Factor XI replacement for inherited factor XI deficiency in routine clinical practice: results of the HEMOLEVEN prospective 3-year postmarketing study.

Factor XI (FXI)-deficient patients may develop excessive bleeding after trauma or surgery. Replacement therapy should be considered in high-risk situations, especially when FXI levels are below 20 IU dL(-1) . HEMOLEVEN is a human plasma-derived factor XI concentrate available in France since 1992, but there are few data regarding its use by physicians. This prospective study assessed the use, efficacy and safety of HEMOLEVEN in common clinical practice. HEMOLEVEN was evaluated in FXI-deficient patients in 13 French centres in a 3-year postmarketing study. Forty-four patients (30 females, 14 males) received 67 treatments. The median age was 37 years (8 months-91 years). Basal FXI levels were <1 to 51 IU dL(-1) (median: 5.5); 29 patients were severely FXI-deficient (<20 IU dL(-1) ). FXI was administered prophylactically before 43 surgical procedures, 10 invasive procedures, 8 vaginal deliveries, or as curative treatment for six bleeds. The efficacy was assessed as excellent/good in 63, moderate in two and undetermined in two treatments. Seven patients experienced seven adverse effects, including two rated as serious: one sudden massive pulmonary embolism with fatal outcome and one case of inhibitor to FXI. HEMOLEVEN is effective for bleeding prevention in FXI deficiency. However, considering the benefit/risk ratio observed in relation to dosage in this study; firstly, it should be used sparingly due to its potential prothrombotic effect; secondly, new prescription procedures should be defined to adapt the dosage, especially in patients with intrinsic and/or acquired risk factors for thrombosis.

[Treatment of iron deficiency anemia during pregnancy with oral iron: State of practice among midwives]. / Traitement par fer oral de l'anémie ferriprive lors de la grossesse : état des pratiques chez les sages-femmes.

OBJECTIVES: Iron deficiency anemia represents a public health issue which is usually managed by midwives. Because it is associated with maternal and fetal risks, a treatment is warranted. Oral iron represents the main option for treating this condition. Despite the existence of national and international guidelines no consensus about its modality of use has emerged so far. The primary objective of this study was to analyze midwives'practice with regards to iron deficiency anemia treatment using oral iron formulations. METHODS: We conducted an observational and descriptive cross-sectional in a sample of midwives from the Gironde administrative region using a questionnaire. RESULTS: We obtained 85 questionnaires from midwives working in private or public health facilities. Doses of iron and duration of treatment seem insufficient for a majority of responders. Folic acid and vitamin C are often associated with oral iron. Most midwives assess the efficacy of oral iron at one month with hemoglobin and ferritin levels. A significant fraction of these midwives shares similar practices which are in good accordance with the literature such as patient counselling with regards to drug intake, management of gastrointestinal side effects and inefficacity of oral iron. Noticeably, some of these midwives don't follow any guidelines. CONCLUSION: The majority of participants demonstrated practices in accordance with various national guidelines although no precise therapeutic algorithm is available as reference. Larger studies on the management of iron deficiency anemia in pregnancy by health professionals and harmonization of practices are necessary.

Transfusional iron overload in patients with myelodysplastic syndromes: A 10-year retrospective survey from a French general hospital.

We retrospectively assessed the characteristics of 165 MDS patients from our institution having received at least 20 RBC units. In the vast majority of them various comorbidities (range: 1-6 per patient) were registered including mainly cardiovascular disorders. Serum ferritin was over 1000µg/L in about half of tested individuals. A chelator agent was initiated in 43.6% of patients (mainly low-risk MDS). Transformation in AML occurred in 46 cases (27.8%). Overall, 112 patients died during follow up. The cause of death was documented in 65 cases and included mainly MDS or AML resistance to therapy. There was a context of bacterial or fungal-related sepsis in 35.3% of cases. We noticed a correlation between survival and number of RBC transfusions. Median OS from the 20th RBC unit was significantly prolonged among the chelated subgroup. Consequences of transfusional iron overload and chelation need to be clarified in MDS patients.

