eMedicine Specialties > Hematology > Coagulation, Hemostasis, and Disorders

Factor VII: Treatment & Medication

Author: Jeyanthi Ramanarayanan, MD, Attending Physician, Department of Medicine, Division of Hematology and Medical Oncology, Stratton Veterans Affairs Medical Center
Coauthor(s): Ganapathy S Krishnan, MBBS, Fellow, Department of Hematology and Oncology, Michigan State University; Francisco J Hernandez-Ilizaliturri, MD, Assistant Professor, Departments of Medicine and Immunology, Roswell Park Cancer Institute, State University of New York at Buffalo
Contributor Information and Disclosures

Updated: Feb 14, 2008

Treatment

Medical Care

Replacement therapy for persons with factor VII deficiency depends on the site and severity of bleeding and the baseline factor VII activity.

  • Long-term prophylaxis with 10-50 U/kg 1-3 times per week has been successful in children with severe factor VII deficiency. Mild bleeding associated with bruising and skin lacerations may not require any replacement and can be controlled by applying local pressure at the bleeding site. Minimal mucosal bleeding episodes, such as occurs with epistaxis and during dental procedures, can be managed with antifibrinolytic agents or fibrin glue.
  • For spontaneous hemorrhage or mild trauma, therapeutic factor VII levels of 5-10% are sufficient to stop bleeding. This level may be achieved by administering plasma at a dose of 5-10 mL/kg of body weight and repeating the dose every 8-12 hours for 1-2 days.
  • For major hemorrhage or surgery, plasma may be administered in a loading dose of 15-20 mL/kg and followed by 3-6 mL/kg every 8-12 hours until the surgical wound heals. This may require 5-7 days of treatment. Plasma infusion may be associated with disadvantages such as volume overload, infectious complications, or an inability to achieve high levels of factor VII. Highly purified factor VII concentrates are useful in patients with severe bleeding or as prophylaxis for surgery. Unlike factor VIII and factor IX deficiencies, for which levels of 100% are required before surgery, factor VII deficiency requires levels in the range of 10-15% to produce efficient hemostasis. For major surgery, trough levels of factor VII must not fall to less than 20 U/dL.
  • Prothrombin complex concentrates are also a source of factor VII but carry the risk of infectious complications and thrombosis. When prothrombin concentrates are used, doses of 50 U/kg every 8 hours for 24 hours, followed by plasma infusions, have been shown to be effective for major orthopedic surgery.
  • Recombinant factor VIIa (rFVIIa) has proven effective in clinical trials as a treatment for bleeding in hemophilia A patients with inhibitors and in limited numbers of factor VII–deficient patients. rFVIIa is produced by recombinant technology and thus does not carry the risk of infectious complications.
    • rFVIIa may be the treatment of choice for previously untreated patients with factor VII deficiency but is currently an expensive treatment. An online registry, the Seven Treatment Evaluation Registry (STER) has been set up, which helps in prospective study to evaluate the efficacy and safety of various therapies with which FVII-deficient patients may be treated.17
    • rFVIIa has been effective in the treatment of blood loss associated with various conditions, but reports from larger studies are not yet available to confirm these findings.18
    • rFVIIa is reportedly effective in controlling intracranial bleeding when administered within 3-4 hours of onset (from phase II studies, class IIb, level of evidence B), this is being confirmed in larger studies.19

Surgical Care

Prophylactic administration of factor VII concentrates or plasma may help minimize bleeding during surgery. For surgery, factor VII concentrates have been used in doses ranging from 8-40 U/kg every 4-6 hours.

  • Fibrin glue or fibrin tissue adhesives have been used as adjunctive therapy to achieve hemostasis. Fibrin glue contains fibrinogen, thrombin, and factor XIII.
  • Antifibrinolytic agents such as epsilon-aminocaproic acid and tranexamic acid have been used to enhance hemostasis during dental procedures as an adjunct to replacement therapy.

Consultations

Obtain consultations with orthopedists, physical therapists, general surgeons, dental surgeons, and genetic counselors as needed.

