Factor XI deficiency

Related Terms

Anemia, bleeding, blood disorder, clotting, coagulation, factor XI, FXI deficiency, hemophilia, hemophilia C, hemorrhage, menorrhagia, plasma thromboplastin antecedent deficiency, PTA, Rosenthal's syndrome, Rosenthal syndrome, thrombosis.

Background

Factor XI deficiency is a rare inherited bleeding disorder that occurs when an individual has too little of a protein called factor XI. Factor XI is a clotting factor that plays a key role in the clotting, or coagulation, cascade that is triggered when a blood vessel is damaged. Factor XI may also be called hemophilia C or Rosenthal syndrome. Hemophilia refers to an inherited clotting disorder. There are three types of hemophilia: A, B, and C. Dr. Rosenthal first described Factor XI deficiency in 1953 and originally called it "plasma thromboplastin antecedent deficiency."
Clotting or coagulation disorders occur when the blood does not form clots properly. Blood clots are clumps of different types of blood cells and proteins called clotting factors that stop bleeding after an injury. The process of blood clotting is called coagulation or hemostasis.
When a blood vessel breaks due to an injury or surgical incision, it narrows to slow blood flow so that clotting can begin. At the same time, the blood that has leaked outside of the injured blood vessel presses against the vessel to help prevent further blood loss. Blood cells called platelets are activated to move toward the site of injury. Once platelets reach the site of injury, a series of reactions started by enzymes called coagulation factors lead to the activation of a protein called thrombin. Factor XI is one of the coagulation factors. These factors convert a blood clotting factor, fibrinogen, into long strands that form a net around the platelets and blood cells to help trap more platelets to form a blood clot.
The blood clot, called a thrombus, is a temporary plug to control bleeding. Once the platelets are clumped together, they become activated and stick together. Sometimes blood clots are visible and appear as bruises under the skin or scabs on the skin. Once the blood vessel is healed, other blood factors are released to destroy the clot by dissolving it into the blood.
People with Factor XI deficiency are unable to properly form clots and may experience prolonged bleeding in response to severe injuries. However, they do not experience spontaneous bleeding in the absence of injury or other trauma. Patients may experience excessive and potentially fatal bleeding after undergoing surgical or dental procedures. The risk of hemorrhaging, or uncontrolled bleeding, may vary throughout an affected person's life.
Factor XI deficiency is the fourth most common coagulation disorder after von Willebrand's disease and hemophilia A and B. Bleeding episodes associated with Factor XI deficiency are milder and occur less frequently than bleeding episodes in these other bleeding disorders. Although the symptoms of Factor XI deficiency can occur at any age, many people with this condition do not even know they have it. Factor XI deficiency is often first detected during the routine blood testing that happens before a surgical procedure.
Treatment of Factor XI deficiency is usually necessary only in the case of a surgery or a severe injury. Treatment involves replacement of factor XI using fresh frozen plasma, which contains factor XI and other clotting factors.
Factor XI deficiency is caused by a genetic defect, or mutation, in the F11 gene that codes for the factor XI protein. The disease is caused by different mutations in different people. More than 80 different mutations have been found that result in Factor XI deficiency and some are found in genes other than the F11 gene. Men and women are affected in equal numbers. This disorder affects approximately one out of 100,000 people worldwide.

Signs and symptoms

Hemorrhaging, or uncontrolled bleeding, is the main symptom of coagulation disorders. People with Factor XI deficiency are unable to properly form blood clots and may experience prolonged bleeding in response to injuries. Patients may also experience excessive and potentially fatal bleeding after undergoing surgical or dental procedures. The risk of hemorrhaging may vary throughout an affected person's life.
In contrast to hemophilias A and B, bleeding episodes in Factor XI deficiency (also called hemophilia C) occur less frequently and are not likely to occur spontaneously. Many people with Factor XI deficiency are not aware that they have the condition. For unknown reasons, the level of factor XI does not act as a predictor of bleeding risk. Within a single patient and among family members, highly variable and unpredictable bleeding patterns can occur.
Hemorrhaging may occur in infants when undergoing circumcision. Some people with Factor XI deficiency may be more prone to bruising, nosebleeds, or blood in the urine. The highest risk of hemorrhaging occurs with dental extractions, severe injuries, or surgery, especially surgeries of the mouth, tonsils, and urinary tract. Females may experience longer and heavier bleeding during the menstrual period, which is called menorrhagia. A mother with Factor XI deficiency may hemorrhage after giving birth.

