Pediatric Factor VII Deficiency

Inherited factor VII deficiency can be classified as type 1 or type 2, depending on the absence or presence of factor VII antigen in plasma.[3] 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 factor VII gene located on chromosome 13.[4] 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, 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.

However, using data from the European Network of Rare Bleeding Disorders (EN-RBD) registry, the International Society on Thrombosis and Haemostasis devised what Jain et al reported to be an effective classification scheme for congenital factor VII deficiency based on factor VII activity. Classification is as follows[5] :

• Severe - Factor VII activity of less than 10%; risk of spontaneous major bleeding
• Moderate - Factor VII activity of 10-20%; risk of mild spontaneous or triggered bleeding
• Mild - Factor VII activity of 20-50%; primarily asymptomatic

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.[6]

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.

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.

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

• Neurologic findings commensurate with CNS bleeding, particularly in infants

See Pathophysiology.

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.

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.

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.[7] 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. However, venous and arterial thromboses have been reported via postmarketing sources.[8]

A literature review by Ramezanpour et al of patients with congenital factor VII deficiency found that of the 380 individuals in the study, 7% developed a factor VII inhibitor. Of these 27 inhibitor patients, severe factor VII deficiency was noted in the 26 with available coagulation levels (coagulation activity < 10%). About 58% of those 26 patients experienced intracerebral hemorrhage, with the rate for non-inhibitor patients being below 10%. The presence of an inhibitor represents a challenge to replacement therapy in patients with factor VII deficiency.[9]

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.[10]

Maintaining factor VII levels of at least 15-25% provides adequate hemostasis levels for most surgical procedures.[11]

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.

A literature review by Rajpurkar and Cooper indicated that in patients with congenital factor VII deficiency, continuous infusion with rFVIIa can be a safe and effective alternative to bolus injection for perioperative bleeding management. The review included 26 patients with the deficiency, who received the treatment over a total of 46 major and minor surgeries.[12]

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.

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.

Class Summary

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.

Factor VIIa, recombinant (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.

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.

Class Summary

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.

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.

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.

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 may include the following:

• 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.

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.