Insulinoma: A retrospective study analyzing the differences between benign and malignant tumors.

BACKGROUND/OBJECTIVES: Insulinoma is a rare pancreatic tumor and, usually, a benign disease but can be a malignant one and, sometimes, a highly aggressive disease. The aim of this study was to determine differences between benign and malignant tumors. METHODS: Retrospective study of 103 patients with insulinoma treated in a tertiary center. It was analyzed demographic, clinical, laboratory, localization and histologic analysis of tumor and follow up data of subjects in order to identify differences between individuals benign and malignant disease. RESULTS: Almost all patients (87%) had a benign tumor and survival rates of 100% following pancreatic tumor surgery. Those with malignant tumors (13%) have a poor prognosis, 77% insulinoma-related deaths over a period of 1-300 months after the diagnosis with a survival rate of 24% in five years. The following factors are associated with an increased risk of malignant disease: duration of symptoms < 24 months, fasting time for the occurrence of hypoglycemia < 8 h, blood plasma insulin concentration ≥ 28 µU/mL and C-peptide ≥ 4.0 ng/mL at the glycemic nadir and tumor size ≥ 2.5 cm. CONCLUSIONS: Our data help to base the literature about these tumors, reinforcing that although insulinoma is usually a single benign and surgically treated neoplasia, the malignant one is difficult to treat. We highlight the data that help predict a malignancy behavior of tumor and suggest a long follow up after diagnosis in these cases.

Borderline tuberculoid leprosy in childhood onset systemic lupus erythematosus patient.

Leprosy is a contagious and chronic systemic granulomatous disease caused by the bacillus Mycobacterium leprae. To our knowledge, no case of leprosy in a childhood-onset systemic lupus erythematosus (c-SLE) patient has been reported. For a period of 31 years, 312 c-SLE patients were followed at the Pediatric Rheumatology Unit of our University Hospital. One of them (0.3%) had tuberculoid leprosy skin lesions during the disease course and is here reported. A 10-year-old boy from Northwest of Brazil was diagnosed with c-SLE based on malar rash, photosensitivity, oral ulcers, lymphopenia, proteinuria, positive antinuclear antibodies, anti-double-stranded DNA, anti-Sm and anti-Ro/SSA autoantibodies. He was treated with prednisone, hydroxychloroquine and intravenous cyclophosphamide, followed by mycophenolate mofetil. At 12-years-old, he presented asymmetric skin lesions characterized by erythematous plaques with elevated external borders and hypochromic center with sensory loss. Peripheral nerve involvement was not evidenced. No history of familial cases of leprosy was reported, although the region where the patient resides is considered to be endemic for leprosy. Skin biopsy revealed a well-defined tuberculoid form. A marked thickening of nerves was observed, often destroyed by granulomas, without evidence of Mycobacterium leprae bacilli. At that time, the SLEDAI-2K score was 4 and he had been receiving prednisone 15 mg/day, hydroxychloroquine 200 mg/day and mycophenolate mofetil 3 g/day. Paucibacillary treatment for leprosy with dapsone and rifampicine was also introduced. In conclusion, we have reported a rare case of leprosy in the course of c-SLE. Leprosy should always be considered in children and adolescents with lupus who present skin abnormalities, particularly with hypoesthesic or anesthesic cutaneous lesions.

Childhood-onset bullous systemic lupus erythematosus.

