Congenital Factor XIII Deficiency
What is Factor XIII Deficiency?
Your body takes a series of complex steps to stop bleeding. It begins when small blood vessels called capillaries are injured, resulting in vessel constriction and formation of a platelet plug at the site of injury. This triggers a process called clotting, in which a group of proteins, or factors, work together to create a firm blood clot. This process results in a protein called fibrin. Fibrin then forms strands that link together, much like a net weaving in and around the platelets. This net makes the blood clot stable and stops the bleeding until the vessel wall can heal.
Factor XIII (13) is one of the factors that plays a unique role in helping your blood clot. While it’s not one of the factors that make your blood clot, it’s important in making a strong clot. In order to work, factor XIII is turned on, or activated, by a protein called thrombin and also calcium in the blood. As the last step in the blood clotting pathway, it does this by helping to cross link the fibrin strands, essentially turning a group of strings of fibrin into a strong mesh, or net. This also makes it harder for the clot to break down. This is why it was originally called fibrin-stabilizing factor (FSF).
1. Upon vessel injury, the clotting cascade initiates. Fribrinogen (factor I) is converted to fibrin through various simultaneous reactions involving the clotting factors, forming a mesh-like structure.
2. Activated factor XIII cross-links the fibrin mesh to stabilize the clot.
People with congenital (or inherited) factor XIII deficiency are born with low levels of factor XIII in the blood. Congenital factor XIII deficiency is very rare, affecting only 1 in 2 million people – about 100-125 people in the US.
Even though the initial clot forms and bleeding stops, the clot will eventually break down. The bleeding resumes within 12 to 48 hours following surgery or trauma due to the breakdown of the blood clot. This results in a lifelong tendency to develop severe bruising, muscle and joint bleeding, miscarriages, bleeding in the brain, bleeding associated with pregnancy/delivery, and bleeding following surgery or trauma. People with congenital factor XIII deficiency also can have problems with wound healing after an injury or surgery, and can have problems in conceiving and carrying a pregnancy to full term.
The normal amount of factor XIII activity in the blood varies greatly, between about 53% and 221%. Recently, an international organization proposed a classification of factor XIII severity based upon the percentage of factor activity and associated symptoms although the connection between factor activity and symptoms is much less strong in congenital factor XIII deficiency than in some other factor deficiencies like hemophilia. Measuring factor XIII levels is more challenging than in some other bleeding disorders too (see “How is it diagnosed?” below).
- Mild (≥ 30% activity): Patients are mostly asymptomatic, but might have problems with bleeding during trauma, a surgical procedure or with pregnancy/delivery.
- Moderate (<30% activity): Patients may have mild spontaneous bleeding, or bleeding triggered by trauma, a surgery, or pregnancy/delivery.
- Severe (undetectable activity): Patients may have spontaneous, severe, and even life-threatening bleeding.
There are 2 types of congenital factor XIII deficiency because factor XIII actually is made in 2 parts. The A-part (called A-subunit) of factor XIII is responsible for linking the fibrin together; it’s called the enzyme or enzymatic part. The B-part (called B-subunit) acts like a protective glove (picture a baseball in a mitt) that travels around in the bloodstream with the A-part and protects it from being broken down so it stays in the bloodstream longer. Most people with congenital factor XIII deficiency actually area missing or have a non-functional A-part. This occurs in about 95% or in 19 of 20 affected people.
Interestingly, the A- and B-parts of factor XIII aren’t even made in the same place in your body. Cells in your bone marrow produce the A-part and it’s made in pairs. The B-parts are made in your liver, which enter the bloodstream, where they join together with the A-parts – like a ball and glove.
What causes it?
About 1 in 2 million people worldwide have congenital factor XIII deficiency. Men and women are affected equally and it impacts all ethnicities. Children are often diagnosed early in life after experiencing bleeding at the umbilical cord, by family history or due to serious bleeding episodes including potential bleeding in the brain if routine replacement therapy is not instituted.
Humans have 22 pairs of chromosomes (autosomes) plus the sex chromosomes (X and Y). Unlike congenital hemophilia which is a recessive gene defect within the X-chromosome and is therefore typically seen in boys only, congenital factor XIII deficiency is an “autosomal recessive” disorder that affects both males and females. The “recessive” part means you need to inherit one affected gene from each of your parents to have the disorder. Parents may either have congenital factor XIII deficiency (2 affected genes – called homozygous) or be “carriers” (one unaffected and one affected gene – called heterozygous). The illustrations below show the potential inheritance patterns of an autosomal recessive disorder.
