eMedicine Specialties > Pediatrics: General Medicine > Hematology

Factor VII Deficiency

Sara J Israels, MD, FRCPC, is a member of the following medical societies: American Society of Hematology, American Society of Pediatric Hematology/Oncology, Canadian Medical Association, Children's Oncology Group, International Society on Thrombosis and Haemostasis, and Royal College of Physicians and Surgeons of Canada

Updated: Jan 22, 2010

Introduction

Background

Inherited factor VII (FVII) deficiency is a rare autosomal recessive hemorrhagic disorder.^{[1 ]}Clinical bleeding can widely vary and does not always correlate with the level of factor VII coagulant activity measured in plasma.

Factor VII is one of the vitamin K–dependent coagulation factors synthesized in the liver. It is present in plasma in low concentrations (0.5 mcg/mL) and has a short circulating half-life of 3-4 hours. Plasma factor VII predominantly exists in the form of the inactive single-chain zymogen; however, approximately 1% circulates in the activated form (FVIIa). Activation of factor VII is the initiating event of in vivo coagulation. The ability of factor VIIa to cleave other clotting factors depends on binding to its cofactor tissue factor (TF), which is expressed on the surface of endothelial cells and monocytes in response to injury or inflammation. With formation of the TF/VIIa complex, factor VIIa rapidly activates clotting factors VII, IX, and X, initiating the coagulation cascade.

Factor VII plasma levels are influenced by both environmental and genetic factors. Dietary fat, age, obesity, and sex hormones influence factor VII levels. Five identified allelic polymorphisms also affect plasma levels of factor VII and factor VIIa, with variations of as much as 25-30% in levels of activity and antigen.

Pathophysiology

Correlations between the factor VII genotype, factor VII clotting activity and the clinical phenotype are not tight. Although individuals with the lowest factor VII levels are most likely to be symptomatic, patients with identical mutations may have marked differences in clinical bleeding, suggesting that other factors may contribute to the clinical manifestations of factor VII deficiency. Investigations to determine the contribution by factor VII polymorphisms, other hemostatic proteins, and environmental factors have not yielded specific predictors of bleeding risk. At present, classification based on clinical history (age and type of presentation) rather than on factor VII activity levels has proved to be more useful in predicting future risk of bleeding.

Intrinsic and extrinsic pathways of coagulation are shown in the image below.

Intrinsic and extrinsic pathways of coagulation. Factor VII/tissue factor complex activates factor IX and factor X. Factor IXa along with factor VIIIa results in formation of more factor Xa. Factor Xa along with factor Va converts prothrombin to thrombin.

Frequency

United States

Inherited factor VII deficiency is rare. Incidence is 1 case per 500,000 population.

International

The frequency is higher in countries where consanguineous marriage is more common. For example, the reported incidence of factor VII deficiency in Iran is 3 times higher than that in the United Kingdom or Italy.^{[3 ]}

Mortality/Morbidity

Mortality is related to severe bleeding, most often resulting from CNS hemorrhage.

Sex

Factor VII deficiency is autosomal recessive; the male-to-female ratio is 1:1. However, women are more likely to be symptomatic because of menorrhagia.

Age

Although this is a congenital disorder, the age at presentation varies widely, depending on the clinical severity; patients with CNS or GI bleeds present at a younger age, often during infancy, and some in the neonatal period.

Clinical

History

Most severe cases of factor VII (FVII) deficiency are diagnosed during childhood, often during the first 6 months of life. In infancy, the most common bleeds occur in the GI tract or CNS, accounting for 60-70% of bleeds in this age group. Spontaneous hemarthrosis also presents more frequently in children younger than 5 years (occurring in 20% of patients with factor VII deficiency). These children usually have factor VII levels of more than 2%.

The most common bleeding manifestations involve easy bruising and mucosal bleeding, particularly epistaxis or oral mucosal bleeding. Women are over represented among symptomatic patients because of menorrhagia (as high as 60%). Postoperative bleeding is also common, reported in association with 30% of surgical procedures, including procedures for which replacement therapy was administered.