When genetic and surname analyses meet historical sources: The C56R mutation associated with factor XI deficiency as a marker of human migration during the Spanish Reconquista.

The C56R mutation associated with factor XI deficiency has been first evidenced in individuals from the French Basque Country. Genetic investigations revealed that this mutation occurred about 5400 years ago as a founder effect in this zone. Other cases were subsequently described in Southwestern Europe. Noticeably a cluster of cases was evidenced in Yecla, a small city from the province of Murcia, in Southeastern Spain. In correlation with historical sources our genetic data and surname analysis argue for associating this mutation with the migration of people from Western Pyrenees (and more probably from the Navarra province) toward Southeastern Spain during the Reconquista period.

[How to reduce rapidly destruction of labile blood components at the health facilities level? The experience of Centre Hospitalier de la Côte Basque]. / Comment réduire rapidement la destruction des produits sanguins labiles à l'échelle d'un établissement de santé ? L'expérience du centre hospitalier de la Côte Basque.

OBJECTIVE: The destruction of labile blood components (LBC) is of major concern. The objective was to carry out actions aiming to rapidly reduce this rate and to evaluate results in a single institution. METHODS: From 2017 we developed in the Centre Hospitalier de la Côte Basque a strategy in order to struggle against this problem including: 1/general information of prescriptors for reducing LBC waste, 2/fractioned delivery of RBC unit per unit, 3/recommendations to nurses, 4/information on platelets reserve, 5/new policy for ambulances and emergency unit: transfusion emergency package conditioned in single RBC units including a temperature recorder. Following the implementation of these measures, we analyzed the evolution of waste regarding number and distribution of causes. RESULTS: In contrast to stability of LBC destructions during these recent years between 0.84 and 0.97% we observed a marked decrease in 2017 (0.56%) and the first six months of 2018 (0.28%). Considering the evolution of causes between 2016 and 2017 we noticed for instance a disappearance of destructions due to patient' refusal and out of time of expiry or at level of the mobile emergency unit. Of note reduction of destruction is marked in the three categories of LBC. However, there still remains a large room for improvement regarding avoidable causes of destruction. CONCLUSION: It is possible to reduce very rapidly and significantly the fraction of LBC destruction in a health facility thanks to measures including information, teaching, organization and material conducted both in the blood bank and in clinical departments.

Evidence of an ancient (2000 years ago) goiter attributed to iodine deficiency in North America.

The Adena pipe figurine was found in the 2000 year-old Adena burial mound in Ross County, Ohio, USA by William C. Mills in 1901. The pipe reportedly represents an achondroplastic dwarf male Native American. However, the clinical aspect (swelling of the neck), the environmental/cultural characteristics in this area (iodine-poor soils, absence of seafood and milk consumption, tobacco smoking), and the marked prevalence of goiter among Native American populations favor the diagnosis of a goiter associated to iodine deficiency. Similar indigenous art representations found in South America and Mesoamerica strengthen this hypothesis. To our knowledge the Adena pipe is the first example of goiter depicted in Native North American art and one of the oldest from the continent.

C282Y/H63D hemochromatosis mutations and microevolution: Speculations concerning the Basque population.

The Basques live at the Western extremity of the Pyrenees. According to linguistic and genetic data they could be considered as one of the most ancient European populations. Numerous studies have evidenced particular patterns in the frequency of several genetic polymorphisms in this relatively unmixed human group. We discuss herein the puzzling distribution of the two major hemochromatosis HFE mutations associated with hereditary hemochromatosis. Thus, one can observe a low frequency of C282Y and, in contrast, one of the highest European frequencies of H63D. Genetic drift (enhanced by the long history and the small size of this population), long persistence of Paleolithic iron-rich diet, lower exposure to major infectious threats and limited mixing with both Celts and Vikings (who demonstrate the highest prevalence of C282Y) could be the underlying factors explaining these particular genetic features. Historical and environmental data represent key elements for understanding the role of the different evolutionary forces which shape the genetic profile of human populations.