These risks apply to each pregnancy. For example, if both parents are carriers, then each pregnancy has a 1 in 4 chance the child will be affected. The chance of having 2 children with factor XIII deficiency is ¼ (1st pregnancy) x ¼ (2nd pregnancy) or 1/16 (1 in 16).
It’s a little more complicated than this in congenital factor XIII deficiency since there are actually 2 genes, one for the A-part and one for the B-part. The gene for the A-part of factor XIII (called FXIIIA) is on chromosome 6, and there have been more than 60 abnormalities identified; 95% of patients with congenital factor XIII deficiency have this gene defect. The gene for the B-part (called FXIIIB) is on chromosome 1, and there are only a few families around the world with this extremely rare deficiency, about 1 in 20 patients with congenital factor XIII deficiency.
In addition to the 2 different genes coding 2 proteins, congenital factor XIII deficiency is also a little more complicated in that patients who only have 1 affected gene (carriers) can actually show symptoms, which is referred to as heterozygous deficiency. Carriers who have only one affected copy of the A- or B- gene can bleed after surgery, trauma, or dental work. In addition, women may have menorrhagia (heavy menstrual periods) and postpartum hemorrhage (bleeding after childbirth). The results of a recent study suggest that even though true factor XIII B-subunit deficiency is rare, symptomatic carriers of B- abnormalities (heterozygous B-subunit deficiency) are more common than previously thought.
What are the symptoms?
The first case of congenital factor XIII deficiency was described by Dr. Duckert in Zurich, Switzerland in 1960, and demonstrates many of the cardinal symptoms of the disease. He saw a 7 year old boy with a history of bleeding from the umbilical cord 12 days after birth, bleeding in the head after a minor trauma at one year of age, and numerous other bumps and bruises that bled for weeks to months from wounds that healed very slowly. His 18 month old brother had similar symptoms. Two great-uncles on his mother’s side died of bleeding – one from the umbilical cord after birth and the other from bleeding in the brain.
Twenty years later, Dr. Lorand pooled all the case descriptions that had been written about congenital factor XIII deficiency, which at that point totaled 90 proven cases and 22 additional suspected cases (eg. relatives of known patients). These data highlight 80% of patients demonstrating umbilical bleeding just after birth, and the 30% of patients without replacement therapy experiencing bleeding in the head, often leading to death. The figure below from that data continues to be noted as one of the best summaries of bleeding types in this very rare disease.
Looking at these symptoms in a little more detail:
- Umbilical bleeding - Frequently, the first clinical sign of congenital factor XIII deficiency a few days after birth or when the cord separates.
- Bruising/Skin/Muscles - Patients experience a lifelong tendency to superficial bruising (60%) as well as bleeding in and under the skin, in the mouth and gums, and in muscles.
- Bleeding in the brain - The high incidence of bleeding in the brain (30%, nearly 1 in 3 patients) is a hallmark of congenital factor XIII deficiency. Brain bleeds can occur with or without trauma, and often at an early age. They are the main cause of death for patients with severe factor XIII deficiency that do not receive monthly/regular replacement therapy.
- Surgery/Trauma - Bleeding after surgery/trauma is common, and delayed wound healing can also occur in up to 17% of patients.
- Pregnancy/Delivery - Women with congenital factor XIII deficiency are often unable to carry a pregnancy to term and suffer early spontaneous miscarriages.
Generally, bleeding severity depends on the level of factor XIII activity in the blood. Those with very low levels may experience severe spontaneous bleeding. Other people with congenital factor XIII deficiency may have no symptoms at all. Patients with severe congenital factor XIII deficiency may develop life-threatening bleeds in the head without routine replacement of factor XIII. However, there is not an exact match between bleeding symptoms and factor level, and the lab tests used to measure factor levels are not very exact at low levels (less than 10% activity).
Since this is a pretty rare disorder with less than a thousand patients known in the world, you might wonder just how many patients are “severe”, and how many have “no symptoms”. While congenital factor XIII deficiency may be rare, there are a few “large” studies that have pooled data from across many countries to try to answer this question. In the International FXIII Deficiency Registry of 104 people with congenital factor XIII deficiency, just over half have severe bleeding, and most of the rest have moderate or mild bleeding.
