Recombinant factor VIIa use in patients with the rarest forms of inherited coagulation-factor deficiencies: a study of cases from the www.haemostasis.com registry

Abstract The persistence of abnormal coagulation test results and bleeding after standard treatment in the setting of disseminated intravascular coagulation (DIC) can pose a significant challenge. Recombinant Factor VIIa (Novo Nordisk) has been used in the pediatric population for treatment of hemophilia patients with inhibitors and in various other instances as a single agent to manage coagulopathy. (1) The use of NovoSeven and FEIBA (Baxter Hyland Immune) has been reported in use of adult patients with factor deficiencies and coagulation factor inhibitors. (2) The synergistic use of NovoSeven and FEIBA to improve clinical bleeding caused by DIC in a pediatric patient is being described. A 15 year old African American male presented with a 2 month history of leg pain and a WBC of 400K. He was diagnosed with Philadelphia chromosome positive CML and treated with Allopurinol and Imatinib. After 7 months on Imatinib, he presented in septic shock. His WBC increased to 50.8K with 44% myeloblasts. Flow cytometry confirmed myeloid blast crisis. The patient was admitted to the PICU on broad spectrum antibiotics. Within 12 hours of admission, he required ventilatory assistance. Central lines were placed in the right subclavian vein, right femoral vein and left radial artery. He began bleeding from his nostrils, endotracheal tube and all of his central line sites. Mitoxantrone and Cytarabine were started. Patient was noted to have DIC with PT> 20 sec, APTT> 40 sec, platelets of 23K and D-Dimers of 11.86 (normal <0.42 mcg/ml). His Fibrinogen level was maintained above 300mg/dl during the first 8 days of admission. By hospital day 2, the patient received numerous units of FFP, platelets and PRBC, but he continued to bleed. NovoSeven was started due to volume concerns and increased bleeding. He had improvement in his coagulation tests but no improvement in his bleeding. On hospital day 3, NovoSeven was given intravenously alternating with FEIBA. The patient received NovoSeven 100 micrograms/kg IV q 12 hours. About 6 hours from the NovoSeven dose, FEIBA was given on a q 12 hour schedule at 50 units/kg IV. Significant improvement was seen with the coagulation profile immediately and the bleeding improved in 6 hours. The patient was discharged from the PICU 15 days from his admission with no clinical adverse events associated with the administration of the NovoSeven and FEIBA. He has subsequently tolerated a haploidentical transplant from his sister and he remains in continuous remission. Nigel Key and colleagues have described improved clinical clotting response with prothrombin complex concentrate (PCC) and NovoSeven. They hypothesized that the coagulation proteins in PCC have a longer half life impacting on the effectiveness of NovoSeven. (2) The use of FEIBA and NovoSeven is risky without a widely available clinical assay to assess responsiveness to NovoSeven. This anecdotal report suggests that FEIBA and NovoSeven can be given sequentially without adverse thrombotic events. Further study in monitoring NovoSeven and using sequential agents may be helpful in patients who prove unresponsive to NovoSeven alone.

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Continuous Infusion of Coagulation Factor Products

Annals of Pharmacotherapy ◽

10.1345/aph.1a338 ◽

2002 ◽

Vol 36 (5) ◽

pp. 882-891 ◽

Cited By ~ 20

Author(s):

Joan M Stachnik ◽

Michael P Gabay

Keyword(s):

