As part of laboratory investigations for identification of a possible bleeding disorder by determining if the level (amount or concentration) of one or more of your coagulation factors are reduced or absent, called a coagulation factor deficiency or in the case of Hypercoagulable Disorders (looking at risk factors for developing an inappropriate or excessive blood clot), determining if there are any increased level of coagulation factors.
There are a few situations when these tests may be performed:
- If you have unexplained or excessive bruising or prolonged bleeding, either spontaneously or from injuries or surgery.
- For women and girls who experience very heavy periods
- Further investigation of an abnormal Prothrombin Time (PT) or Activated Partial Thromboplastin Time (aPTT) screening test, result.
- You have a relative with a known hereditary coagulation factor deficiency.
- If you have been diagnosed with a coagulation factor deficiency your healthcare professional may test your factor level to determine the effectiveness of any treatment given and guide further therapy. Your factor level may also be measured at a routine clinic appointment to provide a current result.
- You have another medical condition that may affect level of coagulation factors, and cause bleeding this is called an Acquired Deficiency (not inherited).
- As part of investigations for a Hypercoagulable Disorder (increased clotting).
A blood sample taken using a needle from a vein in your arm. The blood sample is collected into a sodium citrate blood tube to prevent your blood clotting prior to testing. The correct volume of blood must be collected in the tube for an accurate result and unfortunately if the tube is over or underfilled it may not be suitable for testing and sample will need to be collected again.
In general, no test preparation is needed, however:
- Eating a high fat meal prior to the blood test should be avoided as may interfere with testing.
- If you have recently been ill, inform your healthcare professional as inflammation can affect coagulation factor levels.
- Ideally, blood samples for these tests need to be received in the laboratory quite promptly, therefore it may not be possible to have the samples collected in your local GP surgery for example.
Specific levels of individual coagulation factors.
Coagulation factors are a group of proteins that circulate through the body in the blood and are triggered following an injury to the blood vessel to work together in a sequence to make a blood clot. This is an essential process for stopping bleeding. When a patient has experienced unexplained bruising or excessive bleeding,or they have a history within the family of these symptoms one possible cause is a reduction in the level of a coagulation factor in their blood. Measuring the level of these factors can help a healthcare professional determine the cause of bruising and/or bleeding and provide guidance on the appropriate treatment for the future.
In most cases, the level of an individual coagulation factor in the blood is determined by using a functional assay, which measures the amount of activity. This type of test actually measures how well the protein is working, therefore a reduced activity level is found if there is a deficiency of the protein or if the protein is present but not working correctly. iRarely, coagulation factor antigen tests may be perform this can measure how much of the protein is present but not whether it is working correctly. This test can be helpful in some coagulation factor deficiencies in identifying different sub-types.
When an injury occurs that results in bleeding, a number of processes are triggered, between the vessel wall, circulating platelets and coagulation factors, this results in plugging the hole in the bleeding vessel with a clot while still keeping blood flowing through the vessel by preventing the clot from getting too large. The first part of the process involves activation of platelets and interaction with von Willebrand factor and subendothelium of the damaged vessel wall. This provides a scaffold which is reinforced by the second part of the process, the coagulation system which consists of a series of proteins (coagulation factors) that activate in a step-by-step process called the coagulation cascade. This results in the formation of insoluble fibrin threads that link together at the site of injuryto form a stable blood clot. The clot prevents additional blood loss and remains in place until the injured area has healed.
Blood clotting is dynamic; once a clot is formed other factors are activated that slow clotting and begin to dissolve the clot in a process called fibrinolysis. The clot is eventually removed as the injured site is healed. In normal healthy individuals, this balance between clot formation and removal ensures that bleeding does not become excessive, and that clots only occur where and for as long as they are needed.
The key coagulation factor proteins that form the coagulation cascade are listed in the table below and commonly today they are referred to by Roman numerals. However, the level of each coagulation factor is not routinely measured for all investigations. For some of the coagulation factors there is no evidence that a reduced level causes any bleeding symptoms, while for others deficiency only causes mild bleeding and for some deficiency causes a range of symptoms from mild to severe bleeding. Due to this variation, the patients clinical and family history, bruising and/or bleeding symptoms and results of coagulation screening tests, help inform the healthcare professional on the most appropriate coagulation factors to measure.