In a different study by the European Network of Rare Bleeding Disorders (EN-RBD), just about half of 42 patients with congenital factor XIII deficiency had severe symptoms with major bleeding, but a higher percentage (almost 4 in 10) had no symptoms.
People who have congenital factor XIII deficiency should watch for these signs and symptoms in the parts of the body listed below:
Symptoms of bleeding in the brain
- Drowsiness or loss of consciousness
- Headache or neck ache
- Nausea and vomiting
- Sensitivity to light
- Difficulty with walking, coordination or confusion/disorientation balance
- Personality change, crying, irritability, or behavioral change
- Change in size of one of the pupils of the eye
- Slurred or difficult speech
Symptoms of bleeding in the stomach or intestines
- Vomit that is black and syrupy, bright red or looks like coffee grounds
- Upset stomach or nausea
- Red- or black-colored stool
- Abdominal pain
Symptoms of joint bleeding
- Swelling, pain, redness, tingling sensation or warmth around a joint
- Inability to straighten or bend a joint normally
- Tight and shiny appearance of skin over the joint
Symptoms of muscle bleeding
- Tight and shiny appearance of skin
- Swelling in a limb around muscles
- Weakness, tingling, or pain in the arms or legs
- Color change may occur causing the surrounding area to turn blue
Symptoms of bleeding in and around the spinal cord
- Difficulty with urination or bowel movements
- Weakness, tingling, or pain in the arms or legs
Other symptoms to report
- Bleeding from the nose, gums, or mouth
- Bleeding after surgery
- Easy bruising
- Heavy menstrual bleeding in women
How is it diagnosed?
Congenital factor XIII deficiency is difficult to diagnose. Standard blood clotting tests do not detect the deficiency, and many laboratories are not equipped with more specialized tests that measure the amount of factor XIII in a blood sample or how well factor XIII is working. The high rate of bleeding at birth (umbilical cord, circumcision) usually leads your health care professional to suspect a bleeding disorder.
International guidelines have been developed to help your health care professional to diagnose congenital factor XIII deficiency:
- Screening tests - Results from standard hemostatic screening tests such as prothrombin time (PT) and activated partial thromboplastin time (aPTT) are normal in congenital factor XIII deficiency. The number of platelets (platelet count) is also normal.
- Clot solubility assay - Assessment of the stability of a blood clot looking at how long it takes to break down is a common test that can be run in many labs. Called the clot solubility assay (CSA), it involves taking the plasma from the patient’s blood and mixing with calcium and thrombin to make a clot. In the presence of factor XIII, the clot is stable for 24 hours or more; in its absence, the clot dissolves in minutes to hours. Patients must have severe deficiency (less than 1-3% activity) for the CSA to be abnormal.
- Factor XIII activity – There are some tests that can measure the factor XIII activity levels in the blood, including most commonly the Berichrom assay. These use a chemical reaction to determine the amount of factor XIII. This is pretty accurate for factor XIII levels above 10-20%, but is less precise for low levels (below 10%). Normal factor XIII activity is between 53% and 221%.
- Immunologic assays of protein – There are tests that involve identifying the exact amount of the A- and B- proteins, and in their absence whether the patient with congenital factor XIII deficiency is missing the A- or B- part of factor XIII.
- Genotyping – The genes that code for the A-part and B-part of factor XIII (FXIIIA and FXIIIB) can be examined by looking at the exact genetic makeup in your specific genes and determine if the sequences have abnormalities. This also may provide some insight into whether a patient has a problem with the A- or B- part of factor XIII.
How is it treated?
Treatment can depend on the severity of the congenital factor XIII deficiency (how low the factor XIII activity level), whether you have bleeding symptoms and what type of bleed you may have, or what type of procedure you may be undergoing. Your health care professional or treatment center team will make specific recommendations on the best approaches for each situation.
There are some general guidelines that have been developed to help physicians to manage patients with congenital factor XIII deficiency.
In general, because of the risk of bleeding in the brain, it is typically recommended that patients with severe congenital factor XIII deficiency be placed on routine replacement therapy to prevent bleeding, called prophylaxis. Because factor XIII lasts a long time in the blood, patients only need to have an injection of a factor XIII product into their vein about every month. Replacement can be done with recombinant and plasma derived products that increase factor XIII levels.