Diet

Instruct patients to maintain a regular, healthy diet without restrictions.

Activity

Recommend that patients limit activity of the involved joints or muscles during acute bleeding episodes. Early physical therapy is recommended once bleeding is resolved to prevent contractures or deformity.

Medication

Recombinant factor VIIa

rFVIIa is licensed by the US Food and Drug Administration for the treatment of bleeding in individuals with hemophilia A and B with acquired inhibitors and for persons with congenital factor VII deficiency. rFVIIa is produced in vitro in baby hamster kidney cells that are transfected with F7.

Although originally developed for the treatment of inhibitor-complicated hemophilia A and B, novel indications for rFVIIa (based on case reports and smaller clinical trials) include use in patients with liver disease, thrombocytopenia, or qualitative platelet dysfunction and in patients with no coagulation disorders who are bleeding as a result of extensive surgery or major trauma.5,20,13,21,22

Antihemophilic agents, drug-product derivatives

The mechanism by which factor VIIa maintains normal hemostasis is unknown. Clot-promoting activity of rFVIIa is primarily mediated through the tissue factor pathway, although direct activation of primary hemostasis may also occur.

Tissue factor-dependent and tissue factor-independent enhancement of thrombin generation have been suggested to play a role.23,21 Factor VIIa alone, in the absence of tissue factor, can generate factor IXa and factor Xa on the surface of activated platelets, which, in turn, induces the coagulation cascade to form thrombin.24

Mechanism of action of rFVIIa in patients with Glanzmann thrombasthenia and Bernard-Soulier syndrome is thought to be from thrombin generation on the surface of platelets, resulting in faster platelet activation and aggregation.5

In a recent study that evaluated rFVIIa in patients with acute intracerebral hemorrhage, the mortality was relatively reduced by 38% at 3 months when rFVIIa was administered within 4 hours of the hemorrhage. Accelerated thrombin generation from activated platelets at the sites of ruptured arterioles after administration of rFVIIa provides hemostatic effect and improved the outcome of these patients.25

By similar mechanisms, rFVIIa is also effective at controlling refractory bleeding in trauma patients.26 Gastrointestinal bleeding in patients with cirrhosis has responded positively to rFVIIa.


Coagulation factor VIIa, recombinant (NovoSeven)

Supplied in 1.2- and 4.8-mg vials. Half-life of rFVIIa is 2-3 h. Cleared from plasma more rapidly in children than in adults.

Adult

35-120 mcg/kg IV bolus q3-6h; dose adjustments made depending on severity of bleeding; in hemophilia A or B with inhibitors, 90 mcg/kg IV bolus q2h
Administration of rFVIIa as a single 270 mcg/kg dose to treat hemarthroses in patients with hemophilia and inhibitors was at least as efficacious and safe as the 90 mcg/kg x 3 regimen, in a multicenter study (Kavakli, 2006)
Bleeding in patients with factor VII deficiency has responded to lower doses (15-20 mcg/kg IV q2-3h) (Roberts, 2004)
The megadose (300 mcg/kg) of rFVIIa in persons with hemophilia is thought to result in higher peaks of thrombin generation and to be effective; this off-label use is not FDA approved

Pediatric

Not established

Documented hypersensitivity to mouse, hamster, or bovine proteins; DIC; advanced atherosclerotic disease; septicemia; crush injury

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Administer only under direct supervision of physician specialized in management of bleeding disorders; extent of thrombotic events unknown (considered to be low); patients should be monitored for signs and symptoms of activation of coagulation system or thrombosis; if intravascular coagulation or thrombosis confirmed, reduce dosage or cease administration; caution in prolonged administration (limited studies available on posthemostatic dosing); counsel patients on early signs of hypersensitivity reactions; assays of PT, aPTT, and factor VII clotting activity (FVII:c) may yield different results with different reagents (monitor patients for bleeding); avoid simultaneous use of activated prothrombin complex concentrates

Blood products

These agents are indicated for the correction of abnormal hemostatic parameters.


