Factor X Deficiency

Disease Overview

Factor X deficiency is a rare genetic blood disorder that causes the normal clotting process (coagulation) to take longer than normal. This causes people to bleed for a longer amount of time spontaneously or after trauma/surgery. Factor X is a clotting protein (also called a clotting factor). Clotting factors are specialized proteins that are essential for proper clotting, 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 X, 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. Factor X deficiency is caused by a change (variant or mutation) in the F10 gene. The U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) approved a drug called Coagadex for adults and children over 12. This medication restores functional factor X levels.

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Synonyms

congenital factor X deficiency
congenital Stuart factor deficiency
F10 deficiency
Stuart-Power factor deficiency

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Signs & Symptoms

The signs and symptoms of factor X deficiency are highly variable; this means that how the disorder affects one person can be very different from how it affects another person. Symptoms can develop at any age. Generally, the more severe the disorder, the earlier the symptoms begin.

Sometimes, factor X deficiency is broken down based on the residual amount of factor X activity. 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). This is not true for all bleeding disorders but is true for factor X deficiency – generally the less protein activity the more severe the bleeding complications.
Individuals with about 40% or more protein activity have mild disorder and often do not have symptoms (asymptomatic). Individuals with 10%-40% activity have moderate disease and general symptoms associated with bleeding disorders. Individuals with 10% or less factor X activity have severe disease, particularly those with less than 1% of factor X. In some instances, the amount of secreted factor X is normal or near normal, but cannot function normally; in other cases, FX is not secreted at all.

Symptoms of moderate forms can include bruising easily, nosebleeds and bleeding from the mouth and the gums. There may be blood in the urine (hematuria). Some individuals may not have any symptoms except for when they experience trauma or surgery. Without treatment, these symptoms can occur throughout life.

With the most severe forms, symptoms can begin at or shortly after birth and, in addition to the symptoms common to moderate forms, patients with the severe deficiency may present bleeding into the joints. This is called hemarthrosis and can result in progressive joint damage and degeneration, eventually limiting the range of motion of an affected joint. Bleeding into the muscles (intramuscular bleeds) can also occur, which can cause pain and stiffness in the affected muscles. Some affected individuals will develop masses of congealed blood called hematomas that can cause symptoms due to compression of nearby structures or organs. Bleeding in the stomach and intestines (gastrointestinal tract) is frequent in severe factor X deficiency. The urogenital tract can also be affected resulting in blood in the urine (hematuria) or black, tarry bloody stools (melena).

There is a high risk of intracranial hemorrhaging, a life-threatening complication in which there is bleeding inside the skull. This risk can be present from birth. Sometimes, umbilical stump bleeding can result at birth. The umbilical stump is the small piece of the umbilical cord that remains in the bellybutton after birth. The stump usually dries up and falls off about 7 to 21 days.

People with factor X deficiency may experience heavy menstrual bleeding (menorrhagia). Pregnant people are at a greater risk of complications with their pregnancies including miscarriage or heavy bleeding during birth. Some people can experience heavy bleeding in the time after delivery (postpartum hemorrhaging).

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Causes

The F10 gene creates (encodes) factor X. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, absent or overproduced. Variants in the F10 gene result in deficient levels of functional factor X, which in affected individuals, prevents the blood from clotting properly. Depending upon the functions of the protein, this can affect many organ systems of the body. 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.

Factor X deficiency is inherited in an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits a mutated gene from each parent. If an individual receives one normal gene and one mutated 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 the mutated gene and have an affected child is 25% with each pregnancy. The risk of having a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.

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Affected populations

Factor X deficiency affects males and females and can occur in individuals of any ethnic or racial group. The disorder is estimated to affect about 1 in every 500,000-1,000,000 people in the general population. Rare disorders like factor X deficiency often go unrecognized or misdiagnosed, making it difficult to determine the true frequency in the general population.

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Disorders with Similar Symptoms

Symptoms of the following disorders can be similar to those of factor X deficiency. Comparisons may be useful for a differential diagnosis.