Thrombosis in inherited factor VII deficiency has been reported; most, but not all, cases are associated with the administration of factor VII replacement therapy and/or surgical procedures.

Physical

The physical manifestations are related to bleeding and include the following:

• Mucosal bleeding: Epistaxis and bleeding from the oral cavity or GI tract have been observed.
• Menorrhagia and associated anemia
• Hemarthrosis: Patients with hemarthrosis have the same clinical presentation as those with hemophilia. Recurrent hemarthroses can lead to joint damage and chronic arthropathy.
• Bruising, soft tissue hematomas
• Neurological findings commensurate with CNS bleeding, particularly in infants

Causes

See Pathophysiology.

Differential Diagnoses

Other Problems to Be Considered

• Acquired factor VII (FVII) deficiency due to vitamin K deficiency, vitamin K antagonist therapy, or liver disease: In these situations, reduced factor VII levels are associated with reduced levels of other vitamin K–dependent factors. Acquired factor VII deficiency is far more common than inherited deficiency.
• Other congenital coagulation factor deficiencies

Workup

Laboratory Studies

• The prothrombin time (PT) is prolonged in factor VII (FVII) deficiency and the international normalized ratio (INR) is elevated. The activated partial thromboplastin time (aPTT) is within the reference range in isolated factor VII deficiency.
• Specific factor VII assays are required for diagnosis.
  • Factor VII assays are performed by using a tissue factor (TF; thromboplastin)–dependent one-stage clotting assay.
  • The sensitivity of the assay depends on the choice of assay reagents. The less sensitive animal-derived thromboplastins cannot be used to accurately measure levels less than 5%.
  • The more sensitive thromboplastins, usually recombinant human thromboplastin, are preferred for measuring factor VII activity in the very low range.
  • When the deficiency is due to mutations that affect formation of the TF/factor VIIa/FX complex, the measured factor VII levels may significantly vary depending on the type of reagent used (ie, rabbit vs human thromboplastin).
• Genetic studies, including genotyping, may be warranted for counseling and prenatal diagnosis.
• Factor assays in family members are indicated to identify other affected individuals.
• Although factor VII levels are statistically lower in "bleeders" than in "nonbleeders," they may not predict bleeding risk in individual patients.

Imaging Studies

• Appropriate imaging studies may be useful in the evaluation of suspected bleeding. For instance, CT scanning or MRI of the brain is indicated for suspected CNS hemorrhage.

Treatment

Medical Care

• Acute bleeds: Management of acute hemorrhage primarily consists of factor VII (FVII) replacement therapy to treat bleeding. Levels of more than 10% are usually hemostatic, although higher levels may be advisable in the event of a severe bleeding episode. Because factor VII has a short half-life (3-4 h), repeat treatment may be necessary in all except minor bleeding episodes. Treatment alternatives include the following:
  • Fresh frozen plasma is the least effective because of the volume required to provide adequate factor VII replacement. No viral attenuation of this product means that a risk of viral transmission is present.
  • Prothrombin complex concentrates contain factors II, IX, and X in addition to factor VII. These concentrates have undergone viral attenuation during manufacturing. Determining the appropriate dosage for treatment of factor VII deficiency can be difficult. These agents carry a risk of thrombogenic complications, particularly with repeated administration.
  • Factor VII concentrates are purified plasma–derived preparations that have undergone a vapor-heat viral-inactivation process. If available, factor VII concentrates are preferred over untreated plasma.^{[4 ]}When given at high doses, these concentrates carry a risk of thrombosis, likely because of other vitamin K-dependent factors that are present in significant concentrations.
  • Recombinant activated factor VII (rFVIIa) was originally developed to treat patients with hemophilia and inhibitors, but it can be used at lower doses for patients with congenital factor VII deficiency. With increasing experience and evaluation of rFVIIa for treatment and prophylaxis in factor VII deficiency, the benefits and safety profile in this setting are becoming clearer.
• Prophylaxis: The decision to embark on a program of prophylaxis is determined by the patient's clinical presentation and the number of clinically significant bleeding episodes requiring intervention. Consider prophylaxis for patients with recurrent hemarthrosis or intracranial hemorrhage. Beneficial results have been reported with regimens that vary from twice daily to twice weekly treatment.^{[5 ]}

