APTT

What is being tested?
The activated partial thromboplastin time (APTT, sometimes shortened to PTT) is a measure of how well the intrinsic and common pathways of the coagulation cascade work. The coagulation cascade produces clots to plug an injury in blood vessels, stop bleeding and allow the tissue to heal. The cascade is made up of the clotting factors, a series of proteins activated in sequence starting with factor VII, which, after binding to the tissue factor released by endothelial cells following damage to a vessel, triggers the extrinsic pathway of coagulation. The factor VII–tissue factor complex activates both the common pathway and the intrinsic pathway. While the extrinsic pathway triggers the coagulation cascade, the intrinsic pathway sustains and amplifies the process, also converging on the activation of the common pathway. At the end of the common pathway, the combined action of the extrinsic and intrinsic pathways leads to the formation of a stable clot. When bleeding starts after an injury, all three pathways must work effectively to ensure proper haemostasis.
Every component of the coagulation cascade must be present in the right amount and work effectively to ensure a proper, stable clot forms. If there are inherited or acquired deficiencies of one or more clotting factors, or if the factors do not work properly, an abnormal clot may form and there may be a tendency to excessive bleeding or thrombosis.

In short, the APTT measures the time (in seconds) it takes for a clot to form after suitable reagents are added to the patient’s plasma (the liquid part of the blood) in a reaction cuvette.

How is it used?
The APTT is usually requested when there is apparently unexplained bleeding or, more rarely, thrombosis. Together with the PT (which assesses the extrinsic and common pathways of the coagulation cascade), the APTT is generally requested as an initial test to find the cause of unexplained episodes of bleeding or, more rarely, thrombosis. It may be requested as screening in people with episodes of thrombosis to check for antiphospholipid antibodies. Although there is no unanimous agreement on their predictive value and cost-effectiveness, the APTT and PT are sometimes requested during pre-operative screening to assess the risk of bleeding.
The APTT is also used to monitor anticoagulant treatment with standard heparin, and sometimes to assess the effect of alternative anticoagulant treatments with hirudin and argatroban. These medicines are used instead of heparin in patients with heparin-induced thrombocytopenia, a rare but serious complication of heparin treatment characterised by increased platelet turnover (the development of anti-platelet autoantibodies) following a cross-reaction between the medicine and a protein on the platelet membrane.

If the APTT is prolonged and heparin contamination or pre-analytical variables (difficult blood draw, clotted sample, wrong anticoagulant) can be ruled out, a mixing study is advisable to distinguish between a clotting factor deficiency and the presence of autoantibodies (inhibitors or antiphospholipid antibodies). In this test the patient’s plasma is mixed in equal amounts with pooled plasma from normal people (who have previously been checked for the absence of factor deficiencies or autoantibodies). If the patient’s plasma has a factor deficiency, the APTT should “correct” (shorten) accordingly, as the pooled normal plasma makes up for the deficiency in the patient’s plasma. In this case further tests are needed to identify the factor deficiency precisely. If the APTT remains prolonged after the mixing study, the most likely explanation is the presence of specific or non-specific autoantibodies (inhibitors or antiphospholipid antibodies). In this second case, suitable further tests are carried out to assess the nature of any inhibitor (the factor against which it is directed) or the presence of antiphospholipid antibodies.

When is it requested?
The APTT may be requested, together with other tests such as the PT, when there are episodes of prolonged or unexplained bleeding; in patients with suspected disseminated intravascular coagulation (DIC), a condition characterised by widespread thrombosis and severe bleeding due to progressive consumption of clotting factors; in chronic liver disease (liver failure); and sometimes in patients with venous thromboembolism or recurrent miscarriages, as a screening test for antiphospholipid antibodies.
It may also be requested as part of pre-operative screening to assess the patient’s risk of bleeding, especially before surgery with a high risk of bleeding, in patients with a personal or family history of bleeding episodes (frequent nosebleeds, bleeding gums, bruising) that could suggest an inherited or acquired deficiency of clotting factors or inhibitors.

In patients on anticoagulant treatment with standard heparin given by injection into a vein (sodium heparin) or under the skin (calcium heparin), the APTT is requested at regular intervals to monitor and adjust the effect of treatment, preventing over- or under-dosing. When oral anticoagulants (warfarin or acenocoumarol) are started while the patient is still on heparin, the APTT and PT may be requested at the same time until the patient is stable on oral anticoagulant treatment and heparin is stopped.

What does the test result mean?
Although a normal APTT usually reflects normal haemostatic function, mild factor deficiencies may still be present. As a rule, a deficiency of intrinsic pathway factors does not prolong the APTT until the factor’s activity falls below 30-40%. However, this limit can vary considerably from laboratory to laboratory and depends mainly on the type of reagent used to measure the APTT. A normal APTT also does not rule out antiphospholipid antibodies, especially of the lupus type (lupus anticoagulant); here too, the type of reagent used for the APTT affects the sensitivity of the test. Specific tests must therefore be used when antiphospholipid antibody syndrome is suspected.
A prolonged APTT reflects delayed clotting of the plasma in vitro and/or in vivo, for the many reasons described above. The prolongation is often due to a factor deficiency or to specific or non-specific inhibitors that alter the normal working of the coagulation cascade. Factor deficiencies can be congenital or acquired. Some clotting factors need vitamin K to work properly. Impaired liver function or vitamin K deficiency (low dietary intake, coumarin medicines, cholestasis) are a common cause of deficiencies of the so-called vitamin K-dependent factors (factors II, VII, IX and X). Congenital clotting factor deficiencies can affect both the amount and the function of the factor involved.

