You are in: eMedicine Specialties > Pediatrics: General Medicine > Hematology Factor VII DeficiencyArticle Last Updated: Dec 11, 2007AUTHOR AND EDITOR INFORMATIONSection 1 of 10
  Author: Sara J Israels, MD, FRCPC, Professor of Pediatric Hematology/Oncology, Section Head of Pediatric Hematology/Oncology/BMT, Department of Pediatrics and Child Health, University of Manitoba Sara J Israels 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 Editors: Gary R Jones, MD, Associate Medical Director, Clinical Development, Berlex Laboratories; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; 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; 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; Max J Coppes, MD, PhD, MBA, Executive Director, Center for Cancer and Blood Disorders, Children's National Medical Center, Washington, DC; Professor of Medicine, Oncology, and Pediatrics, Georgetown University Author and Editor Disclosure Synonyms and related keywords: inherited factor VII deficiency, FVII deficiency, vitamin K–dependent coagulation factors, hemorrhagic disorder, activated FVII, FVIIa, menorrhagia, hemarthrosis, thrombosis, epistaxis, anemia, hematoma INTRODUCTIONSection 2 of 10
  BackgroundInherited factor VII (FVII) deficiency is a rare autosomal recessive hemorrhagic disorder. Clinical bleeding can widely vary and does not always correlate with the level of FVII coagulant activity measured in plasma. FVII 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 FVII predominantly exists in the form of the inactive single-chain zymogen; however, approximately 1% circulates in the activated form (FVIIa). Activation of FVII is the initiating event of in vivo coagulation. The ability of FVIIa 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, FVIIa rapidly activates clotting factors VII, IX, and X, initiating the coagulation cascade. FVII plasma levels are influenced by both environmental and genetic factors. Dietary fat, age, obesity, and sex hormones influence FVII levels. Five identified allelic polymorphisms also affect plasma levels of FVII and FVIIa, with variations of as much as 25-30% in levels of activity and antigen. PathophysiologyInherited FVII deficiency can be classified as type 1 or type 2, depending on the absence or presence of FVII antigen in plasma. Type 1 deficiencies result from decreased biosynthesis or accelerated clearance; type 2 abnormalities represent a dysfunctional molecule. More than 100 mutations, mostly missense mutations, have been identified in the FVII gene located on chromosome 13.1 Mutations have been identified throughout the gene, affecting all domains of the transcribed protein, most frequently the catalytic domain. Correlations between the factor VII genotype, FVII clotting activity and the clinical phenotype are not tight. Although individuals with the lowest FVII 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 FVII deficiency. Investigations to determine the contribution by FVII 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 FVII activity levels has proved to be more useful in predicting future risk of bleeding. FrequencyUnited StatesInherited FVII deficiency is rare. Incidence is 1 case per 500,000 population. InternationalThe frequency is higher in countries where consanguineous marriage is more common. For example, the reported incidence of FVII deficiency in Mortality/MorbidityMortality is related to severe bleeding, most often resulting from CNS hemorrhage. SexFVII deficiency is autosomal recessive; the male-to-female ratio is 1:1. However, women are more likely to be symptomatic because of menorrhagia. AgeAlthough this is a congenital disorder, the age at presentation varies widely, depending on the clinical severity; patients with CNS or gastrointestinal bleeds present at a younger age, often during infancy, and some in the neonatal period. CLINICALSection 3 of 10
HistoryMost 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 gastrointestinal 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 FVII deficiency). These children usually have FVII 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 FVII deficiency has been reported; most, but not all, cases are associated with the administration of FVIII replacement therapy and/or surgical procedures. PhysicalThe physical manifestations are related to bleeding.
CausesSee Pathophysiology. DIFFERENTIALSSection 4 of 10
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| Drug Name | Coagulation FVII, plasma-derived (FVII Concentrate) |
|---|---|
| Description | 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. |
| Adult Dose | 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 Dose | Administer as in adults |
| Contraindications | Documented hypersensitivity; presence of inhibitory antibodies |
| Interactions | None reported |
| 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 |
| Drug Name | Coagulation FVIIa, recombinant (NovoSeven) |
|---|---|
| Description | 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. |
| Adult Dose | 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 Dose | Administer as in adults |
| Contraindications | Documented hypersensitivity |
| Interactions | None reported |
| 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 |
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.
| Drug Name | Aminocaproic acid (Amicar) |
|---|---|
| Description | Lysine analogue that inhibits fibrinolysis by blocking binding of plasmin or plasminogen activators to lysine residues on fibrin. |
| Adult Dose | 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 Dose | 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 |
| 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) |
| Interactions | Coadministration with estrogens may increase clotting factors, leading to hypercoagulable state |
| 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 |
| Drug Name | Tranexamic acid (Cyklokapron) |
|---|---|
| Description | Alternative to aminocaproic acid. Lysine analogue that inhibits fibrinolysis by blocking binding of plasmin or plasminogen activators to lysine residues on fibrin. |
| Adult Dose | 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 Dose | Administer as in adults |
| Contraindications | Documented hypersensitivity; evidence of DIC; bleeding from upper urinary tract (risk of clots being retained in ureter or bladder) |
| Interactions | None reported |
| 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 |
Article Last Updated: Dec 11, 2007
