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Slide 1:
Hello, my name is Dot Adcock. I am the Medical Director of Colorado Coagulation, a wholly owned subsidiary of Laboratory Corporation of America. Welcome to this Pearl of Laboratory Medicine on “Practical Considerations in the Evaluation of an Isolated, Elevated APTT” that was developed with the help of Bob Gosselin at University of California Davis. This program also serves as a NASCOLA initiative (NASCOLA: North America Specialized Coagulation Laboratory Association).
Slide 2:
An isolated, elevated APTT, which I will now refer to as simply PTT (rather than APTT), is a common phenomenon in the coagulation laboratory that can sometimes be difficult and frustrating to investigate. This presentation provides information that will be useful in this investigation. During the very initial phase of the elevated APTT work-up, the following questions should be considered:
- Are there other coagulation test results?
- How elevated is the APTT?
- When, where, and how was the sample collected?
- What is the patient’s past and current medical history?
- Is there a history of bleeding or thrombosis?
- What are the patient’s current medications?
Slide 3:
This slide presents a cartoon of the coagulation cascade and depicts coagulation as it occurs in the laboratory. Although not physiologic, this cartoon allows an understanding of the factors that are included within the 3 common coagulation screening assays: the activated partial thromboplastin time (APTT) that includes contact factors, factors of the intrinsic pathway, and common pathway; the prothrombin time (PT) that includes factors of the extrinsic and common pathways; and the thrombin time (TT) that evaluates the conversion of fibrinogen to fibrin following the addition of thrombin. By evaluating the components of these 3 assays one against another, the basis of an elevated APTT, PT, and/or TT can be investigated and determined.
Slide 4:
In the evaluation of an elevated APTT, it is helpful to determine if this is an isolated elevation; that is, are the PT and TT normal? If the PT and TT have not been ordered, it is advantageous to perform these assays. Ideally, before embarking on the work-up of an elevated APTT, this abnormality should be confirmed on a new plasma sample.
Slide 5:
This slide lists the diagnostic considerations of an isolated, elevated, APTT. A deficiency or inhibitor of the contact factors or intrinsic factors may lead to an elevated APTT, as can the combination of several low normal factors, especially in a pediatric patient. Deficiencies or inhibitors of the contact pathway factors do not lead to bleeding. Inhibitors to the contact factors are rarely described. Mixing patient plasma with an equal volume of normal plasma, known as a mixing study or mixing test, can help distinguish the presence of an inhibitor from a factor deficiency. The addition of normal plasma tends to correct the clotting time in a factor-deficient plasma but generally leads to incomplete correction into the normal reference range in the presence of an inhibitor. A common cause of an elevated APTT is a lupus anticoagulant and this is not associated with bleeding unless the patient also suffers thrombocytopenia and/or hypoprothrombinemia. The APTT may be elevated spuriously due to a variety of causes, which will be discussed shortly.
Slide 6:
How elevated is the APTT? If the APTT is only mildly elevated, isolating the problem becomes a little more challenging. Mixing studies cannot be interpreted accurately when the APTT is slightly elevated (within about 3 to 5 seconds) above the upper end of the reference interval. In this instance, it may be necessary to measure factors VIII, IX, and XI and evaluate for a lupus anticoagulant. In addition, a weak inhibitor (such as some lupus anticoagulants) may be masked in a normal 1:1 plasma mixing study.
Another important consideration is the variability of different reagents to underlying factor deficiency, which will be described in more detail.
Slide 7:
Using this cartoon of the coagulation cascade, the position of the factor within the cascade can help determine its role in the APTT elevation. The closer to the top of the cascade an abnormality lies, typically, the greater the impact on that cascade. Deficiencies of factor XII, High Molecular Weight Kininogen (HMWK), or Prekallikrein (PK), which are at the top of the APTT cascade, often yield APTT values that are greater than 100 sec, although this is partially dependent on the reagent sensitivity. The APTT loses sensitivity to factors farther down the cascade and is not very sensitive to deficiencies of the common pathway factors and also fibrinogen. Mild deficiencies of these factors may lead to only slight or no elevation of the APTT.
Slide 8:
Here is an example of a factor sensitivity table. This depicts the level of individual factor deficiency needed to cause elevation of either the APTT or PT. Notice that typically factor VIII must fall below about 30% before the APTT will elevate, and factor IX activity must often be even lower. Note also that the PT is more sensitive to deficiencies of the common pathway factors than the APTT. This sensitivity, which is better termed responsiveness, varies with each reagent.
Slide 9:
Improper pre-analytical conditions are an important and common cause of an elevated APTT. Factor VIII and von Willebrand factor (VWF) are cryoprecipitable proteins. If a whole blood sample is stored on ice or refrigerated prior to centrifugation, these proteins may be lost from the supernatant. Warming and thoroughly mixing a cold sample prior to centrifugation can prevent loss of factor VIII and VWF, as described in the Refaii publication. Factor VIII is also a labile factor and this means that its activity will diminish over time if the sample is stored or shipped at room temperature. Both cryoprecipitation and loss at room temperature can lead to significant reduction in factor VIII activity.
Slide 10:
When possible, it is useful to investigate when, where, and how the sample was collected.
- If the sample is >4 hours old and it has not been frozen, then degradation of factor VIII should be considered. If the sample was stored or shipped on wet ice or refrigerated prior to centrifugation, precipitation of factor VIII is possible.
- If the sample was collected outside the testing laboratory, it is important to question if the APTT is elevated in one laboratory and not the other. If this occurs, consider variable reagent responsiveness to lupus anticoagulants and variable reagent responsiveness to underlying factor deficiencies, or that perhaps one of the abnormal results is spurious.
- If the sample was collected from a peripheral stick, find out if the sample was collected above an IV.
- If the sample was collected from a vascular access device, consider contamination by the intravenous fluid.
- Was the sample collected in a tube with the same sodium citrate concentration that the reference interval was determined using? 3.8% sodium citrate leads to longer clotting times than 3.2% sodium citrate.
- Were the contents of 2 blue top tubes combined to obtain adequate volume, which will certainly lead to elevation of the APTT?
Slide 11:
When possible, determine if the patient has had a previous APTT and what that result was. It is also valuable to determine if there are underlying conditions that may be associated with an elevated APTT, such as autoimmune disorders or factor deficiency.
Slide 12:
An elevated APTT when previously normal suggests an acquired condition such as a lupus anticoagulant or acquired factor deficiency or possible spurious elevation due to one or more pre-analytic conditions. In a patient with a bleeding diathesis, factor VIII, IX, and XI activities should be measured. In a patient without bleeding, consider a lupus anticoagulant, contact factor deficiency, or possibly drug effect as the cause of the elevated APTT (see next slide).
Slide 13:
Finally, certain medications may lead to elevation of the APTT. While heparin will elevate the APTT, it will also elevate the thrombin time as well, and this is true of direct thrombin inhibitors. Direct factor Xa inhibitor anticoagulants tend to elevate the PT to a greater extent than the APTT, although there is considerable reagent variability. Certain lipoglycopeptide antibiotics, such as telavancin or daptomycin, may cause drug concentration dependent spurious elevation of the APTT, as can certain pegylated drugs, such as PEG-hemoglobin. Polyethylene glycol (PEG) is often added to small biologics to enhance their half-life in the circulation.
Slide 14: References
Slide 15: Disclosures
Thank you for joining me for this Pearl of Laboratory Medicine on “Practical Considerations in the Evaluation of an Isolated, Elevated APTT.” I am Dot Adcock.