Factor Viii ◽

Continuous Infusion ◽

Recombinant Factor Viia ◽

Factor Viia ◽

Case Reports ◽

Coagulation Factor ◽

Data Sources ◽

Pharmacokinetic Data ◽

Open Label ◽

Intermittent Bolus

OBJECTIVE: To review clinical information related to the use of continuous infusion factor products in patients with hemophilia. Specifically, case reports and open-label trials are summarized involving the use of factor VIII and recombinant factor VIIa for a variety of indications including surgical prophylaxis, acute bleeding, primary prevention, and management of inhibitors. In addition, issues surrounding the use of continuous infusion of factor products such as pharmacokinetic rationale, stability/sterility, and cost are reviewed. DATA SOURCES: Primary and review articles were identified through a MEDLINE search (1990–June 2001) and through secondary sources. STUDY SELECTION AND DATA EXTRACTION: All articles identified from the data sources were evaluated, and all information deemed relevant was included in this review. DATA SYNTHESIS: Data concerning the administration of factor products are primarily detailed in open-label trials and case reports. Comparisons between intermittent bolus injections and continuous infusion of factor products are limited and primarily compare continuous infusion regimens with historical controls. The rationale behind the continuous-infusion approach is linked to the pharmacokinetics of factor products administered via this route. Pharmacokinetic data reveal that, with continuous infusion of factor products, a reduction in clearance and a maintenance of factor serum concentrations are noted. CONCLUSIONS: Administration of factor products (factor VIII and recombinant factor VIIa) via continuous infusion has produced favorable hemostatic effects compared with intermittent bolus injections. The advantages of continuous infusion include maintenance of a constant factor concentration, thereby reducing risk of bleeding from excessively low trough concentrations, and a decrease in factor consumption related to a reduction in factor clearance with constant infusion. Manufacturers recommend using reconstituted factor products either immediately or within 1–3 hours after reconstitution; however, several studies have found the products to be stable and sterile for longer periods.

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Peri-interventional control of haemostasis in a patient with combined coagulation factor V- and factor VIII-deficiency and anaphylaxis to fresh frozen plasma - a rare indication for recombinant factor VIIa

Haemophilia ◽

10.1111/j.1365-2516.2010.02240.x ◽

2010 ◽

Author(s):

D. LECHNER ◽

S. EICHINGER ◽

A. WANIVENHAUS ◽

P. A. KYRLE

Keyword(s):

Factor Viii ◽

Recombinant Factor Viia ◽

Factor Viia ◽

Coagulation Factor ◽

Fresh Frozen Plasma ◽

Factor V ◽

Factor Viii Deficiency ◽

Fresh Frozen ◽

Coagulation Factor V ◽

Frozen Plasma

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Use of recombinant factor VIIa in the perioperative period

Hämostaseologie ◽

10.1055/s-0037-1616943 ◽

2009 ◽

Vol 29 (01) ◽

pp. 68-70 ◽

Cited By ~ 3

Author(s):

M. Levi

Keyword(s):

Blood Loss ◽

Recombinant Factor Viia ◽

Factor Viia ◽

Coagulation Factor ◽

Perioperative Period ◽

Factor Vii ◽

Clinical Settings ◽

Recombinant Activated Factor Vii ◽

Activated Factor Vii ◽

Life Threatening

SummaryRecombinant activated factor VII (rFVIIa) is a pro-haemo -static agent that can be used for patients with haemophilia and inhibiting antibodies towards a coagulation factor. Recombinant factor VIIa is, however, increasingly used for several other indications, including patients who experience serious and life-threatening bleeding. In addition, rFVIIa has been evaluated for the prevention of major blood loss in patients undergoing surgical procedures that are known to be associated with major blood loss. In this manuscript we review the data on efficacy and safety of rFVIIa in the prevention of excessive blood loss and trans-fusion requirements in the perioperative period.We conclude that recombinant factor VIIa is a promising agent for perioperative prevention of major blood loss but that its efficacy will probably vary between specific clinical settings. Its exact place in surgery warrants further clinical trials in various situations that will also more precisely determine the safety of this intervention.

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Engineering of a membrane-triggered activity switch in coagulation factor VIIa

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1618713114 ◽

2017 ◽

Vol 114 (47) ◽

pp. 12454-12459 ◽

Cited By ~ 4

Author(s):

Anders L. Nielsen ◽

Anders B. Sorensen ◽

Heidi L. Holmberg ◽

Prafull S. Gandhi ◽

Johan Karlsson ◽

...

Keyword(s):

Recombinant Factor Viia ◽

Factor Viia ◽

Membrane Surface ◽

Coagulation Factor ◽

Wild Type ◽

Physiological Conditions ◽

Bleeding Episodes ◽

Increased Activity ◽

Magnitude Increase ◽

Covalent Complex

Recombinant factor VIIa (FVIIa) variants with increased activity offer the promise to improve the treatment of bleeding episodes in patients with inhibitor-complicated hemophilia. Here, an approach was adopted to enhance the activity of FVIIa by selectively optimizing substrate turnover at the membrane surface. Under physiological conditions, endogenous FVIIa engages its cell-localized cofactor tissue factor (TF), which stimulates activity through membrane-dependent substrate recognition and allosteric effects. To exploit these properties of TF, a covalent complex between FVIIa and the soluble ectodomain of TF (sTF) was engineered by introduction of a nonperturbing cystine bridge (FVIIa Q64C-sTF G109C) in the interface. Upon coexpression, FVIIa Q64C and sTF G109C spontaneously assembled into a covalent complex with functional properties similar to the noncovalent wild-type complex. Additional introduction of a FVIIa-M306D mutation to uncouple the sTF-mediated allosteric stimulation of FVIIa provided a final complex with FVIIa-like activity in solution, while exhibiting a two to three orders-of-magnitude increase in activity relative to FVIIa upon exposure to a procoagulant membrane. In a mouse model of hemophilia A, the complex normalized hemostasis upon vascular injury at a dose of 0.3 nmol/kg compared with 300 nmol/kg for FVIIa.

