Factor XIII Deficiency

What is Factor XIII Deficiency?

Factor XIII (FXIII) is a protein that plays an important role in blood clotting or preventing excessive bleeding. A deficiency in this protein can cause a rare bleeding disorder with symptoms ranging from delayed detachment of the umbilical cord in newborns to bleeding in the brain. This protein, when ‘activated’, increases the stability of blood clots and helps to ensure that blood clotting occurs effectively.

Deficiencies in Factor XIII can be either inborn (congenital) or acquired later in life, both of which can lead to poor blood clot formation and a tendency to bleed more than normal. The more common type, acquired FXIII deficiency, usually results due to overconsumption, dilution of the blood, or decreased production of the protein. In rare cases, these individuals may produce antibodies that attack FXIII, causing the deficiency. On the other hand, congenital FXIII deficiency is an inherited disorder, where most people affected typically lack the ‘A’ subunit of the Factor XIII protein.

Apart from its function in blood clotting, FXIII also assists with wound healing, removal of foreign particles by immune cells, tissue repair, and helps the body resist and clear out bacterial infections. The deficiency involves complex genetics, with more than 100 known changes (mutations) in the gene encoding for the ‘A’ subunit of FXIII.

Signs of Factor XIII deficiency can range from delayed separation of the baby’s umbilical cord and bleeding from the stump, to unexplained bleeding in the brain. Patients may also experience poor wound healing, heavier than normal menstrual bleeding, joint bleeding, and spontaneous miscarriages early in pregnancy.

To diagnose any FXIII deficiency, doctors will take into account family history, an individual’s reaction to bleeding events, and specifically designed laboratory tests that find deficiencies. However, this condition is rare, so doctors need to be proactive in recognising it. Although there are preventive and treatment options available, they come with challenges such as limited availability, high cost, potential risk of infection, and complications related to administration. Doctors need to navigate these challenges to provide full care to people with Factor XIII deficiency, emphasizing the need for a team-based treatment approach.

What Causes Factor XIII Deficiency?

Congenital FXIII Deficiency means a person is born with a shortage of a certain blood clotting factor, called Factor XIII or FXIII. This exists mainly in two types: FXIII-A and FXIII-B. They are produced in different types of cells in the body and they come together to form a complex in the blood. There are two versions of this deficiency: acquired and congenital.

Congenital FXIII deficiency is less common and is typically passed down from parents to their children. It’s mostly linked to changes in a gene situated on a specific location on chromosome 6. This gene is responsible for making the FXIII-A part of the complex. To date, scientists have found 153 different genetic changes connected to FXIII deficiency.

Moreover, the FXIII-B part of the complex can also be affected by different genetic changes, mainly in the gene found on chromosome 1. The known alterations in this gene are not very common. But having an issue with the FXIII-B can make the whole complex unstable and lead to a deficiency in FXIII-A. This deficiency is usually less severe.

Acquired FXIII Deficiency on the other hand, happens later in life. It can be due to conditions where the body’s immune system mistakenly attacks itself, such as systemic lupus erythematosus and rheumatoid arthritis, or due to certain medications. Additional causes include conditions that overuse the clotting factor, such as surgery, sepsis, leukemia, and thrombosis. It might also be due to a failure to produce enough clotting factors because of liver disease or treatment with certain medications.

Risk Factors and Frequency for Factor XIII Deficiency

FXIII deficiency is a rare condition that usually affects 1 in 2 to 3 million live births. It’s a bit more common in places like Iran, where more people are related by blood. However, the likelihood of having this condition doesn’t change based on ethnicity or race anywhere in the world. It’s important to note that the calculations of how many people have FXIII deficiency might change as more people become aware of it, testing for it improves, and more people globally use the tuberculosis treatment isoniazid.

