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

• Coagulation Factor 12 Deficiency
• HAF Deficiency
• Hageman Factor Deficiency

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

• Factor XII Deficiency is an extremely rare condition that is caused by the depletion of factor XII in blood. The deficiency of factor XII leads to delayed clotting in affected individuals
• Factor XII (F XII or factor 12) is one of the 12 clotting factors that are labeled factors I to XIII (factors V and VI actually denote the same clotting factor)
• 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
• There are two subtypes of Factor XII Deficiency, namely:
  • Inherited Factor XII Deficiency: It is the most common subtype of the disorder, caused by mutation(s) in the F12 gene. An individual is born with the disorder
  • Acquired Factor XII Deficiency arises as a result of a pre-existing condition that include certain autoimmune disorders, liver failure, or nephrotic syndrome
• Most individuals with Factor XII Deficiency are asymptomatic. Oftentimes, the only indication that an individual has the disorder is the extended blood clotting time recorded during a lab test
• The blood of individual with the disorder may take an unusually long time to clot in tests such as the partial thromboplastin time (PTT) or serum prothrombin (PT) time
• Thus, in many cases, the diagnosis of Factor XII Deficiency is often incidental, such as when blood tests are done before a surgery. Since, affected individuals in most cases are asymptomatic, treatment is typically not required for Factor XII Deficiency and the prognosis is generally good

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

• Factor XII Deficiency is an extremely rare disorder, estimated to occur at a frequency of 1:1,000,000. Since many of those affected do not present any symptoms, the exact prevalence of the disorder is unknown
• Males and females are affected in equal numbers
• Individuals of Asian descent are more susceptible to the condition than those from other racial or ethnic backgrounds
• It is reported that Factor XII Deficiency has been identified in 1.5% to 3% of healthy blood donors

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

The risk factors for Factor XII Deficiency may include:

• A family history of the condition
• Autoimmune disorders such as anticoagulant positive lupus
• Antiphospholipid syndrome
• Von Willebrand disease
• Factor VIII or factor IX deficiency disorder
• Nephrotic syndrome
• Advanced liver dysfunction
• Liver transplantation, when the donor liver carries the condition

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 XII Deficiency? (Etiology)

Inherited Factor XII Deficiency is caused by mutations in the F12 gene.

• The F12 gene codes for the glycoprotein known as factor XII or Hageman factor. This protein is generated in the liver
• This glycoprotein is a clotting factor and may also play important roles in tissue repair and formation of new blood vessels
• When the F12 gene is mutated, the factor XII glycoprotein levels are depleted, leading to prolonged clotting time

Factor XII Deficiency is inherited in an autosomal recessive manner. In this type of inheritance, an individual must possess both copies of the causative F12 gene in the defective form in each of his/her body’s cells for the disorder to occur. An affected individual inherits a single defective copy pf the gene from each parent.

Acquired Factor XII Deficiency can also be caused by the following conditions/factors:

• Nephrotic syndrome, in which factor XII may be lost in urine resulting in deficient levels of factor XII
• Antiphospholipid syndrome, in which anti-factor XII can be generated, depleting the levels of factor XII in the body
• Anti-coagulant positive lupus, in which antibodies to factor XII have been reported
• Advanced liver disease
• Liver transplantation
• Von Willebrand disease
• Factor VIII or factor IX deficiency disorder

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 XII, are central to the action of these pathways. Each factor activates the next in a stepwise manner

Factor XII is active in the intrinsic pathway. It assists in activating thrombin. Factor XII is made in the liver and circulates in blood in its active form (unlike most of the other factors, which circulate in the inactive form and must be activated).

What are the Signs and Symptoms of Factor XII Deficiency?

Generally, individuals with Factor XII Deficiency do not exhibit any significant signs and symptoms. However, in very rare cases, mild to severe symptoms can occur. When signs and symptoms of Factor XII Deficiency do occur, they may include: 

• Easy bruising
• Nosebleeds
• Bleeding from the gums
• Blood in urine or stools

Additionally, the signs and symptoms of the pre-existing condition causing acquired Factor XII Deficiency may be noted.

How is Factor XII Deficiency Diagnosed?

The diagnosis of Factor XII Deficiency is usually made accidentally, through a routine coagulation blood test done prior to a surgery, or following a family history of coagulation conditions.

• Blood tests to measure time taken for clot formation include:
  • Serum prothrombin or PT time test
  • Partial thromboplastin time (PTT) test
• The test results may prompt further tests, such as:
  • A thorough physical examination
  • Evaluation of one’s family medical history
  • Blood tests to measure factor XII levels
• Liver function test
• In addition, if Factor XII Deficiency is acquired, relevant tests pertaining to pre-existing conditions may be necessary

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 XII Deficiency?

The following are some potential complications of Factor XII Deficiency:

• Increased incidence of brain stroke 
• Clot formation in the lung
• Deep vein thrombosis

There are also reports that suggest an association between Factor XII Deficiency and repeated unexplained miscarriages in some affected women. However, such an association is not well-understood and presently remains controversial.

How is Factor XII Deficiency Treated?

• Inherited Factor XII Deficiency generally does not require any treatment 
• In cases of acquired Factor XII Deficiency, appropriate treatment for the pre-existing condition that caused the disorder is provided

How can Factor XII Deficiency be Prevented?

Inherited Factor XII Deficiency is a genetic disorder, and presently there are no methods or guidelines available for the prevention of this condition.

• 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 XII Deficiency
• The acquired form of Factor XII Deficiency can be addressed through proper treatment of the causative (pre-existing) condition

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

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

The prognosis of Factor XII Deficiency depends on the severity of one’s signs and symptoms, the individual’s overall health, and his/her response to treatment.

• Generally, in the inherited form, the affected individuals are able manage the condition and live normal lives
• Most individuals with Factor XII Deficiency are able to withstand procedures, such as dental extraction, as well as major surgery, without abnormal bleeding episodes
• However, if Factor XII Deficiency occurs secondary to a pre-existing condition (acquired), then the outcome may be determined by the severity of the underlying disorder

Additional and Relevant Useful information for Factor XII Deficiency:

The following are some additional synonyms for Factor XII Deficiency:

• F XII Deficiency
• F12 Deficiency
• Factor 12 Deficiency
• Hageman Trait

Factor XII Deficiency was identified by Ratnoff and Colopy during routine preoperative coagulation studies on John Hageman, an adult who had no evidence or history of abnormal bleeding. The disorder was subsequently named Hageman Factor Deficiency to honor this patient.