The effect of administering preprocedural VITamin K on the international normalized ratio in patients anticoagulated with ACEnocoumarol (VITKACE-study): a prospective cohort study.

BACKGROUND: The effect of the vitamin K antagonist acenocoumarol on coagulation needs to be reversed when patients undergo an invasive procedure with considerable bleeding risk. A strategy to achieve this is by administering oral vitamin K before a procedure while continuing acenocoumarol. OBJECTIVES: To assess the effect on periprocedural international normalized ratio (INR) values and safety using oral vitamin K as anticoagulant reversal method. METHODS: In this prospective cohort study, consecutive patients using acenocoumarol undergoing elective procedures between 2019 and 2022 were included. According to standard of care in our hospital, patients took 10 mg oral vitamin K 36 to 48 hours before the procedure while continuing their normal use of acenocoumarol. Effectiveness to lower INR to <1.8 preprocedural was assessed. Bleeding and thrombotic complications within 30 days after the procedure were assessed. Periprocedural course of INR was monitored by collecting additional blood samples. RESULTS: Seventy-four patients were included for analysis. On the day of the procedure, an adequate INR of <1.8 was achieved in 99% of patients. One clinically relevant nonmajor bleeding complication and no thrombotic complications were observed during the first 30 days after the procedure. INR gradually restored to therapeutic level during the days after the procedure. CONCLUSION: Using oral vitamin K while patients continue acenocoumarol intake is an effective way to adequately lower INR before an invasive procedure. Low amount of bleeding complications and absence of thromboembolic complications suggest that this is a safe strategy. The INR values returned gradually to therapeutic range after the procedure, probably contributing to the observed low bleeding rate.

Reticulocyte hemoglobin content in a large sample of the general Dutch population and its relation to conventional iron status parameters.

BACKGROUND: No full consensus exists on which iron status parameters to use for iron status assessment. In this study, we assessed the usefulness of measurement of the hemoglobin content of reticulocytes (CHr) in the general population. METHODS: The following iron status parameters were assessed in 1024 adults: CHr, reticulocytes, hemoglobin (Hb), ferritin, serum iron, transferrin, transferrin saturation and mean corpuscular volume (MCV). Mean parameter values and correlation coefficients for CHr and other parameters were calculated. In addition, mean CHr levels in subgroups based on low and normal values of other iron status parameters were compared. RESULTS: Mean CHr values in men were 31.81 (SD = 1.50) pg and in women 31.32 (SD = 1.51) pg. A positive correlation was observed between CHr and Hb, ferritin, serum iron, transferrin saturation and MCV; a negative correlation was observed between CHr and transferrin. CHr levels were lower in subjects with low values of Hb, ferritin, serum iron and MCV compared to subjects with normal values for these parameters. CONCLUSION: Mean CHr values in this population were comparable to values reported in small healthy control groups. Associations with other parameters were in agreement with associations reported in literature. CHr measurement might have additional value in iron status assessment.

Alloreactivity against repeated HLA mismatches of sequential islet grafts transplanted in non-uremic type 1 diabetes patients.

BACKGROUND: Islet transplantation can restore insulin production in type 1 diabetes patients. However, survival of the islet allografts will face rejection or recurrence of autoimmunity or a combination of both. In a study on islet-after-kidney transplants, we previously reported that islet cell recipients presented low T-cell alloresponses for HLA mismatches that were shared by the islet cell graft and the prior kidney graft, that is, repeated mismatch, while vigorous responses were measured against novel HLA mismatches. METHODS: We now investigated T-cell alloreactivity to repeated HLA-mismatches in three non-uremic type 1 diabetic patients each receiving three sequential islet cell implants. RESULTS: These islet-after-islet recipients patients exhibited low or absent responses to repeated mismatches to the first graft which was accompanied by sustained graft function, and reduced responsiveness towards subsequent grafts. In one patient, T-cell responses towards these mismatches were noticed following new mismatches in subsequent grafts, with loss of graft function. CONCLUSION: These case reports further support the view that subsequent islet implantations can reduce alloreactivity for repeated HLA mismatches. They demonstrate the usefulness of monitoring T-cell reactivity against islet allografts to correlate immune function with graft survival and to identify conditions for preservation of beta-cell function.

Activated HLA class I-reactive cytotoxic T lymphocytes associated with a positive historical crossmatch predict early graft failure.