Bullous systemic lupus erythematosus has rarely been described in pediatric lupus population and the real prevalence of childhood-onset bullous systemic lupus erythematosus has not been reported. From January 1983 to November 2013, 303 childhood-onset SLE (c-SLE) patients were followed at the Pediatric Rheumatology Unit of the Childrens Institute of Hospital das Clínicas da Faculdade de Medicina Universidade da Universidade de São Paulo, three of them (1%) diagnosed as childhood-onset bullous systemic lupus erythematosus. All three cases presented tense vesiculobullous lesions unassociated with lupus erythematosus lesions, with the median duration of 60 days (30-60). All patients fulfilled bullous systemic lupus erythematosus criteria. Two had nephritis and serositis and presented specific autoantibodies. The histological pattern demonstrated subepidermal blisters with neutrophils-predominant infiltrates within the upper dermis. Direct immunofluorescence (DIF) showed deposits of IgG and complement along the epidermal basement membrane, in the presence or absence of IgA and/or IgM. A positive indirect immunofluorescence on salt-split skin demonstrating dermal binding was observed in two cases. All of them had moderate/severe disease activity at diagnosis with median Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) of 18 (14-24). Two patients received dapsone and one with severe nephritis received immunosuppressive drugs. In conclusion, in the last 30 years the prevalence of bullous lupus in childhood-onset lupus population was low (1%) in our tertiary University Hospital. A diagnosis of SLE should always be considered in children with recurrent tense vesiculobullous lesions with or without systemic manifestations.

Cannabinoid type 2 receptor inhibition enhances the antidepressant and proneurogenic effects of physical exercise after chronic stress.

Chronic stress is a major risk factor for neuropsychiatric conditions such as depression. Adult hippocampal neurogenesis (AHN) has emerged as a promising target to counteract stress-related disorders given the ability of newborn neurons to facilitate endogenous plasticity. Recent data sheds light on the interaction between cannabinoids and neurotrophic factors underlying the regulation of AHN, with important effects on cognitive plasticity and emotional flexibility. Since physical exercise (PE) is known to enhance neurotrophic factor levels, we hypothesised that PE could engage with cannabinoids to influence AHN and that this would result in beneficial effects under stressful conditions. We therefore investigated the actions of modulating cannabinoid type 2 receptors (CB2R), which are devoid of psychotropic effects, in combination with PE in chronically stressed animals. We found that CB2R inhibition, but not CB2R activation, in combination with PE significantly ameliorated stress-evoked emotional changes and cognitive deficits. Importantly, this combined strategy critically shaped stress-induced changes in AHN dynamics, leading to a significant increase in the rates of cell proliferation and differentiation of newborn neurons, overall reduction in neuroinflammation, and increased hippocampal levels of BDNF. Together, these results show that CB2Rs are crucial regulators of the beneficial effects of PE in countering the effects of chronic stress. Our work emphasises the importance of understanding the mechanisms behind the actions of cannabinoids and PE and provides a framework for future therapeutic strategies to treat stress-related disorders that capitalise on lifestyle interventions complemented with endocannabinoid pharmacomodulation.

The clinical impact of MTHFR polymorphism on the vascular complications of sickle cell disease.

Sickle cell disease (SCD) is one of the most common inherited diseases in the world and the patients present notorious clinical heterogeneity. It is known that patients with SCD present activation of the blood coagulation and fibrinolytic systems, especially during vaso-occlusive crises, but also during the steady state of the disease. We determined if the presence of the factor V gene G1691A mutation (factor V Leiden), the prothrombin gene G20210A variant, and methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism may be risk factors for vascular complications in individuals with SCD. We studied 53 patients with SCD (60% being women), 29 with SS (sickle cell anemia; 28 years, range: 13-52 years) and 24 with SC (sickle-hemoglobin C disease; 38.5 years, range: 17-72 years) hemoglobinopathy. Factor V Leiden, MTHFR C677T polymorphism, and prothrombin G20210A variant were identified by PCR followed by further digestion of the PCR product with specific endonucleases. The following vascular complications were recorded: stroke, retinopathy, acute thoracic syndrome, and X-ray-documented avascular necrosis. Only one patient was heterozygous for factor V Leiden (1.8%) and there was no prothrombin G20210A variant. MTHFR 677TT polymorphism was detected in 1 patient (1.8%) and the heterozygous form 677TC was observed in 18 patients (34%, 9 with SS and 9 with SC disease), a prevalence similar to that reported by others. No association was detected between the presence of the MTHFR 677T allele and other genetic modulation factors, such as alpha-thalassemia, beta-globin gene haplotype and fetal hemoglobin. The presence of the MTHFR 677T allele was associated with the occurrence of vascular complications in SCD, although this association was not significant when each complication was considered separately. In conclusion, MTHFR C677T polymorphism might be a risk factor for vascular complications in SCD.

