Epidural/spinal anesthesia during delivery in women with factor XI deficiency, a single center experience.

INTRODUCTION: The safety of neuro-axial anaesthesia (epidural/spinal) at labour of women with partial factor XI (FXI) deficiency is uncertain. Although FXI deficiency is frequent in Ashkenazi Jews, it is not routinely measured before labour. Our institute serves a large Ashkenazi population. We assumed that 10% of them have undiagnosed FXI deficiency. AIM: Assess the incidence, bleeding tendency and coagulation status among Jewish Ashkenazi women with FXI deficiency that underwent neuro-axial anaesthesia at delivery. METHODS: Jewish Ashkenazi women who underwent neuro-axial anaesthesia at labour completed the SSC ISTH bleeding assessment tool (BAT) and had blood drawn for coagulation tests, FXI and thrombin generation after labour. Estimation for 10 years was calculated from the 1-year sample. RESULTS: We recruited 261 women during 12 months. Among them, 39 (15%) had FXI deficiency (<70%) with median FXI levels of 63% (range: 33%-70%). Around 50% of them underwent amniocentesis in the current pregnancy and prior neuro-axial anaesthesia with no bleeding complications. BAT score and thrombin generation did not differ between women regardless of FXI status. aPTT was longer in women with partial FXI deficiency (median - 28.6 sec vs 26.3 sec, P < .001, Table 2), although within the normal range in all women. No bleeding complications after neuro-axial anaesthesia at delivery were reported in our centre in the last decade though, and according to our estimation, at least 2150 women had partial FXI deficiency. CONCLUSIONS: A significant number of Jewish Ashkenazi women with undiagnosed partial FXI deficiency undergo neuro-axial anaesthesia at labour without bleeding complications.

TNF-α increases the expression and activity of vitamin D receptor in keratinocytes: role of c-Jun N-terminal kinase.

Several inflammatory mediators increase calcitriol production by epidermal keratinocytes. In turn calcitriol attenuates the keratinocyte inflammatory response. Since the effect of the in-situ generated calcitriol depends also on the sensitivity to the hormone we studied the effect of inflammatory cytokines on the response of HaCaT human keratinocytes to calcitriol by examining the expression and transcriptional activity of VDR. Treatment with TNF, but not with IL-1ß or interferon γ, increased VDR protein level, while decreasing the level of its heterodimerization partner RXRα. This was associated with increased VDR mRNA levels. c-Jun N-terminal kinase, but not P38 MAPK or NFκB, was found to participate in the upregulation of VDR by TNF. The functional significance of the modulation of VDR and RXRα levels by TNF is manifested by increased induction of VDR target gene CYP24A1 by calcitriol. Calcitriol, in turn, inhibited the enhanced expression of VDR by TNF. In conclusion, the inflammatory cytokine TNF increases the response of keratinocytes to calcitriol through upregulation of its receptor VDR, which in turn is subject to negative feedback by the hormone accelerating the return of the keratinocyte vitamin D system to its basal activity. We surmise that the increased generation and sensitivity to calcitriol in keratinocytes play a role in the resolution of epidermal inflammation.

Two modes of ERK activation by TNF in keratinocytes: different cellular outcomes and bi-directional modulation by vitamin D.

Inflammation, elicited in the skin following tissue damage or pathogen invasion, may become chronic with deleterious consequences. Tumor necrosis factor (TNF) is a key mediator of cutaneous inflammation and the keratinocyte an important protagonist of skin immunity. Calcitriol, the hormonally active vitamin D metabolite, and its analogs attenuate epidermal inflammation and inhibit the hyperproliferation of keratinocytes associated with the inflammatory disorder, psoriasis. Since activation of extracellular signal-regulated kinase (ERK) promotes keratinocyte proliferation and mediates epidermal inflammation, we studied the effect of calcitriol on ERK activation in HaCaT keratinocytes exposed to the ubiquitous inflammatory cytokine TNF. By using the EGF receptor (EGFR) tyrosine kinase inhibitor, AG1487 and the Src family inhibitor, PP-1, we established that TNF activated ERK in an EGFR and Src dependent and an EGFR and Src independent modes. EGFR dependent activation resulted in the upregulation of the transcription factor, c-Fos, while the EGFR independent activation mode was of a shorter duration, did not affect c-Fos expression but induced IL-8 mRNA expression. Pretreatment with calcitriol, enhanced TNF-induced EGFR-Src dependent ERK activation and tyrosine phosphorylation of the EGFR, but abolished the EGFR-Src independent ERK activation. These effects were mirrored by enhancement of c-Fos and inhibition of IL-8 induction by TNF. Treatment with calcitriol increased the rate of the de-phosphorylation of activated ERK, accounting for the inhibition of EGFR-Src independent ERK activation by TNF. It is possible that effects on the ERK cascade contribute to the effects of calcitriol and its synthetic analogs on cutaneous inflammation and keratinocyte proliferation.