Diagnosis

General: Many people with Factor XI deficiency do not know that they have the disorder. It is often first detected during the routine blood testing that happens before a surgical procedure. Factor XI deficiency is distinguished from hemophilia A and B by the fact that it does not lead to bleeding into the joints. The first signs of severe bleeding may occur at circumcision or much later in life, for example, during surgery.
Bleeding time test: The bleeding time test is a blood test that looks at how fast small blood vessels close following a bleeding incident. In this test, a blood pressure cuff is inflated around the upper arm and then two small cuts are made on the lower arm to cause a tiny amount of bleeding. The blood pressure cuff is immediately deflated and then blotting paper is touched to the cuts every 30 seconds until the bleeding stops. The results are the time that it takes for the cuts to stop bleeding. People with Factor XI deficiency have a longer than normal bleeding time. A normal bleeding time is between two and seven minutes.
Family history: A family history of bleeding episodes resulting from severe injuries or during dental procedures or surgeries may indicate that a person carries the mutation for Factor XI deficiency.
Genetic testing: Genetic testing is generally not available for this disorder because the gene that causes Factor XI deficiency may have one of more than 80 identified mutations. If the variation of the mutation is known to be common in a certain family, genetic testing may be available in some cases.
Platelet function test: A platelet function test may be performed to rule out platelet function disorders as a cause of bleeding. In this test, blood is drawn and mixed with chemicals in order to determine whether platelets are functioning properly. There are a variety of platelet function tests available.
Prothrombin time (PT) test: Prothrombin, a precursor to thrombin, is important in the blood clotting process. The prothrombin time test is a blood test that measures the time it takes for the liquid portion of the blood (plasma) to clot. A blood sample is taken, mixed with chemicals that trigger coagulation, and the time that it takes to form a clot is measured. People with Factor XI deficiency have a longer than normal prothrombin time. A normal prothrombin time is between 12 and 15 seconds.
Activated partial thromboplastin time (aPTT) test: Thromboplastin is a coagulation factor that is necessary for forming a blood clot. In the activated partial thromboplastin time test, blood is collected and mixed with an activator such as silica, celite, kaolin, or ellagic acid. The time it takes to form a clot is measured. People with Factor XI deficiency have a longer than normal activated partial thromboplastin time. A normal activated partial thromboplastin time is between 20 and 40 seconds.
Factor XI assay: A factor XI assay is a blood test in which the amount and activity of factor XI is measured in a diagnostic laboratory. It is useful in the diagnosis of coagulation disorders and for ruling out combined coagulation factor deficiencies.

Complications

Anemia: Anemia is caused when there are not enough red blood cells or when the red blood cells do not contain enough hemoglobin, a protein that makes the blood red and carries oxygen in the bloodstream. People with anemia do not get enough oxygen delivered to their tissues by the blood. Without oxygen, the organs and tissues cannot work as well as they should. People with anemia may feel dizzy and faint. One cause of anemia is excessive blood loss, which may occur in patients with Factor XI deficiency.
Excessive bleeding: If bleeding is not stopped following surgery or major injuries, excessive blood loss may lead to death. This is uncommon and usually occurs only in situations in which emergency treatment is not available.
Factor XI inhibitors: Rarely, people with Factor XI deficiency will develop inhibitors to factor XI protein after exposure to clotting factors. Because treatment with fresh frozen plasma is ineffective in patients with inhibitors, other therapies must be used. Traditionally, such patients have been treated with plasma exchange, the chemotherapy drug cyclophosphamide, intravenous (IV) immunoglobulin (which boosts the immune system), or prothrombin complex concentrate, which contains clotting factors. Newer alternatives include recombinant activated factor VII and the antifibrinolytic agent, tranexamic acid.
Hepatitis C virus (HCV) or HIV: In the past, donated blood that was used to obtain replacement clotting factors was not routinely screened, and the blood was frequently contaminated with the hepatitis C virus (HCV) or HIV. Therefore, many patients who received replacement clotting factor treatment were at risk for HCV or HIV infection. Although this risk is lower today, care should always be taken to ensure that blood is screened for HCV, HIV, and other blood-borne infections before a blood transfusion begins.
Surgery: Certain procedures carry an increased risk of bleeding, such as dental extractions, tonsil removal, surgery in the urinary and genital tracts, and nasal surgery.
Thrombosis: Thrombosis is the formation of a clot or thrombus inside a blood vessel that obstructs the flow of blood. Thrombosis may occur following prolonged treatment with clotting factors, especially in patients with liver disease. If prolonged fresh frozen plasma infusion is necessary, a small amount of heparin (a blood thinner) may be added to decrease the risk of excessive clotting.

