Activated partial thromboplastin time (APTT). New indications for an old test?

The activated partial thromboplastin time (APTT) has been designed in 1953 (see Ref. [1] as an historical sketch) and was aimed at assisting the pioneer work of Brinkhous et al. who were purifying factor VIII (FVIII) from plasma. At the very beginning, the APTT was the coagulation time of the test plasma added with exogenous phospholipids (cephalin) as platelet substitutes and calcium chloride [2]. Later on, it was modified by Proctor and Rapaport [3] who added kaolin to optimize the activation of the contact phase of coagulation. This modification was instrumental in making the coagulation times shorter and the results less variable. Since then, the APTT has been extensively used as a research tool that helped discovering many coagulation factors and elucidating their interactions for thrombin generation and fibrin formation. However, the use of the APTT spread widely in the early 1960s of the last century when the availability of commercial kits made it the test of choice to screen patients for congenital and acquired hemorrhagic diseases. Another step forward to the use of the APTT was the incidental discovery made by Conley and Hartmann [4] of patients, with lupus erythematosus, who had frequently prolonged APTTs even upon addition of normal plasma to the test plasma because of the presence of a circulating anticoagulant. At the very beginning, this was considered as a laboratory nuisance as patients bearing the circulating anticoagulant did not have coagulation factor deficiencies and did not present with hemorrhagic problems. Laboratory workers, who had to investigate many prolonged coagulation times without any obvious advantage, began searching for APTT reagents that were less responsive to the useless circulating anticoagulant named lupus anticoagulant . This attitude changed sharply when Bowie et al. [5] described thrombotic events in patients, with systemic lupus erythematosus, who had circulating anticoagulants and prolonged APTT. Since then, the APTT has been extensively used to search for lupus anticoagulants in patients with history of thrombosis or fetal loss [6]. In the early 1970s of the last century, unfractionated heparin started to be the drug of choice for the treatment of acute venous thromboembolism (VTE) and the APTT soon became the test of choice for dose-adjustment [7]. The success of the APTT in this context was high; the therapeutic range 1.5–2.5fold APTT prolongation over the normal coagulation time, which was established in a clinical study using an APTT reagent of well-defined composition, was adopted indiscriminately regardless of the responsiveness of the reagent used for testing [8]. This problem notwithstanding the APTT has been instrumental for the successful treatment of patients with thrombosis. Looking at the story, one may notice that the APTT results have been taken as an index of loss-of-function and much less as an index of gain-of-function of the coagulation factors. Although studies addressing the significance of shortened APTT have been carried out in the past (reviewed in Ref. [9]), it was not until recently that a case–control study addressed this issue and found an association between shortened APTT and the risk of VTE [9]. The association is biologically plausible if one considers that hypercoagulability because of high levels of such coagulation factors as fibrinogen, prothrombin, FVIII, FIX, and FXI is associated with the risk of occurrence (and recurrence) of VTE (reviewed inRef. [9]). TheAPTT is a global test sensitive to low levels of all the coagulation factors except FVII and FXIII. Therefore, it is not surprising that the APTT may also be responsive to high levels of these factors. Interestingly, when the risk of VTE was adjusted for the high levels of FVIII, the odds ratio (OR) decreased to some extent, but remained statistically significant [9], suggesting that FVIII Correspondence: Armando Tripodi, Department of Internal Medicine, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, University and IRCCS Maggiore Hospital, Mangiagalli and Regina Elena Foundation, Via Pace 9, 20122 Milan, Italy. Tel. : +39 02 5503 5437; fax: +39 02 503 20723; e-mail: armando. tripodi@unimi.it