Fresh frozen plasma

FFP is used to correct coagulation factor deficiency when hemostasis is urgently required. FFP is separated within 8 h of whole blood collection and frozen at -18°C. Each unit of FFP contains 200 U of each coagulation factor. Volume transfused should correct factor VII level to at least 30% of normal levels.

Adult

Initial: 15-20 mL/kg IV
Maintenance: 5 mL/kg IV q6-24h

Pediatric

Administer as in adults

Pregnancy

A - Fetal risk not revealed in controlled studies in humans

Precautions

Carries risk of transmitting viral infections; allergic or anaphylactic reactions occur infrequently; volume overload may occur in patients with poor cardiac reserve


Factor IX complex (Proplex, BeneFix, Hemodyne)

Contains factor VII 68-91 U/mL. Viral inactivation with dry heat (60°C [140°F] for 144 h). Prothrombin complex concentrates contain variable amounts of factors II, VII, IX, and X.

Adult

50 U/kg IV q8h for 24 h, followed by plasma infusion or maintenance prothrombin complex concentrates at 10-20 U/kg IV q6-24h

Pediatric

Administer as in adults

Simultaneous administration with rFVIIa may cause thrombotic complications; risk of thrombosis may increase when used in combination with antifibrinolytic agents

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Earlier preparations of PCCs were themselves associated with a risk of thromboembolic events; more recent preparations have largely eliminated this complication; may induce an anamnestic response

Antifibrinolytic agents

These agents increase circulating plasmin levels and decrease plasminogen levels.


Aminocaproic acid (Amicar)

Inhibits fibrinolysis via inhibition of plasminogen activator substances and, to a lesser degree, through antiplasmin activity. Main problem is that the thrombi that form during treatment are not lysed and effectiveness is uncertain.

Adult

5 g PO initially, followed by 1 g/h PO for 8 doses or until active bleeding controlled, then taper; alternatively, 5 g IV over 30 min to 1 h initially, followed by 1 g/h IV; 1 g q1h or equivalent dose q2-4h PO/IV or 0.1 g/kg q4-6h IV maintenance; not to exceed 30 g/d

Pediatric

100-200 mg/kg IV over 30 min initially, followed by 30 mg/kg IV q1h or 100 mg/kg q6h maintenance; not to exceed 18 g/m2

Coadministration with estrogens may result in hypercoagulable state

Documented hypersensitivity; evidence of active intravascular clotting process

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Do not administer unless a definite diagnosis of hyperfibrinolysis has been made; caution in cardiac, hepatic, or renal disease; because aminocaproic acid can be fatal in patients with DIC, important to differentiate between hyperfibrinolysis and DIC; thrombi that forms during treatment are not lysed and effectiveness is uncertain

More on Factor VII

Overview: Factor VII
Differential Diagnoses & Workup: Factor VII
Treatment & Medication: Factor VII
Follow-up: Factor VII
Multimedia: Factor VII
References

References

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  9. Meade TW, Ruddock V, Stirling Y, et al. Fibrinolytic activity, clotting factors, and long-term incidence ofischaemic heart disease in the Northwick Park Heart Study. Lancet. Oct 30 1993;342(8879):1076-9. [Medline].

  10. Moor E, Silveira A, van't Hooft F, et al. Coagulation factor VII mass and activity in young men with myocardial infarction at a young age: role of plasma lipoproteins and factor VII genotype. Arterioscler Thromb Vasc Biol. 15(5):655-664.

  11. Rodgers GM, Greenberg CS. Inherited coagulation disorders. In: Lee GR, Foerster J, Lukens J, Paraskevas F, Greer JP, Rodgers GM, eds. Wintrobe's Clinical Hematology. Vol 2. 10th ed. Baltimore, Md: Williams & Wilkins; 1999:1682-732.

  12. Heywood DM, Carter AM, Catto AJ, et al. Polymorphisms of the factor VII gene and circulating FVII:C levels in relation to acute cerebrovascular disease and poststroke mortality. Stroke. Apr 1997;28(4):816-21. [Medline].

