In a small study of pediatric patients treated with L-asparaginase-based therapy, levels of protein C, S and vitamin K-dependent factors (such as factors IX and X) of eight patients with thrombosis were compared with those of nine patients without any thrombosis

In a small study of pediatric patients treated with L-asparaginase-based therapy, levels of protein C, S and vitamin K-dependent factors (such as factors IX and X) of eight patients with thrombosis were compared with those of nine patients without any thrombosis. Zatebradine hydrochloride agent, the use of L-asparaginase has several potential toxicities including the risk of thrombosis [8C10]. In this review, we summarize the key studies on L-asparaginase-related venous thromboembolism (VTE) in patients with ALL with a focus on identification of high-risk patients, approaches to prevent VTE and management of patients who develop VTE. Epidemiology The incidence of VTE in ALL patients has been reported to vary from 1 to 36% depending upon the age group of the patients, study designs, treatment protocols, symptomatic thromboembolism versus detection with screening radiography [10C12]. Caruso asparaginase was associated with a greater likelihood of coagulation abnormalities (defined as any clinical or biologic abnormality, e.g., hypofibrinogenemia requiring a modification of chemotherapy or supportive care) [25]. In another small study (n = 20), the use of asparaginase was associated with a higher risk of decline in protein C level below 70%, compared with Erwinia asparaginase (50 vs 0%; p = 0.03) [27]. The use of L-asparaginase encapsulated within erythrocytes, compared with the native form of the enzyme, is thought to allow gradual serum asparagine depletion with lower doses. This is speculated to be associated with a lower risk of toxicities including thrombotic complications [28]; however, it remains to be established in larger studies. The use of CVC may be a potential risk factor for site-specific thrombotic events with 25 out of 91 VTE events (27.5%) associated with CVC in the Caruso study; CVC-associated thrombosis accounted for more than half of non-CNS thrombosis. Although unclear in asparaginase-related VTE, the risk of line-related thrombosis in general appears to be higher with the use of peripherally inserted central catheter than CVC [29]. The use of anthracycline as well as prednisone (vs dexamethasone), particularly during postinduction therapy, were other potential risk factors [12]. In another pediatric study, all of the CNS thromboses occurred during the induction phase and were associated with the use of prednisone as steroid [21]. Prior studies have assessed the presence of any correlation between the level of coagulation proteins or inherited thrombophilia and the risk of L-asparaginase-related thrombosis. In a small study of pediatric patients treated with L-asparaginase-based therapy, levels of protein C, S and vitamin K-dependent factors (such as factors IX and X) of eight patients with thrombosis were compared with those of nine patients without any thrombosis. The frequency of protein C deficiency (37 vs 33%; p = 0.38) and protein S deficiency (83 vs 28%; p = 0.10) was numerically different but statistically similar between patients with versus without thrombosis. The lower levels of protein C and S were also associated with reduced levels of factors IX and X. Furthermore, the ratio of protein C and S to each other and to factors IX and X was similar in the two groups [30]. Although this study demonstrated no clear evidence of the reduced levels of these proteins in identifying at-risk patients, this may Zatebradine hydrochloride have been related to small sample size. An Israeli pediatric study (n = 41) utilizing enoxaparin prophylaxis (discussed later in detail) demonstrated a high incidence of genetic thrombophilia in 27 children (11% prothrombin G20210A and 18% factor V Leiden), who were Arabs and Jews in ethnic origin; Rabbit polyclonal to IL27RA however, no one had any VTE [31]. Another underpowered prospective trial Zatebradine hydrochloride of 85 pediatric patients demonstrated no significant association between thrombosis and the presence of factor V Leiden mutation, prothrombin gene 20210A and antiphospholipid antibodies [32]. An Italian study of 48 children demonstrated a numerically higher prevalence of factor V Leiden (20 vs 3C7%; p-value unavailable) and prothrombin mutation (10 vs 1C3%; p-value unavailable) in the ALL patients with VTE, as compared with the general population [22]. In the Dana-Farber study, the prevalence of activated protein C resistance (9% of 23 patients tested) and factor V Leiden mutation (4%) was felt to be similar to that expected in the general population [11]. In an adult study, none of the patients with VTE who underwent thrombophilia testing (54% of 24), were found to have factor V Leiden mutation or prothrombin gene 20210A [13]. The aforementioned meta-analysis assessed the impact of genetic thrombophilia in 557 children; the presence of genetic prothrombotic abnormalities was similar to that of Zatebradine hydrochloride general population. In pooled analysis, the presence of.