Replacement therapy does not mean you won’t bleed if you get in an accident or have a surgical procedure. Trauma and surgery result in bleeding in people without congenital factor XIII deficiency. Depending on the timing of any trauma or surgery relative to when the last infusion was given, your health care professional may recommend additional factor XIII infusions. In various clinical studies, bleeding requiring additional factor XIII treatment happened about once in every 7-10 years of treatment, and were more common in younger, more active children and adolescents.
For abnormal/excess bleeding associated with monthly periods in women, use of hormonal treatment may be recommended. In situations where bleeding does not stop quickly or more serious bleeds or trauma, oral agents (eg. antifibrinolytic medications), and/or factor XIII replacement may be recommended to get your bleed under control.
Surgery and dental procedures
Surgery and dental procedures require some planning for patients with congenital factor XIII deficiency. Your healthcare professional or treatment center team will help decide on a strategy for preventing unwanted bleeding during the procedure, and decide on a post-operative course to make sure that you heal properly. A combination of local strategies, medications, and/or factor XIII replacement therapy may be recommended. They will also coordinate with the dentist, surgeon, and anesthesiologist. Given the long time factor XIII stays in your blood, you may only need one or two infusions of factor XIII.
People with congenital factor XIII deficiency often have trouble becoming pregnant and carrying a baby to term. Therefore, it is very important that any women who want to become pregnant should first develop a plan with their healthcare professional or treatment center team to decide if any treatment is needed around pregnancy, delivery, or in case of bleeding after birth.
People with inherited bleeding disorders should not take aspirin, nonsteroidal anti-inflammatory drugs (such as ibuprofen and naproxen), and blood thinners, and should avoid certain herbal supplements which impact platelet function and thus can make bleeding symptoms worse. Call your doctor or treatment center team about any medications you are not sure of so instructions may be given before they are used.
Complications of treatment
Antibodies and inhibitors
Factor XIII replacement therapy may be given in patients with congenital factor XIII deficiency. Because your body does not have the normal factor XIII, your body might not recognize the factor XIII replacement therapy. Your body may react and produce antibodies to factor XIII replacement therapy. If the antibodies block the activity of factor XIII, they are called inhibitors. Congenital factor XIII deficiency is very uncommon, and there are only a handful of cases where antibodies of any kind have been found.
Tips for staying healthy
Develop a comprehensive care plan
Be sure to follow any maintenance or preventive measures your health care professional has planned for you. Congenital factor XIII deficiency can be a severe condition for some patients, but with the right care and support it can be properly managed. Even for those with mild or moderate deficiency, you should develop a care plan that accounts for potential treatment associated with trauma or dental or surgical procedures.
- Know where to receive emergency care and how to contact your treatment center for immediate treatment.
- Wear a medic alert bracelet AND carry other emergency medical identification stating your bleeding disorder and recommended therapy. EMT’s are not trained to look into wallets for medical information cards. When they do look there it is usually too late. Wearing a medic alert is the best way to alert anyone in the case of an emergency when the patient cannot speak for themselves.
- Maintain good dental hygiene to avoid gum disease that could lead to bleeding.
- Avoid anti-inflammatory drugs (e.g., aspirin, ibuprofen, naproxen) or herbal supplements that affect platelets, unless your health care professional directs you to use them.
- Discuss your desired activities and sports participation with your healthcare professional to determine which activities are most appropriate for you. At different ages, certain activities pose a higher risk of bleeding.
- Women - Discuss your menstrual bleeding and any issues with planned pregnancy/childbirth with your hematologist and obstetrician/gynecology.
Share your Congenital Factor XIII Deficiency experience
Because it is rare, congenital factor XIII deficiency often goes undiagnosed. And, unlike other rare bleeding disorders, there is not a lot of information available to help people with congenital factor XIII deficiency understand their condition. It’s probably also harder because those on routine replacement therapy might not have a bleed requiring treatment for many years, so you many not think about reaching out until you need to have a surgery or want to become pregnant.
Once you have a greater understanding and gain experience, you have an opportunity to become an advocate for yourself and others. If you know family members, friends, or families with congenital factor XIII deficiency in your community or region, it is important that you share what you know with them as well as your local HTC. Doing so may help build a stronger congenital factor XIII deficiency community.