Summary
Terminal complement blockade has been shown to decrease the incidence of early acute antibody‐mediated rejection (eAMR) in the first month after positive cross‐match kidney transplant recipients, yet some patients still develop eAMR. The current study investigated possible mechanisms of eAMR despite eculizumab treatment. Of the 26 patients treated with eculizumab, two developed clinical eAMR and another patient developed histologic signs of eAMR without graft dysfunction (‘subclinical eAMR’). Twenty‐three did not have histologic injury on early surveillance biopsies. All 26 patients had therapeutic levels of eculizumab and showed complete blockade of complement in hemolytic assays. High levels of donor‐specific alloantibody (DSA) including total IgG, IgG3, and C1q+ DSA were present in patients with and without eAMR, and none correlated well with eAMR. In contrast, IgM DSA was present in only four patients after transplantation: the two patients with clinical eAMR, one patient with subclinical AMR, and one patient without eAMR (P = 0.006 correlation with eAMR). Both clinical eAMR episodes were easily treated with plasma exchange which removed IgM more completely and rapidly than IgG, resulting in normalization of function and histology. These data suggest a possible role of antidonor IgM DSA in the pathogenesis of eAMR in patients treated with terminal complement blockade (ClinicalTrials.gov Identifier: NCT00670774).
SummaryA modified form of the activated whole blood clotting time was used to evaluate response of blood from hemophilia patients to factor VIIa. Repeated assays of individuals over a one-year period showed consistency for each individual and significant difference between individuals. Four hemophilia patients with inhibitors gave low response to factor VIIa in the assay and were characterized as low or moderate clinical responders to factor VIIa therapy. Another four patients with moderate to good clinical responsiveness to factor VIIa therapy showed a strong response to factor VIIa in the assay. A factor VIIa mutant with enhanced membrane affinity showed 10 to 13-fold higher activity than wild type factor VIIa. The results may justify larger studies to determine the utility of this assay for evaluation of patient responsiveness and to set factor VIIa therapy levels.
If there is a genetic predisposition to excessive bleeding, there should be an association in excessive blood loss between multiple cardiac surgeries. We retrospectively determined in 174 patients the association of excessive bleeding between 2 cardiac surgeries with cardiopulmonary bypass between January 19, 1990 and June 25, 2002. Excessive bleeding was defined by 2 criteria: (a) postoperating room chest tube blood loss over 24 h more than or equal to 750 mL (chest tube drainage [CTD] > or = 750) and (b) transfusion of any non-red blood cell (RBC) blood products. Logistic regression was used to estimate the association between excessive bleeding at the first and second cardiac procedures. The logistic regression models for CTD > or = 750 in the second surgery determined that CTD > or = 750 in the first surgery compared to CTD < 750 had an unadjusted odds ratio of 2.18 (P = 0.03) and an odds ratio of 2.42 (P = 0.03) when adjusted for age, sex, body surface area, preoperative anticoagulant use, cardiopulmonary bypass duration, and procedure type at second surgery. The logistic regression model for any non-RBC use in the second surgery determined that any non-RBC use in the first surgery compared with no non-RBC use had an unadjusted odds ratio of 2.32 (P = 0.02) and an odds ratio of 2.55 (P = 0.02) when adjusted for age, sex, body surface area, preoperative anticoagulant use, cardiopulmonary bypass duration, and procedure type at second surgery. We conclude that a history of excessive bleeding during the first operation is associated with more than two times increased risk for excessive bleeding in the second surgery.
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