Signs and Symptoms of Factor XIII Deficiency

Individuals who have inherited two copies of the same faulty gene (a condition known as “homozygosity”) may experience various symptoms related to problematic bleeding. This can include delayed detachment and bleeding of the child’s umbilical cord, joint bleeds, bleeding within the skull, heavy menstrual bleeding in women, recurrent miscarriages in early pregnancy, delayed bleeding after a surgical operation, and prolonged bleeding following accidents or surgeries. It may also be noticed by caregivers that children bruise easily or bleed from soft tissues when they start to walk or during times of emotional stress. On the other hand, individuals who only possess one copy of the faulty gene (“heterozygotes”) typically do not show any symptoms.

Additionally, up to 80% of newborn babies may experience umbilical cord bleeding, often seen within the first 3 weeks after birth. If the blood plasma level of factor XIII (FXIII), a protein involved in blood clotting, is low, the risk of bleeding can increase dramatically. Severe symptoms are usually seen in those with less than 5% of the normal levels of this protein. Also, it has been observed that the likelihood of significant spontaneous bleeding increases when the FXIII activity falls below 15%. Newborn babies with undetectable FXIII levels usually show symptoms during the neonatal period.

Delayed detachment and bleeding of the umbilical cord
Joint bleeds
Bleeding within the skull
Heavy menstrual bleeding in women
Recurrent miscarriages in early pregnancy
Delayed bleeding after a surgical operation
Prolonged bleeding following accidents or surgeries
Easy bruising or bleeding in children

About 30% of newborn babies with FXIII level less than 1% may unnecessarily experience spontaneous, life-threatening bleeding within the skull. This frequency is notably higher in comparison to other bleeding disorders such as Hemophilia A or B. Also, traumatic bleeding inside the skull is often detected as the first sign of FXIII deficiency in older children, with one-third of them experiencing it recurrently. This condition is associated with a higher risk of death in patients with an FXIII deficiency.

Acquired FXIII deficiency is a rare condition, and the way it shows itself can depend on the cause. In situations where it is arising due to the immune system’s abnormal response, acquired FXIII deficiency commonly results in spontaneous bleeding in the tissues under the skin or the muscles. This primarily affects people aged 70 and above who already have diseases like lupus (SLE), rheumatoid arthritis, and leukemia.

Testing for Factor XIII Deficiency

If there’s a concern that you or your unborn baby might have a bleeding disorder, the first step is usually a thorough review of your personal and familial medical backgrounds. If there’s a history of a bleeding disorder in your family, the doctor will look at the family patterns to get a better understanding of how this disorder could be inherited. From this, they may perform tests on the newborn’s blood from the umbilical cord shortly after birth.

Pregnant individuals might opt to undergo chorionic villous sampling (which involves taking a sample from the placenta) between 10 and 12 weeks of gestation, or amniocentesis (which involves extracting a small amount of amniotic fluid) between 16 and 20 weeks of gestation. These procedures obtain fetal cells which are then used for DNA analysis. Sometimes, doctors may need to take a sample of the fetus’ blood via fetoscopy, a procedure performed at around 20 weeks of gestation. It’s important to know that these procedures carry a small risk – 0.5% of maternal-fetal complications and 1% to 6% of fetal death. Therefore, discussions with experts in genetics and obstetrics are especially important before making a decision about these procedures.

Regular clotting tests like the prothrombin time (PT), activated partial thromboplastin time (aPTT), and international normalized ratio (INR) are helpful in diagnosing many factor deficiencies but do not detect FXIII deficiency. In this deficiency, these tests usually show normal results due to the role FXIII plays in blood clotting. To assess FXIII deficiency, specific lab tests are needed, including the clot solubility test, FXIII activity assay, FXIII antigen assay, inhibitor assay, and genetic analysis.

The clot solubility test is simple and does not require specialised equipment, making it cost-effective. This test looks at how quickly a clot dissolves in 5M urea or 1% monochloroacetic acid. If the clot dissolves quickly (within a few hours), the patient likely has a severe FXIII deficiency. However, other conditions or factors can affect the test results, leading to false positives. Therefore, this test alone is not a confirmation of FXIII deficiency.

