Characterizing hospital pathways for the care of acquired hemophilia in France using comprehensive national health data.

PURPOSE: Acquired hemophilia (AH) is a rare, serious bleeding disorder most often associated with older age and life-threatening complications. The patient care pathway for AH is complex because of the different types of bleeding, the presence of comorbidities, and the heterogeneity of medical specialists who care for these patients. METHODS: This observational study used the French national PMSI (Programme de médicalisation des systèmes d'information) database to characterize patients with AH in real-life practice and analyze their hospital pathway. In total, 180 patients with AH were identified over a 5-year study period (January 2010 to December 2014), based on three criteria: bypassing agent use, International Classification of Diseases, 10th revision code allocation, and aged over 65 years. Comparison of the incidence rate of AH versus registry data validated the PMSI as an epidemiological database. RESULTS: Rituximab was prescribed more often (60/180; 33.3%) than expected following guidelines and was associated in half of cases to early infections (32/60; 53.3%), surgery procedures were frequently performed during the year before AH onset (29/159; 18.2%), which may suggest a triggering effect, extended hospital stays (median: 20 days) and mortality remaining high (66/180; 36.7%) that occurred mainly during the first month after AH diagnosis. Median costs and number of injections were comparable between recombinant activated factor VII and plasma-derived activated prothrombin complex concentrate. CONCLUSION: These findings could inform future medico-economic approaches in this AH population (duration of stays, bypassing agents, rituximab use, comorbidities, hospitalizations with infections).

Post-authorization safety study of Clottafact® , a triply secured fibrinogen concentrate in congenital afibrinogenemia. A prospective observational study.

BACKGROUND AND OBJECTIVES: A new fibrinogen concentrate Clottafact® was developed according to European guidelines on plasma-derived products. A post-authorization safety study was set up in 2009 as part of the risk management plan. This was a non-interventional, prospective, non-comparative, multicenter study of the use of fibrinogen concentrate for congenital afibrinogenemia in real-life medical practice in France. MATERIALS AND METHODS: The analysis was descriptive and performed on 3 subgroups: prophylaxis vs. on-demand treatment, age (<6, <12 and ≥12) and severity of the deficiency. RESULTS: Fourteen patients [1-78 years] were included in 7 centres and followed for 1 year. Twenty-one adverse drug reactions (ADRs) classically reported with fibrinogen (pallor, chills, cough, vomiting, headache, urticaria and erythematous rash) were reported in 5 of 14 patients. Two ADRs were serious: an anaphylactic shock and a subclavian venous thrombosis with a favourable outcome without sequelae. In the nine patients under prophylaxis, 365 of 367 infusions were considered as successful (99·5%) and 2 as failures. For the five patients treated on-demand, the efficacy was rated as excellent for 27 of 48 infusions and good for the 21 others. CONCLUSION: This study confirms that the benefit/risk balance for this fibrinogen concentrate is favourable.

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.

FEIBA in the treatment of acquired haemophilia A: results from the prospective multicentre French 'FEIBA dans l'hémophilie A acquise' (FEIBHAC) registry.

Factor VIII inhibitor bypass activity (FEIBA) is a recommended first-line bypassing agent for bleeding episodes in patients with acquired haemophilia A (AHA). Due to the low incidence of AHA, available clinical data on FEIBA treatment are limited. The study aim was to delineate practice patterns in FEIBA treatment of AHA patients, the haemostatic efficacy of FEIBA, including criteria for its assessment, and safety. A prospective registry was established of AHA patients receiving FEIBA for bleeding episodes or prophylaxis at the time of invasive procedures. Data were collected at 16 participating centres in France. Patients were followed up for 3 months. Haemostatic efficacy, FEIBA regimen and FEIBA-related adverse events were documented. Thirty-four patients averaging 81.8 years old with standard deviation (SD) 8.1 years were included in the study: 33 for acute bleeding and one for haematoma evacuation. The mean initial dose of FEIBA for acute bleeding was 75.4 U kg(-1) (SD, 7.7 U kg(-1) ), most often administered twice daily, and the median duration of FEIBA treatment was 4.0 days (interquartile range, 2.2-8.0 days). FEIBA was effective in managing 88.0% of bleeding episodes (95% confidence interval, 75.8-94.5%). No baseline variables influencing treatment response could be identified. The sensitivity and specificity of an objective haemostatic efficacy scale in predicting sequential investigator assessments of haemostatic efficacy were 45.3% and 84.1% respectively. Four patients experienced a total of six serious adverse events possibly related to FEIBA. In the first prospective study specifically focused on FEIBA treatment of patients with AHA, 88.0% of bleeding episodes were effectively managed.

