CASE During an office visit, 23-year-old John K tells you that he recently experienced excessive bleeding after a dental extraction. He says that he has no personal or family history of a bleeding disorder and is not taking any medication that might have contributed to the problem.
His lab work shows a normal complete blood count and international normalized ratio (INR). His activated partial thromboplastin time (APTT), however, is 67 seconds (normal=24-37 seconds).
How would you manage his care?
Correct interpretation of abnormal APTT readings requires an understanding of the clinical context in which the test is ordered and the test’s limitations. In cases like Mr. K’s, the top priorities are taking a careful history and performing a thorough physical examination.
Specifically, you need to ask about any personal or family history of spontaneous mucosal bleeding, menorrhagia, hemostatic difficulties with previous surgeries or dental extractions, medication use (including anticoagulants), and alcohol use. Find out whether there is a history of liver disease or malnutrition/malabsorption. Does the patient bruise easily? Ask patients with an elevated APTT about a personal or family history of spontaneous mucosal bleeding, menorrhagia, or hemostatic difficulties with previous surgeries or dental extractions.
As you would expect, such signposts warrant further investigations. And if the personal or family history does suggest a bleeding disorder, the patient should be referred to a hematologist.
CASE Mr. K’s physical examination is unremarkable and his renal and liver panel—including serum albumin—are within the normal range. As noted earlier, he had no history of bleeding before the tooth extraction; his family history is negative for excessive bleeding, as well.
Consider an artifactual cause
It’s important to rule out artifactual causes of an abnormal APTT before undertaking a more detailed investigation. Although not applicable in this case, unfractionated heparin in a central venous or arterial catheter can prolong APTT.
A high hematocrit value will give falsely prolonged APTT. This is due to the increased concentration of citrate relative to the small volume of plasma.1 The lab should be alerted if the hematocrit is high so that the volume of anticoagulant in the collection tube may be adjusted for more reliable results.
Lipemic, hemolyzed, or icteric plasma specimens interfere with the optical system of the instruments and may also give false results.2
Delays and extreme temperatures can also alter results. The specimen should not be delayed for more than 4 hours as factor VIII is labile and longer time will result in an artifactually prolonged APTT.3 (See “APTT: Understanding the test”.) In addition, prolonged exposure to high temperatures may enhance degradation of factors V and VIII, whereas prolonged exposure to cold temperatures may activate factor VII.4
APTT: Understanding the test
Activated partial thromboplastin time (APTT) measures the integrity of the intrinsic and common pathways of the coagulation cascade. Any deficiency or inhibitor of the clotting factors within the intrinsic or common pathways will result in a prolonged APTT. The factors involved in the intrinsic and common pathways are II (prothrombin), V, VIII, IX, X, XI, XII, and fibrinogen (factor I).
CASE Because there is no physical evidence of liver, renal, or connective tissue disease in Mr. K’s case and artifactual causes are not at work, the next logical step is a mixing study.
Does the mixing study correct the prolonged APTT?
A mixing study with normal plasma will differentiate between a coagulation factor deficiency and the presence of an inhibitor. Correction of the prolonged APTT to the reference range after mixing a sample of the patient’s blood with normal plasma in a 1:1 ratio implies a deficiency of a clotting factor in the intrinsic or common final pathway of the coagulation cascade. The deficiency may involve one or more of the following: factors VIII, IX, XI, or XII; high-molecular-weight kininogen (HMWK); and prekallikrein (PK). A clotting factor assay will identify the deficient factor. A mixing study with normal plasma will differentiate between a coagulation factor deficiency and the presence of an inhibitor.
Congenital or acquired? Assuming that a clotting factor deficiency exists, the next step is to determine the nature of the deficiency in terms of congenital or acquired defects. Congenital causes of factor VIII, IX, and XI deficiency are hemophilia A, B, and C, respectively. Hemophilia affects one in 5000 males born in the United States;5 about 9 out of 10 have hemophilia A.6
Acquired causes of factor deficiencies are liver disease, warfarin use, disseminated intravascular coagulation, and vitamin K deficiency due to malabsorption or malnutrition.
Is an inhibitor at work? The presence of an inhibitor is suggested if the mixing studies do not result in correction of the prolonged APTT to normal range.