Functional assays, if available, are the preferred first-line tests in diagnosing FXIII deficiency. One such test is the ammonia release assay, which measures the release of ammonia during a transglutaminase reaction.

Immunological tests can separate and identify whether the deficiency is in FXIII-A, FXIII-B, or the FXIIIA2B2 complex. However, they might not detect certain rare forms of FXIII deficiency, such as where the FXIII-A subunit is inactive despite being present.

For patients suspected of developing antibodies to FXIII, inhibitor assays are essential. It’s important to note that some tests are available only in certain countries or institutions and might not cover all possible genetic variations. Therefore, ongoing research and collaboration across countries are essential to improve the diagnosis and treatment of FXIII deficiency.

Treatment Options for Factor XIII Deficiency

If a newborn baby is suspected to have FXIII deficiency, it is essential to delay any invasive procedures like circumcision until the diagnosis is confirmed. Treatment plans for each patient should be tailored according to their specific needs.

For those confirmed with FXIII deficiency, healthcare providers typically use products that replace the missing FXIII to manage and prevent episodes of acute bleeding. Two types of these replacement products are catridecagog or products purified from human plasma. Catridecagog, which is also known as Tretten, only contains one part of FXIII but works for most patients with FXIII deficiency. Products derived from human plasma contain both parts of FXIII, making them effective at controlling bleeding in all patients with FXIII deficiency.

In cases where FXIII replacement products are not available, cryoprecipitate (a portion of plasma) and fresh frozen plasma are suitable alternatives. However, use of these alternatives varies by country due to varying safety standards. For instance, many European countries have stopped using cryoprecipitate due to safety concerns like the potential transfer of pathogens, but it remains available in Canada, the United States, and some other countries.

If a patient is experiencing acute bleeding due to FXIII deficiency, the goal is to increase FXIII activity levels in their blood above 5%. A single dose of replacement product will typically achieve this goal.

For patients undergoing surgery with FXIII deficiency, maintaining FXIII activity levels above 5% is crucial. However, additional treatment might be required to manage bleeding during certain procedures.

Pregnant patients who have severe FXIII deficiency also require FXIII replacement. The start of this treatment should ideally be by the fifth week of pregnancy to reduce the risk of miscarriage. FXIII activity levels should be kept above 2% to 3%, and levels above 10% are optimal. Doses typically increase as the pregnancy progresses, and further treatment is given at the onset of labor.

Prophylactic therapy, which is preventative treatment, is necessary for patients with FXIII activity levels below 5% or a history of repeated bleeding episodes. For patients diagnosed with a specific type of FXIII deficiency, they should be treated with a plasma-derived replacement product.

Patients diagnosed with an acquired form of FXIII deficiency might need treatment strategies that include FXIII replacement, medications that prevent the breakdown of blood clots, and treatment to eradicate inhibitors of FXIII. Treatment decisions will vary depending on how severe the inhibitor is.

If you have a bleeding disorder, it might be due to a deficiency in Factor XIII. However, there are other conditions that can mimic this deficiency. These conditions can be due to either a lack of certain substances in your blood, problems with your blood platelets, or other factors. Here are some possibilities:

Inherited conditions such as afibrinogenemia, dyshypofibrinogenemias, α2-plasmin inhibitor deficiency, plasminogen activator inhibitor-1 deficiency, hemophilia A or B, and type III von Willebrand disease
Conditions due to problems with blood platelets, such as Glanzmann thrombasthenia, Bernard Souilier syndrome, and von Willebrand disease types I and II
Lack of other coagulation factors in your blood, including FII, FV, FVII, FX, and FXI
Conditions that may have led to a decrease in factor XIII, such as cancers, autoimmune disorders, certain medications, overuse of this factor, a condition called disseminated intravascular coagulation (DIC) which is severe abnormal clotting in your blood vessels, and liver disease

Your doctor needs to take these possibilities into account to reach the correct diagnosis.