[Evolutionary medicine: A new look on health and disease]. / La médecine évolutionniste : un nouveau regard sur la santé et les maladies.

Evolutionary medicine represents an innovative approach deriving from evolutionary biology. It includes the initial Darwin's view, its actualization in the light of progresses in genetics and also dissident theories (i.e. non gene-based) particularly epigenetics. This approach enables us to reconsider the pathophysiology of numerous diseases, as for instance, infection, and our so-called diseases of civilization especially obesity, type 2 diabetes, allergy or cancer. Evolutionary medicine may also improve our knowledge regarding inter-individual variation in susceptibility to disease or drugs. Furthermore, it points out the impact of our behaviors and environment on the genesis of a series of diseases.

Use of recombinant human granulocyte colony-stimulating factor to increase chemotherapy dose-intensity: a randomized trial in very high-risk childhood acute lymphoblastic leukemia.

PURPOSE: To determine whether the use of a recombinant human granulocyte colony-stimulating factor ([G-CSF] lenogastrim) can increase the chemotherapy dose-intensity (CDI) delivered during consolidation chemotherapy of childhood acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS: Sixty-seven children with very high-risk ALL were randomized (slow early response to therapy, 55 patients; translocation t(9;22) or t(4;11), 12 patients). Consolidation consisted of six courses of chemotherapy; the first, third, and fifth courses were a combination of high-dose cytarabine, etoposide, and dexamethasone (R3), whereas the second, fourth, and sixth courses included vincristine, prednisone, cyclophosphamide, doxorubicin, and methotrexate (COPADM). G-CSF was given after each course, and the next scheduled course was started as soon as neutrophil count was > 1 x 10(9)/L and platelet count was > 100 x 10(9)/L. CDI was calculated using the interval from day 1 of the first course to hematologic recovery after the fifth course (100% CDI = 105-day interval). RESULTS: CDI was significantly increased in the G-CSF group compared with the non-G-CSF group (mean +/- 95% confidence interval, 105 +/- 5% v 91 +/- 4%; P <.001). This higher intensity was a result of shorter post-R3 intervals in the G-CSF group, whereas the post-COPADM intervals were not statistically reduced. After the R3 courses, the number of days with fever and intravenous antibiotics and duration of hospitalization were significantly decreased by G-CSF, whereas reductions observed after COPADM were not statistically significant. Duration of granulocytopenia was reduced in the G-CSF group, but thrombocytopenia was prolonged, and the number of platelet transfusions was increased. Finally, the 3-year probability of event-free survival was not different between the two groups. CONCLUSION: G-CSF can increase CDI in high-risk childhood ALL. Its effects depend on the chemotherapy regimen given before G-CSF administration. In our study, a higher CDI did not improve disease control.

A phase II trial of induction and consolidation therapy of acute myeloid leukemia with weekly oral idarubicin alone in poor risk elderly patients.

We have conducted a phase II outpatient trial testing weekly oral administration of idarubicin (ZAVEDOS-ZVD) alone to determine the rate of objective response and toxicity in poor risk acute myeloid leukemia (AML) patients over 60 years of age. The treatment consisted of three phases: induction, with 20 mg/m2 of ZVD on days 1, 8, 15 and 22; consolidation with 20 mg/m2 of ZVD for 4 weeks; and maintenance with six cycles lasting 3 months and consisting of oral 6 mercapto-purine 2 mg/kg/day, 4 days a week for 2 months; subcutaneous cytarabine 1 mg/kg, once a week for 2 months; and oral ZVD 20 mg/m2 on day 1 and day 8 of the third month. In case of failure after induction course, patients received salvage treatment with 4 weekly oral doses of 40 mg/m2 ZVD. Fifty-one patients with a median age of 76 years were enrolled and could receive induction course. Of these 51 patients, 37 could receive subsequent courses, which consisted either of consolidation, or salvage. Only 11 patients underwent maintenance treatment. Sixty-three percent of patients had to be hospitalized during induction, for a median duration of 14.5 days, and 87% required hospitalization during salvage for a median duration of 17.5 days. Only five patients (38%) required hospitalization during consolidation. There were three toxic deaths (6%), two from hemorrhage and one from pulmonary embolism. The overall response rate was 29%, with 12 patients in complete response (25%) and two in partial response (4%). The median overall survival rate is 4 months for the whole population, and the median DFS is 9.6 months among the 14 responding patients. The results of this trial show that this new weekly schedule of oral ZVD chemotherapy is feasible and effective in poor risk elderly patients with AML. This regimen may be helpful for patients unable to tolerate intensive intravenous regimens, and is a real alternative to palliative treatments.