Impaired adrenocorticotropin-adrenal axis in combined pituitary hormone deficiency caused by a two-base pair deletion (301-302delAG) in the prophet of Pit-1 gene.

The Prophet of Pit-1 gene (PROP1) encodes a paired-like homeodomain protein, which is expressed early in pituitary gland development. When mutated, it is responsible for combined pituitary hormone deficiency (CPHD) in humans, as well as in Ames dwarf mice (df/df). Several independent mutations in the homeodomain of PROP1 have been identified as causative for the human CPHD phenotype, which has been characterized, thus far, as absence or low levels of GH, PRL, TSH, LH, and FSH. Here, we report 10 CPHD cases, 9 of which were born to consanguineous marriages occurring in a large family living in an isolated area in the Southeast of Brazil. All affected patients present complete absence of puberty and low GH, PRL, TSH, LH, and FSH associated with severe hypoplasia of the pituitary gland, as seen by MRI. All 3 exons of the PROP1 genes of these patients were sequenced. The 301-302delAG frameshift mutation was found in both alleles of each affected case. Surprisingly, we observed ACTH/cortisol insufficiency associated with the PROP1 phenotype. The patients' ages varied between 8 and 67 yr, and cortisol response impairment was identified in 5 of 6 of the older patients and in an 11-yr-old patient. Previous studies have not fully characterized patients at advanced ages, leading us to conclude that the phenotype of this PROP1 mutation includes late-onset adrenal insufficiency. We present an extensive clinical analysis of all of these patients. The presence of ACTH/cortisol deficiency in this family bearing the PROP1 301-302delAG mutation indicates the importance of a complete endocrine characterization and of life-long monitoring of PROP1 patients.

Effect of standard heparin and a low molecular weight heparin on thrombolytic and fibrinolytic activity of single-chain urokinase plasminogen activator in vitro.

The effect of unfractioned heparin (UH) and low molecular weight heparin (LMWH) (Kabi 2165 - Fragmin) on in vitro scu-PA thrombolytic and fibrinogenolytic activity was investigated. Thrombolytic activity was evaluated by following lysis of radiolabeled plasma clot immersed in plasma in presence of scu-PA alone or with either form of heparin. A 200 IU/ml scu-PA concentration produced clot lysis within 7 hr. UH or LMWH led to a slightly faster clot lysis which was statistically significant only at the 2nd and 3rd hour. No significant difference could be evidenced between UH and LMWH effect. During clot lysis, plasmin, generated within the clot led to a gradual transformation of scu-PA to tcu-PA, specially after a 4-hr incubation. Appearance of tcu-PA activity in the plasma surrounding the clot was significantly inhibited by either form of heparin. This finding contrasts with results observed in purified systems and suggests the presence of heparin-dependent plasma factor(s) inhibiting tcu-PA formation or its activity. Possible candidates might be anti-thrombin III and PAI-3. No fibrinogen breakdown was observed when plasma was incubated for 7 hr at 37 degrees C in presence of scu-PA alone (200 IU/ml) or with either form of heparin. However, in presence of a plasma clot, an important fibrinogen breakdown was observed during clot lysis reflecting the action of plasmin and/or tcu-PA generated within the clot, in the surrounding plasma. Fibrinogenolysis was less pronounced in the presence of both heparin preparations possibly as a consequence of the reduction in the tcu-PA level. These results underline the importance of plasma factors in the interaction of heparin with plasminogen activators such as scu-PA.

