Reversal of excessive oral anticoagulation with a low oral dose of vitamin K1 compared with acenocoumarine discontinuation. A prospective, randomized, open study.

We performed a prospective, randomized, open study in 109 outpatients under chronic anticoagulation with acenocoumarine, presenting with International Normalized Ratios (INRs) > or = 6.0 and no or minor bleeding. All the patients withheld one dose of acenocoumarine; in addition, a treated group also received 1 mg oral vitamin K1. We aimed at a post-intervention INR < 6.0, with a target zone of 2.0-4.0. The INRs were lowered from a mean of 8.1 +/- 1.7 to 4.9 +/- 2.5 in the controls (P = 0.0000) and from 8.4 +/- 2.4 to 3.3 +/- 3 in the treated patients (P = 0.0000). There were no differences in the percentage of patients with post-intervention INRs < 6.0 or within the therapeutic zone. One-third of the treated patients and only 2% of the controls reached INRs < 2.0 (P = 0.0003). Oral vitamin K1 offered no advantage to the simple discontinuation of one dose of acenocoumarine. A substantial number of treated patients were consequently exposed to under-anticoagulation.

Erythrocytapheresis with recombinant human erythropoietin in hereditary hemochromatosis therapy: a new alternative.

BACKGROUND AND OBJECTIVES: The purposes of this study were to evaluate the tolerance, efficacy and safety of isovolemic erythrocytapheresis (EA) in nonanemic patients with hereditary hemochromatosis (HH), and to assess the usefulness of recombinant human erythropoietin (rHuEPO) associated with EA to reduce treatment duration. MATERIALS AND METHODS: In 10 asymptomatic patients with serum ferritin >400 microg/l, transferrin saturation >50%, and GPT elevation, EA with rHuEPO and folic acid was performed. RESULTS: Red cell indices, serum ferritin, and other iron metabolism parameters (serum iron, transferrin, and transferrin saturation); GPT and other laboratory data were considerably improved. CONCLUSION: This method offers better results in less time than traditional phlebotomy. EA with rHuEPO is an effective therapeutic alternative for patients with HH.

Circulating platelet/polymorphonuclear leukocyte mixed-cell aggregates in patients with mechanical heart valve replacement.

There is convincing evidence that cell adhesion plays an important role in cardiovascular pathology and is frequently associated to "in vivo" cellular activation. This study involves patients with mechanical heart valve replacement (MHVR patients) who have increased platelet polymorphonuclear leukocyte (PMN) reactivity. Dual-color cytometry was used to determine the expression of adhesive molecules on cellular surfaces, platelet, and PMN-bound fibrinogen as well as the presence of circulating platelet/PMN mixed-cell aggregates (MCA) in 55 MHVR patients, 49 control patients under oral anticoagulant therapy, and 22 healthy volunteers. The results demonstrated that (a) PMN from MHVR patients showed an increased PMN-bound fibrinogen (mean +/- SEM: 1,420 +/- 169 anti-fibrinogen fluorescence intensity, P= 0.0012), when compared to controls (mean +/- SEM: 747 +/- 32 anti-fibrinogen fluorescence intensity) and healthy volunteers (mean +/- SEM: 692 +/- 25 anti-fibrinogen fluorescence intensity; (b) platelet activation in MHVR patients was evidenced by the higher expression of CD62P (mean +/- SEM: 128 +/- 19 anti-CD62P fluorescence intensity, P = 0.003) compared to controls (mean +/- SEM: 65 +/- 15 and 50 +/- 10 anti CD62P fluorescence intensity) and by increased levels of platelet-bound fibrinogen (mean +/- SEM: 625 +/- 20 anti-fibrinogen fluorescence intensity, P = 0.0043 versus 496 +/- 45 and 480 +/- 30 for control patients and for healthy volunteers, respectively); and (c) the proportion of MCA in MHVR patients (15 +/- 2%) was significantly higher (P = 0.009) compared to controls (7 + 1%) and healthy volunteers (6 +/- 2%). The results indicate that the presence of stable circulating MCA represents another marker of "in vivo" PMN activation in MHVR patients.

Bleeding risk factors in chronic oral anticoagulation with acenocoumarol.