  13. Friederich PW, Henny CP, Messelink EJ, et al. Effect of recombinant activated factor VII on perioperative blood loss in patients undergoing retropubic prostatectomy: a double-blind placebo-controlled randomised trial. Lancet. Jan 18 2003;361(9353):201-5. [Medline].

  14. Seligsohn U, White GC. Inherited deficiencies of coagulation factors II, V, VII, XI and XIII and the combined deficiencies of factors V and VII and of the vitamin K-dependent factors. In: Beutler E, Lichtman MA, Coller BS, Kipps TJ, Seligsohn U, eds. William's Hematology. 6th ed. New York, NY: McGraw-Hill; 2001:1617-38.

  15. Giansily-Blaizot M, Schved JF. Potential predictors of bleeding risk in inherited factorVII deficiency. Clinical, biological and molecular criteria. Thrombosis and Hemostasis. 2005;94:899-900.

  16. Mariani G, Herrmann FH, Dolce A, et al. Clinical phenotypes and factor VII genotype in congenital factor VII deficiency. Thromb Haemost. Mar 2005;93(3):481-7. [Medline].

  17. Mariani G, Lapecorella M, Dolce A. Steps towards an effective treatment strategy in congenital factor VII deficiency. Seminars in Hematology. 2006;43:42-47.

  18. Mannucci PM and Levi M. Prevention and treatment of major blood loss. NEJM. MAY/2007;356:2301-2311. [Medline].

  19. Broderick J, Connolly S, Feldmann E, Hanley D, Kase C, Krieger D, et al. Guidelines for the Management of Spontaneous Intracerebral Hemorrhage in Adults. Stroke 2001-23. JUNE/2007;38:2001-2023. [Medline].

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  21. Lisman T, Moschatsis S, Adelmeijer J, et al. Recombinant factor VIIa enhances deposition of platelets with congenital or acquired alpha IIb beta 3 deficiency to endothelial cell matrix and collagen under conditions of flow via tissue factor-independent thrombin generation. Blood. Mar 1 2003;101(5):1864-70. [Medline].

  22. Ludlam CA, Smith MP, Morfini M, et al. A prospective study of recombinant activated factor VII administered by continuous infusion to inhibitor patients undergoing elective major orthopaedic surgery: a pharmacokinetic and efficacy evaluation. Br J Haematol. Mar 2003;120(5):808-13. [Medline].

  23. Butenas S, Brummel KE, Branda RF, et al. Mechanism of factor VIIa-dependent coagulation in hemophilia blood. Blood. Feb 1 2002;99(3):923-30. [Medline].

  24. Monroe DM, Hoffman M, Oliver JA, Roberts HR. A possible mechanism of action of activated factor VII independent of tissue factor. Blood Coagul Fibrinolysis. Mar 1998;9 Suppl 1:S15-20. [Medline].

  25. [Best Evidence] Mayer SA, Brun NC, Begtrup K, et al. Recombinant activated factor VII for acute intracerebral hemorrhage. N Engl J Med. Feb 24 2005;352(8):777-85. [Medline].

  26. Barletta JF, Ahrens CL, Tyburski JG, Wilson RF. A review of recombinant factor VII for refractory bleeding in nonhemophilic trauma patients. J Trauma. Mar 2005;58(3):646-51. [Medline].

  27. Bidot CJ, Jy W, Horstman LL, et al. Factor VII/VIIa: a new antigen in the anti-phospholipid antibody syndrome. Br J Haematol. Feb 2003;120(4):618-26. [Medline].

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  29. Deveras RA, Kessler CM. Reversal of warfarin-induced excessive anticoagulation with recombinanthuman factor VIIa concentrate. Ann Intern Med. Dec 3 2002;137(11):884-8. [Medline].

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  31. Iacoviello L, Di Castelnuovo A, De Knijff P, et al. Polymorphisms in the coagulation factor VII gene and the risk of myocardial infarction. N Engl J Med. Jan 8 1998;338(2):79-85. [Medline].