Outcome of acquired haemophilia in France: the prospective SACHA (Surveillance des Auto antiCorps au cours de l'Hémophilie Acquise) registry.

Although extremely rare, acquired haemophilia A (AHA) can cause severe bleeding, which may be fatal. The underlying causes of autoantibody development are not fully understood. Treatment goals are bleeding control and autoantibody eradication. At the time of our study, there was no consensus on a standard treatment strategy for AHA. Previous data were mainly retrospective or from single-centre cohorts. We conducted a prospective, controlled, registry-based study of patients with AHA in France. The prospective French registry (Surveillance des Auto antiCorps au cours de l'Hémophilie Acquise [SACHA]) collected data on prevalence, clinical course, disease associations and outcomes for haemostatic treatment and autoantibody eradication in 82 patients with a 1-year follow-up. Similar to earlier studies, the prevalence of AHA was higher in the elderly, with two thirds of patients aged >70 years. Around half of AHA cases were associated with underlying disease, most commonly autoimmune disease and cancer in younger and older patients respectively. Haemostatic treatment was initially administered to 46% of patients. Complete resolution or improvement of initial bleeding occurred in 22/27 (81%) rFVIIa-treated patients and in all six cases receiving pd-aPCC. The majority of patients (94%) received immunosuppressive therapy, with complete remission at 3 months in 61% (36/59) and in 98% (50/51) at 1 year. Overall mortality was 33%: secondary to bleeding in only three patients but to sepsis in 10. Bypassing agents were effective at controlling bleeding in patients with AHA. Immunosuppressive therapy should be used early but with caution, particularly in elderly patients.

The IgG autoimmune response in postpartum acquired hemophilia A targets mainly the A1a1 domain of FVIII.

BACKGROUND: Acquired hemophilia A (AHA) is a severe life-threatening autoimmune disease due to the development of autoantibodies that neutralize the procoagulant activity of factor VIII (FVIII). In rare cases, AHA occurs in the postpartum period as a serious complication of an otherwise normal pregnancy and delivery. Due to its rarity, little is known about the features of the antibody response to FVIII in AHA. OBJECTIVES: Our study wanted to (i) determine the epitope specificity and the immunoglobulin (Ig) subclasses of anti-FVIII autoantibodies in plasma samples from a large cohort of AHA patients, and (ii) compare the epitope specificity of anti-FVIII autoantibodies in plasma samples from postpartum AHA and other AHA patients. PATIENTS/METHODS: Seventy-three plasma samples from patients with postpartum AHA (n = 10) or associated with malignancies (n = 16) or autoimmune diseases (n = 11) or without underlying disease (n = 36) were analyzed with three multiplexed assays. RESULTS AND CONCLUSIONS: Our results showed a stronger response against the A1a1-A2a2-B fragments of FVIII and more specifically against the A1a1 domain in patients with postpartum AHA than in the other AHA groups (P < 0.01). Moreover, although IgG4 was the predominant IgG subclass in all groups, anti-A1a1-A2a2-B and anti-A1a1 domain autoantibodies of the IgG(1) and IgG3 subclasses were more frequently detected in postpartum AHA than in the other AHA groups. These findings support the involvement of the Th1-driven response in the generation of autoantibodies in women with postpartum AHA compared with the other groups of AHA patients in whom production of Th2-driven IgG4 was predominant.

[MYH9 syndrome and auto-immune haemolytic anaemia: an unrelated association?]. / Syndrome MYH9 et anémie hémolytique auto-immune : une association fortuite?

INTRODUCTION: The MYH9 syndrome is a group of rare autosomal dominant platelet disorders associating in most of the cases a macrothrombocytopenia and characteristic leukocyte inclusions. Clinical features may include renal, visual, or hearing impairment. The bleeding tendency is usually moderate. CASE REPORT: We report a 28-year-old-man, with an auto-immune haemolytic anaemia associated with a MYH9 syndrome. CONCLUSION: To our knowledge, this is the first report of such an association.

[Predictive value of uterine artery velocity waveforms in monitoring of pregnancies with high obstetrical risk antiphospholipid syndrome: the Rouen experience]. / Valeur prédictive du Doppler utérin et suivi des patientes avec syndrome des anti-phospholipides à haut risque obstétrical: l'expérience rouennaise.