We studied major bleeding complications, death related to hemorrhage, and tried to identify predisposing factors for bleeding in outpatients treated with acenocoumarol. We evaluated 811 outpatients attending a specialized anticoagulant therapy unit. The intended INR range was 3.5-4.5 for mechanical heart valve replacement (N= 384) and 2.0-3.0 for other indications (N= 427). The variability of INR for the total follow-up and the 2 months before the hemorrhage was calculated. The total follow-up was 1,963.26 years with 27,321 control tests. We observed 47 major bleeding episodes, including 2 fatal (central nervous system hemorrhages), in 37 patients. 49.5% of the patients had underlying diseases. The rate of major and fatal hemorrhage was 2.39 and 0.10 episodes per 100 patients year, respectively. Hemorrhagic complications were more frequently observed in patients with a more intense intended range (8.2% in the INR 3.5-4.5 group vs. 1.5% in the 2.0-3.0 INR group). The risk of major bleeding increased in patients with an achieved INR higher than 6 and in those with higher INR variability during follow-up. The estimated probability of bleeding also increased with time: it was 0.102% at 78 months, and at the beginning of therapy it was 0.006% and 0.007% at 1 and 4 months, respectively. The intensity of anticoagulation and the deviation of the INR from the target are the most important risk factors for bleeding in patients taking acenocoumarol. Monitoring the variability of INR can help identifying patients predisposed to bleeding. However, the screening for underlying disease should always be performed.

Anticoagulation in pregnant women with mechanical heart valve prostheses.

OBJECTIVE: To evaluate the outcome of pregnancy in women with mechanical heart valve prostheses in relation to the anticoagulant treatment used in the first trimester and the incidence of thrombotic and bleeding complications. METHODS: 92 pregnancies in 59 women were followed between 1986 and 1997. In 31 pregnancies, oral anticoagulants were discontinued when pregnancy was diagnosed and subcutaneous heparin was started (12 500 U every 12 hours) adjusted to prolong the adjusted partial thromboplastin time to twice the control level. In the second trimester oral anticoagulants were resumed but changed to heparin again 15 days before the expected delivery date. In 61 pregnancies oral anticoagulants were continued during the first trimester. The same regimen of heparin was used for delivery. RESULTS: Abortion or fetal losses were similar (p = 0. 5717) in women exposed to oral anticoagulants in the first trimester (13/61; 25%) compared with those who received adjusted subcutaneous heparin (6/31; 19%). Embolic episodes were more common (p = 0.0029) in women who received heparin (4.92%) compared with those on oral anticoagulants (0.33%). Embolic episodes were cerebral and transient. No valve thromboses were observed. No malformations appeared in the 71 newborns, except for one case of hydrocephalus. There were no maternal deaths secondary to thrombotic complications. The only death was the result of major bleeding after the delivery of a premature stillborn. CONCLUSIONS: Oral anticoagulants seem to be safer for the mother than adjusted subcutaneous heparin. Heparin does not offer a clear advantage over oral anticoagulation in the pregnancy outcome.

Low-intensity oral anticoagulation plus low-dose aspirin versus high-intensity oral anticoagulation alone: a randomized trial in patients with mechanical prosthetic heart valves.

BACKGROUND: Mechanical heart valve replacement requires lifelong anticoagulant treatment. Aspirin has proved useful in further reducing thromboembolic events when added to oral anticoagulants. However, increased (gastrointestinal) bleeding was observed at the doses previously tested for this combination in heart valve prostheses. METHODS: We performed a prospective randomized trial to compare the combination of low-intensity oral anticoagulants (international normalized ratio 2.5 to 3.5) plus aspirin (100 mg/day) (arm A) versus high-intensity oral anticoagulants alone (arm B) (international normalized ratio 3.5 to 4.5). Arm A included 258 patients and arm B 245 patients. The two groups were comparable for all baseline characteristics. RESULTS: The outcomes of the study were embolism, valve thrombosis, and major hemorrhage. The median follow-up was 23 months. The two treatments offered similar antithrombotic protection. The incidence of embolic episodes was 1.32 per 100 patient-years (95% confidence interval 0.53 to 2.7) for arm A and 1.48 per 100 patient-years (95% confidence interval 0.59 to 3.03) for arm B. Major hemorrhage occurred in 1.13 per 100 patient-years (95% confidence interval 0.41 to 2.45) for arm A and 2.33 per 100 patient-years (95% confidence interval 1.17 to 4.14) for arm B. Gastrointestinal bleeding was not increased by this combined reduced dose of aspirin and coumarin.