Inhibitors are antibodies that bind specifically to clotting factors, such as factors VIII and IX, or they may be non-specific antibodies, such as antiphospholipid and/or lupus-type antibodies, which react with platelet phospholipids. Because phospholipids are essential components of the coagulation cascade included in the APTT reagents, these antibodies can prolong the clotting time, even though clinically they are associated with thrombosis rather than bleeding.

Heparin prolongs the APTT, whether it is used as treatment or contaminates the sample. Heparin is given by injection into a vein or under the skin to prevent or treat venous thromboembolism. Unfractionated (standard) heparin may require laboratory monitoring to avoid overdosing (excessive risk of bleeding) or underdosing (ineffective treatment with a risk of thrombotic episodes). The APTT may therefore be requested to monitor treatment with standard heparin or similar medicines (hirudin or argatroban). Treatment with low-molecular-weight heparin does not usually need monitoring. In particular situations (lack of clinical effect, patients with kidney failure) monitoring of low-molecular-weight heparin may be indicated; in these circumstances the APTT is of little value and an anti-activated factor X (anti-Xa) assay is preferable, although it is available only in some reference laboratories.

A shortened APTT can be found with high concentrations of factor VIII. This can happen particularly in patients with inflammatory reactions, injuries or inflammatory conditions. These are generally temporary situations that do not need monitoring with the APTT, as the APTT returns to within the reference range once the condition resolves. However, a permanently shortened APTT, not directly linked to a concurrent inflammatory condition, may be an additional risk factor for venous thromboembolism.

A falsely prolonged (or shortened) APTT may be due to:

Pre-analytical problems, including:

Small, insufficient samples (prolongation), in which the ratio of anticoagulant to blood in the tube is not respected.
Patients with a low or high haematocrit.
Heparin contamination (prolongation). This is the most common situation, especially when the sample is taken from permanent or semi-permanent infusion devices (particularly catheters) flushed with heparin to keep them open.
Clotted samples, due to activation (shortening) or consumption (prolongation) of clotting factors.
Non-specific inhibitors, such as lupus anticoagulant (LA). When LA is present, the prolonged APTT or tests derived from it cannot be fully corrected by the mixing study with normal plasma, but they can be corrected by adding excess phospholipids to the reaction mixture.
A specific inhibitor. Although this is rare, some patients can develop antibodies that neutralise the activity of certain clotting factors, especially factors VIII and IX. Inhibitors generally develop in patients with severe congenital deficiencies of these factors who are on replacement therapy (for example, patients with haemophilia A are given factor VIII) and, much more rarely, in non-haemophilic patients in association with systemic autoimmune diseases, during pregnancy or spontaneously. In these cases too, specific inhibitors prolong the APTT in a way that is not fully corrected by the mixing study with normal plasma.
Anticoagulant treatment with standard heparin (the therapeutic range of the APTT is usually 1.5 to 2.5 times the patient’s baseline value).
Warfarin and other coumarin medicines. Although the APTT is not used to monitor treatment with these medicines, its value may be increased.
Increased PTT levels may also be seen with leukaemia and with von Willebrand disease.

Is there anything else I should know?
Once heparin treatment has been started, identifying the exact cause of a prolonged APTT is very complex. In patients with unexplained thrombosis or bleeding, the APTT is often requested, together with other tests to assess the risk of thrombosis or bleeding, before starting the appropriate treatment. If this is not possible, it is better to postpone the patient’s diagnostic assessment until the condition has resolved.

Other tests that may be requested together with the APTT are: the platelet count (always to be requested in patients on heparin to identify promptly any development of heparin-induced thrombocytopenia), the thrombin time (which can help assess possible heparin contamination) and fibrinogen, which can be useful to rule out hypofibrinogenaemia as a possible cause of a prolonged APTT.

1. Is the APTT always used to monitor heparin treatment?
2. Should everyone have an APTT?
3. How can the APTT value be changed?

1. Is the APTT always used to monitor heparin treatment?
It is not used in two situations. 1) During high-dose heparin treatment, as in heart surgery, the doses given are so high that the test loses sensitivity or the blood may not clot at all. In this case the activated clotting time (ACT) is more useful. 2) Treatment with low-molecular-weight heparin (LMWH), used mainly to prevent venous thromboembolism, does not usually need monitoring, except in some cases (kidney failure, lack of therapeutic effect). In these cases, however, the APTT is not used; an activated factor X (anti-Xa) assay is done instead.

2. Should everyone have an APTT?
An APTT is not generally needed in all healthy people without symptoms, as it should not be considered a routine screening test. It may instead be requested in patients with bleeding or, more rarely, thrombotic symptoms. The test can be done in patients without symptoms as part of pre-operative screening. In this case it may be requested when the medical history is unreliable or unavailable, or depending on the nature of the operation (surgical procedures with a high risk of bleeding), to establish the risk of bleeding in advance.

3. How can the APTT value be changed?
The APTT value rarely changes with lifestyle changes (unless a clotting factor deficiency develops because of vitamin K deficiency). In general the APTT reflects the integrity of the haemostatic system. If the APTT is prolonged because of factor deficiencies or inhibitors, treating these conditions can bring it back to normal. If the APTT is prolonged because of a temporary or acquired condition, it can return to normal quickly once the condition resolves.