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Background: 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.Methods: 120 patients admitted to the ICU with an ATIII concentration < 70% were randomized to receive ATIII (total dose 24000 units) or placebo treatment for 5 days; 56 patients had septic shock.Results: 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.Conclusions: The results of ATIII treatment in this population of patients suggests that replacement therapy reduces mortality in the subgroup of septic shock patients only. [ABSTRACT FROM AUTHOR]

Aim: In the developed countries the frequency of life threatening post-partum hemorrhages (PPH) is 1 in 1,000 deliveries with a risk of death of 1-2/100,000 deliveries. Hysterectomies for intractable bleeding are carried out in approximately 50% of the cases. The majority of PPH have obstetrical causes, most frequently atony of the uterus. Hereditary and acquired hemostatic defects are very rare. Guidelines of standard surgical and medical measures are available. In this paper we focus on the use of activated recombinant factor VII (rFVIIa) in PPH., Methods: A computerized literature search was carried out in PubMed and Ovid for papers published between 2001 and 2005 in the English literature reporting on life-threatening PPH treated with rFVIIa after failure of conventional therapy, including hysterectomy., Results: We identified 11 papers including 39 patients; in 18 of them the laboratory data were indicative for disseminated intravascular coagulation and in 24 hysterectomy was carried out. Controlled or reduced bleeding was reported in 38 out of 39 treated patients., Conclusions: The bleeding can occur in a series of events conductive to metabolic complications, hypoxia, disseminate intravascular coagulation, organ damage and multiorgan failure, progressively exhaustive. The therapeutic intervention must be instituted as early as possible before successive complications ensue. These preliminary reports in PPH after failure of conventional standard therapy suggest that rFVIIa is an active agent but should be administered as early as possible before the consequences of severe and intractable bleeding.

Objective: To review the clinical problems related to the inhibitor of factor VIII (FVIII) in pregnancy., Design: Retrospective analysis., Setting: Haemophilia and haemotology centres., Population: Patients registered and followed up at the centres., Methods: Data were collected from the Italian Haemophilia Register of acquired FVIII inhibitor., Results: Twenty of 96 cases with FVIII inhibitor were identified postpartum. The time of appearance was 3-150 days postpartum. All but one of the cases were idiopathic; 11/20 patients required blood transfusions. In six patients, the inhibitor was identified because of surgical bleeding, four after hysterectomies carried out because of postpartum haemorrhage. A prolonged activated partial thromboplastin time was present in all women in whom the test was carried out. Nine women did not require treatment because the bleeding was mild; in 11 patients bleeding was promptly controlled by different therapeutic modalities. Immunosuppressive therapy was used to suppress the inhibitor. The majority of the patients who achieved complete remission received steroids; in 6/6 patients who relapsed, a second remission was obtained with combined therapy., Conclusions: In a review of 20 pregnancies with FVIII inhibitor, over a 15 year period, bleeding was controlled in all cases with no fatalities. Correct evaluation of coagulation screening tests, in particular, activated partial thromboplastin time, is essential.