Anti-factor VIII inhibitors and lupus anticoagulants in haemophilia A patients.

In a study of 170 haemophilia A patients, 43 were found to have an inhibitory effect; seven had anti-factor VIII inhibitors (a-fVIII)(A), 18 had lupus anticoagulants (LAs) with a strong (B: 12) or weak (C: 6) time-dependent effect and 18 had no time-dependent LAs (D). The a-fVIII showed a neutralizing effect only against factor VIII and negative diluted Russell viper venom time (dRVVT). The LAs were diagnosed by dRVVT; the Staclot LA agreed with the dRVVT. During the study, three patients changed from an a-fVIII to an LA pattern; they also modified their clinical response. Our prevalence of a-fVIII was low (4%) and we found 21% of LA, with a high (50%) prevalence of time-dependent inhibition. This pattern raises the possibility of the coexistence of LA and a-fVIII, stressing the need to develop specific tests to identify a-fVIII and LA.

Very low doses of unfractionated heparin potentiate the anti-Xa activity of low molecular weight heparin (enoxaparin)

Some previous reports indicated that a minimal amount of anti-IIa is necessary for the optimal anti-Xa activity of low molecular weight heparin (LMW-H). To know if we could improve the prophylactic activity of LMW-H, providing a mild antithrombin effect, we conducted an experiment in which we administered subcutaneously to 10 volunteers, very low doses of unfractionated heparin (UFH), (1000 IU), a LMW-H (enoxaparin, 2000 IU = 20mg), or both heparins together on alternate days, and measure the anti-Xa activity before, and 4 hours after injection. We found that the anti-Xa activity in the first group (UFH), increased by 33%, over the basal values; in the second group (LMW-H), by 93%, but it increased by 282%, in the third group (UFH + LMW-H) showing clearly (p < 0.0069), that UFH could increase synergistically, more than additive, the anti-Xa activity of enoxaparin. The impact on the cost-effectiveness of antithrombotic prophylaxis and the therapeutic results with the herein combined scheme should be evaluated.

Combined intensive chemoradiotherapy for organ preservation in patients with resectable and non-resectable oesophageal cancer.

From January 1990 to April 1993, 60 oesophageal cancer patients were enrolled in a protocol of non-surgical treatment that consisted of induction chemotherapy followed by concurrent chemoradiotherapy. Induction chemotherapy consisted of cisplatin 40 mg/m2 intravenous bolus days 1, 2, 14, 15; 24 h continuous infusion of 5-fluorouracil (5-FU) 1000 mg/m2 days 1 and 14; leucovorin 20 mg/m2 days 1 and 14 given before and with 5-FU; bleomycin 30 UI days 1 and 14; mitomycin C 10 mg/m2 day 14. Concurrent chemoradiotherapy consisted of 60 Gy (6 weeks) from day 21 and cisplatin 70 mg/m2 days 28, 42 and 56; leucovorin 20 mg/m2 followed by 5-FU 425 mg/m2 days 28, 35, 42, 49 and 56. Complete response occurred in 44 of 55 evaluable patients (80%). The median survival is 32 months; the actuarial survival at 40 months is 35% (CI 18-53). These results appear improved over those reported with surgery or radiation alone, and suggest that organ preservation as a secondary treatment goal should be vigorously investigated.

Results of treatment with an intensive combination induction regimen containing idarubicin in children with acute myeloblastic leukemia: preliminary report of the Argentine Group for Treatment of Acute Leukemia.