BACKGROUND: Preexisting alloantibodies against the mismatched HLA class I antigens of the donor, when present in current sera, are believed to be detrimental for kidney graft survival. The relevance of a positive crossmatch with historical sera only is still a matter of debate. Previous studies showed a correlation between the presence of alloantibodies and the presence of alloactivated cytotoxic T lymphocytes (CTLs). We wondered whether the persistence of activated CTLs might explain the poor results in a proportion of patients with a historical positive crossmatch. METHODS: We tested 10 sensitized patients to determine whether activated CTLs persist when the antibodies disappear. Limiting dilution assays were performed in the presence and absence of cyclosporine (CsA) to distinguish between activated (primed) (CsA resistant) and naive (CsA sensitive) CTLs. To test the clinical relevance of the persisting CTLs, eight sensitized patients, who underwent a kidney transplantation across a positive historical crossmatch, were retrospectively tested for the presence or absence of activated donor-specific CTLs at the day of transplantation. RESULTS: In the first group, four patients had CsA-sensitive CTLs, three patients had CsA-resistant CTLs, and three other patients had CsA-sensitive CTLs for a particular HLA antigen and CsA-resistant CTLs for another HLA antigen. In the transplant group, four patients with CsA-sensitive CTLs at the day of transplantation were found to have a good graft function. In the other four patients, the presence of CsA-resistant donor-specific CTLs was associated with rejection and early graft loss. CONCLUSION: The present study suggests that determining the activation state of CTLs specific for the HLA mismatch against which antibodies were present in historical sera, may be relevant to transplant outcome in patients who undergo transplantation across a positive historical crossmatch.

Kinetics of the pregnancy-induced humoral and cellular immune response against the paternal HLA class I antigens of the child.

Pregnancy can prime the maternal humoral immune response against paternal human leukocyte antigens (HLA) of the child. Previous studies have reported that formation of antibodies against inherited paternal HLA is associated with the presence of primed cytotoxic T lymphocytes (CTLs) specific for these antigens. Recently, we reported that primed CTLs can persist for more than 10 years after pregnancy even if the antibodies have disappeared. In the present study we studied the kinetics of the pregnancy induced immune response of the T-cell and B-cell compartment. In 12 women, who had specific antibodies against the paternal HLA antigens of the child (child mismatch) at the time of delivery, we analyzed the CTLp frequencies against the paternal HLA antigens from the time of delivery up to 2 years after. The contribution of primed CTLs to these CTLp frequencies was tested by limiting dilution analysis in the absence and presence of monoclonal antibodies specific for CD8. In contrast to naïve CTLs, primed CTLs are resistant to CD8 antibodies. Disappearance of the antibodies was not associated with a decrease of the number of CTLp directed against the paternal antigens, towards which the antibodies were originally directed. However, in women where the antibodies disappeared, a decrease of primed child mismatch specific CTLs was found, whereas in women where the antibodies persist, the population of primed CTLs remained stable up to 2 years after delivery. Our data suggest a functional correlation between the T-cell and B-cell allorepertoire. Although the kinetics do not run completely in parallel, disappearance of the anti-HLA antibodies in the first 2 years after delivery is related with a decrease of primed child mismatch specific CTLs. These data may be relevant for transplantation of female recipients with historical, pregnancy-induced HLA alloantibodies.

Primed CTLs specific for HLA class I may still be present in sensitized patients when anti-HLA antibodies have disappeared: relevance for donor selection.

BACKGROUND: The presence of donor-specific HLA antibodies is generally considered to be a contraindication for transplantation, even when these antibodies are only present in historical sera. Previous studies showed that donor-specific antibodies in current sera were associated with the presence of primed cytotoxic T cells (CTLs) with a high avidity for donor HLA class I antigens. The presence of these CTLs is considered to be a reflection of an activated immune system and a contraindication for transplantation with a donor sharing these particular HLA antigens. METHODS: In the present study we compared the incidence of primed CTLs in patients with anti-HLA antibodies in current sera and in patients with anti-HLA antibodies in historical sera only. Cytotoxic T lymphocyte precursor (CTLp) frequencies and the incidence of primed CTLs directed against HLA class I antigens to which the patient had formed antibodies were studied in 37 sensitized renal patients. As controls, antigens to which a patient has never formed antibodies were tested. RESULTS: In patients with antibodies in current sera mainly primed CTLs were detected, whereas in patients where the antibodies had disappeared mainly naive CTLs were detected. However, in four patients primed CTLs persisted despite the fact that the HLA antibodies had disappeared. CONCLUSION: Considering the previously described association between primed CTLs and graft rejection, these findings may be relevant for the selection of patients who can be transplanted across a positive historical crossmatch. If the antibodies have disappeared and only naive CTLs are present, a successful transplantation should be feasible. A prospective study will reveal whether this is indeed the case.