Other Common Name
Proaccelerin, labile factor
Proconvertin, stable factor
Antihaemophilic factor A
Antihaemophilic factor B, Christmas factor
Antihaemophilic factor C
Fibrin stabilising factor
How is it used?
Coagulation factor levels are used by health care professionals for:
- Investigation and diagnosis to determine if there is a reduced or absent (very low) coagulation factor level, that would provide an explanation for a person’s bruising or bleeding symptoms.
- Monitoring of coagulation factor level during treatment.
Identification of high coagulation factor levels as part of risk assessment for a hypercoagulable disorders.
When is it requested?
Coagulation factor tests may be requested when someone is experiencing increased bleeding or bruising or has a prolonged Prothrombin Time (PT) or Activated Partial Thromboplastin Time (aPTT). The PT and aPTT tests are used as screening tools to determine if there is a potential problem with any of the coagulation factors, however, they may not be prolonged with all mild deficiencies.
Coagulation factor testing may be requested when there is suspicion that a patient has an inherited or acquired factor deficiency. If an inherited deficiency is suspected, other family members may also be tested to help confirm the diagnosis and to establish the pattern of inheritance.
Coagulation factors are made in the liver and may be measured when the patient is suspected of having an acquired condition that is causing bleeding, such as vitamin K deficiency (vitamin K is needed to make some of the coagulation factors function), liver disease or suspected autoantibodies. Coagulation factor testing is routinely performed on a patient with a known deficiency to monitor effectiveness of treatment particularly during surgery or major trauma.
What does the test result mean?
Coagulation factor activity levels within the normal range usually means that coagulation function is normal. Reduced activity of one or more coagulation factor levels usually means that the coagulation system is impaired and not working optimally. Each coagulation factor must be present in sufficient quantity and quality in order for normal coagulation to occur, but the critical level required to prevent symptoms varies for each factor. Results are usually reported in iu/dL or as a percentage %. In general, the normal range for each coagulation factors is 50 – 150 iu/dL or %, however, there may be some minor local variation.
Coagulation factor deficiencies are categorised as mild, moderate or severe (see table example below). In most cases mild or moderate deficiencies will require little, if any day-to-day treatment but will usually need treatment to cover any surgery or trauma. Severe deficiencies associated with significant bleeding will require ongoing treatment and clinical support.
Factor Deficiency Guidance Level of Coagulation Factor iu/dL or % Mild Moderate Severe FII >10 to Normal <10 <1 FV >10 to Normal <10 <1 FVII >20 to Normal 10-20 <10 FVIII >5-30 1-5 <1` FIX >5-30 1-5 <1 FX >40 to Normal 10-40 <10
Key: > = greater than < = less than
Inherited coagulation factor defiencies are rare and tend to involve only one factor, which may be reduced or absent. The severity of symptoms experienced by a patient with an inherited factor deficiency depends on the coagulation factor involved and the amount available. Site and severity of bleeding symptoms depends on which coagulation factor is deficient, e.g Factor XI deficiency is associated with mucosal bleeding (oral and nasal cavities), whereas Haemophilia Factor VIII or IX are associated with soft tissue and joint bleeds. Patients with a modest reduction in a coagulation factor level may experience few symptoms and frequently may not discover their deficiency until an adult, after a surgical procedure, trauma or during a routine coagulation screening . Those with severe factor deficiencies may have their first bleeding episode very early; for example, a male infant with a deficiency of Factor VIII or IX severe haematomas when starting to crawl or XIII may bleed excessively after circumcision. If there is a known family history and identified risk that a baby may be affected, then it is pre-natal testing may be possible and appropriate precautions taken during delivery.
Acquired deficiencies may be due to chronic diseases, such as liver disease or cancer; to an acute condition which uses up coagulation factors at a rapid rate; development of autoantibodies to specific coagulation factors, or to a deficiency in vitamin K or treatment with a vitamin K antagonist like warfarin (the production of factors II, VII, IX, and X require vitamin K). If more than one clotting factor is decreased, it is usually due to an acquired condition. Factors may be decreased because of:
- consumption due to extensive clotting
- liver disease
- some cancers
- severe infections
- development of autoantibodies to coagulation factors
- exposure to snake venom
- vitamin K deficiency
- warfarin anticoagulation therapy
- accidental ingestion of the anticoagulant warfarin or some poisons
- multiple blood transfusions (stored units of blood lose some of their clotting factors)
Elevated levels of several factors are seen in situations of acute illness, stress, or inflammation. Some patients have persistent elevations of coagulation factors that may be associated with an increased risk of venous thrombosis.