In April 1990, the Argentine Group for Treatment of Acute Leukemia began a multicenter trial for the treatment of previously untreated acute myeloblastic leukemia patients who were under 21 years of age. Initial treatment consisted of an 8-day induction phase with cytarabine together with idarubicin on days 3 to 5 and etoposide on days 6 to 8. A multidrug consolidation phase was subsequently administered and, after a treatment-free interval of 2 to 4 weeks, two 5-day intensification courses with high-dose cytarabine and etoposide were delivered with a 4-week interval between each course. Continuation therapy was started 2 to 4 weeks after the second course, with 6-thioguanine daily and cytarabine daily for 4 days every 4 weeks. Treatment was stopped after 18 months in children in continuous complete remission. A preliminary evaluation of this ongoing study included 36 patients with a mean age of 7.5 years (age range, 5 months to 16 years). The majority of patients had a French-American-British classification of M2 (n = 13) or M4 (n = 8). Complete remission was achieved by 91.7% of patients, while one died from sepsis in bone marrow hypoplasia and two were regarded as treatment failures. At a median follow-up of 12 months (range, 2 to 23 months) there were 12 adverse events: six bone marrow relapses, one bone marrow/skin relapse, and five deaths in complete remission (all deaths occurred during the consolidation phase). During the induction phase most of the patients experienced prolonged myelosuppression, and grade 3 to 4 toxicity (according to the Children's Cancer Group criteria) was frequently seen. Alopecia was universal. However, toxicity was manageable. We conclude that idarubicin in combination with cytarabine and etoposide is a highly effective regimen for induction in children with acute myeloblastic leukemia.

[Analysis of a national serological survey for diseases transmitted by blood transfusion]. / Análisis de un relevamiento serológico nacional para enfermedades transmisibles por transfusión de sangre. Miembros de la Sociedad Argentina de Hemoterapia e Inmunohematologia.

In August 1992 information was requested from 49 Blood Banks in national hospitals and private institutions in order to carry out a serological screening of blood donors for diseases transmitted by transfusion. Data was requested from 1987 to the first semester of 1992 and included the total annual number of blood donors and the incidence of seropositivity for Chagas disease, brucellosis, syphilis, hepatitis B and C, and HIV. Out of a total of 1,075,051 blood donors registered (Table 1), there was 4.36% incidence of seropositivity for Chagas disease measured by indirect hemagglutination (Table 6): depending on the Province evaluated, the values fluctuated from 2.23 to 11.64% (Table 7). Seropositivity incidence for brucellosis, using Huddleson test, was 0.94% (Table 2 & 3), for syphilis, 0.93% (Table 4 & 5), for hepatitis B, 0.92% (Table 8 & 9), for hepatitis C, 0.56% (Table 10 & 11) and for HIV, 0.21% (Table 12 & 13). This first national screening has yielded important data which represent 60% of the total blood donations pertaining to the period evaluated.

Análisis de un relevamiento serológico nacional para enfermedades transmisibles por transfusión de sangre. Miembros de la Sociedad Argentina de Hemoterapia e Inmunohematologia. / [Analysis of a national serological survey for diseases transmitted by blood transfusion]

In August 1992 information was requested from 49 Blood Banks in national hospitals and private institutions in order to carry out a serological screening of blood donors for diseases transmitted by transfusion. Data was requested from 1987 to the first semester of 1992 and included the total annual number of blood donors and the incidence of seropositivity for Chagas disease, brucellosis, syphilis, hepatitis B and C, and HIV. Out of a total of 1,075,051 blood donors registered (Table 1), there was 4.36

incidence of seropositivity for Chagas disease measured by indirect hemagglutination (Table 6): depending on the Province evaluated, the values fluctuated from 2.23 to 11.64

(Table 7). Seropositivity incidence for brucellosis, using Huddleson test, was 0.94

(Table 2 & 3), for syphilis, 0.93

(Table 4 & 5), for hepatitis B, 0.92

(Table 8 & 9), for hepatitis C, 0.56

(Table 10 & 11) and for HIV, 0.21

(Table 12 & 13). This first national screening has yielded important data which represent 60

of the total blood donations pertaining to the period evaluated.

Combination of rubidazone and cytosine arabinoside in the treatment of first relapse in acute myelocytic leukemia.

This study tested the efficacy of rubidazone and cytosine arabinoside in 35 patients (13 children and 22 adults) with acute myelocytic leukemia in first relapse. Induction consisted of 1-2 courses of rubidazone 200 mg/m2 days x 4 days plus cytosine arabinoside 100 mg/m2 x 7 days in CI followed by 2 consolidation courses of 3 days and 5 days. Nineteen patients (54%) achieved complete remission, 8 failed to respond, and 8 died. Twelve patients relapsed after 1 to 9 months, at a median of 4 months, 1 patient died of cardiac failure and 1 remains in complete remission at 12 months. Five patients underwent bone marrow transplantation, 3 of them autologous, 1 was still in complete remission at 29 months, 1 relapsed, and 1 died of sepsis. Two received allogeneic marrow transplants and died at 3 and 4 months afterwards of VOD and graft failure. The main toxicity was severe and prolonged myelosuppression.

