Coagulation factors

What is being analysed?
Clotting factors are proteins essential for clot formation. After being produced by the liver, the clotting factors, which are normally present in the blood in inactive form, go through a process of sequential activation known as the “cascade”. The coagulation cascade model is typically represented by two branches: the extrinsic pathway, which is the initial or triggering phase, activated after damage to a blood vessel, and the intrinsic pathway, which amplifies the initial activation. The combined activity of the two pathways, which rely on different clotting factors, converges in the common pathway to complete the clotting process. Normally, at the end of the common pathway, soluble fibrinogen is converted into insoluble fibrin, which forms a dense mesh and is stabilised at the site of vessel damage by clotting factor XIII. The stabilised fibrin mesh, together with other cellular elements, especially platelets, forms a stable clot. The barrier created in this way prevents further blood from leaking out of the vessel and stays in place until the wound has fully healed. Normally, once the clot has done its job, other factors of the fibrinolytic system dissolve and remove it.

Although all 20 clotting factors are important for the coagulation cascade to work properly, 12 of them are essential. These 12 factors have specific names (see table) but are better known by their number, for example factor VIII. Partial or complete lack of one or more of these factors, or their failure to work properly, can cause excessive bleeding and lead to bleeding disorders.

Clotting factor deficiencies can be acquired or inherited, mild, moderate or severe, temporary or congenital. Inherited deficiencies are rare and usually involve only one factor, which may be missing (partly or completely) or not working. Haemophilia A (factor VIII deficiency) and haemophilia B (factor IX deficiency) are the most common and serious inherited disorders. They are X-linked inherited deficiencies and therefore mainly affect males (women are usually carriers without symptoms). Other inherited clotting factor deficiencies not linked to the X chromosome can occur equally often in both sexes.

The severity of symptoms in patients with an inherited clotting factor deficiency depends on the type of factor involved, how much of the factor is lacking and how severe its functional abnormality is. Symptoms vary greatly, ranging from minor nosebleeds to recurrent bleeding in critical areas such as joints and muscles. While the patient may not have serious problems after small knocks or cuts, dental procedures, surgery or injuries can trigger serious bleeding episodes. Patients with severe deficiencies may have their first bleeding episodes very early; for example, a child with factor VIII deficiency may bleed excessively after an appendix or tonsil operation. On the other hand, patients with mild disorders may have few symptoms and may discover their deficiency in adulthood, after surgery or an injury, or during laboratory tests that include PT and/or APTT.

Acquired deficiencies may be due to chronic diseases, such as liver disease or cancer, to acute conditions such as disseminated intravascular coagulation (DIC, in which clotting factors are used up by excessive activation), or to vitamin K deficiency (vitamin K is needed to produce working factors II, VII, IX and X). Deficiency may partly be due to the use of anticoagulant or antithrombotic medicines, especially coumarins (warfarin and acenocoumarol) and, to a lesser extent, heparins. A very rare but equally serious cause is the development of autoantibodies against clotting factors (especially factors VIII and IX). The development of these autoantibodies, called inhibitors, mainly affects patients with severe haemophilia on long-term treatment with replacement factors, but can occur, much more rarely, in normal people. Acquired deficiencies can sometimes involve more than one factor and must therefore be carefully identified and assessed.

How is it used?
When is it requested?
What does the test result mean?
Is there anything else I should know?

How is it used?
Clotting factors are usually measured after abnormal results of the activated partial thromboplastin time (APTT) or prothrombin time (PT). These tests are recommended as initial screening to assess whether the coagulation cascade is working properly. The PT mainly looks at abnormalities of the extrinsic pathway, the APTT at abnormalities of the intrinsic pathway. If one or both tests are prolonged, further tests are needed to identify the type and nature of any clotting factor deficiency. Functional tests (which assess the factor’s activity) or quantitative tests (antigen tests, which assess the presence of the factor) can identify precisely which factor or factors are involved and how severe the deficiency is. An antigen test is not available or useful for all factors.

Additional tests may be carried out, especially when there are multiple deficiencies, to look for diseases that may have caused an acquired deficiency. When there is an inherited clotting factor deficiency, other family members should be tested, both to confirm the patient’s diagnosis and to identify any other carriers of the abnormality, who may have no symptoms or a milder form.

Clotting factors are sometimes measured in patients with a known deficiency to check the extent of the deficiency and the effectiveness of treatment. With acquired deficiencies, clotting factors may be measured to see whether the situation is getting worse or better after treatment of the underlying disease.