Results of a phase II trial of a combination of oral cytarabine ocfosfate (YNK01) and interferon alpha-2b for the treatment of chronic myelogenous leukemia patients in chronic phase.

Cytarabine ocfosfate (YNK01) is a prodrug analogue of cytarabine which is resistant to systemic deamination after oral administration. Following initial studies indicating significant anti-tumour activity of YNK01 a phase II trial was initiated in order to assess the tolerability and efficacy of a combination of this agent with interferon alpha-2b (IFN-alpha2b) in recently diagnosed chronic phase CML patients (n = 98). The treatment was subdivided into cycles consisting of 4 weeks of continuous administration of IFN-alpha-2b (3 MU/m(2)/day 1st week and then 5 MU/m(2)/day) and 14 days of oral YNK01 (600 mg/day 1st cycle). At the end of each cycle the dose of YNK01 was adjusted according to the blood count observed during the previous 4 weeks. The median time from diagnosis to inclusion in the trial was 2 months (range 6 days to 7.5 months). At 12 weeks, 62 patients (63%; 95% CI, 54-73) achieved a complete hematological response. At 24 weeks, of 98 patients, two achieved a complete cytogenetic response, 14 a partial response (16% major cytogenetic response rate; 95% CI, 9-24) and 34 a minor response; 19 patients were not evaluable for cytogenetic response. During the trial, 20 patients progressed to accelerated (6) or blastic phases (14). The median time to progression was 15 months (range 2-38 months). At 3 years the overall survival was 79% (95% CI, 70-88). Although the complete hematological response rate compared favorably with the 40% response rate previously obtained with the subcutaneous formulation of Ara-c, the cytogenetic response rate was less than expected. Most of the patients experienced side-effects and all permanently stopped YNK01. Although the combination seems attractive the initial dose of 600 mg per day is probably too high and should be reconsidered in further trials.

Why is factor V Leiden so rare in the Basques?

Factor V Leiden is the most common inherited trait in Caucasians that predisposes individuals to venous thrombosis. However, it is almost absent amongst the Basque people that live in the south western part of Europe. To explain this finding, we speculate upon the putative contribution of various evolutionary forces through which the Basque genome may have been shaped.

Is the assessment of von Willebrand disease prevalence an achievable challenge? The example of the French Basque Country where blood group O and factor XI deficiency are highly prevalent.

The diagnosis of type I von Willebrand disease (VWD) is not straightforward because of the absence of a single clear-cut biological criteria and the interference of several acquired conditions on phenotype expression. We illustrate here this challenge with the French Basque population characterised by a marked high frequency in both blood group O and factor XI deficiency. From this example one may question the validity of epidemiological studies reporting on VWD prevalence.

Epidemiology of myelodysplastic syndromes in a French general hospital of the Basque country.

