Última actualización:
05/09/2023
Años publicados: 2012, 2015, 2018
NORD gratefully acknowledges Helge Hartung, MD, Attending Physician, Children’s Hospital of Philadelphia, Division of Hematology, for assistance in the preparation of this report.
Summary
Factor VII deficiency is a rare genetic bleeding disorder characterized by a deficiency or reduced activity of clotting factor VII. Clotting factors are specialized proteins that are essential for the blood to clot normally. Individuals with factor VII deficiency can experience prolonged, uncontrolled bleeding episodes. The severity of factor VII deficiency can vary greatly from one person to another. Some individuals may have no symptoms (asymptomatic); others may develop mild, moderate or potentially severe, life-threatening complications as early as in infancy. Factor VII deficiency is caused by mutations of the F7 gene and is inherited as an autosomal recessive disorder.
Introduction
Factor VII deficiency was first described in the medical literature by Dr. Alexander, et al. in 1951 and was referred to as prothrombin conversion accelerator deficiency. The disorder has also been known as Alexander’s disease. In extremely rare instances, factor VII deficiency can be acquired during life; this report deals with the genetic form, which is present at birth (although symptoms may develop later).
The symptoms and severity of factor VII deficiency are highly variable; no consistent correlation between the amount of factor VII in the blood and overall severity is seen. Some individuals may not develop any symptoms (asymptomatic), including individuals with relatively low levels of factor VII. Other individuals may have mild cases that are only apparent after trauma or surgery. Mild symptoms can include chronic nosebleeds, easy bruising, and bleeding from the gums. People who menstruate may develop heavy and prolonged periods (menorrhagia).
More serious bleeding complications occur in some individuals and may mimic bleeding patterns seen in hemophilia. Bleeding into the joints (hemarthrosis) can result in progressive joint damage and degeneration, eventually limiting the range of motion of an affected joint. Soft tissue bleeding can result in bruising that seems spontaneous or out of proportion to an injury. Affected individuals can develop masses of congealed blood called hematomas that can cause symptoms due to compression of nearby structures or organs. Bleeding in the stomach, intestines and urogenital tract can also occur resulting in blood in the urine (hematuria) or black, tarry, bloody stools (melena or hematochezia).
Bleeding in severe factor VII deficiency can result in life-threatening complications. These include major gastrointestinal bleeds as well as head bleeds (intracranial hemorrhage), often during the first few weeks or months of life. Although quite rare, head bleeds have been reported in adults as well.
Individuals with factor VII deficiency may experience bleeding after surgery or minor procedures or following trauma or injury. They may also bleed excessively following childbirth (postpartum bleeding). Some newborns have experienced abnormal bleeding from the umbilical cord stump at birth.
A seemingly paradoxical increased incidence of clotting (thrombosis) has been noted in factor VII deficiency in recent years. These thromboses can be arterial or venous and they can occur spontaneously or in conjunction with treatment.
Factor VII deficiency is caused by mutations of the F7 gene. These mutations are inherited in an autosomal recessive manner. Genetic diseases are determined by the combination of genes for a particular trait that are received from the father and the mother.
Recessive genetic disorders occur when an individual inherits the same abnormal gene from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass on the defective gene and, therefore, have an affected child is 25 percent with each pregnancy. The risk to have a child who is a carrier like the parents is 50 percent with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25 percent. The risk is the same for males and females.
The F7 gene creates (encodes) factor VII, which is a clotting factor. Clotting factors are specialized proteins that play an essential role in enabling the blood to clot. Clotting is the process by which blood clumps together to plug the site of a wound to stop bleeding. Clotting requires a series of reactions to ultimately form a clot to plug a wound. This is referred to as the clotting (coagulation) cascade. The clotting cascade involves different substances in addition to clotting factors. Factor VII, which is produced (synthesized) in the liver, eventually interacts with other clotting factors and certain cells or substances, e.g. platelets or fibrinogen, to help to form a clot. Mutations of the F7 gene result in deficient levels of functional factor VII, which in affected individuals, prevents the blood from clotting properly. Consequently, affected individuals have difficulty stopping the flow of blood from a wound; but they do not bleed faster or more profusely than healthy individuals.
Individuals with factor VII deficiency often have varying levels of residual factor VII deficiency. In many disorders, the amount of residual protein activity correlates with the severity of the disease (e.g. little to no residual protein activity results in severe disease). However, in factor VII deficiency the severity of the disorder does not always correlate with the residual activity of factor VII, suggesting that additional genetic and environmental factors play a role in the severity of the disorder.
Factor VII deficiency affects males and females in equal numbers. The disorder is estimated to affect 1 in 300,000 to 500,000 individuals in the general population. However, many cases of factor VII deficiency go undiagnosed or misdiagnosed, making it difficult to determine the true frequency in the general population. The incidence of factor VII deficiency tends to be higher in countries where marriage to close relatives (consanguineous marriage) is more common. According to the medical literature, more than 200 cases of true factor VII deficiency have been reported. Because of the variable severity of factor VII deficiency, the age of presentation can vary widely from birth until adulthood.
A diagnosis of factor VII deficiency is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized blood tests.
Clinical Testing and Work-Up
Specialized tests will include screening coagulation tests that measure how long it takes the blood to clot, specifically two tests known as activated partial thromboplastin time (aPTT) and prothrombin time (PT). Individuals with factor VII deficiency have a normal aPTT and a prolonged PT.
Further tests known as assays are required to confirm a diagnosis. An assay is a test that can measure the activity of certain substances in the blood. In affected individuals a factor VII assay will demonstrate reduced activity of factor VII.
