Cost related to replacement therapy during hospitalization in haemophiliacs with or without inhibitors: experience of six French haemophilia centres.

Replacement therapy in haemophiliacs has a major economic impact on health establishments. We assessed in this prospective study the cost of clotting factor concentrate therapy for haemophilia A or B patients. We compared the overall costs of treated patients with or without inhibitors. In six French haemophilia centres, 278 consecutive hospitalizations were collected and analysed between June 97 and June 99. Haemophilia must be considered as the main cost factor during hospitalization. The severity of bleeds and surgical procedures increase the total cost. Furthermore, the daily and total costs are closely linked to the presence or the absence of inhibitors. This study should enable the hospital administration to evaluate the necessary resources to the clotting factor therapy in haemophiliacs with or without inhibitors during hospitalization.

Mutations in the fibrinogen aalpha gene account for the majority of cases of congenital afibrinogenemia.

Congenital afibrinogenemia is a rare, autosomal, recessive disorder characterized by the complete absence of detectable fibrinogen. We previously identified the first causative mutations in a nonconsanguineous Swiss family; the 4 affected persons have homozygous deletions of approximately 11 kb of the fibrinogen alpha (FGA) gene. Haplotype data implied that these deletions occurred on distinct ancestral chromosomes, suggesting that this region may be susceptible to deletion by a common mechanism. We subsequently showed that all the deletions were identical to the base pair and probably resulted from a nonhomologous recombination mediated by 7-bp direct repeats. In this study, we have collected data on 13 additional unrelated patients to identify the causative mutations and to determine the prevalence of the 11-kb deletion. A common recurrent mutation, at the donor splice site of FGA intron 4 (IVS4 + 1 G > T), accounted for 14 of the 26 (54%) alleles. One patient was heterozygous for the previously identified deletion. Three more frameshift mutations, 2 nonsense mutations, and a second splice site mutation were also identified. Consequently, 86% of afibrinogenemia alleles analyzed to date have truncating mutations of FGA, though mutations in all 3 fibrinogen genes, FGG, FGA, and FGB, might be predicted to cause congenital afibrinogenemia.

Heparin-induced hyperkalemia in chronic hemodialysis patients: comparison of low molecular weight and unfractionated heparin.

Aldosterone suppression and subsequent hyperkalemia are well described reversible side effects of prolonged treatment with heparin. This study was designed to examine whether the discontinuous use of heparin three times a week to prevent thrombosis formation during hemodialysis sessions could also induce hypoaldosteronism and might contribute to increased predialysis kalemia in hemodialysis patients. Two different heparinization regimens were prospectively compared in a crossover study of 11 chronic hemodialysis patients. During 2 consecutive weeks, the patients were dialyzed each week with either their usual doses of unfractionated heparin (UH) (6,160 IU +/- 1,350 IU) or low molecular weight heparin (LMWH) (15 anti-Xa activity [aXa] U/kg + 5 aXa U/kg/h). In all but 2 patients, the predialysis level of plasma K+ was higher with UH than with LMWH, and the mean value was higher (5.66+/-0.83 versus 5.15+/-0.68 mM, p = 0.01) while no differences in the predialysis plasma concentrations of creatinine, phosphate, urea, and bicarbonate were observed, excluding the potential role of differences in diet and dialysis efficacy in explaining the higher plasma K+ concentration with UH. The mean plasma aldosterone to plasma renin activity (pRA) ratio was higher with LMWH than with UH (149.54+/-123.1 versus 111.91+/-86.22 pg/ng/ h, p < 0.05). Individual plasma aldosterone values were found to be correlated to pRAs both during the UH period and the LMWH period, and the slope of the positive linear relation between plasma aldosterone and pRA was lower during the UH treatment period (63 versus 105 pg/ng/h). Finally, a negative linear correlation was found between the differences in individual predialysis plasma K+ observed during the 2 protocols and the differences in the corresponding plasma aldosterone levels, suggesting a link between the higher kalemia and the lower aldosterone responsiveness to angiotensin with unfractionated heparin. Although it cannot be concluded whether or not LMWH inhibits aldosterone synthesis, should LMWH decrease aldosterone production, this side effect is 33% less marked than that of UH so that the predialysis plasma K+ levels are 10% lower. This property makes LMWH use preferable to that of UH in patients with elevated predialysis kalemia.

