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C Negrier

Publications and source records attributed to C Negrier.

28 records · Page 2Linked to original sources
PubMed1997

Multicenter retrospective study on the utilization of FEIBA in France in patients with factor VIII and factor IX inhibitors. French FEIBA Study Group. Factor Eight Bypassing Activity.

Factor VIII or factor IX replacement is frequently impossible in inhibitor-developing hemophiliacs, because of the level of the inhibitor titer. Activated prothrombin complex concentrates are one of the available options to treat the bleeding episodes in such patients. However, the efficacy of these products and the associated thrombogenic risk, particularly in prolonged administration such as employed during surgeries, are important concerns for hemophilia care providers. We performed a multicenter retrospective study to evaluate the use of FEIBA (Factor Eight Bypassing Activity) in France, and data is presented on 433 bleeding episodes, including surgical procedures, concerning 60 patients from 15 hemophilia centers. The efficacy was judged as good or excellent in 352 episodes (81.3%), poor in 73 episodes (16.9%) and non-existent in 8 episodes (1.8%). Minor and major surgical procedures were successfully performed using FEIBA as a second-line therapy after human or porcine factor VIII, and in some occasions FEIBA was utilized as the only substitution product. The tolerance was assessed as good in 428 episodes (98.8%), but in 5 cases adverse effects were reported. Only 3 patients out of 52 regularly evaluated (5.8%) were HIV-seropositive, and for two of them the seroconversion occurred prior to the first use of FEIBA. In contrast, 80.4% of the patients were HCV-seropositive. An anamnestic response after the administration of FEIBA was noted in 31.5% of cases. This study points out the main features of the use of FEIBA in France, and particularly the low HIV seroprevalence in the patients treated. The good efficacy and the excellent tolerance still confer to this product a place to consider in the therapeutic options for the treatment of inhibitor-developing hemophiliacs or in acquired hemophilia.

Adolescent↗
PubMed1997

The treatment of bleeding in acquired haemophilia with recombinant factor VIIa: a multicentre study.

Recombinant factor VIIa was used to treat 38 patients with acquired haemophilia participating in the Novoseven compassionate-use program. 19 were male, median age 59, range 2-89 years. The median pre-treatment anti-human (H) and anti-porcine (P) inhibitor titre was H 43 BU/ml (range 1-4500) and P 4.5 BU/ml (range 0-1600). Recombinant factor VIIIa was used as first-line therapy for 14 bleeding episodes and as salvage-therapy for 60 episodes which failed to respond to blood-product therapy given for a median of four days (range 1-21 days) prior to treatment with rVIIa. Pre-rVIIa treatment was not reported for four episodes. The indications for treatment were 7 haemarthroses, 40 muscle haematomas, 20 urinary or GI haemorrhages and 3 surgical interventions. The median starting dose of rVIIa was 90.4 microg/kg (range 45-181). A median of 28 doses (range 1-541) were given per episode, over a median 3.9 days (range 0-43). Efficacy was assessed clinically 8 and 24 h after the start of rVIIa and at the end of treatment. A good response was obtained in all 14 bleeds for which rVIIIa was used as first-line therapy. The response after 24 h of rVIIa salvage-therapy for 60 bleeds was good in 75%, partial in 17% and poor in 8%. Efficacy was unreported in 4 cases. The median prothrombin time (PTT) shortened from 12 s (range 9.3-20) pre-treatment to 8.8 s (range 6-14) during treatment. The clinical response did not correlate with the dose of rVIIa used, the type of bleed or the degree of shortening of the PTT following rVIIa infusion. Three patients died from haemorrhagic complications of acquired haemophilia. This mortality of 7.9% is lower than previously reported for this condition. Although one patient developed DIC during treatment with rVIIa, this was probably attributable to hypovolaemic shock, massive transfusion and the use of PCCs. This study demonstrates that rVIIa is a safe, useful and effective treatment for bleeding in patients with acquired haemophilia.

Adolescent↗
PubMed1996

A nonsense mutation in the GPIIb heavy chain (Ser 870-->stop) impairs platelet GPIIb-IIIa expression.

Glanzmann thrombasthenia (GT) is a rare autosomal recessive bleeding disorder, caused by a quantitative or qualitative defect of the GPIIb-IIIa integrin (alpha IIb beta 3), which functions as the platelet fibrinogen receptor. We report a case of type I GT due to a homozygous mutation resulting in Ser 870 to stop codon substitution. This residue is located near the proteolytic cleavage site of proGPIIb. The mutation results in a GPIIb truncated of 138 amino acids, including transmembrane and intracytoplasmic domains. Cotransfection of an expression vector containing the mutant GPIIb and wild-type GPIIIa showed that the mutant Ser 870-->stop GPIIb was able to associate to GPIIIa. However, this heterodimer failed to mature as shown by endoglycosidase-H digestion and was therefore not expressed at the COS-7 cell surface. This report is the first description of a homozygous nonsense mutation in the GPIIb gene and highlights the role of the GPIIb light chain.