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Current Concepts of Hemostasis

Anesthesiology ◽

10.1097/00000542-200403000-00036 ◽

2004 ◽

Vol 100 (3) ◽

pp. 722-730 ◽

Cited By ~ 80

Author(s):

Harold R. Roberts ◽

Dougald M. Monroe ◽

Miguel A. Escobar ◽

Richard B. Weiskopf

Keyword(s):

Replacement Therapy ◽

Conventional Therapy ◽

Perioperative Management ◽

Recombinant Factor Viia ◽

Factor Viia ◽

Coagulation Factor ◽

Clotting Factor ◽

Excessive Bleeding ◽

Off Label ◽

Clotting Factor Concentrates

The revised model of coagulation has implications for therapy of both hemorrhagic and thrombotic disorders. Of particular interest to anesthesiologists is the management of clotting abnormalities before, during, and after surgery. Most hereditary and acquired coagulation factor deficiencies can be managed by specific replacement therapy using clotting factor concentrates. Specific guidelines have also been developed for perioperative management of patients using anticoagulant agents that inhibit platelet or coagulation factor functions. Finally, recombinant factor VIIa has been used off-label as a hemostatic agent in some surgical situations associated with excessive bleeding that is not responsive to conventional therapy.

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Recombinant Coagulation Factor VIIa in Major Liver Resection

Anesthesiology ◽

10.1097/00000542-200502000-00006 ◽

2005 ◽

Vol 102 (2) ◽

pp. 269-275 ◽

Cited By ~ 156

Author(s):

J Peter A. Lodge ◽

Sven Jonas ◽

Elie Oussoultzoglou ◽

Massimo Malagó ◽

Christian Jayr ◽

...

Keyword(s):

Blood Loss ◽

Partial Hepatectomy ◽

Recombinant Factor Viia ◽

Factor Viia ◽

Surgical Techniques ◽

Coagulation Factor ◽

Red Blood Cell Transfusion ◽

Double Blind ◽

Safety Issues ◽

Number Of Patients

Background Prevention of bleeding episodes in noncirrhotic patients undergoing partial hepatectomy remains unsatisfactory in spite of improved surgical techniques. The authors conducted a randomized, placebo-controlled, double-blind trial to evaluate the hemostatic effect and safety of recombinant factor VIIa (rFVIIa) in major partial hepatectomy. Methods Two hundred four noncirrhotic patients were equally randomized to receive either 20 or 80 microg/kg rFVIIa or placebo. Partial hepatectomy was performed according to local practice at the participating centers. Patients were monitored for 7 days after surgery. Key efficacy parameters were perioperative erythrocyte requirements (using hematocrit as the transfusion trigger) and blood loss. Safety assessments included monitoring of coagulation-related parameters and Doppler examination of hepatic vessels and lower extremities. Results The proportion of patients who required perioperative red blood cell transfusion (the primary endpoint) was 37% (23 of 63) in the placebo group, 41% (26 of 63) in the 20-microg/kg group, and 25% (15 of 59) in the 80-microg/kg dose group (logistic regression model; P = 0.09). Mean erythrocyte requirements for patients receiving erythrocytes were 1,024 ml with placebo, 1,354 ml with 20 microg/kg rFVIIa, and 1,036 ml with 80 microg/kg rFVIIa (P = 0.78). Mean intraoperative blood loss was 1,422 ml with placebo, 1,372 ml with 20 microg/kg rFVIIa, and 1,073 ml with 80 microg/kg rFVIIa (P = 0.07). The reduction in hematocrit during surgery was smallest in the 80-microg/kg group, with a significant overall effect of treatment (P = 0.04). Conclusions Recombinant factor VIIa dosing did not result in a statistically significant reduction in either the number of patients transfused or the volume of blood products administered. No safety issues were identified.

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