Abstract Objectives This study audited pregnancies where the mother received tinzaparin (at any stage before delivery), with a primary objective of determining the maternal safety of this low ...molecular weight heparin when administered as treatment and/or prophylaxis; the secondary objective was to audit fetal and neonatal safety in this cohort. Efficacy outcomes were also recorded. Study design The audit period was 1996–2009; consecutive, retrospective pregnancy records at participating hospitals were reviewed. For those records documenting tinzaparin use and pregnancy outcome, information was extracted into a standardised case report form; these were reviewed for adverse events, which were submitted for adjudication by independent experts in obstetric medicine and haematology. Endpoints were presented using descriptive statistics for all pregnancies, and by reason for tinzaparin use (treatment of venous thromboembolism VTE and prophylaxis). Results There were 28 participating hospital centres in eight countries (Belgium, Canada, Denmark, Ireland, Netherlands, Sweden, Spain and the UK). Data were collected from 1267 pregnancies (1120 women; 1303 fetuses); in 254 pregnancies the women received tinzaparin as treatment (median dose 13,000 international units IU/day, range 3500–23,100 IU/day; median duration 72 days; 94.1% once-daily), and in 1013 pregnancies the women received tinzaparin for prophylaxis (median dose 4500 IU/day, range 2500–21,811 IU/day, median duration 183 days, 94.6% once-daily). There were 871 (70.2%) vaginal deliveries (78 assisted) and 369 (29.8%) caesarean sections (27 delivery data missing). Overall, 495 (39.3%) women had neuraxial anaesthesia; however, there were no reported associated haematomas. There were no maternal deaths. Of pregnancies with available data (1060), 86.9% had blood loss ≤500 mL, 11.0% of >500 to ≤1000 mL, 0.9% >1000 to ≤1500 mL and 1.1% >1500 mL. There were 1245 (95.5%) live births, 15 (1.2%) stillbirths, 40 (3.1%) miscarriages and 3 (0.2%) terminations. Six (0.5%) neonatal deaths occurred (five at <27 weeks, one Ebstein's anomaly). No neonatal haemorrhages occurred. Adjudicated safety outcomes included 125 (9.9%) ‘any bleeding’ cases considered related to tinzaparin; 16 (1.3%) of these required medical intervention. In the treatment group, five (2%) recurrent VTEs were reported and 10 (1%) occurred in the prophylaxis group. Conclusions These data provide reassuring maternal and fetal outcome information in pregnancies exposed to tinzaparin.
Objective
To assess the role of Toll‐like receptors (TLRs) in antiphospholipid antibody (aPL)–mediated vascular abnormalities in patients with primary arterial antiphospholipid syndrome (APS).
...Methods
Forty‐eight subjects participated in the study. Arterial function and structure and TLR pathway activation were determined in patients with primary arterial APS and matched controls. The pathogenic effects of aPL isolated from patients were assessed in wild‐type (WT) and TLR‐knockout mice.
Results
APS patients had endothelial dysfunction, arterial stiffening, and hypertrophy, as evidenced by decreased brachial artery endothelium‐dependent flow‐mediated dilation (FMD) and increased aortic pulse wave velocity and carotid intima‐media thickness (IMT), as compared with controls. Plasma samples from APS patients revealed decreased nitric oxide (NO) availability and a pro‐oxidative, proinflammatory, and prothrombotic state illustrated by a decrease in nitrite and an increase in lipid peroxidation, tumor necrosis factor α levels, and tissue factor (TF) levels. Furthermore, TLR pathway activation was found in APS patients with increased TLR‐2 and TLR‐4 messenger RNA expression and increased protein levels of the activated TLR transduction protein interleukin‐1 receptor–associated kinase 1 in peripheral blood mononuclear cells. Moreover, agonist‐stimulated cell‐surface expression of TLR‐2 and TLR‐4 in circulating monocytes was higher in APS patients than in controls. These changes were positively associated with IMT and negatively associated with FMD. Finally, aPL injection decreased mesenteric endothelium‐dependent relaxation and increased TF expression in WT mice but not in TLR‐2– or TLR‐4–knockout mice.