Surgical Care

• Maintaining factor VII levels of at least 15-25% provides adequate hemostasis levels for most surgical procedures.
• Preoperative factor VII replacement and monitoring of factor VII levels is essential for major surgical interventions.
• Because of the short half-life (3-4 h), replacement therapy should continue postoperatively; the period of therapy is determined by the nature and extent of the procedure.

Consultations

• Consult a hematologist and/or hemostasis specialist for patients who require factor VII replacement therapy.
• Genetic counseling and family studies are part of a complete evaluation.

Activity

• In patients with severe factor VII deficiency and a history of clinical bleeding, consider the risk of bleeding when choosing activities.
• Individuals should stay fit because good muscle strength protects joints.
• Patients are encouraged to avoid contact sports, wear appropriate protective gear, and choose activities, such as swimming, that promote muscle strength and flexibility with a low risk of joint injury.

Medication

Clotting factor concentrates

Clotting factor concentrates promote hemostasis by providing the deficient clotting factor to the coagulation cascade. Used for control and prevention of hemorrhagic episodes and surgical prophylaxis in patients with factor VII (FVII) deficiency.

Coagulation FVII, plasma-derived (FVII Concentrate)

Vitamin K–dependent glycoprotein that promotes hemostasis by activating extrinsic pathway of coagulation cascade. FVII concentrates, available from Baxter or Bio Products Laboratory (United Kingdom), are purified plasma–derived concentrates that have undergone viral inactivation with vapor heat.

Dosing

Adult

10-50 IU/kg/dose IV; because of short half-life, repeat therapy may be required q6-12h to maintain hemostasis
Prophylaxis: 10-50 IU/kg 1-3 times/wk

Pediatric

Administer as in adults

Interactions

None reported

Contraindications

Documented hypersensitivity; presence of inhibitory antibodies

Precautions

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

Monitor FVII coagulant activity levels to evaluate response and recovery; monitor for signs of thrombosis or activation of coagulation system; thrombotic events are a risk in patients with crush injury, sepsis, or DIC

Coagulation FVIIa, recombinant (NovoSeven)

Activated FVII promotes hemostasis by activating the extrinsic pathway of coagulation cascade. Originally developed to treat patients with FVIII inhibitors. Doses lower than those recommended for patients with hemophilia are usually effective in patients with FVII deficiency.

Dosing

Adult

15-30 mcg/kg/dose IV; because of short half-life, repeat therapy may be required q4-6h to maintain hemostasis after acute bleeding or for surgical procedures.

Pediatric

Administer as in adults

Interactions

None reported

Contraindications

Documented hypersensitivity

Precautions

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

FVII coagulant levels are difficult to interpret in the presence of infused FVIIa because standard assays are not designed for monitoring activated factors; monitoring for correction of PT may be more useful; monitor for signs of thrombosis or activation of coagulation system; thrombotic events are a risk in patients with crush injury, sepsis, or DIC

Antifibrinolytic agents

These agents are used to enhance hemostasis when fibrinolysis contributes to bleeding. They inhibit lysis of the fibrin clot and thus maintain hemostasis once achieved. Antifibrinolytics are particularly useful for bleeding from mucosal surfaces where fibrinolytic activity is high, such as the nose or oropharynx.

Aminocaproic acid (Amicar)

Lysine analogue that inhibits fibrinolysis by blocking binding of plasmin or plasminogen activators to lysine residues on fibrin.