Comparison of thrombolytic, fibrinolytic, and fibrinogenolytic properties of tissue plasminogen activator, streptokinase, single-chain urokinase, high molecular weight and low molecular weight urokinase in human plasma in vitro.

Thrombolytic, fibrinolytic, and fibrinogenolytic properties of tissue plasminogen activator (t-PA) from melanoma cells (mt-PA), recombinant t-PA (rt-PA), streptokinase (SK), single-chain urokinase plasminogen activator (scu-PA), and high and low molecular weight urokinase (HMW UK, LMW UK) were compared in vitro by means of systems using human plasma. Thrombolytic activities were tested on standard or labeled hanging clots. When compared on the basis of urokinase international units, t-PA appeared to be slightly more active than scu-PA and streptokinase, and about 10-fold more active than both preparations of UK when they were diluted in plasma. Fibrinolytic activity was evaluated by measuring the lysis time of recalcified plasma containing variable amounts of thrombolytic agents. t-PA was shown to be twice as active as HMW UK, which was itself more active than LMW UK. When scu-PA and both types of UK were compared on bovine fibrin plates, they showed similar fibrinolytic activity, but the t-PA calibration curve was not parallel to those obtained with UK and scu-PA. Relative thrombolytic and fibrinogenolytic properties were studied for each thrombolytic agent. For similar thrombolytic activities, fibrinogenolysis provoked by scu-PA was less marked than with t-PA and with both UK, while SK showed the highest activity. Our results demonstrate that the thrombolytic/fibrinogenolytic ratio is much more favorable to t-PA and scu-PA than to both forms of UK. Another observation clearly shows that fibrinogenolysis can be induced in vitro in human plasma by high doses of t-PA. This consequence may be important since the therapeutic use of t-PA can be associated with high concentrations of t-PA, and thus t-PA infusion could lead in vivo to severe fibrinogen breakdown. In addition, the methodology described could be useful in standardizing comparison between different species of thrombolytic agents.

Hyperhomocysteinemia increases the risk of venous thrombosis independent of the C677T mutation of the methylenetetrahydrofolate reductase gene in selected Brazilian patients.

Fasting total homocysteine (tHcy) and the methylenetetrahydrofolate reductase (MTHFR) C677T mutation were evaluated in 91 patients with venous thromboembolism and without acquired thrombophilia, and in 91 age-matched and sex-matched controls. Hyperhomocysteinemia was detected in 11 patients (12.1%) and in two controls (2.2%), yielding an odds ratio (OR) for venous thrombosis of 6.1 [95% confidence interval (CI), 1.3-28.4]. After excluding 21 patients and four controls with other known genetic risk factors for venous thrombosis, the OR was not substantially changed (7.0; 95% CI, 1.5-33.1). The prevalence of the MTHFR 677TT genotype was not significantly different in patients (9.9%) and in controls (5.5%), with an OR for venous thrombosis of 1.8 (95% CI, 0.6-5.8). Subjects with the MTHFR 677TT genotype showed higher levels of tHcy compared with the 677CC genotype in patients (P = 0.010) and in controls (P = 0.030). In conclusion, we found that fasting hyperhomocysteinemia is a risk factor for venous thrombosis in patients without known acquired thrombophilia and other genetic risk factors for venous thrombosis. Although tHcy levels are significantly higher in those homozygous for the MTHFR C677T mutation, this genotype does not increase the thrombotic risk in our study population.

Level of fetal hemoglobin as an indicator of clinical complications in sickle cell anemia.