Conclusion
This translational study supports the notion that TLR‐2 and TLR‐4 play a role in mediating vascular abnormalities in patients with primary arterial APS. TLRs thus constitute a promising pharmacologic target for preventing cardiovascular complications in APS.
Objective To assess the maternal, fetal and neonatal safety of enoxaparin in pregnant women who require antithrombotic therapy.
Design Retrospective analysis of case notes of women who received ...enoxaparin during pregnancy, irrespective of dose, duration and reason for treatment.
Setting Fifty‐five French perinatal centres.
Sample Data from 624 pregnancies in 604 women between 1988 and 1997. The incidence of previous thromboembolism was 29.8%, known thrombophilia 15.2%.
Methods Indication, regimen of enoxaparin and outcome measures were reported for each pregnancy. Information was obtained from case records, validated by research staff and analysed by an independent scientific committee.
Main outcome measures Incidence, seriousness and causality of maternal, fetal and neonatal adverse events, pregnancy outcome, and incidence of venous thromboembolism.
Results Enoxaparin was administered for treatment of an acute episode in 49 cases and for thromboprophylaxis in 574 cases. Serious maternal haemorrhage occurred in 11 cases during pregnancy (1.8%), one being reasonably related to enoxaparin, and in nine cases at delivery (1.4%), all unrelated to enoxaparin. Maternal thrombocytopenia was reported in 10 cases (1.6%), two being serious but unrelated to enoxaparin. Eight pregnancies ended in stillbirth (1.1%). Among the 693 live births, 17 major congenital abnormalities (2.5%) and 10 serious neonatal haemorrhages (1.4%) were reported. None of the fetal or neonatal adverse events was related to enoxaparin. Eight venous thromboembolic events (1.3%) were reported.
Conclusions The incidence of adverse events reported could be explained by the high risk profile of the study population. Overall, this retrospective study suggests enoxaparin is well tolerated during pregnancy.
Acquired hemophilia A (AHA) is an autoimmune disease caused by an autoantibody to factor VIII. Patients are at risk of severe and fatal hemorrhage until the inhibitor is eradicated, and guidelines ...recommend immunosuppression as soon as the diagnosis has been made. The optimal immunosuppressive regimen is unclear; therefore, data from 331 patients entered into the prospective EACH2 registry were analyzed. Steroids combined with cyclophosphamide resulted in more stable complete remission (70%), defined as inhibitor undetectable, factor VIII more than 70 IU/dL and immunosuppression stopped, than steroids alone (48%) or rituximab-based regimens (59%). Propensity score-matched analysis controlling for age, sex, factor VIII level, inhibitor titer, and underlying etiology confirmed that stable remission was more likely with steroids and cyclophosphamide than steroids alone (odds ratio = 3.25; 95% CI, 1.51-6.96; P < .003). The median time to complete remission was approximately 5 weeks for steroids with or without cyclophosphamide; rituximab-based regimens required approximately twice as long. Immunoglobulin administration did not improve outcome. Second-line therapy was successful in approximately 60% of cases that failed first-line therapy. Outcome was not affected by the choice of first-line therapy. The likelihood of achieving stable remission was not affected by underlying etiology but was influenced by the presenting inhibitor titer and FVIII level.
To establish a new and reliable assay for quantification of the soluble fibrin (SF) in combination with that of D-dimer for early diagnosis of venous thromboembolism.
The SF assay is based on D-dimer ...generated after incubation of plasma with tissue-type plasminogen activator (t-PA). SF and standard D-dimer assays, run in blind, were used to test 119 untreated outpatients with clinically suspected deep-vein thrombosis (DVT, 49 patients) or pulmonary embolism (PE, 70 patients) consulting at the emergency unit of the hospital. Thromboses were confirmed by current imaging methods such as ultrasonography, scintigraphy, computed tomographic pulmonary angiography (CTPA) and ventilation/perfusion scan.
