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

• F13 Deficiency
• Fibrin Stabilizing Factor Deficiency
• Laki-Lorand Factor Deficiency

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

• Factor XIII Deficiency is an extremely rare bleeding disorder caused by the depletion of factor XIII in blood. Factor XIII is a protein that stabilizes blood clots
• Factor XIII (F XIII or factor 13) 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 XIII
• 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 XIII Deficiency can be of two types:
  • Inherited Factor XIII Deficiency, owing to mutation(s) in the F13A1 or F13B genes
  • Acquired Factor XIII Deficiency that arise from immune disorders or liver dysfunction
• The affected individuals may present with tendency to bruise easily, abnormal bleeding during surgery or post-trauma, as well as spontaneous bleeding in the brain. Newborn children may present bleeding from umbilical stump (soon after birth)
• Women may experience severe bleeding during menses, repeated miscarriages, and, complications during and after pregnancy
• The treatment for Factor XIII Deficiency may include infusion of fresh frozen plasma and the administration of factor XIII concentrate. However, in some individuals, spontaneous bleeding in the brain may be life-threatening

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

• Factor XIII Deficiency is an extremely rare condition affecting about 1 in 2-5 million individuals. This bleeding disorder is considered to be among the rarest of all bleeding disorders
• The manifestation of symptoms typically occurs soon after birth in the inherited form. However, those with the acquired form may develop symptoms later in life
• Factor XIII Deficiency occurs without a gender bias and affects both males and females
• The disorder is reported to occur without any racial or ethnic bias

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

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

• Having a family history of the disorder
• Children of parents who are close blood relatives (such as first cousins) may have an increased risk
• Immune disorders (such as lupus and scleroderma)
• Liver disease
• Chronic kidney failure
• Myeloid forms of certain cancers
• Use of certain medications such as penicillin, phenytoin, and valproate

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 XIII Deficiency? (Etiology)

Inherited Factor XIII Deficiency is caused by mutation(s) in the F13A1 or F13B genes. The F13A1 gene mutation is more commonly observed among the affected individuals.

• The two genes code for two subunits of the factor XIII protein
• The factor XIII protein plays a crucial role in the end of the clotting cascade, in stabilizing the newly formed clots
• Mutation(s) in F13A1 or F13B genes can lead to non-assembly of factor XIII protein, thereby effectively reducing its concentration in the body
• This results in the weakening of clots, leading to the bleeding disorder

Factor XIII 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.

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

• Liver disease, since liver is the site of factor XIII subunit B synthesis
• Autoimmune disorders, in which an individual’s antibodies mistakenly attack his/her own healthy cells
• Chronic kidney failure
• Certain types of cancer
• Medications such as penicillin, valproate and phenytoin

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 XIII, are central to the action of these pathways. Each factor activates the next in a stepwise manner
• Factor XIII is a protein that is necessary for the stabilization of newly-formed clots. Absence of this factor weakens the clots, leading to bleeding

In addition to stabilizing clots, Factor XIII also plays important roles in the following:

• Generation of new blood vessels (angiogenesis)
• Proper wound healing
• Maintaining pregnancy to full term

Therefore, depletion in factor XIII may also affect the above events and result in symptoms.

What are the Signs and Symptoms of Factor XIII Deficiency?

The signs and symptoms develop soon after birth in inherited form of Factor XIII Deficiency, and later in life in the acquired form of Factor XIII Deficiency. The signs and symptoms are more severe in the inherited form and milder in the acquired form.

The signs and symptoms may vary from one individual to another. The signs and symptoms reported in Factor XIII Deficiency include:

• Bleeding from umbilical stump: About 80% of those affected by inherited Factor XIII Deficiency are reported to have umbilical stump bleeding after birth
• Nosebleeds
• Bleeding from the gums
• Easy bruising
• Bleeding following circumcision
• Excessive bleeding after trauma
• Bleeding from the mouth following a dental procedure
• Problems with wound healing and formation of abnormal scars
• Hematoma (pooled, congealed blood) formation
• Bleeding in the joints (hemarthrosis), which may cause the following:
  • Swelling
  • Stiffness and pain
  • Tingling sensation
  • The joint may feel warm to touch
• Bleeding in the central nervous system, including the brain and spinal cord, which may cause:
  • Headaches
  • Seizures
  • Numbness
  • Nausea and vomiting
  • Vision changes
  • Confusion
• Bleeding in the gastrointestinal tract, causing:
  • Abdominal pain
  • Black, tarry stools
  • Weakness
  • Light-headedness
• Bleeding in the muscles, causing:
  • Severe pain
  • Difficulty in moving the affected muscle tissue
  • Loss of sensation in the affected area
• Bleeding in lungs in rare cases, causing
  • Difficulty breathing
  • Cough, which may contain blood
• Bleeding from the eyes, ears and spleen, which may occur on rare occasions
• Infertility in men

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

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

In cases with Acquired Factor XIII Deficiency, the signs and symptoms may include those of the pre-existing condition that caused Factor XIII Deficiency.

How is Factor XIII Deficiency Diagnosed?

The diagnosis of Factor XIII 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
• Clot solubility test:
  • In Factor XIII Deficiency, the clot formation is normal. Therefore, the usual blood tests to check for prolonged clotting times will be normal
  • The clot solubility test uses a blood clot to specific strengths of monochloroacetic acid or urea
  • Clots with low concentrations of factor XIII disintegrates during this test
• Blood tests to assess the quantity and activity of factor XIII
• Liver function test
• In addition, if Factor XIII 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 XIII Deficiency?

The potential complications of Factor XIII Deficiency may include: 

• Anemia from excessive bleeding
• Problems with movement owing to pain in the muscles and joints
• Increased incidence of brain stroke
• Spontaneous bleeding in the brain (intra-cranial bleeding) may cause seizures, and can be life-threatening
• Treatment complication: Thrombosis due to treatment with factor XIII concentrate

How is Factor XIII Deficiency Treated?

The treatment options for Factor XIII Deficiency are tailor-made for each individual’s specific needs. The treatment methods may include:

• Infusion of factor XIII concentrate, which may be done prophylactically to minimize development of symptoms 
• Infusion of fresh frozen plasma
• Infusion of cryoprecipitate: This method is only used when factor XIII concentrate is unavailable during life-threatening emergencies
• In women, the following methods may be adopted to avoid excessive bleeding during menstruation:
  • Use of intra-uterine contraceptive devices
  • Contraceptive pills 
  • Antifibrinolytic drugs, such as aminocaproic acid
• Additional treatments pertaining to the particular predisposing condition in case of acquired Factor XIII Deficiency

How can Factor XIII Deficiency be Prevented?

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

• Seeking medical attention for treatment of conditions known to predispose an individual to Factor XIII Deficiency may help minimize one’s 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 XIII Deficiency

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

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

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

• Prophylactic treatment with factor XIII concentrate can help minimize the development of symptoms
• However, spontaneous bleeding in the brain occurs in 30% of the cases, which can cause life-threatening complications. Intra-cranial bleeding is the main cause of death in Factor XIII Deficiency

Additional and Relevant Useful Information for Factor XIII Deficiency:

Factor XIII Deficiency may also be known as the following:

• F XIII Deficiency
• Factor 13 Deficiency