Sepsis and septic shock are the most frequent cause of mortality in non cardiologic intensive care units. Mortality of the severe form is still elevated in spite of the progress in the antibiotic therapy and in the hemodynamic and respiratory support. The most frequent cause of death is the Multi Organ Dysfunction Syndrome (MODS). The excessive inflammatory reaction and the damage of the microvascular bed secondary to the inflammation and to the disseminated intravascular coagulation (DIC) are important pathogenetic factors. In the sepsis a complex system of cellular activation initiates the release and the interaction of activators and inhibitors of the inflammation (cytokines), the activation of the enzymatic cascade systems (coagulation, fibrinolytic and complement systems) and the synthesis of proteases and anti proteases. The activation of the coagulation system, uncontrolled by the fibrinolytic system with formation of fibrin in the micro vascular bed, has an important role in the MODS. Experimental data and clinical observations suggest a possible therapeutic role of antithrombin III (AT) in sepsis; its plasma concentration is constantly decreased in patients with sepsis or septic shock and the entity of the decrease is correlated with the severity of the clinical picture and the outcome. At has a double function: regulation of the coagulation system and anti inflammatory properties. The anti inflammatory properties depend in part on the binding to the glycosaminoglycans of the endothelial cells and the consequent release of prostacyclin (PGI2). The anti inflammatory effect is independent from the anticoagulant one. The preliminary studies on the clinical use of AT were carried out in small groups of patients with DIC associated with pathologies of different etiology and often in very critical conditions. In general the evaluation criteria were the improvement or the normalization of the laboratory data. The interpretation of the therapeutic effect of AT is difficult because the dysomogeneity of these studies. The effect on mortality is controversial. Recently three prospective, randomized, double blind studies have been published in patients with severe sepsis and septic shock. The results of the single studies are inconclusive but the limited number of patients included in each study may explain the results. A meta-analysis of the data referring to the patients with severe sepsis and septic shock evidenced an odd ratio (OR) of 0.43 with 95% confidential interval of 0.20-0.92 (p = 0.029). The preliminary analysis of the results of a phase III study is unconclusive. Time, dosage and duration of treatment are still open to question. In perspective AT may be used in other clinical conditions associated with activation of the hemostatic system (cardiac surgery, stem cell transplantation, burns) even though the preliminary results must be confirmed by prospective studies. All these data suggest severe sepsis and septic shock as main criteria for treatment.

The standard modality of administration of rFVIIa to patients with FVIII and FIX inhibitors is the intermittent infusion every 2 to 6 hours. No untoward local or systemic effects have been reported; laboratory data of activation of coagulation were reported in the presence of coexistent problems (sepsis, septic shock) or with high doses. We treated four patients with FVIII inhibitor with rFVIIa administered by continuous infusion by a central vein catheter, monitoring the signs of systemic activation of the hemostatic system. The F(1+2) prothrombin fragments and the D-dimer increased after the bolus, and remained above the baseline values throughout the treatment period. These variations observed during the infusion period were not accompanied by clinical events.

Within this phase II trial of the European Organization for Research and Treatment of Cancer, we have investigated the safety and efficacy of pentostatin (Nipent; SuperGen, San Ramon, CA) in refractory lymphoid malignancies. Pentostatin was administered at a dosage of 4 mg/m2 every week for the first 3 weeks, then every 14 days, followed by maintenance therapy of 4 mg/m2 monthly for a maximum of 6 months. We have previously reported the results in T- and B-cell prolymphocytic leukemia, B-cell chronic lymphocytic leukemia, and hairy cell leukemia This report focuses on the outcome in T-cell malignancies: T-cell chronic lymphocytic leukemia, Sézary syndrome, mycosis fungoides, and T-zone lymphoma. Of 92 patients with these diagnoses enrolled, 76 were evaluable for response and toxicity, ie, 25 of 28 with T-cell chronic lymphocytic leukemia, 21 of 26 with Sézary syndrome, 22 of 26 with mycosis fungoides, and eight of 12 with T-zone lymphoma. All patients had progressive and advanced disease. Sixteen patients (21%) died during the first 9 weeks of treatment: 12 of progressive disease, two of infectious complications thought to be unrelated to treatment, one of myocardial infarction, and one of renal failure related to administration of intravenous contrast. Major toxicity (grades 3 and 4) included infection in 10.5% of patients, nausea/vomiting in 5%, and hepatotoxicity in 3%. One patient (1.3%) achieved a complete remission and 15 (19.7%) a partial remission. Better results were achieved in patients with Sézary syndrome or mycosis fungoides (complete remission + partial remission = 33.4% and 22.7%, respectively) than in patients with T-cell chronic lymphocytic leukemia (8%) or T-zone lymphoma (25%). We conclude that pentostatin is active in low-grade T-cell malignancies. Toxicities are mild to moderate at the dose schedule administered. Severe hematologic toxicity has not been observed. The efficacy at the present dose level is moderate. A higher dose might be necessary for some T-cell malignancies.