Evaluation of a Prolonged Activated Partial Thromboplastin Time (APTT) [Hot Topic]

Rajiv Pruthi, M.B.B.S.
Rajiv Pruthi, M.B.B.S.

An activated partial thromboplastin clotting time (APTT) can be abnormal in a heterogeneous group of disorders and evaluation is best accomplished in conjunction with patient history. A prolonged APTT can indicate the risk of hemorrhage or thrombosis or can be of no hemostatic consequence. Therefore, an abnormal APTT should always be evaluated, especially if there is no obvious explanation (eg, liver disease, warfarin, or heparin use).

Presenter and Credentials:
Rajiv Pruthi, M.B.B.S., Co-Director of both the Special Coagulation Laboratory and Special Coagulation DNA Diagnostic Laboratory in the Division of Hematopathology, and Consultant and Director of the Comprehensive Hemophilia Center in the Division of Hematopathology at Mayo Clinic in Rochester, Minnesota

Transcript

Our speaker for this program is Dr.  Rajiv Pruthi, Co-Director of both the Special Coagulation Laboratory and Special Coagulation DNA Diagnostic Laboratory in the Division of Hematopathology.  He is also a Consultant and Director of the Comprehensive Hemophilia Center in the Division of Hematology at Mayo Clinic in Rochester, Minnesota. Dr.  Pruthi, thank you for presenting today.Thank you for the introduction. In this hot topic presentation, I will be discussing the differential diagnosis of a prolonged activated partial thromboplastin time also called APTT, and I will be discussing an approach to the evaluation of a prolonged APTT. I have nothing to disclose.Welcome to Mayo Medical Laboratories Hot Topics.  These presentations provide short discussion of current topics and may be helpful to you in your practice.  Today our topic is evaluation of a prolonged activated partial thromboplastin time and associated clinical implications.

Objectives/Utilization Messages

At the end of this presentation, the audience will know the causes of a prolonged APTT, recognize the optimal reflexive testing in the evaluation of a prolonged APTT and understand the importance of clinical correlation in the interpretation of coagulation testing.

Acquired Bleeding Disorder

The case upon which we will base today’s discussion is a 67-year-old male who had no previous history of a bleeding disorder.  He has heart disease for which he has undergone coronary artery bypass grafting 6 months prior to his current presentation.  While playing tennis he developed extensive bruise on his right arm.  Quite understandably, he was very concerned.  Initial laboratory testing demonstrated a normal complete blood count and prothrombin time, but he had a prolonged activated partial thromboplastin time.

Components of Hemostasis

When faced with the patient with bleeding symptoms, one has to keep in mind the physiology of hemostasis.  Initial hemostatic response consists of vasoconstriction, thereby reducing blood flow to the injured blood vessel, simultaneously, platelets adhere to the injured endothelium, and this is mediated by von Willebrand factor.  Platelets also get activated and attract other platelets resulting in platelet aggregation and formation of a stable hemostatic plug. There is a simultaneous activation of the secondary hemostatic response which consists of activation of the procoagulant factors.  This results in generation of a fibrin clot. The prothrombin time, also known as the PT, and the APTT assays are screening tests that evaluate the functionality of the procoagulant factors.

Prolonged APTT

A variety of factors influence the PT and APTT.  These can be broadly categorized into preanalytical variables and analytical variables.  Of the preanalytical variables, the PT and APTT may be artifactually prolonged in patients with a high hematocrit.  If these assays are performed on a plasma that has been clotted, the clotting process consumes coagulation factors and this results in prolongation of the PT and APTT.  Samples obtained from patients with poor venous access that may result in traumatic venipuncture generally have activation of the coagulation cascade that results in clot formation within the tube also termed as clotted specimen.  And finally, if the sample is not assayed within the appropriate period of time, activation of the coagulation cascade may result in a clotted specimen and artificially prolonged PT and APTT. Plasma samples that contained heparin or direct thrombin inhibitors will result in a prolonged APTT and finally if the patient has a hemostatic abnormality such as a coagulation factor deficiency or inhibitor, the APTT may be prolonged.

Coagulation Cascade

This slide shows the complexity of the coagulation cascade that consists of coagulation factors within the extrinsic, intrinsic, and final common pathway.  As each clotting factor is activated there are some complicated feedback activation steps that occur.

For practical purposes the coagulation cascade can be simplified into a framework as shown on this slide.  Factor VII is a member of the extrinsic pathway. Members of the intrinsic pathway consist of factors VIII, IX, XI, XII and 2 additional proteins the high molecular weight kininogen and prekallikrein.  And finally, members of the final common pathway consist of factors V, X, II, and fibrinogen.

Prolonged PT/APTT

Steps in evaluation of a prolonged APTT consist of initially excluding the presence of a drug like heparin or a direct thrombin inhibitor like argatroban or dabigatran.  Once drug effect is excluded, the next step consists of performing mixing study with normal plasma.  In this step, correction of the prolonged APTT suggests a coagulation factor deficiency state; however, failure of correction of the prolonged clotting time suggests presence of an inhibitor.  This inhibitor may be directed against a specific coagulation factor, which results in bleeding, or the inhibitor may be, what is termed a nonspecific inhibitor, like a lupus anticoagulant, which is a risk factor for thrombosis.