  32. Kavakli K, Makris M, Zulfikar B. Home treatment of haemarthroses using a single dose regimen of recombinant activated factor VII in patients with haemophilia and inhibitors. A multi-centre, randomised, double-blind, cross-over trial. Thrombosis and hemostasis. 2006;95:600-605.

  33. Mariani G, Herrmann FH, Bernardi F, et al. Clinical manifestations, management, and molecular genetics in congenitalfactor VII deficiency: the International Registry on Congenital Factor VII Deficiency (IRF7). Blood. Jul 1 2000;96(1):374. [Medline].

  34. Roberts HR, Monroe DM, White GC. The use of recombinant factor VIIa in the treatment of bleeding disorders. Blood. Dec 15 2004;104(13):3858-64. [Medline].

Further Reading

Keywords

FVII, F7 gene, proconvertin, stable factor, serum prothrombin conversion accelerator, SPCA, autoprothrombin I, recombinant factor VIIa, rFVIIa, NovoSeven, coagulation, procoagulants, coagulation cascade, anticoagulant factors, Dubin-Johnson syndrome, Rotor syndrome, prothrombin conversion accelerator deficiency, coagulation disorder, blood disorder blood disease, hemophilia A, hemophilia, hemophilia B

Contributor Information and Disclosures

Author

Jeyanthi Ramanarayanan, MD, Attending Physician, Department of Medicine, Division of Hematology and Medical Oncology, Stratton Veterans Affairs Medical Center
Jeyanthi Ramanarayanan, MD is a member of the following medical societies: American Association of Physicians of Indian Origin, American Society of Clinical Oncology, and American Society of Hematology
Disclosure: Nothing to disclose.

Coauthor(s)

Ganapathy S Krishnan, MBBS, Fellow, Department of Hematology and Oncology, Michigan State University
Disclosure: Nothing to disclose.

Francisco J Hernandez-Ilizaliturri, MD, Assistant Professor, Departments of Medicine and Immunology, Roswell Park Cancer Institute, State University of New York at Buffalo
Francisco J Hernandez-Ilizaliturri, MD is a member of the following medical societies: American Association for Cancer Research, American Society of Clinical Oncology, and American Society of Hematology
Disclosure: Nothing to disclose.

Medical Editor

Paul Schick, MD, Emeritus Professor, Department of Internal Medicine, Thomas Jefferson University Medical College; Research Professor, Department of Internal Medicine, Drexel University College of Medicine
Paul Schick, MD is a member of the following medical societies: American College of Physicians, American Heart Association, American Society of Hematology, International Society on Thrombosis and Haemostasis, and New York Academy of Sciences
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

Managing Editor

Ronald A Sacher, MB, BCh, MD, FRCPC, Director of the Hoxworth Blood Center, Professor, Departments of Internal Medicine and Pathology, University of Cincinnati Medical Center
Ronald A Sacher, MB, BCh, MD, FRCPC is a member of the following medical societies: American Society of Hematology
Disclosure: Glaxo Smith Kline Honoraria Speaking and teaching; Talecris Honoraria Board membership

CME Editor

Rebecca J Schmidt, DO, FACP, FASN, Professor of Medicine, Section Chief, Department of Medicine, Section of Nephrology, West Virginia University School of Medicine
Rebecca J Schmidt, DO, FACP, FASN is a member of the following medical societies: American College of Osteopathic Internists, American College of Physicians, American Medical Association, American Society of Nephrology, International Society of Nephrology, National Kidney Foundation, Renal Physicians Association, and West Virginia State Medical Association
Disclosure: Abbott Grant/research funds Speaking and teaching; Genzyme Honoraria Consulting; Roche Honoraria Consulting

Chief Editor

Emmanuel C Besa, MD, Professor, Department of Medicine, Division of Hematologic Malignancies, Kimmel Cancer Center, Thomas Jefferson University
Emmanuel C Besa, MD is a member of the following medical societies: American Association for Cancer Education, American College of Clinical Pharmacology, American Federation for Medical Research, American Society of Clinical Oncology, American Society of Hematology, and New York Academy of Sciences
Disclosure: Nothing to disclose.

 
 
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