SF assay was validated in 270 healthy volunteers 51.8% males; mean age years ± SD: 41±13; age range 19 to 65. Among these normal plasmas, SF levels were ≤200 ng/mL in 97.8% of them, and 200-250 ng/mL in the remainder 26-46 years old; 50% males. ROC curves were used to determine the SF cut-off value for plasma SF positivity, which was found to be 300 ng/mL. In patients with suspected venous thromboembolism, SF sensitivities for DVT and PE (92% and 94%, respectively) were comparable to those of D-dimer (96% and 94%), whereas SF specificities (86% and 95%) were higher than those of D-dimer (50% and 54%). Positive-predictive values for SF (89% and 94%) were again higher than those of D-dimer (70% and 65%) in DVT and PE. The amount of circulating SF normalized rapidly after anticoagulant therapy.
Results from this small group of patients suggest that the evaluation of plasma SF, in combination with that of D-dimer, represents a potentially useful tool for the early diagnosis of venous thromboembolism, provided that the patients have not been treated previously by anticoagulants.
Perioperative management of patients treated with the non-vitamin K antagonist oral anticoagulants is an ongoing challenge. Due to the lack of good clinical studies involving adequate monitoring and ...reversal therapies, management requires knowledge and understanding of pharmacokinetics, renal function, drug interactions, and evaluation of the surgical bleeding risk. Consideration of the benefit of reversal of anticoagulation is important and, for some low risk bleeding procedures, it may be in the patient's interest to continue anticoagulation. In case of major intra-operative bleeding in patients likely to have therapeutic or supra-therapeutic levels of anticoagulation, specific reversal agents/antidotes would be of value but are currently lacking. As a consequence, a multimodal approach should be taken which includes the administration of 25 to 50 U/kg 4-factor prothrombin complex concentrates or 30 to 50 U/kg activated prothrombin complex concentrate (FEIBA®) in some life-threatening situations. Finally, further studies are needed to clarify the ideal therapeutic intervention.
The efficacy and safety of recombinant activated factor VII (rFVIIa; NovoSeven®) in patients with acquired haemophilia A (AHA) are established; however, data on daily use in clinical practice for ...bleeding episodes are limited. The ACQUI-7 study aimed to provide additional data on managing bleeding episodes with rFVIIa in patients with AHA.
ACQUI-7, a prospective, observational, multicentre study in 20 sites in France, recruited patients from 2010 to 2013. Treatment was by physician’s judgement and therapeutic practice at each site. Inclusion criteria: anti-factor VIII (FVIII) auto-antibodies > 1 Bethesda Unit, FVIII activity < 50% and bleeding episodes treated with rFVIIa. Data collected included description of patient characteristics, bleeding episodes leading to haemostatic treatment and rFVIIa therapy.
A total of 27 patients with 27 bleeding episodes (24 88.9% severe) were treated with first-line rFVIIa. Most (81.5%) were affected in more than 1 site (44.4% in muscle). Nineteen patients (70.4%) were treated for up to 5 days; 24 (88.9%) had their bleeding episode controlled (including 21 severe bleeds). The maximum daily dose for controlling severe bleeds decreased from 900 μg/kg/24 h on day 1–630 μg/kg/24 h on day 5, with a corresponding reduction in maximum number of daily injections from 10 to 7. The use of rFVIIa in this population did not raise any safety concerns.
These real-world data confirm the effectiveness and safety of rFVIIa and provide additional information on the daily use of rFVIIa to support the management of patients with AHA.
•Real-world evidence on usage of rFVIIa for bleeds in patients with AHA is lacking.•ACQUI-7 study was designed to describe rFVIIa usage for bleeds management in France.•Few rFVIIa doses were required to control and maintain haemostasis of severe bleeds.•The use of rFVIIa in patients with AHA did not raise any safety concerns.•These real-world data confirm effectiveness/safety of rFVIIa in patients with AHA.