Acquired Bleeding Disorder

Coming back to our patient, mixing study demonstrated inhibition, and additional testing revealed a marked reduction in factor VIII activity.  Reflexive testing confirmed presence of a factor VIII inhibitor of 19 Bethesda units.

So this patient had developed an autoantibody against factor VIII.  This is a rare, potentially fatal condition.  Management consists of preventing or stopping bleeding with use of factor VIII bypassing agents, and elimination of the antibody using immune suppressant agents.

Prolonged APTT with Bleeding risk

So a prolonged APTT may reflect presence of an underlying condition that predisposes to bleeding, such as factor deficiencies of varying severity, which may be congenital or acquired; or presence of a specific factor inhibitor, which is always an acquired condition and poses a high risk for bleeding.

Prolonged APTT with No Bleeding Risk

However, there are conditions that prolong the APTT, sometimes quite markedly, but are not risk factors for bleeding.  For example, deficiencies of high molecular weight kininogen or prekallikrein, and factor XII, may markedly  prolong the APTT, but are not bleeding disorders.  In addition, as indicated, presence of a lupus anticoagulant is a risk for thrombosis.

How low do factors need to be for the PT/APTT to prolong?

A commonly asked question is just how low does the factor level need to be in order to prolong the APTT, which is another way of asking, how sensitive is the APTT to low coagulation factors.  This will vary with the APTT reagent and the instrument on which the assay is performed.

APTT Sensitivity to Factor VIII

As example, in this experiment, we purchased factor VIII deficient plasma and spiked in progressively increasing concentrations of factor VIII and measured an APTT for each factor VIII level.  As you can see, as the concentration of factor VIII declined, the APTT progressively lengthened, but did not prolong above the reference range till the factor VIII got below 35%, after which it markedly increased.  This cutoff-below which the APTT prolong- will vary with reagent and instrument combination.

So it is useful to consider the PT and APTT assays as screening tests, the sensitivities will vary and one cannot establish a cutoff below which evaluation of a prolonged APTT would not need to be pursued.  Interpretation of the abnormal assay should always take into context the patient medical history, medication use, and clinical presentation.

What Does the APTT Not Tell You?

It is important to note that the APTT assay does not consistently provide useful information on presence or absence of von Willebrand disease.  Since von Willebrand factor is a carrier protein for factor VIII, a deficiency of von Willebrand factor will result in a lower factor VIII, but the degree of deficiency may not result in a prolongation of the  APTT.  Thus, to exclude von Willebrand disease, which is the most common congenital bleeding disorder, one should check von Willebrand factor levels.

What Does a Prolonged APTT Tell Us?

To summarize, what abnormalities can prolong an APTT.  It could reflect an artifact, drug effect, coagulation factor deficiency, which may be congenital or acquired, or presence of an inhibitor, which could be a specific inhibitor or a nonspecific inhibitor.

Outcomes of Evaluation of Prolonged APTT: 100 Patients

This slide shows results of a study of consecutive outpatients evaluated for a prolonged APTT, a fair proportion were artifactual.  For the subset with a coagulation abnormality, most were of no hemostatic consequence, for example factor XII deficiency.  The remaining reflected variable degrees of risk for bleeding.

Outcomes of Evaluation of Prolonged APTT: 177 Patients

In a second study, which excluded patients with artifactual causes, most abnormalities were of no hemostatic consequence, the remaining reflected variable degrees of bleeding risk.

Optimal Utilization of Special Coagulation Testing

So the evaluation of a prolonged APTT is best accomplished within context of the patient history.  The optimal approach consists of initial screening tests and reflexive testing depending on the patient history.

Take Home Messages

In conclusion, the PT and APTT are screening tests of hemostasis which can be abnormal in a heterogeneous group of disorders.  The risk of prolonged APTT may reflect a risk for hemorrhage, thrombosis or may be of no hemostatic consequence.  Sensitivities to clotting factor deficiencies will vary with the thromboplastin so one cannot establish a cutoff beyond which a prolonged APTT or prothrombin time should always be evaluated.  It is critical to take the patient history within context of the lab result.

The most important screening hemostatic test is the patient’s personal and family history.  The absence of a history of spontaneous bleeding does not rule out a congenital bleeding disorder and patients with mild congenital bleeding disorders may not always present in childhood.  For suspicion of a bleeding disorder consider checking for von Willebrand factor antigen and activity.  And one should always pursue an abnormal PT and APTT especially if the is no obvious explanation, for example, liver disease, warfarin use, etc.

Approach to a Prolonged PT and APTT

The last slide shows an algorithmic approach that we pursue at Mayo Clinic in the Special Coagulation Laboratory.  This was published in the Mayo Clinic Proceedings in 2007 and is available online for additional study.

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