What are the other Names for this Condition? (Also known as/Synonyms)

• F11 Deficiency
• Hemophilia C
• Rosenthal Syndrome

What is Factor XI Deficiency? (Definition/Background Information)

• Factor XI Deficiency is a rare bleeding disorder caused by the depletion of factor XI in blood, an important protein in the clotting pathway
• Factor XI (F XI or factor 11) is one of the 12 clotting factors that are labeled factors I to XIII (factors V and VI actually denote the same clotting factor). The liver is the site of synthesis of factor XI
• Clotting factors are proteins that help form blood clots at the site of a blood vessel injury. A blood clot stops further blood loss and allows the blood vessel to continue functioning
• Factor XI Deficiency can be of two types:
  • Inherited Factor XI Deficiency, owing to mutation(s) in the F11 gene
  • Acquired Factor XI Deficiency, due to immune disorders or liver dysfunction
• The affected individuals may be symptomatic; or, they may have skin, mucous membrane, or gastrointestinal bleeding, as well as present abnormal bleeding during surgery or post-trauma
• Women may experience severe bleeding during menses, have additional complications during and after pregnancy. In such cases, there is also an increased risk preterm labor
• Treatment for Factor XI Deficiency involves frozen plasma, anti-fibrinolytic therapy, or prothrombin complex concentrate supplementation. If rare complications, such as thrombosis develop, the prognosis may be guarded

Who gets Factor XI Deficiency? (Age and Sex Distribution)

• Factor XI Deficiency is rare; approximately affecting 1 in 100,000 individuals. Severe deficiency of factor XI is rare and occurs at a frequency of 1 in 1,000,000 individuals
• Individuals of all ages may be affected by the disorder
• Factor XI Deficiency occurs without any gender bias and both males and females are affected. Nevertheless, it is the second most common bleeding disorder in women (the first being von Willebrand disease)
• All races and ethnicities are susceptible to Factor XI Deficiency. However, Ashkenazi Jews (Jews of Eastern European descent) are more vulnerable than other populations

What are the Risk Factors for Factor XI Deficiency? (Predisposing Factors)

The following are some known risk factors for Factor XI Deficiency:

• Having a family history of the disorder
• Being of Ashkenazi Jewish descent
• Certain immune disorders
• Liver disease
• Individuals, who receive liver transplants, have a risk for developing the disorder, if the donor (liver) had Factor XI Deficiency.

It is important to note that having a risk factor does not mean that one will get the condition. A risk factor increases one’s chances of getting a condition compared to an individual without the risk factors. Some risk factors are more important than others.

Also, not having a risk factor does not mean that an individual will not get the condition. It is always important to discuss the effect of risk factors with your healthcare provider.

What are the Causes of Factor XI Deficiency? (Etiology)

Inherited Factor XI Deficiency is caused by mutation(s) in the F11 gene, which codes for the F11 protein, a serine protease enzyme.

• The F11 protein activates factor IX in the intrinsic pathway, which, in turn, activates factor X
• A mutation in the F11 gene leads to deficiency of F11 serine protease enzyme and slows down the clotting pathway, causing bleeding problems in the affected individuals
• Factor XI Deficiency is inherited in an autosomal recessive pattern. In this type of inheritance, an individual must possess both copies of a causative gene in the mutated form in every cell or his/her body, for the disorder to manifest itself. An affected individual inherits a defective copy of the gene from each parent. The parents themselves are typically unaffected and are known as the “carriers” of the disorder
• However, in the case of Factor XI Deficiency, individuals carrying a single defective gene may show some symptoms of the disorder

Acquired Factor XI Deficiency is a rare disorder that may be caused by the following factors/conditions:

• Liver disease, since liver is the site of factor XI production
• Autoimmune disorders, in which an individual’s antibodies mistakenly attack his/her own healthy cells
• Noonan syndrome: It is a type of dwarfism and about 25% of individuals with this syndrome have Factor XI Deficiency

The following is the sequence of events that lead to blood clotting:

• The clotting process starts with injury to a blood vessel, which causes it to constrict. Called the vascular phase, this is the first reaction of a blood vessel to damage. Constriction of a blood vessel reduces the flow of blood to the site of injury, which minimizes blood loss
• Next, the circulating platelets clump along the site of blood vessel injury. The platelets form a foundation for a blood clot and release chemicals that stimulate clotting
• The coagulation phase then causes a blood clot to form. Clotting occurs when an enzyme, called thrombin, converts a soluble protein fibrinogen, into its insoluble form, fibrin. Fibrin proteins make up the bulk of a blood clot
• Thrombin is activated by the merging of two pathways, called the intrinsic and extrinsic pathways, into the common pathway. These are initiated by different parts of the body after blood vessel damage:
  • The intrinsic pathway begins in blood with the activation of circulating proteins
  • The extrinsic pathway begins in the blood vessel with the release of protein factors by damaged cells lining the vessel
• The extrinsic pathway is the first to activate. The intrinsic pathway then reinforces the extrinsic pathway and provides longer-lasting clotting effects
• Coagulation factors, such as factor XI, are central to the action of these pathways. Each factor activates the next in a stepwise manner

Factor XI is a serine protease enzyme that is necessary in the intrinsic clotting pathway to activate factor IX, which in turn activates factor X. The activation of factor X is crucial to the conversion of prothrombin to thrombin.

What are the Signs and Symptoms of Factor XI Deficiency?

The signs and symptoms of Factor XI Deficiency may vary in type and severity among affected individuals. The signs and symptoms may depend on the type of Factor XI Deficiency (whether acquired or inherited). It also depends on whether the individual carries one or two defective copies of the F11 gene in the inherited form. While some of those affected may be asymptomatic, others may present with severe bleeding signs and symptoms. Nevertheless, in a majority of individuals, the signs and symptoms of Factor XI Deficiency are usually mild.