Abstract Introduction The value and challenges of long-term prophylaxis (LTP) in adolescents and young adults need further characterisation. Aim To determine the proportions of adolescents and young ...adults with severe or moderately severe haemophilia in France under LTP and treatment on demand (OD). Methods Patients 15 to 25 years old with haemophilia A or B, factor VIII/IX ≤ 2% and no current inhibitor could be included if they had been under factor VIII/IX treatment at least 12 months and kept a treatment and bleeding diary. Results LTP was administered to 169/212 patients (79.7%) and OD treatment to 40/212 patients (18.9%). The most frequent reasons for initiating LTP were joint bleeding, target joints and frequent bleeds; whereas OD treatment was most often selected on the basis of mild bleeding phenotype or because of constraints on LTP. The mean annual bleed rate (ABR) in the OD group (6.33) was higher than in the LTP group (3.07, p < 0.001). Mean ABR did not differ significantly between age strata (15
–
18, > 18
–
21 and > 21
–
25 years), but was significantly higher for patients with severe haemophilia (4.02) as compared to those with moderate haemophilia (1.97, p = 0.002). No significant difference was observed in mean ABR for joint bleeds between the LTP and OD groups. Physician reported LTP compliance was good or excellent in 97.0% of patients. Conclusion LTP is the predominant factor VIII/IX treatment among adolescents and young adults with severe or moderately severe haemophilia in France. LTP was associated with low ABR and high compliance.
To evaluate the applicability and compliance with guidelines for early initiation of long-term prophylaxis in infants with severe hemophilia A and to identify factors associated with guideline ...compliance.
This real-world, prospective, multicenter, population-based FranceCoag study included almost all French boys with severe hemophilia A, born between 2000 and 2009 (ie, after guideline implementation).
We included 333 boys in the study cohort. The cumulative incidence of long-term prophylaxis use was 61.2% at 3 years of age vs 9.5% in a historical cohort of 39 boys born in 1996 (ie, before guideline implementation). The guidelines were not applicable in 23.1% of patients due to an early intracranial bleeding or inhibitor development. Long-term prophylaxis was delayed in 10.8% of patients. In the multivariate analysis, 2 variables were significantly associated with “timely long-term prophylaxis” as compared with “delayed long-term prophylaxis”: hemophilia treating center location in the southern regions of France (OR 23.6, 95% CI 1.9-286.7, P = .013 vs Paris area) and older age at long-term prophylaxis indication (OR 7.2 for each additional year, 95% CI 1.2-43.2, P = .031). Long-term prophylaxis anticipation was observed in 39.0% of patients. Earlier birth year (OR 0.5, 95% CI 0.3-0.8, P = .010 for birth years 2005-2009 vs 2000-2004) and age at first factor replacement (OR 1.9 for each additional year, 95% CI 1.2-3.0, P = .005) were significantly associated with “long-term prophylaxis guideline compliance” vs “long-term prophylaxis anticipation.”
This study suggests that long-term prophylaxis guidelines are associated with increased long-term prophylaxis use. However, early initiation of long-term prophylaxis remains a challenge.
The aims of this case-control study were to identify in vitamin K antagonist (VKA)-treated unselected patients, factors associated with international normalised ratio (INR) values: (i) greater than ...6.0.; and (ii) ranging from 4.0 to 6.0 complicated with bleeding. We also assessed VKA-related morbidity in these patients. During a two-month period, 4,188 consecutive and unselected patients were referred to our Emergency Department. At admission, the medical records of each patient and two age- and sex-matched controls were reviewed for: both duration and indication of VKA therapy, previous medical history of VKA-related haemorrhage, underlying co-morbidities, concomitant medications other than VKA, duration of hospitalization and deaths' causes. Of these 4,188 subjects, 50 case-patients (1.19%) were identified; both case-patients and controls did not differ as regards indications and patterns of VKA therapy. Interestingly, two-thirds of case-patients were women, suggesting that female gender may be a risk factor of VKA over-coagulation onset. We identified the following risk factors of VKA over-coagulation: previous medical history of INR levels over therapeutic range, therapy with antibiotics, amiodarone and proton pump inhibitors, as well as fever. A total of 88% of case-patients were hospitalized; mean duration of patients' hospitalization was seven days range: 1-56 days; no patient died from major bleeding. Our study underscores that it is of utmost importance to consider the strength of indication before starting VKA therapy, as this therapy has been responsible for as high as 1.19% of admissions in unselected subjects referred to an Emergency Department. Our data therefore suggest that internists should be aware of VKA-related high morbidity, particularly in situations at risk of VKA over-coagulation.
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