PARKAA paves the way

In the current issue of Thrombosis and Haemostasis, Mitchell et al. (1) report on the use of an antithrombin (AT) concentrate for the prevention of thromboembolism in children undergoing L-asparaginase containing induction chemotherapy for acute lymphoblastic leukaemia (ALL), the PARKAA study. This paper deserves specific attention given that it reports on the first randomised trial to evaluate a defined antithrombotic treatment strategy in this patient population. The approach the investigators have chosen has been logically developed from the given circumstances. An association between L-asparaginase therapy and increased incidence of thrombotic events has been known for more than 20 years; in addition, it has been recognized early on that acquired AT deficiency secondary to L-asparaginase therapy plays an important role in the development of the prothrombotic state (2-4) although this has been questioned (5). Also, the use of central venous catheters, which is a major facilitation of the management of these children, seems – not unexpectedly – to influence the occurrence of thromboses (6–10). Since the use of fresh frozen plasma does not seem to induce adequate increases in AT concentrations (11, 12), the investigators took the next logical step to evaluate the use of an AT concentrate for the prevention of thrombotic events in central venous catheter bearing children undergoing induction chemotherapy for ALL with an L-asparaginase containing regimen. Given the frequency of thromboses observed in children undergoing such a chemotherapy, the study targets a clinically truly important question. It is to the merit of the PARKAA investigators that they were able to establish a randomised multicenter intervention trial. The primary objective of the study was to determine the prevalence of thrombosis in the arm without AT supplementation, while efficacy and safety data for AT supplementation were secondary objectives. This is important to recognize since the PARKAA study was thus not powered to give any definite answers with regard to questions related to these secondary objectives. Data presented on this study population elsewhere (7, 13) indicate that thrombotic events in this setting are frequently observed and that most of the thromboses occur in the upper central venous system, followed in frequency by the right atrium. Thus, almost all of the thrombotic events are centred in a part of the venous system that is perturbed by the presence of the central venous catheter. Comparable data on the incidence of thromboses in the upper body of central venous catheter bearing children have been independently reported; using Doppler ultrasound, similar incidence data were found in a population not only consisting of ALL patients but also containing children with other types of malignancies (14). It is therefore not far-fetched to assume that the occurrence of these thromboses are at least partially influenced by the use of central venous catheters, although additional risk factors such as genetic factors or treatment variables can be postulated (15-17). The PARKAA investigators already reported from the same patient population that thrombotic events are frequent in the upper central venous system (13) and that Doppler ultrasound might not be an adequate imaging procedure to diagnose (especially upper body) deep venous thrombosis in this clinical setting (18). These findings were similar to those of other investigators (19) and magnetic resonance imaging seems to be a more sensitive approach. However, the clinical implications of these findings need further clarification. Not to use central venous lines in children with ALL is a setback to the practical management of these patients and to their quality of life as well: without central venous catheters, these children have to tolerate many more venipunctures from peripheral veins. Therefore, many clinicians will opt for a central venous catheter, but at the same time will be eager to provide a thromboprophylaxis as optimal as possible given the high risk of thrombotic events related to the use of the catheter. On the other hand, some clinicians will choose not to place a central venous line upfront until the question of an adequate prophylaxis has been satisfactorily answered. There© 2003 Schattauer GmbH, Stuttgart