Prognostic factors in multiple myeloma: definition of risk groups in 410 previously untreated patients: a Grupo Argentino de Tratamiento de la Leucemia Aguda study.

Four hundred ten previously untreated multiple myeloma patients entered onto two consecutive Grupo Argentino de Tratamiento de la Leucemia Aguda (GATLA) protocols were analyzed to identify significant prognostic factors influencing survival. The univariate analysis selected the following variables: performance status, renal function, percentage of bone marrow plasma cells at diagnosis, hemoglobin, and age. A multivariate analysis showed that performance status, renal function, percentage of bone marrow plasma cells, hemoglobin, and age were the best predictive variables for survival. A score was assigned to each patient according to these variables, which led to their classification in three groups: good, intermediate, and poor risk, with a probability of survival of 26% and 10% at 96 months, and 5% at 56 months, and median survival of 60, 37, and 14 months, respectively (P = .0000). In our patient population, this model proved to be superior to the Durie-Salmon staging system in defining prognostic risk groups, and separating patients with significantly different risks within each Durie-Salmon stage.

[Advances in the treatment of acute myeloid leukemia in children. Experience of the Argentinian Group of Acute Leukemia Treatment and the Latin American Group of Malignant Hemopathies Treatment 1967-1987]. / Progresos en el tratamiento de la leucemia mieloide aguda en niños. Experiencia del GATLA/GLATHEM 1967-1987.

Three hundred and seventy-one children below 16 years, with newly diagnosed acute myeloid leukaemia, were included in six consecutive GATLA/GLATHEM protocols, from November 1967 to December 1987. The study was divided in three periods: 1967 to 1975, 1976 to 1982, and 1983 to 1987. Three induction schedules were used during the first two periods, and different maintenance schemes alternating with monthly consolidations were explored; the value of immunotherapy with C. Parvum and androgen therapy with stanozolol was also tested. Protocol 3-AML-83, representing the third period, included a four-week induction phase with vincristine, adriamycin, cytosine-arabinoside, prednisone and 6-mercaptopurine, followed by a consolidation phase with cyclophosphamide, cytosine-arabinoside and 6-mercaptopurine for four weeks. Maintenance phase included daily, oral 6-mercaptopurine, and monthly cytosine-arabinoside, both during two years, and adriamycin every eighth week, for one year. Complete remission rates for the first two periods of therapy were 40% and 55%, whereas that of the last period was 74%. The overall results of the period 1967-1982, showed actuarial duration rates of complete remission, event-free survival and survival, at 60 months, between 2% and 6%, their median duration being of 9, 8 and 10 months respectively. No significant difference was observed between the first two periods or protocols. Protocol 3-AML-83, activated in March 1983, achieved actuarial rates of continuous complete remission, event-free survival, and survival of 51%, 37% and 39% respectively, at 48 months. The difference between the first two periods and the last one was highly significant (P less than 0.0001).(ABSTRACT TRUNCATED AT 250 WORDS)

Randomized trial of chemotherapy versus chemotherapy plus radiotherapy for stage I-II Hodgkin's disease.

A total of 277 patients with untreated Hodgkin's disease, clinical stages I-II, were randomized to cyclophosphamide, vinblastine, procarbazine, and prednisone (CVPP) alone for 6 monthly cycles or to CVPP plus radiation therapy (RT), 3,000 rad, to involved areas (CVPP plus RT). One or more of the following factors were considered as unfavorable prognosis: age greater than 45 years, more than two lymph node areas involved, or bulky disease. In the favorable group, disease-free survival (77% vs. 70%) or overall survival (92% vs. 91%) at 84 months for CVPP versus RT plus CVPP was similar. Patients with unfavorable prognosis treated with RT plus CVPP had longer disease-free survival (75% vs. 34%) (P = .001) and overall survival (84% vs. 66%) than patients treated with CVPP alone.