Pediatric Factor VII Deficiency

Updated: May 22, 2017
  • Author: Helge Dirk Hartung, MD; Chief Editor: Max J Coppes, MD, PhD, MBA  more...
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Overview

Background

Inherited factor VII (FVII) deficiency is a rare autosomal recessive hemorrhagic disorder. [1, 2] 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.

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Pathophysiology

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.

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

Intrinsic and extrinsic pathways of coagulation. F 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.
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Epidemiology

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. [5]

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.

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