Is there anything else I should know?
For inherited coagulation factor deficiencies, there is now a number of treatment options to mitigate the identified reduced or absent coagulation factor(s). In general mild deficiencies do not require day-to-day treatment but need therapy for surgical procedures or trauma and treatment of choice is usually Tranexamic Acid which slows down the breakdown of a blot clot and/or desmopressin (DDAVP, a drug that stimulates the body to increase levels of Factor VIII and von Willebrand Factor. For patients with severe conditions and symptomatic moderates, specific recombinant factor replacement therapy (commercially genetically engineered) , is the most frequently used treatment and depending on the best treatment option for the patient, can be given as regular prophylaxis to prevent bleeds or on-demand to treat, by infusing through a vein. For severe haemophilia A there is now a new treatment option, a drug Emicizumab, which is an antibody and removes the need for factor VIII. This is given as a small sub-cutaneous skin injection, that has many advantages, particularly if antibodies to factor VIII are present. For factor deficiencies where factor replacement therapies have not been developed then a transfusion of fresh frozen plasma (FFP), which contains all of the missing factors or cryoprecipitate as appropriate.
For acquired coagulation factor deficiencies treatment options as appropriate, include vitamin K, fresh frozen plasma, antidotes to anticoagulant therapy and for the serious situation when autoantibodies present, immunosuppression therapy and coagulation factor by-passing agents.
What is von Willebrand factor?
von Willebrand factor (VWF) is not part of the coagulation cascade, but is responsible for helping platelets stick to the injured blood vessel wall, providing a structure for the coagulation factors to form a fibrin clot. A deficiency or abnormality in von Willebrand factor can cause von Willebrand disease, an inherited bleeding disorder, often found in patients with very heavy periods. It is also associated with a decrease in factor VIII levels , as von Willebrand factor also binds to and protects factor VIII in the blood stream. Therefore, its important when investigations have identified a low factor VIII level to also check the VWF level to clarify diagnosis.
Why are some inherited bleeding disorders more severe than others?
Inherited bleeding disorder are rare and due to a faulty gene being passed from a parent to a child, although about 30% of patients diagnosed have no known family history and are thought to be due to random gene mutations. The classification of a coagulation factor deficiency depends on the level i.e. the lower the level the more serious, but the severity of the bruising and bleeding symptoms is also dependent on the inheritance pattern and the specific role of a coagulation factor within the coagulation cascade. Factor XI is an exception where the level does not correlate well with the severity of bleeding symptoms and can cause issues with treatment and in the case of Factor XII deficiency, regardless of severity does not cause bleeding problems. In general, severe bleeding disorders are identified in infancy or early childhood, whereas milder defects identified throughout life due to investigations for easy bruising/bleeding symptoms, increased bleeding associated with surgery or trauma or routine blood tests. It is important to note in general the fault in the gene stays the same within families and is linked to severity of bleeding. Bleeding disorders can be inherited, usually in 3 different ways depending on the coagulation factor:
- X-linked inheritance
Haemophilia A or B are probably the best-known bleeding disorders, which is caused by a gene fault on the X chromosome, one of the two sex chromosomes and depending on the fault in the gene depends on whether mild, moderate or severe haemophilia is inherited. This means that it is normally only males that have symptoms if they have inherited the faulty gene due to only having one X chromosome. If females inherited a faulty gene they are called carriers of haemophilia A or B and are usually asymptomatic or have mild bleeding symptoms as most commonly they have one normal gene and one faulty gene.
Most other bleeding disorders are not linked to the sex chromosomes and the faulty gene is on an autosomal chromosome. Autosomal chromosomes are inherited in pairs, one from each parent and therefore disorders affect men and women equally.
- Autosomal dominance inheritance
This is where the faulty gene is on an autosomal chromosome but a male or female only has to inherit one chromosome with the faulty gene to have the bleeding disorder and symptoms.
- Autosomal recessive inheritance
This is where the faulty gene is on an autosomal chromosome but a male or female has to inherit one chromosome with the faulty gene from each parent to have the bleeding disorder and symptoms or one parent to be a carrier.
- X-linked inheritance