When is it requested?
Clotting factors may be requested when the APTT and/or PT are prolonged or in patients with serious bleeding episodes. In some circumstances the test may be requested in patients with acquired conditions that could cause bleeding, such as DIC, eclampsia of pregnancy, liver disease, suspected inhibitors or vitamin K deficiency.

Clotting factors may be measured when a deficiency is clinically suspected, especially in patients who have had bleeding episodes from a young age or who have a family history of the condition.

To establish the nature and/or severity of the deficiency, both a functional assay of the factor (activity) and a quantitative assay (antigen) may be carried out. It may be advisable to repeat the test whenever a patient with a known deficiency is having dental treatment or surgery, has serious bleeding or does not respond to treatment.

What does the test result mean?
A reduced concentration or activity of one or more clotting factors is generally associated with a reduced ability to stop bleeding. Although every clotting factor must be present in sufficient amounts to ensure normal clot formation, the minimum level needed for haemostasis varies greatly. Results are usually reported as a percentage of a set reference range (generally normalised to 100%); for example, clotting factor VIII may be reported as 60%.

Targeted measurement of clotting factors follows the results of the initial screening tests, the APTT (intrinsic pathway) and PT (extrinsic pathway):

• If the APTT is prolonged and the PT is normal, the most common cause is a deficiency of intrinsic pathway factors (factors VIII, IX, XI, XII), of von Willebrand factor or of contact phase factors.
• If the APTT is normal and the PT prolonged, the most common cause may be a deficiency of an extrinsic pathway factor (factor VII).
• If both APTT and PT are prolonged, the most common cause is a multiple deficiency or a deficiency of common pathway factors (factors I, II, X and V).

Raised clotting factor activity or concentration can be seen in some serious diseases, stress or inflammation. These changes are not generally associated with particular diseases, although in some cases they may help increase the risk of thrombosis, especially with increases in fibrinogen and clotting factor VIII.

Normal clotting factor concentration or activity reflects normal haemostatic function. If the concentration of the factor is normal but its activity is reduced, there is generally a functional (qualitative) deficiency. Reduced activity with an almost normal concentration may also reflect the presence of an inhibitor. Reduced activity or concentration of more than one clotting factor usually reflects an acquired condition.

The concentration of several clotting factors can be reduced by DIC, liver disease, cancer, the venom of some snakes (rare in our latitudes), vitamin K deficiency, accidental ingestion of or treatment with oral anticoagulants, and the development of inhibitors.

Is there anything else I should know?
Clotting factor deficiencies, whether inherited or acquired, can be corrected by giving the specific missing factor or factors. This can be done by giving fresh plasma from healthy donors, which contains all the clotting factors, cryoprecipitate, which contains very high concentrations of clotting factors, or solutions containing only the missing factor. In some cases it may be appropriate to give medicines such as desmopressin (DDAVP), which can increase the activity of some clotting factors, especially von Willebrand factor and factor VIII. This option can be used as a temporary and preventive measure, during a bleeding episode or as prophylaxis in patients with a known deficiency who are having dental treatment or surgery.

Before clotting factors are measured, careful procedures for collecting and handling the sample must be followed. Almost all the factors are very unstable, which means that incorrect handling of the sample can cause a progressive loss of activity and/or concentration over time

1. What is von Willebrand factor?
2. Why are some inherited bleeding disorders more severe than others?

1. What is von Willebrand factor?
Von Willebrand factor is closely associated with factor VIII. It is essential for platelets to stick to damaged blood vessel tissue and to each other, processes that are essential for blood clot formation. The disease caused by von Willebrand factor deficiency is called von Willebrand disease, a relatively common inherited bleeding disorder associated with a secondary reduction in clotting factor VIII activity. Although von Willebrand factor may also be requested as part of further investigations of inherited clotting factor deficiencies, it may be requested on its own, as it falls outside the classic view of the coagulation cascade and its deficiency is associated with abnormal platelet function.

2. Why are some inherited bleeding disorders more severe than others?
The severity of a bleeding disorder depends both on the type of factor that is lacking and on the degree of the quantitative or qualitative deficiency. Patients with very severe deficiencies and/or very low factor activity may have more severe bleeding symptoms. In addition, patients with one abnormal gene and one normal gene (heterozygotes) usually have milder bleeding symptoms than patients with two abnormal genes (homozygotes).

Patients with even a complete deficiency of factor XII usually have no symptoms. This inherited deficiency, even in homozygous form, causes significant abnormalities in clotting tests (APTT) but is not associated with an increased risk of bleeding.