[Factor XI deficiency, a new way of substitution: human purified concentrates]. / Déficit en facteur XI, un nouveau moyen de substitution: les concentrés humains purifíes.

Case report of a 26-year-old patient, admitted for severe craniofacial trauma, with facial injuries and intracranial haemorrhage. Preoperative tests showed an aPTT = 64 s (control = 29 s), rapidly recognized as being caused by a major constitutional factor XI deficiency (0.06 Ul.mL-1). Considering the neurological risk and the indication for surgery, concentrates of factor XI were administered at a dosage of 25 Ul.kg-1. This treatment was associated with a biological normalization and uneventful surgery. In patients experiencing a factor XI deficiency, the use of fresh frozen plasma will probably decrease and only administered in emergency cases when factor XI concentrates are not available.

Characterization of von Willebrand factor gene defects in two unrelated patients with type IIC von Willebrand disease.

Genetic studies were performed in two unrelated patients with the IIC phenotype of von Willebrand disease (vWD) characterized by the increased concentration of the protomeric form of von Willebrand factor (vWF). In patient B, the sequencing of both exons 15 and 16 of the vWF gene showed two sequence alterations: a 3-bp insertion in exon 15 resulting in the insertion of a Glycine at position 625 (625insGly) and a 2-bp deletion in exon 16 leading to a premature translational stop at codon 711 (711 ter), at the heterozygote state. Patient A was found homozygous for a single point mutation also localized in exon 15 and responsible for the substitution Cys623Trp. These candidate mutations were not found in a panel of 96 normal chromosomes, suggesting a causal relationship with IIC vWD phenotypic expression. The composite heterozygote or homozygote state of both patients supports the recessive mode of inheritance already described for this phenotype. Furthermore, the localization of these gene defects in the D2 domain of vWF propeptide, known to play an important role in vWF multimerization, provides another argument in favor of their causative effect regarding the peculiar multimeric pattern of vWF in these patients.

A lifelong bleeding disorder associated with a deficiency of plasminogen activator inhibitor type 1.

A 36-year-old patient was investigated for a lifelong history of epistaxis and delayed bleeding after minor surgeries. Deficiencies or abnormalities of the coagulation system, of platelet function, or of factor XIII and alpha-2-antiplasmin were excluded. Consistently, however, over a period of 7 years, a high basal euglobulin fibrinolytic activity was observed that was characterized by a high tissue-type plasminogen activator (t-PA) activity, normal t-PA antigen, and undetectable plasminogen activator inhibitor type-1 (PAI-1) antigen and activity. The high specific activity of t-PA (640,000 IU/mg) and the minimal amounts of t-PA/PAI-1 complexes detected by fibrin zymography suggest that in this patient all t-PA was active. This is in striking contrast to normal plasma, where the majority of t-PA is complexed to PAI-1. Thus, in this patient, a severe deficiency of PAI-1 is associated with a delayed type bleeding tendency. Our observation underscores the importance of plasma PAI-1 for the stabilization of the hemostatic plug.

Antithrombin III-Amiens: a new family with an Arg47----Cys inherited variant of antithrombin III with impaired heparin cofactor activity.

A family with an antithrombin III variant (AT-III-Amiens) demonstrating abnormal heparin cofactor activity is described. Amplification and direct sequencing of genomic DNA by the polymerase chain reaction procedure permitted the identification of an Arg47----Cys mutation in exon 2 of the variant antithrombin III gene.

Influence of thromboembolism prophylaxis by low molecular weight heparin CY 216 (Fraxiparine) on several parameters of haemostasis in patients under dialysis and receiving either unfractionated heparin or CY 216.