1. The fetal hemoglobin (HbF) level was used as an indicator of the development of severe clinical complications in 89 patients with sickle cell anemia (SCA). 2. HbF was determined by the alkali denaturation technique. The mean HbF level was 6.7 +/- 4.2% (range, 0.7 to 19.2%) of total hemoglobin. 3. Major organ failures were considered to be terminal events of morbidity and included 8 cerebrovascular accidents, 13 aseptic necroses of the femoral head and 17 leg ulcer episodes. 4. The characteristics of the test, including sensitivity, specificity and positive predictive value were analyzed for different levels of HbF. 5. The overall specificities were 76, 76, and 85% for HbF levels greater than or equal to 8, 10 and 12%, respectively. The sensitivity of the test was low. The positive predictive value reached 71% for children with HbF greater than or equal to 8%. The data suggest that HbF level may be a useful indicator of the possibility of a patient developing serious clinical complications.

[Intracardial autonomous nervous system in a fatal case of acute Chagas disease]. / Sistema nervoso autônomo intracardíaco em caso humano fatal de doença de Chagas aguda.

An analysis of the intracardiac autonomic nervous system (ICANS) has been made in 150 histological sections obtained from atrial fragments of a 74 year-old man who died of cardiac failure, as a consequence of acute Chagas' disease (ACD), probably acquired via digestive tract. Small quantities of mononuclear infiltrate around ganglia and/or nerve branches without significant morphologic alterations of the neurons were found in 10 slides; another slide showed ganglionitis and periganglionitis of moderate intensity associated to neuronal alterations. Focal epicarditis, usually of slight degree, was observed in all slides. The findings suggest: a) that the inflammation of ganglia and fibers of the ICANS in the ACD occurs at least in part by expansion from adjacent epicarditis; b) that even in the fatal cases of the trypanosomiasis cruzi the pathologic lesions of the ICANS may be slight.

Hemorrhagic and thrombotic complications in patients with myeloproliferative diseases.

OBJECTIVE: To correlate the incidence of hemorrhage and thrombosis to bleeding time (BT) and platelet aggregation in 27 consecutive patients with myeloproliferative diseases (MPD). DESIGN: Retrospective study. SETTING: Public tertiary referral center. PATIENTS: Eighteen patients with chronic myelogenous leukemia (CML), 5 with polycytemia vera (PV), 2 with essential thrombocytemia (ET) and 2 with idiopathic myelofibrosis (MF). Duke's BT and epinephrine-induced platelet aggregation were performed on the patients and on 10 healthy individuals. RESULTS: Eleven patients presented symptoms (41%):9 with hemorrhage (33%) and 5 with thrombosis (19%). There were less symptomatic patients in the CML group (28%) than in the other MPD (67%), without statistical significance (Fisher, p = 0.06). Duke's BT was longer in symptomatic patients (Mann-Whitney, p < 0.05). Platelet aggregation was abnormal in 7 patients (26%) and 71% of them were symptomatic (Fisher, p = 0.07). CONCLUSIONS: The high incidence of bleeding and thrombosis in patients with MPD was related to prolonged BT, but not to platelet aggregation abnormalities.

[Treatment for overdose of oral anticoagulants]. / Tratamento da superdosagem de anticoagulantes orais.

PURPOSE: To evaluate the response of 73 patients with antivitamin K (AVK) overdose to 3 different therapeutic regimens. METHODS: Seventy three patients were evaluated in 94 occasions: group A (N = 32), consisted of drug withdrawal for 2 days followed by reduced dosage; group B (N = 37), drug withdrawal and reassessment within 4 days; group C (N = 25), oral administration of vitamin K. Therapeutic range was set between INR-values of 2 and 4. RESULTS: Reversal regimens did not result in differences among 61 patients who had initial INR < 8 (chi 2 = 2.352, p = 0.671). There were more patients bellow therapeutic range in group C (N = 14) than group B (N = 19) (chi 2 = 9.998, p = 0.007). After intervention, 7 patients in group B still had INR > 4, but 5 of them were bellow 4.5, without increased bleeding risk. There were 10 patients in group C bellow therapeutic range, 6 of them with INR < 1.6, with risk of thromboembolism. Thirteen patients bled, but none required transfusion. CONCLUSION: Reversal of excessive oral anticoagulation can be safely performed by initial withdrawal of the drug, followed by lower doses. Vitamin K administration may lead to INR bellow the therapeutic range. This should be reserved for patients with high INR or in the presence of bleeding.

