Biomedical subjects

Yesim Dargaud

Publications and source records attributed to Yesim Dargaud.

9 recordsLinked to original sources

PubMed2006

Platelet-dependent thrombography: a method for diagnostic laboratories.

The thrombin-platelet feedback loop was examined at low concentration tissue factor using calibrated automated thrombography in combination with the elimination of contact factor activation by corn trypsin inhibitor. The results indicated that, when contact factor activation was eliminated, the thrombin-platelet feedback loop was a major determinant of thrombin generating capacity and that platelets had a greater role in regulating the propagation of thrombin generation than its initiation. This method has potential application to the measurement of platelet-dependent thrombin generation in clinical diagnostic laboratories and hence the investigation of patients with apparent hypo- or hypercoagulable phenotypes.

Adult↗

PubMed2006

Characterisation of 96 mutations in 128 unrelated severe haemophilia A patients from France. Description of 62 novel mutations.

Direct sequencing of the coding region of factor VIII (F8) gene was used to determine the mutations responsible for severe haemophilia A (FVIII<1%) in 128 unrelated haemophiliacs A, negative for intron 22 and intron 1 inversions. A mutation was found in 122/128 patients (95%). Ninety-six distinct mutations were identified in this cohort, 62 of these are novel. They consisted of deletions (7 large and 24 small deletions), insertions (n = 9), associations of insertion/deletion (n = 2), association of deletion/substitution (n = 1), and single nucleotide substitutions (53 point mutations consisting of 31 missense, 20 nonsense, and 2 splicing mutations). Twenty-two patients had developed inhibitors, and among this subgroup 3 large deletions, 6 frameshift, 9 nonsense and 4 missense mutations were detected. For 6 patients, among which one developed an anti-FVIII inhibitor, no mutations were detected in the coding and splicing regions of factor VIII gene. Different approaches of molecular modelling were performed in addition to familial linkage analysis to determine the pathophysiological responsibility of these novel missense mutations.

Blood Coagulation Tests↗

PubMed2006

A case of Glanzmann's thrombasthenia successfully treated with recombinant factor viia during a surgical procedure: observations on the monitoring and the mechanism of action of this drug.

Recombinant factor VIIa (rFVIIa) has been shown to be efficient for the treatment of haemorrhages in patients with Glanzmann's thrombasthenia presenting anti-glycoprotein IIb-IIIa antibodies, but the mechanism of action is not well established and there is no routine laboratory test for the monitoring of rFVIIa. In this study, thrombin generation (TG) test was used to assess the efficacy of rFVIIa ex vivo in a Glanzmann patient with inhibitor, who had a surgery for cholesteatoma. The day before surgery, TG capacity in platelet rich plasma was significantly diminished (Endogenous thrombin potential = 637nM x min) in comparison with the normal control group (1338+/-353 nM x min). Thirty minutes after the first infusion of 90 microg/kg of rFVIIa, TG was increased by 59% (1010 nM x min). rFVIIa was administered as intravenous bolus injection of 90 microg/kg q x 2h during the first 24h, than 66microg/kg q x 2h during 24h and 53 microg/kg q x 2h on the post-operative day 3. Residual TG capacity measured before rFVIIa administration mostly remained above 1000nM x min and the coagulation capacity was not significantly modified after a new injection of rFVIIa. The fibrin network was studied with 3D confocal microscopy using clots obtained with TG test. After rFVIIa infusion, the fibrin network was tighter in comparison with the sample before rFVIIa injection. These results provide further ex vivo evidence on haemostatic efficacy of rFVIIa in Glanzmann's patients.

Annexin A5↗

PubMed2006

Use of calibrated automated thrombinography +/- thrombomodulin to recognise the prothrombotic phenotype.

There is currently no validated method to detect a prothrombotic phenotype. The question remains, can tissue factor (TF) induced thrombin generation (TG), as measured with the calibrated automated thrombinography (CAT) technique, according to Hemker et al., recognise a prothrombotic state either as such, or when the activated protein C (APC)-system is boosted with thrombomodulin (TM)? We determined the normal range of CAT-TG +/- TM in a group of 71 healthy blood donors, in 11 healthy women using oral contraceptives (OC), and in 89 patients with a history of venous thromboembolism (VTE), divided into a group of 50 in which a prothrombotic risk factor could be found (VTEprf+) and 39 others (VTEprf-). The endogenous thrombin potential (ETP) in the OC, VTEprf+ and VTEprf- group was significantly higher than for the controls. In the presence of TM, the differences were significantly higher than in its absence. The VTEprf+ group had a higher ETP, +/- TM than the VTEprf-group. In conclusion, TG, measured with the CAT technique in the presence of TM is capable of detecting the prothrombotic phenotype with a high sensitivity of 0.93 (95% confidence limits 0.82-0.99).