The hemorrhagic risk of an association of the low molecular weight (LMWH), Fraxiparine injected intravenously at the dose of 7.500 AXalCU or of unfractionated heparin (UFH) injected intravenously at the usual dose used during hemodialysis (3.750 +/- 1.280 IU + 1.000 IU after 2 hours of dialysis) to the subcutaneous administration once daily of a thromboembolism preventive dose of Fraxiparine (7.500 AXalCU) was evaluated on the modification of the following hemostasis parameters: thrombin time, activated partial thromboplastin time (APTT), anti Xa activity, in 13 uremic patients on hemodialysis. The association of intravenous and subcutaneous Fraxiparine prevented efficiently the clotting of the extracorporeal circulation without inducing a detectable antithrombinic activity. In contrast, the association of I.V. UFH to subcutaneous Fraxiparine induced a significant increase of the thrombin time and of the APTT, so explained by the activity of UFH. It is concluded that subcutaneous Fraxiparine at the thromboembolism preventive dose can be associated as well to I.V. Fraxiparine as to UFH without increasing the potential hemorrhagic risk. Nevertheless the association of SC and IV Fraxiparine 7.500 AXalC u seems preferable to the association of SC Fraxiparine with UFH.

[Parameters of hemostasis during treatments associating fractionated heparin administered subcutaneously to standard and fractionated heparin administered intravenously in the chronic hemodialysis patient]. / Etude des paramètres de l'hémostase au cours de traitements associant l'héparine fractionnée par voie sous-cutanée aux héparines standard et fractionnée par voie intraveineuse chez l'hémodialysé chronique.

The hemorrhagic risk of an association of fractioned heparin (Fraxiparine) injected intravenously at the dose of 7500 AXaICU or of unfractionned heparin (UFH) injected intravenously at the usual dose used for a priming dose for hemodialysis (3750 +/- 1280 IU + 1000 IU after 2 hours of dialysis) to the subcutaneous administration of a thrombo-embolism preventive dose of Fraxiparine (7500 AXaICU) was evaluated on the modifications of the following hemostasis parameters: thrombin time, Activated Partial Thrombin Time (APTT), prothrombin time, anti Xa activity in 13 uremic patients on hemodialysis. The association of intravenous and subcutaneous Fraxiparine prevents efficiently the clotting of the extracorporeal circulation without inducing a detectable antithrombinic activity. In contrast, the association of I.V. UFH to subcutaneous Fraxiparine induces a significant increase of the thrombin time and of the APTT. This latter is exclusively explained by the activity of UFH. It is concluded that subcutaneous Fraxiparine at the thromboembolism preventive dose can be associated as well to I.V. Fraxiparine as to UFH without increasing the antithrombinic activity of the plasma.

A new von Willebrand factor (vWF) defect in a patient with factor VIII (FVIII) deficiency but with normal levels and multimeric patterns of both plasma and platelet vWF. Characterization of abnormal vWF/FVIII interaction.

The patients with inherited bleeding diathesis related to quantitative, structural, and/or functional abnormalities of von Willebrand factor (vWF) are said to have von Willebrand's disease (vWD). We report here the clinical and laboratory features of a 50-year-old woman with a life-long history of excessive bleeding. Her particular laboratory data are factor VIII (FVIII) deficiency, subnormal bleeding time, and the presence of all plasma and platelet vWF multimers in normal amounts. Infused with FVIII/vWF concentrate, she showed a persistent increase in FVIII that led us to discard hemophilia A carrier or "acquired hemophilia" diagnoses. vWF devoid of FVIII purified from normal and patient's plasma by immunoaffinity on anti-vWF monoclonal antibody (MoAb) was immobilized onto polystyrene tubes that were further incubated with purified normal FVIII. The bound FVIII was evidenced using radiolabeled anti-FVIII MoAb. The data showed that the patient's vWF, in contrast to vWF purified from normal plasma, was unable to bind FVIII. Furthermore, no inhibitor of FVIII/vWF interaction was evidenced in incubating purified normal vWF with the patient's plasma before the addition of FVIII and anti-FVIII MoAb. These results support the concept that the bleeding diathesis of this patient appears to be due mainly to her abnormal vWF preventing FVIII/vWF interaction. This abnormality, which is not yet described in present classification of vWD, could be considered as a new variant of vWD.

