Pregnancy due to its physiological changes is a procoagulant state. The rate of cardiac valve prosthesis thrombosis, deep venous thrombosis and pulmonary embolism are all increased. Thrombolytic therapy with tissue plasminogen activator (rt-PA) is an approved therapy for ischemic stroke, myocardial infarction, pulmonary embolism and thrombosis of cardiac valve prosthesis. However, there are no data from controlled randomized trials in pregnant patients. Thrombolytic therapy has been rarely used in pregnancy with only 28 cases of rt-PA thrombolysis reported in the literature so far. Indications for rt-PA thrombolysis were stroke (n = 10), thrombosis of cardiac valve prosthesis (n = 7), pulmonary embolism (n = 7), deep venous thrombosis (n = 3), and myocardial infarction (n = 1). Remarkably, all thrombosis of cardiac valve prostheses occurred after switching from warfarin to heparin in order to prevent teratogenicity and fetal loss. Two patients died (7%) and three suffered from complications that were managed conservatively (11%). In another three patients thrombolysis was not successful. Thrombolysis complication rates were similar compared to non-pregnant patients for the above mentioned indications. Six out of the 26 fetus from surviving mothers died (23%), three of them after induced abortion for maternal reasons (12%). A likely causal relation to the prior thrombolysis could only be established in two fetal fatalities (8%). None of the live born children suffered a permanent deficit. Considering that rt-PA does not cross the placenta and taking into account that the complication rates do not exceed those of large randomised controlled trials thrombolytic therapy should not be withheld in pregnant patients in case of life-threatening or potentially debilitating thrombembolic disease.
Despite abundant evidence for changes in mitochondrial membrane permeability in tumor necrosis factor (TNF)-mediated cell death, the role of plasma membrane ion channels in this process remains unclear. These studies examine the influence of TNF on ion channel opening and death in a model rat liver cell line (HTC). TNF (25 ng/ml) elicited a 2-and 5-fold increase in K ؉ and Cl ؊ currents, respectively, in HTC cells. These increases occurred within 5-10 min after TNF exposure and were inhibited either by K ؉ or Cl ؊ substitution or by K ؉ channel blockers (Ba 2؉ , quinine, 0.1 mM each) or Cl ؊ channel blockers (10 M 5-nitro-2-(3-phenylpropylamino)benzoic acid and 0.1 mM N-phenylanthranilic acid), respectively. TNF-mediated increases in K ؉ and Cl ؊ currents were each inhibited by intracellular Ca 2؉ chelation (5 mM EGTA), ATP depletion (4 units/ml apyrase), and the protein kinase C (PKC) inhibitors chelerythrine (10 M) or PKC 19 -36 peptide (1 M). In contrast, currents were not attenuated by the calmodulin kinase II 281-309 peptide (10 M), an inhibitor of calmodulin kinase II. In the presence of actinomycin D (1 M), each of the above ion channel blockers significantly delayed the progression to TNF-mediated cell death. Collectively, these data suggest that activation of K ؉ and Cl ؊ channels is an early response to TNF signaling and that channel opening is Ca 2؉ -and PKC-dependent. Our findings further suggest that K ؉ and Cl ؊ channels participate in pathways leading to TNF-mediated cell death and thus represent potential therapeutic targets to attenuate liver injury from TNF.
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