10.3 (21.8–59.8)38.2 ±11.5 (25.4–60.6)0.591Post24.7±4.2 (19.5–32.2)27.8±4.5 (22.8–30.9)0.058Time from TCP to INR correction (min)Mean ± SD (range)145.4±107 (22–329)267±76 (83–697)0.023Median111240Table 2.Test resultsINRPTPTTFIIFVIIFIXFXPretreatment Mean ± SD (range)3.3±2.0 (1.5–7.4)29.6±17.3 (14.4.–65.1)35.7±9.9 (30.1–54.7)54±41 (6–117)23 ±12 (6–37)57 ±28 (17–96)44 ±30 (5–74)Posttreatment Mean ± SD (range)1.1±0.4 (0.9–2.0)11.0±3.0 (9.4–18.1)25.9±4.1 (19.5–32.2)148±84 (27–323)394±141 (114–600)97±22 (58–130)144±54 (89–268)

Patients with Severe Factor XI Deficiency Who Have An Inhibitor or IgA Deficiency Can Undergo Uneventful Major Surgery by a Single Infusion of Low Dose Recombinant Factor VIIa and Use of Tranexamic Acid.

Inhibitors to factor XI (FXI) can develop following exposure to plasma products in 33% of patients with severe FXI deficiency who are homozygous for the type II nonsense mutation prevalent in Jews (Salomon et al. Blood 2003; 101:4783). Hemostasis in five such patients was previously achieved during surgery by infusion of recombinant factor VIIa (rFVIIa) and tranexamic acid, but two patients experienced arterial thrombosis following surgery (Schulman et al. Hemophilia 2006; 12:223). Conceivably, the rather high dose of rFVIIa used was responsible for the thrombotic events in these patients. In a previous in vitro study, we showed that low concentrations of rFVIIa can correct thrombin generation in plasma of patients with severe FXI deficiency and an inhibitor to FXI (Livnat et al. J Thromb Hemost 2006; 4:192). In the present study we addressed the question whether low doses of rFVIIa and use of tranexamic would be hemostatically effective and less thrombogenic during and after major surgery in patients with severe FXI deficiency in whom plasma derivatives could not be used. Three patients (two with FXI inhibitor and one with severe IgA deficiency) underwent major surgery managed by a single low dose infusion of rFVIIa and administration of tranexamic acid 1 G q.i.d for 7 days (Table). In patient 1 the infusion was given immediately prior to surgery and in patients 2 and 3 at the end of surgery. Hemostasis was achieved in all patients and no thrombosis occurred.No.Sex/ageFXI (U/dL)FXI inhibitor (B.U)OperationSingle dose rVIIa (uG/Kg)Adverse events1M/62< 0.015.0Laparoscopic cholecystectomy30None2M/61< 0.015.0Transuretheral prostatectomy16None3M/630.020*Parathyroidectomy15None* IgA deficiencyThese observations suggest that a single infusion of low dose rFVIIa and use of tranexamic acid can be a safe modality of treatment in patients with severe FXI deficiency who cannot receive blood products. Furthermore, the protocol outlined here may be used to avoid inhibitor formation in patients with extremely severe FXI deficiency who undergo surgery.

Low-Dose Recombinant Factor VIIa in the Management of Uncontrolled Postoperative Hemorrhage in Cardiac Surgery Patients

Low-Dose Recombinant Factor VIIa in the Management of Uncontrolled Postoperative Hemorrhage in Cardiac Surgery Patients

Rapid correction of prothrombin time after low-dose recombinant factor VIIA in patients undergoing orthotopic liver transplantation

Orthotopic liver transplantation (OLTx) is associated with a major risk of blood loss resulting from portal hypertension, collateral circulation, and clotting disturbances. Application of a recombinant factor VIIa (rFVIIa) has been reported to promptly correct clotting abnormalities reducing the risk of intraoperative bleeding. This study included 8 patients who underwent OLTx for end-stage liver cirrhosis, with protrombin times (PT) exceeding the upper limit of normal by more than 4 seconds before surgery. All subjects were administered a small single intravenous dose of rFVIIa [mean 68.37 μg/kg body mass (range, 32.88–71.64)] 10 minutes prior to the skin incision. The PT was then measured 15 minutes later, following graft reperfusion, and 12 hours since drug application. All patients showed rapid correction of PT within 15 minutes after injection (median PT before injection 20.25 seconds vs 11.5 seconds after injection, P < .0001). Following the reperfusion PT was found to be prolonged again. These values are not significantly differ from those before surgery and are comparable to PT values after reperfusion in patients who did not receive rFVIIa. None of the patients developed thromboembolic complications. In conclusion, lower than recommended dose of rFVIIa caused rapid improvement in the PT shortly after injection. After reperfusion PT became prolonged again, which may account for the lack of thromboembolic complications observed in this group of patients.