Low-molecular-weight heparin Fraxiparin in chronic hemodialysis. A dose-finding study.

A two-step dose-ranging study was undertaken with CY216 (Fraxiparin) in 8 patients on 7 sessions each. The different doses were administered each time as a single bolus injection at the start of hemodialysis without heparinized priming nor further administration during the 4-hour session. In the first step, the clinical efficacy of 4 different doses of Fraxiparin was compared with that of standard heparin on the percentage of sessions free of clot formation in the extracorporeal circulation (ECC). Safety was evaluated by the compression time for hemostasis at the puncture sites. The second step was a randomized comparison of 3 Fraxiparin dosages. In addition to the clinical assessment of efficacy, the following biological parameters were measured: fibrinopeptide A (FPA), anti-Xa (AXa) activity calibrated against Fraxiparin, thrombin time (TT), activated partial thromboplastin time, blood counts, hemoglobin, hematocrit, plasma creatinine and urea, and residual blood volume in the dialyzer. A 'standard' dosage of 10,000 AXa Institut Choay units of Fraxiparin was shown to prevent clot formation in the ECC. It resulted in a marked increase in TT, without any lengthening of the puncture site compression time. After 4 h, AXa and FPA levels in the venous line were related to the doses used (p less than 0.05). After 48 h AXa activity was very low. Dialysance and tolerance were excellent. Thus, a single dose of Fraxiparin unrelated to body weight and not determined by the measurement of the whole-blood activated clotting time appeared to be a safe and effective means for preventing fibrin formation in 4-hour dialysis sessions.

[Anticoagulation in hemodialysis sessions with a low molecular weight heparin (CY 222, Choay). Dosage studies in chronic hemodialysis. Its use in patients at high risk of hemorrhage]. / Anticoagulation des séances d'hémodialyse par une héparine de bas poids moléculaire (CY 222, Choay). Etudes de posologies en hémodialyse chronique (HDC). Utilisation chez les patients à haut risque hémorragique.

Efficacy of CY 222 for providing anticoagulation during hemodialysis was evaluated in three successive trials by rating quality of blood restitution (degree of coagulum formation in extracorporeal circulation) and by assay of fibrinopeptide A. Its safety was assessed by measurement of manual compression time necessary to ensure hemostasis of puncture points at end of session. Details of the first preliminary study were: 60 sessions in 11 chronic uremia patients; CY 222: 75, 150 and 300 A-Xa IC U/kg + 1,000 A-Xa IC U/h, then 150 and 300 A-Xa IC U/kg without continuous injection, compared with standard heparin (SH) at the usual dosage for each patient (60 +/- 13 IU/kg). Results showed CY 222 at 150 U/kg + 1,000 U/h to possess the same efficacy as SH and to give a shorter compression test time: for 150 U/kg the efficacy was satisfactory, although less than with SH, and compression times were shorter (interest in patients at risk of hemorrhage). For 300 U/kg, efficacy was superior (improved restitution and lower FPA level at end of seance: 6 ng/ml instead of 15 ng/ml.p less than 0.002) and compression times were identical. The second study to evaluate optimal dosage of CY 222 in chronic hemodialysis (CHD) involved: 10 patients; CY 222: 200 A-Xa IC U/kg and 250 A-Xa IC U/kg by single-dose injection. Results failed to demonstrate any significant difference in evolution of FPA levels, but restitution was better at 250 U/kg. In addition, investigation of the effect of rinsing of ECC with standard heparin before the session showed that its suppression did not alter effectiveness but improved tolerance.(ABSTRACT TRUNCATED AT 250 WORDS)

[Low molecular weight heparin (CY 222) levels during hemodialysis sessions. Comparison of various chromogenic and chronometric methods. Problem of standardization]. / Dosage d'une héparine de bas poids moléculaire (CY 222) au cours des séances d'hémodialyse. Comparaison de différentes méthodes chromogéniques et chronométriques. Problème de l'étalonnage.