Epidemiologic studies concerning myelodysplastic syndromes (MDS) are rare. The estimated incidence varies between 1 and 12.6/100,000/year. The aim of this work was to compare our own experience with these data. Our general hospital represents a structure with 1197 beds which serves a population of 290,000 individuals (French Basques). Most of the inhabitants live in a rural environnement. Twenty percent of the population are aged over 65. During a 4-year period (1993-1996), 90 new cases of MDS were diagnosed on bone marrow studies in our laboratory. Among FAB subtypes refractory anemia (RA) represented 27 cases (31%), RA with ring sideroblasts (RARS): 21 (23%), RA with excess of blasts (RAEB) and in transformation (RAEB-t): 22 (24%), chronic myelomonocytic leukemia (CMML): 10 (11%). Ten cases were unclassifiable (11%). Therapy-related MDS were seen in 8 patients. The sex ratio was 1 and the mean age of the patients was 74.3 (range: 23-96), 37% of them being 80 years or older. The calculated incidence was 7.7/100,000/year for the entire cohort and 31.4/100,000/year for people over 65.

N-terminal peptide of type III procollagen: a marker for the development of hepatic veno-occlusive disease after BMT and a basis for determining the timing of prophylactic heparin.

We have studied the kinetics of the N-terminal peptide of type III procollagen (NP3P) after BMT as a marker for the development of hepatic fibrosis in veno-occlusive disease (VOD). Four patients with clinically apparent VOD were retrospectively assayed and demonstrated a very high NP3P level. NP3P was also prospectively monitored at the beginning of conditioning and every week (8 patients) or every other day (14 patients) from the day of BMT (day 0) to day +28. Before conditioning the NP3P level (15.5 +/- 5.5 ng/ml) was twice normal and increased during the course of BMT in patients without VOD (21 ng/ml; range 6-35 ng/ml). In four patients who experienced VOD, the NP3P level exceeded 40 ng/ml by day 0 in two. The early rise of NP3P indicates that it is a valuable marker for the development of VOD before it becomes clinically apparent. These data suggest that VOD develops during preparation for BMT and that prophylaxis should therefore be started at this time.

Full-term pregnancy with embryos from donated oocytes in a 36-year-old woman allografted for chronic myeloid leukemia.

We report the first case of full-term pregnancy arising from donated oocytes in a 36-year-old woman with chronic myeloid leukemia (CML), 6 years after allogeneic bone marrow transplantation (BMT) following total body irradiation (TBI) (12 Gy) and cyclophosphamide 120 mg/kg. The first attempt at implantation with her own cryopreserved ovocytes was unsuccessful. Thereafter, she became pregnant after donated oocyte implantation using estradiol and progesterone support replacing the defective ovarian function. The baby was normal. Unfortunately, 6 months later, she relapsed in chronic phase of CML.

Virus recovery from stools of patients undergoing bone marrow transplantation.

Diarrhea in marrow transplant recipients is a frequent complication attributable to non-infectious events such as acute GVHD or infectious events such as viral gastroenteritis. Rotavirus and enteric adenovirus are the most frequent viral pathogens. To determine the frequency of these infections, we prospectively examined the stool specimens of 94 patients who underwent autologous BMT (34 cases) or allogeneic BMT (60 cases). Stool specimens were examined from patients twice weekly. Nineteen of the 94 patients were infected with viral pathogens. This study showed: (1) an incidence of viral gastroenteritis identical in autologous and allogeneic BMT (20%), (2) a persistent risk despite treatment in laminar air flow rooms, (3) a significant association with severe acute GVHD, and (4) a significant risk of multiple viral infections in autologous BMT recipients. Rotavirus and adenovirus are a cause of enteritis involvement in patients undergoing BMT and they may be underdiagnosed and confused with GVHD. Screening of stool specimens after BMT should be directed to prevention and treatment of these viral infections to decrease the morbidity and mortality associated with BMT.

Acute myelomonocytic leukemia in a XYY man.

A case of acute myeloid leukemia (M4) in a 29-year-old male with a 47,XYY karyotype is reported. This aneuploidy was found in both bone marrow cells and mitogen-stimulated lymphocytes. Monosomy 7 correlated with myelodysplastic features. The possible role of XYY in increasing the risk of leukemia is discussed.