OBJECTIVES: Anti-phospholipid syndrome (APLS) and obstetrical complications have been associated for years. The purpose of this study was to define a high obstetrical risk subpopulation of APLS and search predictive criteria of complications likely to improve monitoring of pregnancy. PATIENTS AND METHODS: We conducted a retrospective study at the CHU of Rouen between 1998 and January 2008. Pregnancies were included for patients with APLS according to the criteria of Sydney without repeated miscarriages item. RESULTS: The study involved 20 pregnancies from eight patients. Fourteen pregnancies gave birth to living children or 70 %, 28.6 % were complicated with pre-eclampsia, 50 % of haemolysis elevated liver enzymes low platelets (HELLP) syndrome associated with a 28.6 % stunting and 42 % of premature birth. Patients received treatment involving aspirin and heparin. The obstetrical prognosis was significantly poorer in the subgroup with APLS notch bilateral persistent middle of the term of birth of 35.5 versus 28 weeks of gestation, and median birth weight of 950 g versus 2780 g (p<0.05). DISCUSSION AND CONCLUSION: Patients were selected according to the more specific criteria of APLS (thrombosis and fetal loss) and a history of severe obstetrical complications. In some series, these complications play a major role; in others, they are unsignificant. Rate, in this study, is high (47 %) and the presence of bilateral notch seems to be an excellent predictive marker of vascular complications in this population.

[Protein Z, polymorphisms in the protein Z gene and thrombosis]. / Protéine Z, polymorphismes du gène de la protéine Z et thromboses.

Protein Z (PZ) is a vitamin K dependent protein acting as the cofactor of the protein Z dependent inhibitor (ZPI), in the inhibition of activated factor X bound on the phospholipids. Normal plasma protein Z concentrations have wide variations among individuals, partly explained by a genetic control. Several protein Z gene polymorphisms influence plasma concentration, separately and in combination. The role of PZ in blood coagulation regulation has been demonstrated in vitro. The responsibility of low PZ level in the occurrence of thrombosis has been questioned. However, the roles of PZ plasma level and PZ gene polymorphisms remain debated with conflicting results in arterial, venous, or placental thrombosis. These discrepancies can be explained by the heterogeneity of populations chosen as control, by the PZ interindividual variability, by the small size of the cohorts in mainly retrospective studies and perhaps by the lack of real important influence of this protein on coagulation. PZ measurement is not actually considered as a biological marker of thrombophilia. Large prospective studies remain to be done to investigate its possible role in thrombosis.

[Anticoagulation clinics for outpatients: a 5-year experience]. / Expérience d'un centre de suivi et de conseil des traitements anticoagulants oraux en médecine de ville: résultats à cinq ans.

INTRODUCTION: Anticoagulation clinics and computerized management of chronic oral anticoagulation increase the time spent in the therapeutic range with both mortality and morbidity reduction. Usually, anticoagulation clinics are hospital-based medical care centers. We report the five-year results from a general medicine center (CSCTA) using a computer-assisted management. METHODS: A prospective cohort observational study of 530 primary care patients that were receiving long term oral anticoagulation. RESULTS: Cardiac arrhythmia (55%), heart valve disease and venous thrombo-embolic disease (30%) represented the most common indications of oral anticoagulation. Patients received fluindione, warfarin and acenocoumarol in 80%, 13% and 7%, respectively. The duration of treatment was at least one year in 54% of the cases, and was at least three years in 25% of the cases. The rate of patients that were in average within the therapeutic range (INR 2-3) was 72%, while 12% were under and 16% over the therapeutic range. Corresponding rates were 82, 17 and 1% respectively for all anticoagulation targets (INR 1.5-4.5). Twenty-six bleeding events (4.9 per 100 patient-years) and four thrombotic complications (0.75 per 100 patient-years) occurred. Life-threatening hemorrhage occurred in 1.3 per 100 patient-years. After the equilibration of the anticoagulation, the average delay of control between two consecutive INR was 19 days. CONCLUSION: The results obtained with CSCTA were similar to those reported by other anticoagulation clinics regarding hemorrhagic complications and time spent in the therapeutic range. In contrast, thrombotic events were less frequent. Because of the absence of a control group, a medico-economic analysis could not be performed.

The G79A polymorphism of protein Z gene is an independent risk factor for cerebral venous thrombosis.

