CONCISEPROLONGED PT REVIEWAND APTT FOR CLINICIANS How to Interpret and Pursue an Abnormal Prothrombin Time, Activated Partial Thromboplastin Time, and Bleeding Time in Adults ARIF H. KAMAL, MD; AYALEW TEFFERI, MD; AND RAJIV K. PRUTHI, MBBS The prothrombin time (PT) and activated partial thromboplastin vascular system. However, vascular injury and the result- time (APTT) are among the most commonly ordered coagulation ing disruption of the endothelium lead to the initiation of a tests. In 2005, more than 140,000 PT and more than 95,000 APTT tests were performed at Mayo Clinic. The most common complex hemostatic response broadly classified into primary indications for ordering these tests include anticoagulant moni- and secondary hemostatic responses. In primary hemostasis, toring, initial evaluation of hemorrhage, and, although not gener- vascular injury results in (1) vasospasm; (2) endothelial ally indicated, routine preoperative screening. In addition, the bleeding time (BT) test, which is infrequently performed, is still disruption and exposure of subendothelial collagen, leading available in certain institutions. Abnormal results from these to platelet adhesion mediated by von Willebrand factor; and tests (prolonged PT, APTT, and BT), especially from tests con- (3) platelet activation and aggregation, leading to platelet ducted for initial evaluation of hemorrhage or for preopera- tive screening, may pose a diagnostic dilemma to the non- plug formation. In secondary hemostasis, the subendothelial hematologist. We review the essential factors affecting test tissue factor is simultaneously exposed, leading to the acti- results; provide a practical approach to the evaluation of a vation of the procoagulant cascade and the eventual forma- prolonged PT, APTT, and BT; and offer suggestions on which reflexive tests are appropriate and when to consider a subspe- tion of a hemostatic fibrin clot. cialty consultation. Bleeding disorders can be broadly classified into pri- Mayo Clin Proc. 2007;82(7):864-873 mary and secondary hemostatic defects. Primary hemo- static defects include disorders of platelets and von APTT = activated partial thromboplastin time; BT = bleeding time; Willebrand factor, whereas secondary hemostatic defects HMWK = high-molecular-weight kininogen; INR = international nor- are coagulation factor deficiencies that can be congenital or malized ratio; ISI = international sensitivity index; LAC = lupus anti- coagulant; PK = prekallikrein; PT = prothrombin time; TT = thrombin acquired. time Bleeding symptoms in the patient or in a member of the patient’s family can often prompt laboratory evaluation to test for bleeding disorders. To screen for bleeding disorders and to distinguish between congenital and acquired disor- he prothrombin time (PT), activated partial thrombo- ders, physicians should obtain a detailed personal and fam- Tplastin time (APTT), and bleeding time (BT) are ily (hemostatic) history and perform a thorough physical screening tests for hemostasis. Typical indications for or- examination. Spontaneous bleeding (epistaxis, ease of dering these tests include hemorrhagic symptoms, monitor- bruising, joint bleeding) or unusual or unexpected bleeding ing of anticoagulant therapy, and “routine” preoperative after surgery (including dental extractions) makes it more screening. In 2005, more than 140,000 PT and more than likely that the patient has a bleeding disorder. That likeli- 95,000 APTT tests were performed at Mayo Clinic, hood increases if the patient has a family history of a whereas the frequency of BT tests significantly declined. bleeding disorder. Besides the expected prolongations of the PT and APTT in If the hemostatic history raises concern for a bleeding patients receiving anticoagulant therapy, abnormal test re- disorder, the next step is to order screening tests for hemo- sults in patients with or without symptoms warrant further stasis with appropriate follow-up (reflexive) testing as indi- investigation for an underlying acquired or congenital cated. Ordering screening or diagnostic hemostatic tests bleeding disorder, especially if the patient is scheduled to before obtaining a thorough patient history is not an appro- undergo surgery. We provide an overview of hemostasis priate approach. and review the approach to a patient with a prolonged PT and/or APTT and a prolonged BT. From the Department of Internal Medicine (A.H.K.) and Division of Hematology OVERVIEW OF THE HEMOSTATIC SYSTEM (A.T., R.K.P.), Mayo Clinic, Rochester, Minn. A basic understanding of the hemostatic system, which has A question-and-answer section appears at the end of this article. 