Adult↗

PubMed2005

Inherited bleeding disorder due to familial type 2 platelet cyclo-oxygenase deficiency.

Inherited platelet cyclo-oxygenase (COX) deficiency is a rare bleeding disorder. We report here the first case of familial type 2 platelet COX deficiency responsible for a moderate bleeding phenotype. The propositus was admitted in the emergency department for major epistaxis following treatment with aspirin. Epinephrine closure time is very sensitive to drugs which inhibit COX but the test was normal in patients with inherited COX deficiency. This clinical and biological data suggest that the anti-platelet effect of aspirin may be dependent on mechanisms other than the inhibition of COX. Thrombin generation test confirmed mild bleeding phenotype in patients with COX deficiency as they had normal thrombin generating capacity.

Adolescent↗

PubMed2005

Acquired Glanzmann's thrombasthenia associated with acute lymphoblastic leukemia.

Acquired Glanzmann's thrombasthenia is an uncommon event in association with leukemia. The authors describe a patient with acute lymphoblastic leukemia (ALL) who presented with severe hemorrhagic syndrome, without disseminated intravascular coagulation. The patient's course was complicated by the occurrence of severe hemorrhagic episodes, with a thrombasthenia-like profile, requiring multiple transfusions with packed red cells, platelets, and fresh-frozen plasma. Biological explorations detected anti-GPIIb/IIIa complex antibodies. The patient finally died with refractory disease and persistent bleeding. This case is the first reported of autoantibodies to GPIIb/IIIa in ALL. Such paraneoplastic syndrome is potentially responsible for severe life-threatening hemorrhage.

Adolescent↗

PubMed2005

Evaluation of thrombin generating capacity in plasma from patients with haemophilia A and B.

In haemophilia patients, a relationship is usually observed between the clinical expression of the disease and plasmatic factor VIII/factor IX (FVIII/FIX) activity. However, it is known from clinical experience, that some haemophilia patients, despite similar FVIII/FIX plasma levels, could exhibit different bleeding phenotype. After determining preanalytical test conditions, we evaluated the thrombin generation capacity from haemophilia plasma samples in various conditions and the potential usefulness of thrombin generation test (TGT) in haemophilia patients. In a series of 46 haemophilia patients (34 haemophilia A and 12 haemophilia B patients), we found a significant correlation between plasmatic FVIII/FIX levels and endogenous thrombin potential (ETP), peak and time to peak obtained by thrombin generation measurement. In addition, a correlation was found between severe clinical bleeding phenotype and ETP. Our results suggest that TGT could be a promising tool to evaluate haemostasis capacity in patients with haemophilia. Our ex vivo results, obtained 24 hours after FVIII concentrate administration, showed that in patients presenting similar plasmatic FVIIII levels, thrombin generation capacity may be significantly different. These results suggest that in patients with haemophilia, TGT could be useful for individually tailoring prophylactic regimens as well as for adapting clotting factors infusions in surgical situations, in addition to FVIII/FIX plasma clotting activities.

Adult↗

PubMed2003

Two novel factor V null mutations associated with activated protein C resistance phenotype/genotype discrepancy.

Activated protein C (APC) resistance phenotype/genotype discrepancy is a very rare event. The objective of this study was to characterize the molecular mechanisms in two cases of APC phenotype/genotype discrepancy. An approach using direct sequencing of each exon and splicing junctions of the factor V gene showed that two novel factor V null mutations combined with heterozygous factor V Leiden mutation were responsible for this discrepancy. Our results suggest the necessity to use both phenotypic and genotypic analyses in some cases to determine an accurate diagnosis.

Activated Protein C Resistance↗

PubMed2003

Spontaneous proximal deep vein thrombosis in a patient with severe haemophilia A.

Venous thrombosis is a very rare occurrence in patients with haemophilia A. The majority of these cases occurred during or after the administration of clotting factor concentrates. We report the case of a patient with severe haemophilia A, who spontaneously developed a deep venous thrombosis (DVT). The thrombosis occurred in the superficial femoral vein with an extension in the profunda femoris vein. Neither any local anatomic compression nor any predisposing thrombophilic risk factors were identified. Treatment with recombinant factor VIII at prophylactic doses associated with unfractionated heparin led to a successful resolution. This case illustrates the possibility for severe haemophilia patients to develop authentic spontaneous DVT without anti-haemophilic treatment and predisposing risk factors.

Adult↗