Dosing

Adult

30 g/d PO/IV in divided doses q3-6h; not to exceed 30 g/d; can be topically applied as a 10% solution in 0.9% NaCl

Pediatric

50-60 mg/kg/dose PO/IV q3-6h; not to exceed 18 g/m²/d; can be applied topically as a 10% solution in 0.9% NaCl

Interactions

Coadministration with estrogens may increase clotting factors, leading to hypercoagulable state

Contraindications

Documented hypersensitivity; evidence of active intravascular clotting process; potentially fatal in DIC, differentiating between hyperfibrinolysis and DIC is important; bleeding from upper urinary tract (risk of clots being retained in ureter or bladder)

Precautions

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

Caution in cardiac, hepatic, or renal disease

Tranexamic acid (Cyklokapron)

Alternative to aminocaproic acid. Lysine analogue that inhibits fibrinolysis by blocking binding of plasmin or plasminogen activators to lysine residues on fibrin.

Dosing

Adult

25 mg/kg PO tid/qid or 10 mg/kg IV tid/qid if patient unable to take the PO dose; can be topically applied as a 10% solution in 0.9% NaCl

Pediatric

Administer as in adults

Interactions

None reported

Contraindications

Documented hypersensitivity; evidence of DIC; bleeding from upper urinary tract (risk of clots being retained in ureter or bladder)

Precautions

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

Caution in renal impairment

Follow-up

Further Outpatient Care

• Ideally, individuals with severe factor VII (FVII) deficiency should be monitored by a comprehensive hemophilia care team that has experience in the diagnosis and management of inherited bleeding disorders.

Deterrence/Prevention

• Individuals who may require plasma-derived coagulation factor concentrates should be immunized with hepatitis A and hepatitis B vaccines.
• Patients should avoid use of aspirin and other drugs, including alcohol, that affect platelet function.
• Consider prophylactic therapy in patients with recurrent bleeding episodes or CNS hemorrhage.
• Patients should maintain good dental hygiene to prevent dental or periodontal disease.
• Individuals should participate in appropriate physical activity to maintain muscle strength, and they should wear appropriate protective gear for activities.

Complications

• Recurrent bleeding, particularly hemarthroses, which can result in progressive damage to joints and chronic arthropathy. Management of recurrent hemarthroses applies the principles used in hemophilia care.
• A risk of thrombosis can be associated with the combination of surgery and factor VII replacement therapy using prothrombin complex concentrate or high doses of factor VII concentrates.

Patient Education

• Patients and families should be given instruction and educational materials to enable them to understand FVII deficiency, to recognize the symptoms and signs of bleeding, and to identify emergency situations.
• Patients should know how to contact their treatment center for immediate treatment, and they should know where to receive emergency care.
• Patients should wear a MedicAlert bracelet or carry other identification showing their bleeding disorder and recommended therapy.

Miscellaneous

Medicolegal Pitfalls

• Failure to make the specific diagnosis of congenital factor VII (FVII) deficiency
• Failure to investigate family members for factor VII deficiency
• Failure to treat bleeding episodes with appropriate factor VII replacement
• Failure to provide appropriate factor VII replacement before surgical procedures

Multimedia

Media file 1: Intrinsic and extrinsic pathways of coagulation. Factor VII/tissue factor complex activates factor IX and factor X. Factor IXa along with factor VIIIa results in formation of more factor Xa. Factor Xa along with factor Va converts prothrombin to thrombin.

References

1. Mandhyan R, Tiwari A, Cherian G. Congenital factor VII deficiency. Br J Anaesth. Feb 2010;104(2):267-8. [Medline].

2. 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].

3. Peyvandi F, Mannucci PM. Rare coagulation disorders. Thromb Haemost. Oct 1999;82(4):1207-14. [Medline].

4. Mariani G, Bernardi F. Factor VII Deficiency. Semin Thromb Hemost. Jun 2009;35(4):400-6. [Medline].

5. Todd T, J Perry D. A review of long-term prophylaxis in the rare inherited coagulation factor deficiencies. Haemophilia. Nov 11 2009;[Medline].