Treatment
The specific therapeutic procedures and interventions for individuals with factor VII deficiency depend primarily on the severity of the individual’s disease. Factors that will influence therapy decisions include specific symptoms present; the natural course of the disorder including underlying cause (congenital versus acquired); an individual’s age and overall health (e.g., concomitant disease), risks of certain medications or procedures, personal preference; and other factors. Decisions concerning the use of particular therapeutic interventions should be made by physicians and other members of the healthcare team, in careful consultation with the patient and/or parents, and based upon the specifics of the individual’s case. Such a discussion will review the potential benefits and risks including possible side effects and long-term effects; consider patient preferences; and include other appropriate factors in order to come to a consensus.
Specific treatment options for acute bleeds in individuals with factor VII deficiency include recombinant factor VII, prothrombin complex concentrates, and fresh frozen plasma. Antifibrinolytics such as aminocaproic acid can help alleviate the bleeding symptoms.
Coagulation factor VIIa (NovoSeven RT) has been approved by the U.S. Food and Drug Administration (FDA) to treat bleeding episodes in individuals with congenital factor VII deficiency. NovoSeven is a genetically engineered (recombinant) version of factor VII. Because it does not contain human blood or plasma, there is no risk of transmitting blood-borne viruses or other pathogens. NovoSeven has been well-tolerated and associated with few side effects.
Individuals with factor VII deficiency have also been treated with prothrombin complex concentrates (PCCs), which are blood products that contain a concentrated form of four different clotting factors: II, VII, IX and X. However, the amount of each specific factor contained in these products can vary from one preparation to another, making it difficult to determine the most appropriate dosage. PCCs undergo a purification process to eliminate viruses and other pathogens. PCCs are associated with an increased risk of developing blood clots, especially following repeated administration.
Theoretically, factor VII deficiency can be treated with fresh frozen plasma. However, in clinical practice the very large volume required to stop bleeding renders this impractical, primarily due to the short half-life of factor VII. Half-life refers to the time it takes for half of the infused factor to breakdown and to disappear from the bloodstream.
Some individuals with factor VII deficiency may undergo preventative (prophylactic) therapy in an attempt to prevent or minimize future bleeding complications. Prophylactic therapy has been used for individuals with a history of bleeding into the joints or the brain. The decision to undergo prophylactic therapy in factor VII deficiency is made after careful consultation with a patient’s medical team. The specific prophylactic regimen in factor VII deficiency is case dependent.
Additional treatment options for individuals with factor VII deficiency are symptomatic and supportive. For example, excessive menstrual bleeding may be treated by birth control pills or drugs known as antifibrinolytics.
Genetic counseling is recommended for affected individuals and their families.
Individuals with factor VII deficiency will benefit from a referral to a federally-funded hemophilia treatment center. These specialized centers can provide comprehensive care for individuals with hemophilia and rare bleeding disorders, such as factor VII deficiency. The treatment center’s medical team, headed by a hematologist with expert knowledge in bleeding disorders, will develop specific treatment plans and organize the monitoring and long term follow up of affected individuals, thus ensuring state-of-the-art medical care. Treatment at a hemophilia treatment center ensures that individuals and their family members will be cared for by a professional healthcare team (physicians, nurses, physical therapist, social worker and genetic counselor) experienced in treating individuals with rare bleeding disorders.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
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Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com
For information about clinical trials conducted in Europe, contact:
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JOURNAL ARTICLES
Ruiz-Saez A. Occurrence of thrombosis in rare bleeding disorders. Semin Thromb Hemost. 2013 Sep;39(6):684-92. doi: 10.1055/s-0033-1353391. Epub 2013 Aug 8.
Todd T, Perry DJ. A review of long-term prophylaxis in the rare inherited coagulation factor deficiencies. Haemophilia. 2010;16:569-583. https://www.ncbi.nlm.nih.gov/pubmed/19906159
Mandhyan R, Tiwari A, Cherian G. Congenital factor VII deficiency. Br J Anaesth. 2010;2:267-268.
https://bja.oxfordjournals.org/content/104/2/267.long
Boltin D, Boguslavski V, Goor Y, Elkayam. Primary factor VII deficiency. IMAJ. 2008;10:275-276. https://www.ima.org.il/imaj/ar08june-22.pdf
Mariani G, Lapecorella M, Dolce A. Steps toward an effective treatment strategy in congenital factor VII deficiency. Semin Hematol. 2006;43:S42-S47. https://www.ncbi.nlm.nih.gov/pubmed/16427385
Mariani G, Konkle BA, Ingersley J. Congenital factor VII deficiency: therapy with recombinant activated factor VII – a critical appraisal. Haemophilia. 2006;12:19-27. https://www.ncbi.nlm.nih.gov/pubmed/16409171
Acharya SS, Coughlin A, Dimichele M. Rare bleeding disorders registry: deficiencies of factors II, V, VII, X, XIII, fibrinogen and dysfibrinogenemias. J Thromb Haemost. 2004;2:248-256. https://www.ncbi.nlm.nih.gov/pubmed/14995986
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 randomized trial. Lancet. 2003;361:201-205. https://www.ncbi.nlm.nih.gov/pubmed/12547542
Ruiz-Saez A. Occurrence of thrombosis in rare bleeding disorders. Semin Thromb Hemost. 2013 Sep;39(6):684-92. doi: 10.1055/s-0033-1353391. Epub 2013 Aug 8.
INTERNET
Hartung H. Pediatric Factor VII Deficiency.Medscape. Updated: May 22, 2017. Available at: https://emedicine.medscape.com/article/960592-overview Accessed March 5, 2018.
Mir MA. Factor VII. Medscape. Updated: Jul 18, 2017. Available at: https://emedicine.medscape.com/article/209585-overview Accessed March 5, 2018.
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