Mechanism of Platelet Activation and Hypercoagulability by Antithymocyte Globulins (ATG).

T cell depletion with antithymocyte globulins (ATG) can be complicated by thrombopenia and hypercoagulability. The underlying mechanism is still unclear. We found that binding of ATG to platelets caused platelet aggregation, α-granule release, membrane phosphatidylserine exposure and the rapid release of procoagulant platelet microvesicles (MV). Platelet activation and MV release were complement-dependent and required membrane insertion of C5b-8 but not stable lytic pore formation by C5b-9. ATG also activated platelets via binding to the low-affinity Fc gamma receptor FcγRII. However, only complement inhibition but not blockade of FcγRII prevented MV release and subsequent thrombin activation in plasma. In 19 hematopoietic stem cell and kidney transplant patients, ATG treatment resulted in thrombopenia and increased plasma levels of d-dimer and thrombin-antithrombin complexes. Flow cytometric analysis of complement fragments on platelet MV in patient plasma confirmed dose-dependent complement activation by ATG. However, the rapid rise in MV numbers observed in vitro was not seen during ATG treatment. In vitro experiments suggested that this was due to adherence of C3b-tagged MV to red blood cells via complement receptor CR1. These data suggest a clinically relevant link between complement activation and thrombin generation and offer a potential mechanism underlying ATG-induced hypercoagulability.

B-cell activating factor BAFF reflects patients' immunological risk profile after kidney transplantation.

The B-cell activating factor BAFF plays an important role in the development and maturation of B-lymphocytes, which can contribute to the generation of donor-specific antibodies and thus may influence graft function and graft survival. Inconsistent data on the role of BAFF levels after renal transplantation for the formation of donor-specific antibodies and the contribution for allograft rejection exist. The aim of the current study was to determine to what extent the degree of pre-immunization is reflected by each patient's BAFF levels before transplantation and in the follow-up. Furthermore, the impact of BAFF on allograft rejection frequency as well as severity and resulting allograft function over time was analyzed. Additionally, the impact of viral infections on BAFF levels after transplantation - as a potential confounder - was examined. For this purpose, a group of pre-sensitized patients (PRA>0%, (52±24% on average), n=40) was compared with non-sensitized patients (PRA=0%, n=62) and in a subsequent analysis stratification in accordance to the detected BAFF level was performed. Pre-sensitized patients had significantly higher BAFF levels before transplantation and suffered significantly more often from early steroid-resistant, mainly antibody-mediated rejections. A result which was confirmed also in highly sensitized patients with PRA levels >50%. Additionally, in the follow-up patients with either rising BAFF levels over time or BAFF levels above the median also had significantly more often antibody mediated rejections. Additionally, patients with BAFF levels above detected median even displayed impaired creatinine values as well as an induced eGFR slope up to month 48 after transplantation. The occurrence of viral infections (CMV, BKV) was only an additional influencing factor in the absence of concomitant allograft rejections. Therefore, the B-cell proliferation factor BAFF appears not only to reflect the immunological risk profile of patients in the context of kidney transplantation, it may possibly be further developed as a predictor of patients with an increased risk profile for subsequent allograft rejection and impaired allograft function.

Gastrointestinal manifestations associated with systemic lupus erythematosus.

Gastrointestinal symptoms are often difficult to interpret in patients with systemic lupus erythematosus. Symptoms can develop either from symptomatic autoimmune tissue injury, complications of lupus-related organ dysfunction, infections, thrombembolic manifestations of anti-phospholipid antibody syndrome, medication or unrelated disorders. We describe the gastrointestinal manifestations of lupus and discuss the diagnostic approach and therapy.

[Chronic renal failure]. / Neue Konzepte bei der chronischen Niereninsuffizienz.

The elevated cardiovascular mortality seen in patients with renal insufficiency makes it imperative that this condition be detected and treated in good time. The results of recent studies have led to fundamental changes in the therapeutic approach to the patient with kidney disease. A range of new medications is now available for the treatment of complications of renal failure.