What to expect with Factor XIII Deficiency

Congenital FXIII deficiency, an inherited blood disorder, is very rare. Acquired FXIII deficiency, the non-inherited kind, is even less common. However, proper treatment can often help patients with these conditions to enjoy a normal lifespan. Unfortunately, there aren’t extensive studies confirming this, mainly due to the rarity of these conditions.

If not treated properly, the leading cause of death in these patients is usually intracranial hemorrhage, which is bleeding within the skull.

Around 30% of patients with this disorder who experienced brain bleeding once may likely have it happen again. Among these relapsed cases, about half unfortunately result in death.

It’s also worth noting that the severity of FXIII deficiency can vary greatly from one family to another. The development of counteracting substances like FXIII inhibitors, whether naturally occurring (autoantibodies) or induced antibodies from treatment (alloantibodies), can aggravate the condition and potentially even be life-threatening.

Possible Complications When Diagnosed with Factor XIII Deficiency

If FXIII deficiency is left unattended, it can lead to several complications. These may include:

Bleeding at the navel
Brain bleeds
Repeated loss of unborn babies
Bleeding into joints
Delayed bleeding after surgery or injury
Transmission of diseases from blood products
Creation of FXIII inhibitors
Blood transfusion reactions

Additionally, certain complications can arise due to the use of central venous catheters, which include:

Collapsed lung
Heart rhythm problems
Air bubbles in the veins
Injury to the artery
Infection at the site of the catheter
Narrowing of the vein at the catheter site
Blood clots related to the catheter

It is quite common in patients with undetectable factor activity to develop inhibitors or antibodies to the introduced protein or factor.

Preventing Factor XIII Deficiency

Patients and their families should be thoroughly educated about FXIII deficiency, a rare blood disorder, and its nature. This education should cover possible symptoms, risk factors, and the importance of getting medical help quickly. Doctors should make sure patients understand the need to wear alert jewelry that shows they have FXIII deficiency. This jewellery can help emergency healthcare workers to give the right care if unexpected bleeding occurs.

Patients should be encouraged to register with specialized healthcare centers. These centers can provide expert care at any time, especially during uncontrolled bleeding incidents. People with severe FXIII deficiency need to be informed about different preventive methods, especially if they had a past of bleeding in the brain. Making sure patients follow preventative measures can help lower the chances of serious bleeding problems.

Patients who can become pregnant need advice about pregnancy. This advice should address potential challenges and ways to reduce the risk of losing the baby or bleeding during childbirth. Although FXIII deficiency is rare, steps like patient education, alert systems, and spreading awareness among healthcare providers are important. Working together in this way makes sure people with FXIII deficiency get the best care and support. This helps to prevent and manage bleeding problems effectively.

Frequently asked questions

Factor XIII Deficiency is a rare bleeding disorder caused by a deficiency in the Factor XIII protein, which plays a crucial role in blood clotting. This deficiency can be either congenital (inherited) or acquired later in life, leading to poor blood clot formation and a tendency to bleed more than normal. It can result in symptoms such as delayed detachment of the umbilical cord, bleeding in the brain, poor wound healing, and heavier menstrual bleeding.

Factor XIII deficiency is a rare condition that usually affects 1 in 2 to 3 million live births.

Signs and symptoms of Factor XIII Deficiency include: - Delayed detachment and bleeding of the umbilical cord - Joint bleeds - Bleeding within the skull - Heavy menstrual bleeding in women - Recurrent miscarriages in early pregnancy - Delayed bleeding after a surgical operation - Prolonged bleeding following accidents or surgeries - Easy bruising or bleeding in children In newborn babies, umbilical cord bleeding is common, especially within the first 3 weeks after birth. Severe symptoms are usually seen in those with less than 5% of the normal levels of factor XIII (FXIII) protein. The risk of significant spontaneous bleeding increases when the FXIII activity falls below 15%. Newborn babies with undetectable FXIII levels usually show symptoms during the neonatal period. About 30% of newborn babies with FXIII level less than 1% may unnecessarily experience spontaneous, life-threatening bleeding within the skull. This frequency is notably higher compared to other bleeding disorders. Traumatic bleeding inside the skull is often the first sign of FXIII deficiency in older children, with one-third of them experiencing it recurrently. This condition is associated with a higher risk of death in patients with an FXIII deficiency. Acquired FXIII deficiency, which is a rare condition, can result in spontaneous bleeding in the tissues under the skin or the muscles. This is commonly seen in people aged 70 and above who already have diseases like lupus (SLE), rheumatoid arthritis, and leukemia.

