Altered Maturation Status and Possible Immune Exhaustion of CD8 T Lymphocytes in the Peripheral Blood of Patients Presenting With Acute Coronary Syndromes.

OBJECTIVE: Inflammation in response to oxidized lipoproteins is thought to play a key role in acute coronary syndromes (ACS), but the pattern of immune activation has not been fully characterized. We sought to perform detailed phenotypic and functional analysis of CD8 T lymphocytes from patients presenting with ACS to determine activation patterns and potential immunologic correlates of ACS. APPROACH AND RESULTS: We used polychromatic flow cytometry to analyze the cytokine production profiles of naïve, effector, and memory CD8 T cells in patients with ACS compared with control subjects with stable coronary artery disease. ACS was associated with an altered distribution of circulating CD8(+) T-cell maturation subsets with reduced proportions of naïve cells and expansion of effector memory cells. ACS was also accompanied by impaired interleukin-2 production by phenotypically naïve CD8 T cells. These results were validated in a second replication cohort. Naïve CD8 cells from patients with ACS also had increased expression of programmed cell death-1, which correlated with interleukin-2 hypoproduction. In vitro, stimulation of CD8 T cells with oxidized low-density lipoprotein was sufficient to cause programmed cell death-1 upregulation and diminished interleukin-2 production by naïve CD8 T cells. CONCLUSIONS: In this exploratory analysis, naïve CD8(+) T cells from patients with ACS show phenotypic and functional characteristics of immune exhaustion: impaired interleukin-2 production and programmed cell death-1 upregulation. Exposure to oxidized low-density lipoprotein recapitulates these features in vitro. These data provide evidence that oxidized low-density lipoprotein could play a role in immune exhaustion, and this immunophenotype may be a biomarker for ACS.

Transition from argatroban to oral anticoagulation with phenprocoumon or acenocoumarol: effect on coagulation factor testing.

Treatment with the thrombin inhibitor argatroban is often followed by vitamin K-antagonist treatment. In this study, the behavior of coagulation factors measured under these treatment regimens is shown. Healthy subjects received infusions of 1.0, 2.0, or 3.0 microg/kg/hr argatroban before and during phenprocoumon or acenocoumarol dosing. Quantitation of factors II, VII, IX, and X by clot-based assays resulted in dose dependent, approximately 20%, lower than expected values in the presence of argatroban. On the contrary, values for the inhibitors, protein C and protein S, were higher. Cotherapy exaggerated the effect by vitamin K-antagonist alone. However, testing by immunologic and chromogenic assays did not show any effect by argatroban. Coupled with a lack of bleeding in the subjects, these data suggests that argatroban does not affect coagulation proteins and that the observations are only an assay artifact. Assay interferences must be considered when measuring coagulation proteins in patients receiving thrombin inhibitors.

Pulmonary Hemorrhage following Edge-to-Edge Mitral Valve Repair.

Mitral valve repair with the MitraClip device has emerged as an effective treatment option for patients with severe mitral regurgitation and contraindications for surgical interventions. While the procedure is not known to cause pulmonary complications, we describe two cases of pulmonary hemorrhage following percutaneous mitral valve repair. The patients did well with supportive care and reinitiation of anticlotting agents was well tolerated after resolution of bleeding.

Functionality of fondaparinux (pentasaccharide) depends on clinical antithrombin levels.

Fondaparinux (Arixtra) is an antithrombin (AT)-dependent synthetic inhibitor of factor Xa (FXa). We undertook a study to determine the ramifications of varying levels of circulating AT on the pharmacologic activity of fondaparinux. AT-deficient human plasma supplemented with 0.125-2.0 U/ml purified human AT and plasmas from liver disease patients (n = 20; 0.3 U/ml AT) were supplemented with fondaparinux (0.125-12.5 µg/ml) then assayed by an amidolytic anti-FXa assay and the clot-based Heptest. A decrease in fondaparinux activity was observed with AT levels of 0.5 U/ml that became more pronounced with decreasing AT levels. For 0.2-1.5 µg/ml fondaparinux (plasma concentrations achieved with dosages for prophylaxis and treatment of venous thromboembolism) and AT levels of 0.5 U/ml there was 20% loss of activity and with 0.25 U/ml AT there was a 45% loss of activity compared to 1 U/ml AT. Increasing AT levels to over 0.5 U/ml or increasing fondaparinux concentrations for AT levels between 0.5 and 1 U/ml achieved fondaparinux activity comparable to that obtained with 1 U/ml AT. With AT levels above 1.0 U/ml a greater inhibitory activity was achieved. The observed potency of fondaparinux in terms of anti-FXa activity was reduced approximately three-fold in patients with liver disease. These in-vitro findings were confirmed in a rabbit model of stasis thrombosis. With AT levels below 30% of normal induced by anti-AT antibodies, there was a 60% in-vivo reduction in the antithrombotic activity of fondaparinux (ED50 75 vs. 240 µg/kg). In summary, the AT level is a rate-limiting factor for the antithrombotic activity of fondaparinux.