Factor X deficiency belongs to a group of rare forms of bleeding disorders; a group that includes deficiencies of fibrinogen, prothrombin and factors V, VII, XI, and XIII. There are also combined deficiencies of more than one factor. The rare forms of bleeding disorders account for 3-5% of all bleeding disorders collectively. These disorders are inherited in an autosomal recessive pattern. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)

Hemophilia is a general term for a group of rare bleeding disorders. Most forms of hemophilia are rare inherited blood clotting (coagulation) disorders caused by inactive or deficient blood coagulation proteins. There are two major forms of inherited hemophilia: hemophilia A and hemophilia B. Hemophilia A and B are inherited as X-linked recessive genetic disorders since males inherit only one copy of the X chromosome, if that chromosome carries the mutated gene, then they will have the disease. Females have a second, usually normal gene on their other X chromosome, so they maybe carrier of the disease without experiencing its symptoms. Hemophilia A is the most common form of hemophilia and is characterized by a deficiency of factor VIII, one of several specialized proteins required for the blood to clot. Hemophilia may be classified as mild, moderate or severe. The level of severity is determined by the percentage of active clotting factor in the blood (normal percentage ranges from 50 to 150 percent). People who have severe hemophilia have less than one percent of active clotting factor in their blood. (For more information on these disorders, choose “hemophilia” as your search term in the Rare Disease Database.)

Acquired factor X deficiency is a rare bleeding disorder characterized by low levels of factor X. The signs and symptoms are similar to those seen in the inherited form. The acquired form is more common and can be caused by certain liver disorders, systemic amyloidosis, the use of certain drugs and deficiency of vitamin K. Acquired factor X deficiency is treated by managing the underlying cause.

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Diagnosis

A diagnosis of factor X deficiency is based upon identification of characteristic symptoms, a detailed patient and family history, a thorough clinical evaluation and a variety of specialized tests.

Clinical Testing and Workup

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 X deficiency have both prolonged aPTT and PT.

Further tests known as assays are required to confirm a diagnosis and differentiate factor X deficiency from deficiencies in other clotting factors. An assay is a test that can measure the activity of certain substances in the blood. In affected individuals a factor X assay will demonstrate reduced activity of factor X.

Molecular genetic testing can confirm a diagnosis of factor X deficiency but is usually not necessary. Molecular genetic testing can detect a variation in the F10 gene but is available only as a diagnostic service at specialized laboratories.

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Standard Therapies

Treatment of factor X deficiency may require the coordinated efforts of a team of specialists. Pediatricians, general internists, physicians who specialize in diagnosing and treating blood disorders (hematologists), dental specialists and other healthcare professionals may need to plan treatment systematically and comprehensively. Psychosocial support for the entire family is essential as well. Genetic counseling is recommended for affected individuals and their families.

The treatment of factor X deficiency has greatly improved in the last several years, progressing from broad treatments like fresh frozen plasma to prothrombin complexes (PCCs) and then to a dedicated factor X concentrate approved by the FDA.

Coagadex (human coagulation factor X) is a high-purity, high-potency plasma-derived factor X concentrate approved by FDA and EMA for the treatment of hereditary factor X deficiency in adults and children over the age of 12. It is approved for on-demand treatment and control of bleeding episodes, and for individuals, including those with mild disease, who are about to undergo surgical procedure (perioperative management). This therapy restores functional levels of factor X to affected individuals.

Individuals with factor X 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. Monitoring of the therapy with PCCs is therefore mandatory because they are associated with an increased risk of developing blood clots, especially following repeated administration because most people are only deficient in one of these clotting factors. PCCs undergo a purification process to eliminate viruses and other pathogens.

Some affected individuals may be treated with fresh frozen plasma, which is a blood derivative that comes from blood donors. Fresh frozen plasma contains all the blood clotting factors. Fresh frozen plasma can be virally inactivated, but sometimes is not virally inactivated so there can be risk of infection, however, this risk is extremely low because donors are carefully selected, and the products are screened to ensure they do not contain viruses. There is also a risk of allergic reaction.

In people with mild forms of the disorder, drugs known as antifibrinolytics can be used. These drugs prevent the breakdown of clots in the blood. People who experience heavy menstrual bleeding can be treated with hormonal contraceptives such as birth control pills or with antifibrinolytics. Some individuals may be treated with fibrin glue (sealants). Fibrin glue is applied directly to the site of bleeding. Fibrin is a protein that is essential to the formation of a blood clot. Fibrin glue acts to hold platelets together to strengthen a clot. Fibrin glue is often used for surgery or dental procedures in affected individuals. Fibrin glue is manufactured from various clotting factors obtained from donated plasma.

