Search

ATIII is decreased in sepsis and/or shock and its baseline value correlates with mortality. The efficacy of ATIII therapy on mortality was assessed in a selected group of patients admitted to the intensive care unit (ICU) in a double-blind, randomized, multicenter study.120 patients admitted to the ICU with an ATIII concentration70% were randomized to receive ATIII (total dose 24000 units) or placebo treatment for 5 days; 56 patients had septic shock.ATIII concentrations in the treated group remained constant throughout the treatment period (range 97-102%). The Kaplan-Meier analysis showed no difference in overall survival between the two groups: 50 and 46% for ATIII and placebo, respectively. Septic shock and hemodynamic support were unbalanced in the two groups at admission. Therefore the Cox analysis was carried out after adjusting for these two variables. Treatment with ATIII decreases the risk of death with an odds ratio (OR) of 0.56. Of the covariates analyzed, septic shock and the baseline multiple organ failure score were negatively associated with survival and plasma activity level was positively associated with survival with an OR of 0.97 for each 1% increase in the ATIII plasma concentration at baseline.The results of ATIII treatment in this population of patients suggests that replacement therapy reduces mortality in the subgroup of septic shock patients only.

Warfarin, like all the 4-hydroxycoumarin compounds, has an asymmetric carbon atom. The clinically available warfarin preparations consist of a racemic mixture of equal amounts of 2 distinct S and R isomers, the former being 4-times more potent as anticoagulant and more susceptible to drug interaction. Warfarin is highly water soluble and rapidly absorbed from the stomach and the upper gastrointestinal tract; its plasma concentrations peak 60 to 90 minutes after oral administration. Warfarin binds to the enzyme vitamin K 2,3-epoxide reductase in liver microsomes, stopping the cycle of vitamin K and reducing gamma-carboxylation of the precursors of vitamin D-dependent pro- and anticoagulant factors. A variable fraction of the binding with the target enzyme, albeit small, can be reversed by competitive displacers, such as dithiol-reducing agent activity. Differences in dithiol-reducing activity have been suggested as a contributing factor to the wide interindividual differences in sensitivity to oral anticoagulants. The anticoagulant effect is caused by a small fraction of the drug, since most (97 to 99%) is protein bound (mainly to albumin) and ineffective. Drugs that can displace the albumin binding will increase the action of warfarin, even though this effect is counteracted by a more rapid elimination of the drug. The elimination half-life of warfarin varies greatly among individuals, ranging from 35 to 45 hours; the S isomer has, however, an average half-life shorter than the R isomer. The plasma levels of vitamin K-dependent proteins are determined by a dynamic equilibrium between their synthesis and half-life times. The delay before warfarin takes effect reflects the half-life of the clotting proteins; the levels of factor VII and protein C (with shorter half-lives) are reduced earlier, reaching steady inhibited levels in about 1 day, whereas factor II takes more than 10 days. Oral anticoagulant therapy (OAT) with warfarin or other coumarin derivatives is increasingly administered to patients for primary or secondary prevention of various arterial or venous thromboembolic diseases. If in some clinical conditions OAT is given indefinitely, in others--such as venous thromboembolism or after tissue heart valve replacement--anticoagulants are usually given only for the high risk period of thrombotic complication. A recent large prospective study performed by the Italian Federation of Anticoagulation Clinics showed that about 30% of the patients who began OAT for various clinical indications stopped treatment at different times, confirming that withdrawal from OAT is an occurrence that affects a large number of patients. The expression 'rebound phenomenon' was adopted to indicate a hypercoagulant condition occurring after warfarin withdrawal. A possible more frequent recurrence of thromboembolism after cessation of anticoagulation became a matter of controversy and many clinical studies, mostly observational and noncontrolled, reported on the issue with inconsistent results. Most authoritative commentators agreed that rebound phenomenon, though possible, was not clinically relevant and did not differ in frequency and intensity according to mode of withdrawal. Scientific interest in the topic waned until more sensitive methods for investigating blood hypercoagulability became available. In recent years, many studies (reviewed in the text) have investigated the levels of different markers of hypercoagulability [fibrinopeptide A, activated factor VII, prothrombin fragments F1+2, thrombin-antithrombin complexes, D-dimers (DD)], consistently finding an increase in their values after cessation of anticoagulation. Changes in the levels of markers of activated blood coagulation were prospectively investigated by our group in 32 patients with venous thromboembolism who were randomly withdrawn abruptly or gradually from warfarin treatment. Our results indicate that interruption of anticoagulant treatment frequently elicits low grade acti

The presence and inheritance of restriction fragment length polymorphisms (RFLPs) and gene lesions in the coagulation factor VIII gene were investigated in 15 hemophilia families. An abnormal HindIII 2.6-kb band, previously detected in a severe hemophiliac, was observed in a not severely affected patient and also in the normal gene of a woman carrying a hemophilic gene in which the lesions was found. The TaqI site in exon 24 of this defective gene was removed by a C to T transition causing an amino acid change (Arg----Gln). Very low amounts of factor VIII activity and antigen were detected in the severely affected grandson. The presence of the HindIII 2.6-kb fragment in both normal and pathological genes indicates that a factor VIII RFLP without functional meaning was found. Its frequency, determined in 60 chromosomes, is 0.18. Double digestions enabled us to map the polymorphic site 3' to the exon 19.

Defibrotide is a polynucleotide extracted from mammalian lung, which shows antithrombotic and anti-ischaemic activity in animals, probably related to stimulation of fibrinolysis and/or enhancement of prostacyclin production. The effect of a single infusion of defibrotide on fibrinolysis and the levels of certain prostanoids in man has been investigated in a cross-over double-blind placebo-controlled study. Evaluation of changes in fibrinolysis was difficult because of the spontaneous activation observed after placebo. However, the fast-acting plasminogen activator inhibitor was decreased only at end of the defibrotide infusion, suggesting a moderate profibrinolytic effect superimposed on the spontaneous activation. There was a marked and prolonged elevation of the plasma level of 6-keto-PGF1 alpha, the stable metabolite of prostacyclin. In collagen stimulated whole blood, both 6-keto-PGF1 alpha and prostaglandin E2 production were also greatly increased, with no consistent indication of inhibition of thromboxane B2. It is suggested that defibrotide stimulates prostacyclin and prostaglandin E2 production by leucocytes or via platelet/leukocyte interactions. The effects observed here should be useful in guiding subsequent clinical trials.