Factor XIII Deficiency can be acquired later in life due to conditions where the body's immune system mistakenly attacks itself, such as systemic lupus erythematosus and rheumatoid arthritis, or due to certain medications. It can also be caused by conditions that overuse the clotting factor, such as surgery, sepsis, leukemia, and thrombosis. Additionally, it might be due to a failure to produce enough clotting factors because of liver disease or treatment with certain medications.

Inherited conditions such as afibrinogenemia, dyshypofibrinogenemias, α2-plasmin inhibitor deficiency, plasminogen activator inhibitor-1 deficiency, hemophilia A or B, and type III von Willebrand disease Conditions due to problems with blood platelets, such as Glanzmann thrombasthenia, Bernard Souilier syndrome, and von Willebrand disease types I and II Lack of other coagulation factors in your blood, including FII, FV, FVII, FX, and FXI Conditions that may have led to a decrease in factor XIII, such as cancers, autoimmune disorders, certain medications, overuse of this factor, a condition called disseminated intravascular coagulation (DIC) which is severe abnormal clotting in your blood vessels, and liver disease

The types of tests needed for Factor XIII Deficiency include: - Thorough review of personal and familial medical backgrounds - Tests on the newborn's blood from the umbilical cord shortly after birth - Chorionic villous sampling or amniocentesis during pregnancy to obtain fetal cells for DNA analysis - Fetoscopy to take a sample of the fetus' blood - Regular clotting tests like prothrombin time (PT), activated partial thromboplastin time (aPTT), and international normalized ratio (INR) - Specific lab tests for FXIII deficiency, including clot solubility test, FXIII activity assay, FXIII antigen assay, inhibitor assay, and genetic analysis - Functional assays like the ammonia release assay - Immunological tests to identify the specific deficiency subtype - Inhibitor assays for patients suspected of developing antibodies to FXIII

Factor XIII Deficiency is typically treated by using replacement products that replace the missing FXIII in the patient's blood. There are two types of replacement products: catridecagog (Tretten) and products purified from human plasma. Catridecagog contains one part of FXIII and is effective for most patients with FXIII deficiency, while products derived from human plasma contain both parts of FXIII and are effective for all patients with FXIII deficiency. In cases where these replacement products are not available, cryoprecipitate and fresh frozen plasma can be used as alternatives. The goal of treatment is to increase FXIII activity levels in the blood above 5%. Prophylactic therapy is necessary for patients with FXIII activity levels below 5% or a history of repeated bleeding episodes. Patients with an acquired form of FXIII deficiency might require additional treatment strategies depending on the severity of the inhibitor.

The side effects when treating Factor XIII Deficiency may include: - Bleeding at the navel - Brain bleeds - Repeated loss of unborn babies - Bleeding into joints - Delayed bleeding after surgery or injury - Transmission of diseases from blood products - Creation of FXIII inhibitors - Blood transfusion reactions Additionally, when using central venous catheters, the following complications can arise: - Collapsed lung - Heart rhythm problems - Air bubbles in the veins - Injury to the artery - Infection at the site of the catheter - Narrowing of the vein at the catheter site - Blood clots related to the catheter

The prognosis for Factor XIII Deficiency can vary depending on the severity of the condition and the individual's response to treatment. However, with proper treatment, many patients with Factor XIII Deficiency can enjoy a normal lifespan. It is important to note that if the condition is not treated properly, the leading cause of death in these patients is usually intracranial hemorrhage, which is bleeding within the skull.

Hematologist