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Clinical Trials and Studies

Information on current clinical trials is posted on the Internet at https://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:

Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]

Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/for-patients-and-families/information-resources/info-clinical-trials-and-research-studies/

For information about clinical trials sponsored by private sources, contact:
https://www.centerwatch.com/

For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/

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References

JOURNAL ARTICLES

Kulkarni R, James AH, Norton M, Shapiro A. Efficacy, safety and pharmacokinetics of a new high-purity factor X concentrate in women and girls with hereditary factor X deficiency. J Thromb Haemost. 2018;16:849-857. https://www.ncbi.nlm.nih.gov/pubmed/29460388

Escobar MA, Auerswald G, Austin S, et al. Experience of a new high-purity factor X concentrate in subjects with hereditary factor X deficiency undergoing surgery. Haemophilia. 2016;22:713-720. https://www.ncbi.nlm.nih.gov/pubmed/27217097

Siddon AJ, Tormey CA. Successful use of four factor-prothrombin complex concentrate for congenital factor X deficiency in the setting of neurosurgery. Lab Med. 2016;47:e35-37. https://www.ncbi.nlm.nih.gov/pubmed/27378481

Peyvandi F, Menegatti M. Treatment of rare factor deficiencies in 2016. Hematology Am Soc Hematol Educ Program. 2016;2016:663-669. https://www.ncbi.nlm.nih.gov/pubmed/27913544

Austin SK, Kavakli K, Norton M, et al. Efficacy, safety and pharmacokinetics of a new high-purity factor X concentrate in subjects with hereditary factor X deficiency. Haemophilia. 2016;22:419-425. https://www.ncbi.nlm.nih.gov/pubmed/27197801

Unold D, Tormey CA. Clinical applications of 4-factor prothrombin complex concentrate: a practical pathologists’ perspective. Arch Pathol Lab Med. 2015;139:1568-1575. https://www.ncbi.nlm.nih.gov/pubmed/26619030

Girolami A, Cosi E, Sambado L, Girolami B, Randi ML. Complex history of the discovery and characterization of congenital factor X deficiency. Semin Thromb Hemost. 2015;41:359-365. https://www.ncbi.nlm.nih.gov/pubmed/25875733

Karimi M, Vafafar A, Haghpanah S, et al. Efficacy of prophylaxis and genotype-phenotype correlation in patients with severe Factor X deficiency in Iran. Haemophilia. 2012;18:211-215. https://www.ncbi.nlm.nih.gov/pubmed/21854511

Peyvandi F, Palla R, Menegatti M, et al. Coagulation factor activity and clinical bleeding severity in rare bleeding disorders: results from the European Network of Rare Bleeding Disorders. J Thromb Haemost. 2012;10:615-621. https://www.ncbi.nlm.nih.gov/pubmed/22321862

Menegatti M, Peyvandi F. Factor X deficiency. Semin Thromb Hemost. 2009;35:407-415. https://www.ncbi.nlm.nih.gov/pubmed/19598069

INTERNET

MedlinePlus. Factor X deficiency. Available at: https://medlineplus.gov/genetics/condition/factor-x-deficiency/

National Hemophilia Foundation. Factor X. Available at: https://www.hemophilia.org/Bleeding-Disorders/Types-of-Bleeding-Disorders/Other-Factor-Deficiencies/Factor-X Accessed April 27, 2023.

Goudeman J. Congenital factor X deficiency. Orphanet Encyclopedia, October 2020. Available at: https://www.orpha.net/consor4.01/www/cgi-bin/OC_Exp.php?lng=EN&Expert=328 Accessed April 27, 2023.

Mannucci PM. Rare inherited coagulation disorders. UpToDate, Inc. Mar 2, 2022. Available at: https://www.uptodate.com/contens/rare-inherited-coagulation-disorders Accessed April 27, 2023.

McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:227600; Last Update: 05/22/2017. Available at: https://www.omim.org/entry/227600 Accessed April 27, 2023.

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