BACKGROUND AND PURPOSE: Protein Z (PZ), a vitamin Kdependent protein, plays a role in inhibiting coagulation. Its plasma level or PZ gene polymorphisms have been discussed as risk factors for stroke with conflicting results reported between various studies. Only one of these polymorphisms was studied in a cohort of patients suffering from cerebral venous thrombosis (CVT). METHODS: We performed a retrospective genetic study comparing 100 healthy controls to 54 patients referred to our hemostasis unit after CVT occurrence. We compared the distribution of three PZ gene polymorphisms that may influence PZ plasma levels: A-13G in the promoter and G79A in intron F were tested using previously described techniques, and we developed a technique to evaluate the G-103A in intron A. RESULTS: The G79A polymorphism was significantly more frequent in patients than in controls (p = 0.012): the presence of at least one A allele led to an odds ratio of 2.57 with a 95 % confidence interval of 1.23-5.34. The A-13G polymorphism also showed a nonsignificant trend towards a higher prevalence in patients. CONCLUSION: The G79A polymorphism of the PZ gene was shown to be a new independent risk factor for cerebral venous thrombosis. Nevertheless, these results have to be confirmed by a prospective study including plasma PZ evaluation.

Pharmacokinetics and pharmacodynamics of a new highly secured fibrinogen concentrate.

BACKGROUND: Inherited afibrinogenemia is a rare autosomal recessive disorder characterized by the absence or trace amounts of plasma fibrinogen inducing varying bleeding tendencies. Little is known about the pharmacokinetics of plasma-derived fibrinogen concentrates used in the treatment of afibrinogenemic patients. OBJECTIVE: This open, prospective, multicenter study assessed the pharmacokinetic and pharmacodynamic profiles of FIBRINOGENE T1 (FGT1; LFB, Les Ulis, France), a human fibrinogen concentrate treated with three specific biological safety steps. PATIENTS/METHODS: Five adult patients with congenital afibrinogenemia received a single infusion of 0.06 g kg(-1) of FGT1. Plasma samples drawn up to day 14 were assayed for fibrinogen antigen and activity and for coagulation parameters in a central laboratory. RESULTS: Fibrinogen antigen and activity were similar and highly correlated, with very low between-patient variability for pharmacokinetic parameters. Fibrinogen levels increased rapidly and significantly, with a mean plasma concentration of 1.39 g L(-1) being achieved 1 h after the end of the infusion, leading to almost complete in vivo recovery (94%). The mean half-life was 3.4 days, with slow linear elimination, and the distribution was mainly restricted to the vascular compartment. Coagulation parameters were normalized after the infusion and during the following 6-10 days. FGT1 was well tolerated overall. CONCLUSIONS: FGT1 behaves like natural functional fibrinogen, and its pharmacokinetic properties are in line with those expected from a fibrinogen concentrate. Our findings suggest that FGT1 can restore efficient hemostasis in afibrinogenemic patients, and predict good clinical efficacy.

Plasma D-dimer concentration in patients with systemic sclerosis.

BACKGROUND: It has been reported that increased plasma D-dimer is a reliable marker of systemic prothrombotic state in patients with cardiovascular diseases. OBJECTIVES: To evaluate plasma D-dimer concentration in patients with systemic sclerosis (SSc) and healthy controls. We also investigated a possible relationship between the presence of a high plasma D-dimer concentration and clinical and biological parameters in patients with SSc. METHODS: Measurements of plasma D-dimer concentration were performed in 69 consecutive patients with SSc and 69 age- and sex-matched controls. Clinical and biological findings were compared between patients with and without a high concentration of plasma D-dimer (i.e. >or=500 ng mL(-1)). RESULTS: Median plasma D-dimer concentrations appeared significantly increased in patients with SSc compared with control subjects (506 vs. 211 ng mL(-1); P<0.001). Furthermore, a high concentration of plasma D-dimer (>or=500 ng mL(-1)) was detected more frequently in patients with SSc than in healthy controls (47.8% vs. 4.5%; P<0.0001). Among vascular manifestations related to SSc, macrovascular impairment responsible for peripheral ischaemia was more frequent in patients with SSc with high levels of D-dimer (>or=500 ng mL(-1)), compared with those without (21% vs. 6%; P=0.05). CONCLUSIONS: The association between high levels of plasma D-dimer (>or=500 ng mL(-1)) and macrovascular involvement in patients with SSc is likely to be an innovative issue. We suggest that D-dimer levels may be a helpful additional test to identify patients with SSc at risk to develop thrombotic arterial complications (peripheral arterial disease, stroke and coronary event); such patients with high levels of plasma D-dimer (>or=500 ng mL(-1)) may require close monitoring of vascular parameters, including especially macrovascular impairment.

[Protein Z: a new regulator of coagulation in arterial vessels?]. / La protéine Z: une protéine régulatrice de la coagulation au niveau artériel?