[Clinical and laboratory evaluation of patients treated with oral anticoagulation]. / Avaliação clínica e laboratorial de pacientes em uso de anticoagulantes orais.

PURPOSE: To evaluate the clinical and laboratory management of patients taking anti-vitamin K drugs (AVK). METHODS: We studied retrospectively 952 visits of 100 outpatients taking AVK drugs for 7.6 months. There were 56 men and 44 women, 54 patients had acute arterial occlusion, 34 presented venous thromboembolism and 12 had cardiopathy. Anticoagulation level was estimated by the prothrombin time reported as international normalized ratio (INR). RESULTS: Seventy-three patients were considered stable, as they had one visit every at least 3 weeks, and their INR was within the therapeutic range in 59% of their visits, whereas 27 patients were less stable and had 36% of their visits within the therapeutic range. Insufficient anticoagulation was due to poor compliance (22%), vitamin K rich diet (19%) and underdosage (16%). Four patients presented minor bleedings, and there was no recurrence of thromboembolism. CONCLUSION: Careful clinical and laboratory management, using the INR, are necessary to avoid hemorrhage and thrombotic complications in patients taking oral anticoagulants.

[Hemostatic changes in children treated with heart surgery with cardiopulmonary bypass]. / Alterações da hemostasia em crianças submetidas a cirurgia cardíaca com circulação extracorpórea.

PURPOSE: We evaluated hemostasic changes in children undergoing open heart surgery with cardiopulmonary bypass (CPB). METHODS: We studied 17 children before, during surgery, in the immediate, first and between the 4th and 7th postoperative days, measuring hematocrit, prothrombin time, activated partial thromboplastin time, fibrinogen, platelet count, factor V and euglobulin lysis time. Children were divided in those with and without excessive bleeding in the postoperative period. RESULTS: We observed significant prolongation of prothrombin time and activated partial thromboplastin time, reduction of fibrinogen and factor V, and shortening of euglobulin lysis time. Six (35%) children bled excessively. Platelet count reduction was greater in the intra operative period in these cases and the duration of CPB was longer in this group. CONCLUSION: Changes in hemostasis during open heart surgery are due to coagulation cascade disorders as well as fibrinolysis. The incidence of excessive bleeding is higher in the pediatric group. Prolonged CPB time and greater reduction in platelet count differentiated both groups.

[Laboratory control of oral anticoagulation]. / Controle laboratorial da anticoagulação oral.

BACKGROUND: The authors verified the performance of three different thromboplastin preparations, commercially available to Brazilian clinical laboratories, on the anticoagulant level monitoring of anti-vitamin K drugs. MATERIAL: Thromboplastin preparations included: Labtest, lot n degrees 0301, ISI = 1.50; Biolab, lot n degrees 10252, ISI = 1.60; Baxter TPCD, lot n degrees 502A, ISI = 2.55; Baxter TPC, lot n degrees 13, ISI = 1.97; Baxter TPS, lot n degrees 27, ISI = 1.18; and Behring, lot n degrees 505771A, ISI = 1.11. Thirty-one outpatients with thromboembolism were evaluated. All patients were taking the same dose of anti-vitamin K drugs for at least 10 days. METHODS: Laboratorial monitoring has been undertaken by the measurement of Prothrombin Time (TP). A standard curve was obtained for each reagent, using a normal plasma pool. Results were expressed as PT in seconds, and as prothrombin activity (PA) in percentage, according to the standard curve, and also as the International Normalized Ratio (INR), calculated using the International Sensitivity Index (ISI) provided by each reagent producer. RESULTS: There was some discrepancy among results obtained with different reagents, when these results were expressed as PA (p < 0.01), but this effect was minimized when they were expressed as INR. CONCLUSIONS: This fact confirms that results of PT, performed in order to control the action of anti-vitamin K drugs, must be reported as INR to assure reproducibility among tests performed using different thromboplastin reagents, with different ISI.