6. Di Paola J, Nugent D, Young G. Current therapy for rare factor deficiencies. Haemophilia. Jan 2001;7 Suppl 1:16-22. [Medline].

7. Giansily-Blaizot M, Schved JF. Potential predictors of bleeding risk in inherited factorVII deficiency. Clinical, biological and molecular criteria. Thromb Haemost. Nov 2005;94(5):901-6. [Medline].

8. Mariani G, Dolce A, Marchetti G, Bernardi F. Clinical picture and management of congenital factor VII deficiency. Haemophilia. Oct 2004;10 Suppl 4:180-3. [Medline].

9. Mariani G, Lapecorella M, Dolce A. Steps towards an effective treatment strategy in congenital factor VII deficiency. Semin Hematol. Jan 2006;43(1 Suppl 1):S42-7. [Medline].

10. Perry DJ. Factor VII Deficiency. Br J Haematol. Sep 2002;118(3):689-700. [Medline].

11. Tuddenham EG, Pemberton S, Cooper DN. Inherited factor VII deficiency: genetics and molecular pathology. Thromb Haemost. Jul 1995;74(1):313-21. [Medline].

Keywords

inherited factor VII deficiency, FVII deficiency, vitamin K–dependent coagulation factors, hemorrhagic disorder, activated FVII, FVIIa, menorrhagia, hemarthrosis, thrombosis, epistaxis, anemia, hematoma, treatment, symptoms

Contributor Information and Disclosures

Author

Sara J Israels, MD, FRCPC, is a member of the following medical societies: American Society of Hematology, American Society of Pediatric Hematology/Oncology, Canadian Medical Association, Children's Oncology Group, International Society on Thrombosis and Haemostasis, and Royal College of Physicians and Surgeons of Canada
Disclosure: Nothing to disclose.

Medical Editor

Gary R Jones, MD, Associate Medical Director, Clinical Development, Berlex Laboratories
Gary R Jones, MD is a member of the following medical societies: American Academy of Pediatrics, American Society of Pediatric Hematology/Oncology, and Western Society for Pediatric Research
Disclosure: Nothing to disclose.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

Managing Editor

James L Harper, MD, Associate Professor, Department of Pediatrics, Division of Hematology/Oncology and Bone Marrow Transplantation, Associate Chairman for Education, Department of Pediatrics, University of Nebraska Medical Center; Assistant Clinical Professor, Department of Pediatrics, Creighton University; Director, Continuing Medical Education, Children's Memorial Hospital; Pediatric Director, Nebraska Regional Hemophilia Treatment Center
James L Harper, MD is a member of the following medical societies: American Academy of Pediatrics, American Association for Cancer Research, American Federation for Clinical Research, American Society of Hematology, American Society of Pediatric Hematology/Oncology, Council on Medical Student Education in Pediatrics, and Hemophilia and Thrombosis Research Society
Disclosure: Nothing to disclose.

CME Editor

Helen SL Chan, MBBS, FRCP(C), FAAP, Senior Scientist, Research Institute; Professor, Division of Hematology/Oncology, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Canada
Helen SL Chan, MBBS, FRCP(C), FAAP is a member of the following medical societies: American Academy of Pediatrics, American Association for Cancer Research, American Society of Hematology, and Royal College of Physicians and Surgeons of Canada
Disclosure: Nothing to disclose.

Chief Editor

Max J Coppes, MD, PhD, MBA, Senior Vice President, Children's National Medical Center (Center for Cancer and Blood Disorders); Director, Center for Cancer and Immunology Research, Children's Research Institute, Children's National Medical Center; Professor of Medicine, Oncology, and Pediatrics, Georgetown University
Max J Coppes, MD, PhD, MBA is a member of the following medical societies: American Association for Cancer Research, American Society of Pediatric Hematology/Oncology, Idaho Medical Association, and Society for Pediatric Research
Disclosure: Nothing to disclose.

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