Protein Z (PZ) is a vitamin K dependent factor identified in human plasma in 1984 whose physiological function was poorly understood. It was recently shown that protein Z is implicated in the down-regulation of coagulation by forming a complex with a plasma proteinase inhibitor called protein Z-dependent protease inhibitor (ZPI) which inhibits activated factor Xa on phospholipid surfaces. In the absence of an additional challenge, the disruption of PZ gene in mice is asymptomatic, but the association with the factor VLeiden mutation leads to a near complete mortality during the neonatal period with microvascular thrombosis. Unexpectedly, in humans, a relationship between protein Z deficiency and ischemic strokes, was firstly evidenced, but not confirmed by all the epidemiological study. Additional studies suggest that protein Z deficiency could be also a risk factor for acute coronary syndromes, early fetal losses, and increased the arterial risk in antiphospholipid syndrome. This review analyzes the different studies so far published and discusses the different results obtained in order to understand whether or not protein Z deficiency could be considered as an arterial ischemic risk factor.

Analysis of biological phenotypes from 42 patients with inherited factor VII deficiency: can biological tests predict the bleeding risk?

BACKGROUND AND OBJECTIVES: Inherited factor VII (FVII) deficiency is a rare bleeding disorder characterized by a poor relationship between reported FVII clotting activity (FVII:C) and bleeding tendency. Our study was aimed at defining biological parameters that are possibly predictive for bleeding risk in this condition. DESIGN AND METHODS: Forty-two FVII-deficient patients (FVII:C <30%) were classified into two opposite clinical groups defined as severe and non-or-mild bleeders. For each patient, plasma samples were collected and then investigated for FVII:C (using a sensitive method and human recombinant thromboplastin as the reagent), FVII antigen, activated FVII coagulant activity (FVIIa:C) and the free-form of tissue factor pathway inhibitor. RESULTS: None of these tests could be used as highly accurate predictors of bleeding. Nevertheless, both FVII:C and FVIIa:C differed significantly between the two clinical groups. Using ROC-curve analysis, two critical values of 8% and 3mIU/mL for FVII:C and FVIIa:C, respectively, could be proposed to discriminate between severe bleeders and non-or-mild bleeders. INTERPRETATION AND CONCLUSIONS: A highly accurate diagnostic test for predicting bleeding tendency in inherited FVII deficiency still eludes definition, highlighting the fact that factors other than FVII itself interfere with the expression of bleeding phenotypes in this condition. Nevertheless, potential critical values using sensitive FVII:C and FVIIa:C methods may be useful in clinical laboratories for FVII-deficient patients. Those patients with FVII:C levels higher than 8% FVII:C or FVIIa:C higher than 3 mIU/mL, with no other hemostatic defect, seem to have a minimal risk of severe bleeding. Extended clinical studies are needed to support these findings.

Thrombophilia and fetal growth restriction.

OBJECTIVE: Genetic thrombophilia may represent a new risk factor for obstetrical complications. The aim of the study was to determine which subgroups may be associated with genetic thrombophilia for small for gestational age infants (SGA). METHODS: A case-control study was performed in three different maternity wards in Normandy. Cases (n=203) were women who had pregnancies complicated by unexplained SGA infants defined as a birth weight below the 3rd centile and control subjects (n=203) were women who had infants with birth weight > or =10th centile. Patients were tested in the immediate postpartum period and 2 months later for factor V Leiden mutation, and prothrombin 20210A mutation. Frequencies of these mutations were observed in different subgroups of SGA infants depending on pregnancy or neonatal outcomes usually associated with intrauterine growth restriction (IUGR), and were then compared with the overall prevalence for these mutations detected in the control group. RESULTS: Prevalences for factor V Leiden mutation (or=2.58; 95% confidence interval: 0.83-8.04), prothrombin 20210A mutation (or=2.03; 95% confidence interval: 0.51-8.01), were comparable between cases and controls (4.9% versus 1.9% and 2.9% versus 1.4%, respectively). Frequencies for these two polymorphisms significantly increased in subgroups of SGA infants with a normal Pourcelot index (13/133 versus 7/203; P=0.04), a gestational age > or =37 weeks of gestation (15/143 versus 7/203; P=0.01), a vaginal delivery (11/117 versus 7/203; P=0.04), a birth weight > or =2000 g (12/121 versus 7/203; P=0.03), no admission to paediatric ward (11/116 versus 7/203; P=0.01), a low Ponderal index <2.5(e) centile (6/45 versus 7/203; P=0.04), and normal head circumference >10th centile (7/53 versus 7/203; P=0.01) in comparison with the control group. CONCLUSIONS: An association was found between polymorphisms for factor V Leiden and prothrombin, and asymmetrical intrauterine growth restriction with immediate favourable neonatal outcomes.