1 Address reprint requests and correspondence to Rajiv K. Pruthi, MBBS, been reviewed in detail, is required to interpret screening Division of Hematology, Mayo Clinic, 200 First St SW, Rochester, MN 55905 coagulation test results. When platelets and clotting factors (e-mail: [email protected]). circulate in an inactive form, blood flows freely through the © 2007 Mayo Foundation for Medical Education and Research 864 Mayo Clin Proc. • July 2007;82(7):864-873 • www.mayoclinicproceedings.com For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings. PROLONGED PT AND APTT FIGURE 1. Coagulation cascade. a = activated factor; Ca = calcium; PL = phospholipid. Adapted from Biochemistry,2 with permission from American Chemical Society, copyright 1991. SCREENING TESTS FOR HEMOSTASIS the differing sensitivities of the thromboplastin reagents produced by different manufacturers to coagulation factor The PT, APTT, and BT are screening tests for hemostasis. deficiencies. To overcome this interlaboratory variation, The BT test has lost favor in recent years, but the PT and the international normalized ratio (INR) was introduced. APTT remain the most frequently ordered tests in coagula- The INR is a mathematical conversion of a patient’s PT tion medicine. To properly manage patients, physicians that accounts for the sensitivity of the thromboplastin used must determine whether the prolonged PT, APTT, and BT in a given laboratory by factoring in the international sensi- are artifactual, medication related, or representative of he- tivity index (ISI) value supplied by its manufacturer. The mostatic abnormalities. INR is calculated as follows: INR = (patient PT/MNPT)ISI, in which MNPT is the geometric mean of the PT of at least PROTHROMBIN TIME (INTERNATIONAL NORMALIZED RATIO) 20 healthy subjects of both sexes tested at the performing Stated simply, the PT is a measure of the integrity of the laboratory. Since its introduction, INR has reduced the extrinsic and final common pathways of the procoagulant interlaboratory variations in PT results. cascade. The PT represents the time, in seconds, for patient Both PT and APTT reagents have various sensitivities plasma to clot after the addition of calcium and an activator to different clotting factor levels. In general, PT reagents of the extrinsic pathway (thromboplastin) (Figure 1). Thus, are more sensitive to deficiencies of factor VII within the deficiencies or inhibitors of clotting factors within the ex- extrinsic pathway and less sensitive to deficiencies within trinsic and final common pathways result in prolongation the final common pathway (factors V, X, and II and fi- of the PT (Figure 2). Monitoring warfarin anticoagulation brinogen). is the most common indication for PT. However, PT results Unfractionated heparin and low-molecular-weight hep- for identical patient samples can vary with the laboratory, arin exert their anticoagulant effect by antithrombin-medi- making monitoring of warfarin anticoagulation difficult, ated inhibition of thrombin (factor II) in the final common particularly in patients whose samples are tested in more pathway (Figure 2). Thus, in addition to prolonging the than 1 laboratory. This variability in results can be traced to APTT, heparin in theory would prolong the PT, precluding Mayo Clin Proc. • July 2007;82(7):864-873 • www.mayoclinicproceedings.com 865 For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings. PROLONGED PT AND APTT site of heparin infusion) may overwhelm the heparin neu- tralizer and prolong the PT. ACTIVATED PARTIAL THROMBOPLASTIN TIME The APTT is a measure of the integrity of the intrinsic and final common pathways of the coagulation cascade. The APTT represents the time, in seconds, for patient plasma to clot after the addition of phospholipid, an intrinsic pathway activator, and calcium. The APTT reagent is called partial thromboplastin because tissue factor is not present in con- junction with the phospholipid as it is in the PT reagent3 (Figure 1). Thus, deficiencies or inhibitors of clotting fac- tors within the intrinsic and final common pathways result in prolongation of the APTT (Figure 2). DETERMINATION OF THE NORMAL (REFERENCE) RANGE The normal or reference range for PT and APTT assays varies depending on the reagent and instrument combina- tions each laboratory uses. Thus, laboratories need to estab- FIGURE 2. Schematic of coagulation cascade. Factors II, VII, IX, and X are vitamin K–dependent factors. APTT = activated partial throm- lish their own reference ranges by measuring the PT and boplastin time; HMWK = high-molecular-weight kininogen; PK = APTT on plasma from healthy volunteers.4 At Mayo prekallikrein; PT = prothrombin time; RT = reptilase time; TT = Clinic, at least 50 healthy volunteer donors are tested to thrombin time. establish the reference range. Separate reference