The signs and symptoms of Factor XI Deficiency may include:

• Nosebleeds
• Bleeding from the gums
• Easy bruising
• Bleeding from the umbilical stump (soon after birth of the child)
• Bleeding during circumcision 
• Excessive bleeding after trauma

In severe cases, the signs and symptoms may include:

• Bleeding in the gastrointestinal tract, which may manifest as:
  • Abdominal pain
  • Nausea
  • Blood in stools
• Bleeding in the urinary tract that can result in blood in urine
• Abnormal bleeding during (minor) surgery or other invasive dental procedures

The following additional symptoms are observed in women with Factor XI Deficiency:

• Heavy bleeding during menstruation
• Vaginal bleeding during pregnancy
• Abdominal pain
• Premature labor
• Excessive bleeding during and after delivery

How is Factor XI Deficiency Diagnosed?

The diagnosis of Factor XI Deficiency is made on the basis of the following tools:

• A complete physical examination
• Assessment of signs and symptoms
• Evaluation of one’s personal and family medical history
• Blood tests that include:
  • Complete blood count (CBC)
  • Serum prothrombin or PT time test
  • Partial thromboplastin time (PTT) test
  • Checking for activity of factor XI
  • Liver function test
• In addition, if Factor XI Deficiency is acquired, relevant tests pertaining to pre-existing conditions may be necessary

Factor XI Deficiency is usually diagnosed following excess bleeding after a minor surgical procedure, such as tooth extraction, tonsillectomy, and following minor injuries.

Note:

Certain medications that one is currently taking may influence the outcome of the lab tests. Hence, it is important to inform the healthcare provider of the complete list of medications (including any herbal supplements) one is taking. This will help the healthcare provider interpret the test results more accurately and avoid unnecessary chances of a misdiagnosis.

The laboratory test results are NOT to be interpreted as results of a “stand-alone” test. The test results have to be interpreted after correlating with suitable clinical findings and additional supplemental tests/information. The healthcare providers will explain the meaning of the test results, based on the overall clinical scenario.

Many clinical conditions may have similar signs and symptoms. Your healthcare provider may perform additional tests to rule out other clinical conditions to arrive at a definitive diagnosis.

What are the possible Complications of Factor XI Deficiency?

The potential complications of Factor XI Deficiency may include:

• Anemia from excessive bleeding
• Problems with movement owing to pain in the muscles and joints
• Increased incidence of brain stroke 
• Blood in urine (hematuria) can occur very rarely

Complications related to treatment:

• An increased risk of allergies to treatment with plasma or cryoprecipitate, which may contain substances other than fibrinogen
• An increased risk of pathogenic viral transmission owing to treatment with human blood products
• Antibody development to infused clotting factor XI (observed in about 30% of affected individuals). These antibodies can make factor 11 infusions ineffective. If left unrecognized, it can make the symptoms associated with Factor XI Deficiency even worse

How is Factor XI Deficiency Treated?

The treatment for Factor XI Deficiency is often difficult, since the level of Factor XI Deficiency in the body does not always correlate with severity of the presenting symptoms in the body. Many individuals do not require treatment for the disorder on a day-to-day basis. However, in individuals who are planning to undergo elective surgeries, factor 11 infusions may help in decreasing the incidence of excessive bleeding.

The treatment options for Factor XI Deficiency are based on each individual’s specific needs. The treatment methods may include the use of:

• Factor XI concentrate
• Fresh frozen plasma
• Fibrin glue
• In women, the following methods may be adopted to avoid excessive bleeding during menstruation:
  • Use of intra-uterine contraceptive devices
  • Contraceptive pills for controlling bleeding
  • Anti-fibrinolytic drugs, such as aminocaproic acid
• Prothrombin complex concentrates and recombinant activated factor VII in those with development of inhibitors due to infusion of factor XI concentrate
• If Factor XI Deficiency is acquired due to a liver disorder or other disorders, treatments pertaining to the particular predisposing condition is necessary

How can Factor XI Deficiency be Prevented?

At the present time, no methods or guidelines are available for the prevention of Factor XI Deficiency, since it is predominantly an inherited disorder.

• If one has liver abnormalities known to cause acquired Factor XI Deficiency, seeking medical attention for treatment of such conditions may help minimize the risk for the disorder 
• Genetic testing of the expecting parents (and related family members) and prenatal diagnosis (molecular testing of the fetus during pregnancy) may help in understanding the risks better during pregnancy
• If there is a family history of the condition, then genetic counseling will help assess risks, before planning for a child
• Active research is currently being performed to explore the possibilities for treatment and prevention of inherited genetic disorders such as Factor XI Deficiency

Regular medical screening at periodic intervals with tests and physical examinations are strongly recommended in individuals who have been diagnosed with Factor XI Deficiency.

What is the Prognosis of Factor XI Deficiency? (Outcomes/Resolutions)

The prognosis of Factor XI Deficiency is determined by the severity of symptoms, one’s overall health and response to treatment.

• In most cases, the condition can be managed efficiently, as spontaneous bleeding is rare
• However, it is possible for some individuals to develop severe bleeding, which can cause thromboembolism. In such cases, the condition may be life-threatening

Additional and Relevant Useful Information for Factor XI Deficiency:

The following are some additional synonyms for Factor XI Deficiency:

• F XI Deficiency
• Factor 11 Deficiency
• Plasma Thromboplastin Antecedent (PTA) Deficiency
• Rosenthal Factor Deficiency
• Rosenthal's Disease