Treatment

General: Currently there is no known cure for Factor XI deficiency. Treatment is usually not necessary, except in the case of a dental procedure or surgery. In these cases, fresh frozen plasma or recombinant (artificial) factor XI may be used. Patients with Factor XI deficiency generally do not need treatment or preventive therapy for routine functions or activities. Patients should tell their doctors if they are taking any prescription or over-the-counter drugs, herbs, or supplements because they may interact with treatment and worsen disease symptoms.
Aspirin: Aspirin increases the risk of bleeding by inhibiting platelet function. Patients with Factor XI deficiency should therefore not take aspirin or blood-thinning medications such as warfarin or heparin.
Blood transfusions: Patients who suffer from severe bleeding may receive blood transfusions with donated blood. Anyone likely to receive blood derivatives as part of a treatment should be vaccinated against hepatitis A and B.
Clotting factors: Individuals with more severe forms of Factor XI deficiency may require replacement of factor XI using fresh frozen plasma. Successful treatment has been reported during surgeries with the use of plasma, prothrombin complex concentrates, and recombinant activated factor VII. Prothrombin complex concentrates are made from human plasma. They contain clotting factors II, VII, IX, and X; C protein; a small amount of heparin to protect against thrombosis (excessive clot formation); and vitamin K. This therapy works by supplying the necessary enzymes to activate the clotting cascade. It is important to get fresh frozen plasma into the blood during sudden bleeding episodes or before surgery.
Because Factor XI is not concentrated in fresh frozen plasma, considerable amounts of plasma may be required to maintain the factor level. In the case of mouth bleeding, drugs that help with clotting (antifibrinolytic products), such as Amicar, can be helpful. Currently there are two factor XI concentrates produced in Europe. One is manufactured by Bioproducts Laboratories in the UK. The other is produced in France by LFB and is available for only limited patient use.
Invasive surgical procedures often require fresh frozen plasma replacement, which should be continued for seven to 14 days after surgery. Dental procedures have been performed safely with the use of factor replacement. Administration of the antifibrinolytic drug tranexamic acid alone has been successful as a preparation for dental extraction. The treatment is started before the procedure and continued for a week following it.
Childbirth: Pregnant women may need fresh frozen plasma if a cesarean delivery is planned, although this practice is controversial. It is common to treat patients to maintain factor XI levels above 50% during labor and to continue treatment for three to four days after vaginal delivery and seven days after cesarean delivery because of the high risk of hemorrhage.
Medications: The use of desmopressin, an antidiuretic that reduces fluid loss, has been studied in a limited number of patients with Factor XI deficiency to try to reduce clotting time. The true benefit of this treatment is unclear, and it is not recommended for major surgical procedures. Antifibrinolytic therapy has been used in the treatment of women with Factor XI deficiency and menorrhagia (long and heavy menstrual flow).

