No abstract

SummaryRivaroxaban is an oral, direct activated Factor Xa (FXa) inhibitor in advanced clinical development for the prevention and treatment of thromboembolic disorders. Currently available anticoagulants include unfractionated heparin (UFH) and low molecular weight heparins (LMWHs); however, their use can be restricted by heparin-induced thrombocytopenia (HIT). HIT is usually caused by the production of antibodies to a complex of heparin and platelet factor-4 (PF4). This study was performed to evaluate, in vitro, the potential of rivaroxaban as an anticoagulant for the management of patients with HIT. UFH, the LMWH enoxaparin, fondaparinux and the direct thrombin inhibitor argatroban were tested to enable comparative analyses. Rivaroxaban did not cause platelet activation or aggregation in the presence of HIT antibodies, unlike UFH and enoxaparin, suggesting that rivaroxaban does not cross-react with HIT antibodies. Furthermore, rivaroxaban did not cause the release of PF4 from platelets and did not interact with PF4, unlike UFH and enoxaparin. These findings suggest that rivaroxaban may be a suitable anticoagulant for the management of patients with HIT.

Summary. The serotonin release assay (SRA) tests for antibodies responsible for heparin-induced thrombocytopenia (HIT). By definition, SRA-positive antibodies cause platelet serotonin release in vitro, in the presence of low concentrations of heparin, but not with excess heparin. Many SRA-positive sera activate platelets in the presence of saline without drug, either as a result of residual heparin in the specimen, or because of intrinsic features of the HIT antibodies. The present experiments show that neither exhaustive heparinase treatment, nor chromatographic removal of heparin abrogates the spontaneous platelet activation caused by these HIT antibodies. This is the first study to systematically demonstrate that in vitro activity of HIT antibodies can be independent of heparin. In addition, T-gel chromatography demonstrated differences among fractions of enzyme-linked-immunosorbent assay (ELISA)-positive HIT antibodies within individual specimens. Certain ELISA-positive fractions had SRA activity while others did not, and the SRA activity was not proportional to HIT antibody ELISA titer. These data suggest that antibodies formed as a result of heparin treatment are heterogeneous, and that some can contribute to the pathogenesis of HIT even when heparin is no longer present.

No abstract

Circadian (24 h) rhythms of fibrinogen, interleukin-6 (IL-6), and platelet levels were studied in 11 males ages 46 to 72 years. Since there is a known circadian rhythm for fibrinogen and IL-6, we postulated that the peak level (acrophase) of fibrinogen would follow the acrophase of IL-6, based on the fact that IL-6 is the stimulus for fibrinogen production in the liver. Platelet levels were measured to show whether there was any correlation with the IL-6 acrophase because it has been reported that IL-6 affects megakaryocytes and platelets in dogs. We found that the acrophase for IL-6 occurred at 02:03 h and the acrophase for fibrinogen occurred at 09:16 h. Platelet counts peaked at 16:56 h. Thus, there was a positive correlation between IL-6 and fibrinogen acrophases and a negative correlation of each with the acrophase for platelets. The positive linkage of IL-6 with fibrinogen in this study suggests that suppression of IL-6 production would lower those peak fibrinogen levels that occur in the morning in association with arterial ischemic events. This could result in fewer arterial ischemic events, especially in the morning.

Ever since the introduction of low molecular weight heparins (LMWHs) for clinical use, one of the major questions raised relates to product interchangeability and the differences between each of the individual LMWH preparations. Although differences between various commercially available products have been described in terms of molecular weight profile and biologic properties, very limited information on the direct comparison of individual products in a defined clinical setting is available at this time. European Pharmacopeia (EP) and the World Health Organization (WHO) have developed guidelines to characterize these agents in terms of molecular weight and biologic profiles. On a gravimetric basis, these potency assignments differ for anti-Xa and anti-IIa activities in terms of U potency per mg. The relative distribution of various molecular weight components has also been reported to vary. The oligosaccharide composition, microstructural differences in terms of specific sugars and the presence of unique structural features and the interaction with endogenous mediators such as antithrombin (AT) and heparin cofactor II (HC II) also differ. At equivalent anti-Xa levels, the amount of the anti-IIa activity and anticoagulant activity differs. Since the bioavailability and relative pharmacokinetics of the anti-Xa and anti-IIa effects are different, the specific pharmacodynamic effects of these drugs also differ. A large preclinical data base is now available on the differences between various LMWHs. However, only limited clinical data is available in the current literature. To date, the LMWHs have been primarily used for the management of post-surgical DVT. Only smaller dosages (30-40 mg or 2,500 to 4,000 anti-Xa U total dose) have been used. In these studies, because of the low dose and subcutaneous route of administration, the differences in clinical effects are rather small. Since LMWHs are now developed for therapeutic use, where relatively higher doses are used, these pharmacokinetic/pharmacodynamic differences will become more apparent. The reported differences in the clinical efficacy of LMWHs in such indications as unstable angina may be due to their pharmacologic properties and molecular composition. There are also major differences in the non-anticoagulant actions of these agents such as their ability to interact with growth factors and antithrombotic effects. Based on the available literature, it can be concluded that each product exhibits individuality.

No abstract

High doses of cytosine arabinoside (ara-C) have been used in the treatment of refractory forms of acute nonlymphoblastic leukemia (ANLL) and ANLL occurring after previous antineoplastic therapy. In addition to the usual toxicities associated with antimetabolites, neurotoxicity, mainly in the form of cerebellar dysfunction, develops in a significant proportion of patients receiving high-dose cytosine arabinoside HDara-C. This study was performed to determine the incidence of cerebellar dysfunction in our patients and to determine any factors that predict its development. In this series of 30 consecutive patients receiving HDara-C, confusion with cerebellar signs and symptoms developed in seven (23%). Factors that appear to predispose patients to the development of neurotoxicity are (1) past history of neurologic dysfunction and (2) preexisting and progressive hepatic dysfunction. No peripheral neuropathy was seen. In contrast to previous reports, we did not find neurotoxicity to be dose related. Prophylactic use of pyridoxine does not prevent neurotoxicity.