Patient Is Clotting: What Do You Mean, the aPTT Is Prolonged?

Dennis Williams, MD; Duncan C. MacIvor, MD

Disclosures

February 21, 2013

In This Article

Differential Diagnosis

Unexpected prolongation of the PT, the aPTT, or both should prompt further evaluation to characterize and localize the problem. An important early step in evaluating a patient with an isolated prolonged aPTT is acquiring a good medical history, which will guide cost-effective laboratory testing. Does the patient have any personal or family history of inappropriate bruising or bleeding with minor injuries, surgery, dental work, childbirth, or menstrual periods? With a bleeding history, among the secondary coagulation disorders that prolong the aPTT are deficiencies of factor VIII, factor IX, or factor XI (in decreasing order of frequency). Factor VIII (hemophilia A) and IX (hemophilia B) deficiencies are sex-linked, and factor XI deficiency is autosomal recessive. (Hemophilia A may occur without a family history because the factor VIII gene is prone to new mutations.) In the absence of a bleeding history, the most commonly deficient factors are factor XII, PK, and HMWK. Because this complex of factors does not participate in hemostasis in vivo, individuals with these deficiencies do not bleed excessively. These factor deficiencies are very rare, not clinically relevant to hemostasis,[1] and possibly associated with an increased risk for thrombosis.[2]

Factor deficiency or inhibition. The possible causes of the isolated prolonged aPTT in this case include factor deficiencies and factor inhibitors. Prolongation of both the PT and aPTT suggests deficiency or inhibition (via antibodies) of factors in the common pathway; deficiency in both the intrinsic and extrinsic pathways; or a deficiency of the common, intrinsic, and extrinsic pathways. Isolated prolongation of the PT points to deficiency or inhibition of factor VII, whereas isolated aPTT prolongation points to a problem in the intrinsic pathway alone. A mixing study combining the patient's plasma with reagent standard human plasma distinguishes factor deficiency from factor inhibition, based on the principle that restoring a 50% concentration of a deficient factor will "correct" a prolonged clot-based test, whereas factor inhibition will not be corrected. Specific factor deficiencies can be identified and measured with mixing studies using specific factor-deficient reagent plasmas.

Heparin contamination. It is important to rule out heparin contamination of the sample. Heparin exposure is relatively common in the hospitalized patient with prolonged aPTT but with no bleeding history. Heparin contamination might be expected to prolong the PT as well as the aPTT, but typical PT reagents today contain heparinase to neutralize any heparin that is present, or are otherwise manufactured to be insensitive to therapeutic levels of heparin. Coagulation laboratories rule out heparin effect as the cause of prolonged aPTT by repeating the reaction with reagent heparinase.

Lupus anticoagulant. Lupus anticoagulant (LA) is a common cause of prolonged aPTT in patients without a bleeding history, regardless of whether the patient has a history of thrombosis. LA may function as an inhibitor in vitro by binding to the reagent phospholipid and blocking the phospholipid-dependent reactions of the intrinsic pathway. The net effect is prolongation of the aPTT. LA occasionally affects the PT instead of or in addition to the aPTT. The term "lupus anticoagulant" is a double misnomer. The antibody may be, as in this case, associated with lupus or other autoimmune disease, but not all patients with autoimmune disease have LA, nor do all patients with LA have autoimmune disease. Furthermore, whereas the antibody prolongs coagulation test results (hence "anticoagulant"), unlike specific factor inhibitors, LA never causes a bleeding disorder. Thus, although a bleeding tendency is common with either deficiency or inhibition of certain factors (especially factor VIII), a history of hypercoagulability (or at least no history of bleeding) is more consistent with LA. If the prolonged aPTT persists after heparin contamination is ruled out, a mixing study will distinguish a factor deficiency from an inhibitor. True factor deficiencies seen with an isolated prolonged aPTT (with or without a significant bleeding history) include factors XII, XI, IX, and VIII. It is important to use reagent standard human plasma for the mixing study. "Homemade" plasma mixtures from patients with normal aPTT values can contain residual platelet fragments which could adsorb LA, producing a false correction of the aPTT and a misdiagnosis of factor deficiency.

If a properly performed mixing study does not correct the aPTT, an inhibitor should be suspected (eg, a specific factor inhibitor), or more commonly, LA. The most common acquired specific factor inhibitor associated with bleeding is anti-VIII. Although this inhibitor is most often seen in patients with severe hemophilia A treated with recombinant factor VIII, it may also be acquired as an antibody de novo by patients who do not have congenital factor VIII deficiency, and can lead to a severe bleeding disorder. The disorder is rare, with an incidence of 1.48 per million per year. Patients are typically elderly, can be of either sex, and may have associated B-cell malignancies or connective tissue disorders or may be postpartum.[3] Serially diluted factor inhibitor assays are available to quantify the inhibitor.

In this case, heparin neutralization and mixing studies were performed and the aPTT continued to be prolonged. The next step is to test for LA by adding excess phospholipid to the reaction. This test was performed and the aPTT was corrected.

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