Integrative therapies

Note: Currently, there is insufficient evidence available on the safety and effectiveness of integrative therapies for the prevention or treatment of Factor XI deficiency. The therapies listed below have been studied for the prevention or treatment of bleeding or hemorrhaging. They should be used only under the supervision of a qualified healthcare provider and should not be used in replacement of other proven therapies or preventive measures.
Good scientific evidence:
Rhubarb: Rhubarb has been used in traditional Chinese medicine for many disorders associated with the stomach and intestine, including upper gastrointestinal bleeding. Early studies suggest that rhubarb may help reduce upper gastrointestinal bleeding. Higher quality studies are necessary before a firm recommendation can be made. Avoid in individuals who are allergic or sensitive to rhubarb. Avoid using rhubarb for more than two weeks because it may induce tolerance in the colon, melanosis coli (a colon disorder), laxative dependence, pathological alterations in the colonic smooth muscles, and substantial loss of electrolytes. Rhubarb should be avoided in individuals with atony, colitis, Crohn's disease, dehydration with electrolyte depletion, diarrhea, hemorrhoids, insufficient liver function, intestinal obstruction or ileus, irritable bowel syndrome, menstruation, pre-eclampsia (high blood pressure during pregnancy), kidney disorders, ulcerative colitis (colon tumors), and urinary problems. Avoid handling rhubarb leaves, as they may cause allergic skin reactions. Avoid use of rhubarb in children under age 12 because of the potential for water depletion. Use cautiously with bleeding disorders, cardiac conditions, coagulation therapy, constipation, history of kidney stones, or thin or brittle bones. Use cautiously if taking antipsychotic drugs or oral drugs, herbs, or supplements, including calcium, iron, and zinc. Avoid if pregnant or breastfeeding.
Unclear or conflicting scientific evidence:
Bellis perennis: Bellis perennis is a common European species of daisy. Bellis perennis has been used traditionally for treating wounds. In homeopathy, Bellis perennis is often used in combination with Arnica montana to treat bruising and trauma. Common daisy is widely used in homeopathy but is currently only rarely used in herbal medicine. Although homeopathic dosing is Generally Recognized as Safe (GRAS) by the U.S. Food and Drug Administration (FDA), there is a lack of well-designed clinical trials to support claims for efficacy related to the use of Bellis perennis. More research is needed in this area. Avoid if allergic or hypersensitive to Bellis perennis, its constituents, or other plants of the Asteraceae/Compositae family, such as ragweed, chrysanthemums, marigolds, and dandelion. Use cautiously if taking anticoagulants or with bleeding disorders. Use cautiously if at risk for coagulation disorders such as strokes or blood clots. Use cautiously with anemia. Avoid use in children at traditional herbal doses because of the possibility of stunted growth. Avoid if pregnant or breastfeeding because of the possibility of growth retardation in the fetus and infant.
Hypnosis: There is inconclusive evidence from early studies of hypnosis therapy for hemophilia, a bleeding disorder. Additional study is needed before a firm conclusion can be drawn. Use cautiously with mental illnesses such as psychosis or schizophrenia, bipolar disorder, multiple personality disorder, or dissociative disorders. Use cautiously with seizure disorders. Reported side effects include changes in skin temperature, heart rate, intestinal secretions and immune response, decreased blood pressure and brain wave patterns, disturbing memories, and false memories.
Vitamin K: Vitamin K is found in green leafy vegetables, such as spinach, broccoli, asparagus, and watercress, as well as in foods such as cabbage, cauliflower, green peas, beans, olives, canola oil, soybeans, meat, cereals, and dairy products. Vitamin K is essential for normal blood clotting. Because patients with Factor XI deficiency cannot form blood clots normally, supplementation with vitamin K may be beneficial. Vitamin K deficiency in infants may lead to hemorrhagic disease of the newborn, also known as vitamin K deficiency bleeding (VKDB). Although almost half of newborns may have some degree of vitamin K deficiency, serious hemorrhagic disease is rare. Because vitamin K given by injection has been shown to prevent VKBD in newborns and young infants, the American Academy of Pediatrics recommends administering a single intramuscular injection of vitamin K1 to all newborns. Oral dosing is not considered adequate as prevention, particularly in breastfeeding infants. Initial concerns of cancer risk were never proven and are generally not considered clinically relevant. In cases of true VKDB, bleeding may occur at injection sites, at the umbilicus, or in the gastrointestinal tract. Life-threatening bleeding into the head (intracranial) or in the area behind the lower abdomen (retroperitoneum) may also occur. Evaluation by a physician is imperative.