[Antithrombin III dosage using the chromogenic substrate Tos-Gly-Pro-Arg-NAN, in several pathological situations]. / Dosagem da antitrombina III usando o substrato cromogênico Tos-Gly-Pro-Arg-NAN, em diversas situações patológicas.

UNLABELLED: Functional methods for ATIII determination are essential for the diagnosis of deficiencies of this important thrombin inhibitor. PURPOSE: The aim of this work was standardize the method for ATIII level determination in plasma, in microplates. METHOD: ATIII levels were measured, using the chromogenic substrate Tos-Gly-Pro-Arg-NAN, which is specific for thrombin, and which has been sinthesized at the Biophysical Department of the Escola Paulista de Medicina of the Federal University of São Paulo, Brazil. RESULTS: Among 21 patients with deep venous thrombosis (DVT), 20 had ATIII levels above 70% (113 +/- 22%). A 22 year-old female patient, who had recurrent DVT and a familiar DVT antecedent, had a congenital ATIII deficiency (56%). ATIII levels were normal in 6 patients with von Willebrand disease (109 +/- 28%), as expected. In 20 patients with severe hepatic failure, it has been found reduced ATIII levels (42 +/- 19%), since this inhibitor is produced by the liver. In 3 patients with sepsis and DIC, ATIII levels have also been reduced (45 +/- 5%) owing to consumption during blood coagulation activation. There was a significant correlation between ATIII levels and the prothrombin time, as well as the factor V levels, and both are good parameters to assess hepatic function and to monitor DIC. There was a significant correlation between ATIII levels measured using the chromogenic substrate Tos-Gly-Pro-Arg-NAN and those measured using S-2238, produced by Kabi Laboratories. CONCLUSIONS: This method for ATIII determination in plasma is easy to perform and it can detect ATIII deficiency in patients with hepatic failure, disseminated intravascular coagulation and thrombophilia.

[Antithrombin III concentrate use in patients with cirrhosis with coagulation disorders]. / Uso de concentrado de antitrombina III em cirróticos com distúrbios de coagulação.

BACKGROUND: Patients with severe hepatic failure present acquired deficiency of antithrombin III (ATIII) owing to reduced synthesis associated with intravascular activation of blood coagulation, which may be corrected by ATIII infusion. OBJECTIVE: The aim of this uncontrolled trial was to verify the effect of a standard dose of ATIII concentrate (Kybernin), that is, 50 U/kg of body weight per day, every 2 days, on ATIII levels in patients with severe hepatic failure and hemostatic imbalance. PATIENTS AND METHODS: Six cirrhotic patients were studied: mean age of 44 years (14 to 63 years), who presented at least 2 abnormal coagulation tests (PT > 1.40, APTT > 1.25, Fibrinogen < 1.5 g/dL, Platelet count < 80,000/mm3). Mean serum albumin was 2.6 g/dL (1.9 to 3.8 g/dL). Blood was drawn before infusion, 4 h after the first infusion, and just before the next infusion. ATIII levels were measured by amidolytic method. RESULTS: Mean ATIII levels were: initial = 35.8%, 4th h = 56.2%*, 2nd d = 48.7%*, 4th d = 45.7%*, and 8th d = 42.3%. ATIII levels increased significantly after infusion of this standard dose in all patients, although they have not been fully corrected (Friedman test, * p < 0.02), which has been sustained till the 4th day. There was no improvement on the clinical outcome. CONCLUSIONS: These findings suggest that doses of ATIII concentrate higher than 50 U/kg/infusion must be administered to patients with severe hepatic failure, to guarantee normal levels of the inhibitor, in order to verify its influence on the hemostatic mechanism.