Adolescent↗
PubMed1995

Combined factor IX and protein C deficiency in a child: thrombogenic effects of two factor IX concentrates.

We have recently described an unusual situation which involved a combination of a factor IX and a protein C deficiency in a young child who presented, according to the bleeding tendency, as a hemophilia B patient. In this particular hemophiliac, baseline prothrombin fragment F1 + 2 levels were unexpectedly elevated and increased after an injection of a very high purity factor IX concentrate. This observation raised a question regarding the substitution schedule in the case of repeated injections of factor IX, since the thrombotic tendency has been a major concern with some factor IX concentrates. We monitored factor IX, prothrombin fragment F1 + 2, and D-dimer plasma levels before and during the 6 hr following the injection of an immunopurified factor IX concentrate. The results showed an increase in the F1 + 2 levels after the factor IX injection, but an increase lower than previously observed with an ion-exchange chromatography-purified concentrate. Furthermore, the F1 + 2 level returned to baseline value 6 hr after administration. This factor IX concentrate seems to be best for use in the patient where repeated injections are involved (as employed during surgery). Moreover, the data point out the advantage of a monoclonal antibody-purified factor IX concentrate over less purified concentrates in a specific situation, with regard to the thrombogenic risk.

Antibodies, Monoclonal↗
PubMed1995

Molecular study of Glanzmann thrombasthenia in 3 patients issued from 2 different families.

In an effort to further understand Glanzmann thrombasthenia (GT) 3 patients from 2 different families were studied. After biochemical and immunological analysis these patients were classified as type I. We observed in the first family a new restriction site for Stu I in exon II of the glycoprotein (GP) IIIa gene caused by a homozygous nonsense mutation: 62 Arg to stop codon. The parents were heterozygotes for this mutation. We found in the second family a previously described nonsense mutation: 584 Arg to stop codon in exon 17 of the GPIIb gene. The father and his two affected sons were heterozygous for this genetic defect. This mutation 62 Arg to stop codon is a new description of a genetic defect associated with GT. Furthermore, the discovery of the same mutation in 3 affected families from different ethnic groups raises the possibility of either a hot spot mutation in the CG dinucleotide region of GPIIb gene, or an ancient mutant allele present in diffuse populations at a relatively high frequency.

Amino Acid Sequence↗
PubMed1994

Increased thrombosis incidence in a family with an inherited protein S deficiency and a high oxygen affinity hemoglobin variant.

Inherited protein S deficiency and the presence of a rare high oxygen affinity hemoglobin variant: Hb Rainier [beta 145 (HC2) Tyr-->Cys] were found in a family. Among 16 studied members, nine were found as carriers of protein S deficiency (type I with decrease of total, free, and activity levels). Six subjects carried the high-affinity hemoglobin variant, which displayed an increase of blood viscosity. Four members combined both abnormalities. Three had thrombotic accidents before the age of 30. We suggest the combination of protein S deficiency and the presence of this hemoglobin variant can lead to a severe primary hypercoagulable state with pathological consequences compared to each genetic defect alone.

Adult↗
PubMed1993

Increased thrombin generation in a child with a combined factor IX and protein C deficiency.

We report a quantitative protein C deficiency combined with a factor IX deficiency in a one-year-old boy. The inheritance of the two deficiency states was independent, the factor IX defect coming from the mother and the protein C defect from the father. Both factor IX activity and antigen were below 1%, and protein C activity as well as antigen were close to 27% of normal values. This association raises a real therapeutic and prognostic question. Protein C deficiency is indeed associated with a significant thrombotic risk and some factor IX concentrates seem to carry a potential thrombogenicity, particularly following infusion of repeated doses. We evaluated in this patient the potential activation of the coagulation system by measuring the levels of prothrombin fragment F1 + 2 at the basal state and after a single administration of 20 U/kg of a high purity factor IX concentrate. We found an unexpected basal activation of the hemostatic system before infusion (F1 + 2 = 1.6 nmol/L), which further increased during 8 hours. Despite the clinical predominant expression of the hemophilic trait, our results seem to assess the biologic prevalence of the protein C deficiency. This emphasizes the need for a careful follow-up after infusions of repeated doses of factor IX, as used during a surgical procedure. Furthermore, this raises the question of the prognosis because the risk of thrombotic manifestations associated with a protein C deficiency increases with age. Finally, these results highlight a part of the in vivo activation process of prothrombin in case of failure of the intrinsic pathway of coagulation. The protein C defect seems to be responsible for an upregulation of the prothrombin activation through the extrinsic pathway.

Factor IX↗