Prevention

General: Because Factor XI deficiency is inherited, there is currently no known way to prevent the condition. However, individuals can take steps to reduce their risk of excessive bleeding that can be caused or worsened by certain lifestyle or nutritional habits. It is important for patients to tell their doctor if they are trying a new diet or taking any new prescription or over-the-counter drugs, herbs, or supplements (e.g., aspirin or related medicines, nonsteroidal anti-inflammatory drugs, such as ibuprofen, or vitamin K) because they may be causing or worsening symptoms. Regular dental care is important to help avoid dental surgeries. Patients should wear a MedicAlert?bracelet or chain at all times engraved with the type of coagulation problem.
Aspirin: Aspirin increases the risk of bleeding by inhibiting platelet function. Patients with Factor XI deficiency should therefore not take aspirin or blood-thinning medicines such as warfarin or heparin.
Genetic counseling: Individuals who have Factor XI deficiency may meet with a genetic counselor before having children to determine whether they carry the defective F11 gene. Carriers can be determined through detailed family histories. If the variation of the mutation is known to be common in a certain family, genetic testing may be available in some cases.

Author information

This information has been edited and peer-reviewed by contributors to the Natural Standard Research Collaboration (www.naturalstandard.com).

Bibliography

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Franchini M, Veneri D, Lippi G. Inherited factor XI deficiency: a concise review. Hematology. 2006 Oct;11(5):307-9.
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O'Connell NM. Factor XI deficiency. Semin Hematol. 2004 Jan;41(1 Suppl 1):76-81.
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Causes

General: Factor XI deficiency is a rare inherited bleeding disorder that occurs when an individual has too little of a protein called factor XI. Factor XI is a clotting factor that plays a key role in the clotting, or coagulation, cascade that is triggered when a blood vessel is damaged.
Genetic mutations: Factor XI deficiency is caused by a mutation in the F11 gene, which is located on chromosome 4 and provides instructions for making the clotting factor XI protein. The disease is caused by different mutations in different people and sometimes even in different genes. More than 80 different mutations have been found that result in a loss of factor XI function.
Autosomal recessive inheritance: Factor XI deficiency is inherited in an autosomal recessive manner. Genes are inherited on alleles or genetic variants of a specific gene. Individuals receive two copies of most genes, one from the mother and one from the father. Because Factor XI deficiency is an autosomal recessive disorder, an individual must inherit two mutated alleles to have the disease. People who have only one mutated allele do not experience symptoms but are called "carriers" because they can pass the mutated gene to their children. If one parent is a carrier, there is a 50% chance with each birth that the child will also be a carrier and a 0% chance that the child will inherit the disease. If both parents are carriers, there is a 25% chance with each birth that the child will inherit the disease, a 50% chance that each child will be a carrier, and a 25% chance that each child will inherit neither mutated allele.

Risk factors

General: Because Factor XI deficiency is inherited, the only known risk factor is a family history of the disorder. Men and women are affected in equal numbers. This disorder affects approximately one out of 100,000 people.
Ethnicity: Although a rare disorder, the frequency of Factor XI deficiency is high in certain populations, including people of Jewish descent, particularly in individuals of Ashkenazi origin. In Israel, Factor XI deficiency has been estimated to affect about 8% of Ashkenazi Jewish individuals, making it one of the most common genetic disorders in this group. Factor XI deficiency has also been reported in the French Basque population and may be common in persons of African ancestry. It is estimated that 3.7% of Jewish people in Iraq carry a mutation for Factor XI deficiency. Of patients with bleeding disorders in the United Kingdom, 5% have Factor XI deficiency, although most of these patients are not of Jewish heritage.
Autosomal recessive inheritance: Factor XI deficiency is inherited in an autosomal recessive manner. Genes are inherited as alleles or genetic variants of a specific gene. Individuals receive two copies of most genes, one from the mother and one from the father. Because Factor XI deficiency is an autosomal recessive disorder, an individual must inherit two mutated alleles to have the disease. People who have only one mutated allele do not experience symptoms but are called "carriers" because they can pass the mutated gene to their children. If one parent is a carrier, there is a 50% chance with each birth that the child will also be a carrier and a 0% chance that the child will inherit the disease. If both parents are carriers, there is a 25% chance with each birth that the child will inherit the disease, a 50% chance that each child will be a carrier, and a 25% chance that each child will inherit neither mutated allele.