Current evaluation of biological activity of low molecular weight heparins (LMWH) is dependent solely on technics determining Xa inhibition. Comparison of these technics was carried out during 2 studies of the use of CY 222 during hemodialysis. In the first study, 66 plasma samples from 11 patients treated with 200 or 250 U A Xa IC kg/i.v. at start of session (sample collections at 2-4 h) were tested using a chronometric technic (Hepaclot Stago-plasma diluted to 1/3) and 2 chromogenic technics on microplates using C.B.S. 31-39 substrates (Stachrom-modified Stago: incubation time 90" for a wide range) and S 2222 (Coatest-modified Kabi: incubation time 180"). In the second, 28 plasma samples from 7 patients (sample collection 2-4 h, TO following session; anticoagulation CY 222 10,000-15,000-20,000 U A Xa IC) were studied by 2 chronometric methods: Hepaclot (Stago) and Heptest (Hemachem). Standardization was with CY 222 in each case (results expressed as U A Xa IC). Mean blood heparin in the first study was 2.39 +/- 0.7 with Hepaclot, 2.50 +/- 0.55 with Stachrom and 1.94 +/- 0.37 with Coatest. Student's test failed to show any difference between results with Strachrom and Hepaclot (t = 1.48 NS) whereas the difference was very significant between Hepaclot and Coatest and Stachrom and Coatest (p less than 10(-9).(ABSTRACT TRUNCATED AT 250 WORDS)

Low molecular weight heparin in haemodialysis and haemofiltration--comparison with unfractioned heparin.

The low molecular weight heparin CY 222 (CHOAY) has been compared to unfractioned heparin (UFH) in patients on chronic haemodialysis and haemofiltration at various doses as regards it biological activity (measured by Activated Partial Thromboplastin Time and by anti-Xa activity) and its clinical effect on clot formation in the blood lines and bleeding at the puncture sites or recent wounds. Compared to UFH, CY 222 has a greater anti-Xa activity for a shorter APTT. This biological difference is of clinical advantage since clotting in lines is comparable or less than with UFH whereas compression time at puncture sites is shorter and recently bleeding wounds in 28 patients did not bleed again. The long half life of CY 222 allows its use as a single priming dose of 300 anti-Xa U/kg in haemodialysis and 450 anti-Xa U/kg in haemofiltration.

Filterability in children.

The filterability of total blood and erythrocytes has been investigated in 36 children from 2 to 14 years old by the filtration method developed by Reid. Red blood cells being obtained by centrifugation, were washed three times and resuspended in saline. Filterability was recorded as the filtration time of 1 ml of total blood or red cells suspension. The filtration time of total blood was: 49.10 +/- 14.5 s/ml; that of resuspended cells was: 18.19 +/- 6.16 s/ml. These results have been correlated with age, fibrinogen, white blood cells, glycaemia, haematocrit, and compared with the results obtained in 42 adults whose filtration times were: 33.04 +/- 7.40; and red cells' time: 13.99 +/- 2.95. Statistical analysis shows that the difference is very significant and not correlated with the investigated factors. Erythrocyte filterability may be influenced by still unknown factor.

[Willebrand's disease and pregnancy (author's transl)]. / Maladie de Willebrand et Grossesse.

Autosomal dominant hemorrhagic disorder, Willebrand's disease causes hemorrhagic complications during post-partum period. Nevertheless our case-report as well as others's have shown that these complications only occur when there is no spontaneous biologic improvement and can be prevented by prophylactic treatment with cryoprecipitates or anti-hemophilic A fractions. This risk requires thus a regular watch of the biologic aspects during pregnancy and before the delivery date in order to decide of a possible treatment, which will be absolutely necessary in case of obstetrical surgery.