Géraldine Lavigne-Lissalde

Comparative incidence of pregnancy outcomes in treated obstetric antiphospholipid syndrome: the NOH-APS observational study

The incidence of pregnancy outcomes for women with the purely obstetric form of antiphospholipid syndrome (APS) treated with prophylactic low-molecular-weight heparin (LMWH) plus low-dose aspirin (LDA) has not been documented. We observed women without a history of thrombosis who had experienced 3 consecutive spontaneous abortions before the 10th week of gestation or 1 fetal loss at or beyond the 10th week. We compared the frequencies of complications during new pregnancies between treated women with APS (n = 513; LMWH + LDA) and women negative for antiphospholipid antibodies as controls (n = 791; no treatment). Among APS women, prior fetal loss was a risk factor for fetal loss, preeclampsia (PE), premature birth, and the occurrence of any placenta-mediated complication. Being positive for anticardiolipin immunoglobulin M antibodies was a risk factor for any placenta-mediated complication. Among women with a history of recurrent abortion, APS women were at a higher risk than other women of PE, placenta-mediated complications, and neonatal mortality. Among women with prior fetal loss, LMWH + LDA-treated APS women had lower pregnancy loss rates but higher PE rates than other women. Improved therapies, in particular better prophylaxis of late pregnancy complications, are urgently needed for obstetric APS and should be evaluated according to the type of pregnancy loss.

Anti-factor VIII antibodies: a 2005 update

The development of anti-factor VIII (FVIII) antibodies is currently one of the most serious complications in the treatment of haemophilia A patients. Numerous studies in literature report on their epitope specificity, their mechanism of FVIII inactivation, and their relationship with FVIII genetic alterations. During the last two years, however, a particular effort has been made to better understand their generation, with particular emphasis on the interplay of T cells and B cells specific for FVIII and the generation of anti-FVIII antibodies. Moreover, novel strategies to improve the management or treatment of patients with anti-FVIII antibodies have been recently proposed: the use of less immunogenic engineered recombinant FVIII molecules, neutralization of inhibitors by blocking their deleterious activity either by low molecular weight peptide decoys or by anti-idiotypic antibodies, and attempts to suppress the T-cell response involved in the antibody formation. All of these represent promising therapeutic approaches. This review attempts to sum up current knowledge of the nature and properties of anti-FVIII antibodies, their mechanism of action, their neutralization by anti-idiotypic antibodies, and the role of T cells in FVIII inhibitor formation. In the final part, some of the new strategies susceptible to improve the management or the eradication of anti-FVIII antibodies are presented.

Comparative incidence of pregnancy outcomes in thrombophilia-positive women from the NOH-APS observational study

The incidence of pregnancy outcomes in women with constitutive thrombophilia is uncertain. We observed women with no history of thrombotic events (nonthrombotic), who had experienced 3 consecutive spontaneous abortions before the 10th week of gestation or 1 fetal death at or beyond the 10th week of gestation. We compared the frequencies of complications during a new pregnancy attempt among women carrying the F5 rs6025 or F2 rs1799963 polymorphism (n = 279; low-molecular-weight heparin [LMWH] treatment during pregnancy only in case of prior fetal death), and women with negative thrombophilia screening results as control women (n = 796; no treatment). Among women with prior recurrent abortions, thrombophilic women were at increased risk for fetal death. Among women with prior fetal death, thrombophilic women experienced less fetal death recurrences, less preterm births and preeclampsia, and more live births as they were treated with LMWH. In nonthrombotic F5 rs6025 or F2 rs1799963 heterozygous women with prior pregnancy loss, fetal loss may indicate a clinical subgroup in which future therapeutic randomized controlled trials testing the effect of LMWH prophylaxis are required in priority.

Prevalence and epitope specificity of non-neutralising antibodies in a large cohort of haemophilia A patients without inhibitors

Antibodies (inhibitors and non-neutralising antibodies [NNA]) directed against factor VIII (FVIII) remain the main iatrogenic complication in haemophilia A (HA) patients. Inhibitors reduce FVIII pro-coagulant properties, whereas NNA are directed against non-functional epitopes. NNA are poorly studied and their prevalence, epitope specificity and physiopathology inadequately defined. The aim of this study was first to evaluate NNA prevalence in a French retrospective multicentric series of 210 patients without inhibitors, then to determine their epitope specificity (against the heavy chain [HC] or the light chain [LC] of FVIII) and particularly to assess the prevalence of anti-B domain NNA using specifically designed x-MAP assays. NNA occurred in 18.1% of patients (38/210) and their prevalence was not influenced by the severity of the disease. Among the 38 patients with NNA, 73.7% had anti-FVIII Abs against the HC, 13.2% against the LC and 13.2% had anti-FVIII Abs against both chains. There is thus a clear immuno-dominance of the HC of FVIII in the epitope profile of NNA, whatever the severity of HA. The proportion of NNA that recognised the B domain was 18.4% (n=7/38). A multivariate analysis did not highlight differences in NNA occurrence between patients treated with recombinant FVIII or with plasma- derived FVIII (19.6% vs. 14.9%, p=0.53).

Molecular characterization of human B domain-specific anti-factor VIII monoclonal antibodies generated in transgenic mice

The development of antibodies directed against factor VIII (FVIII) represents a major hurdle in the treatment of hemophilia A. Most anti-FVIII antibodies are identified through their ability to inhibit the FVIII procoagulant activity. Many of them, however, do not interfere with the functional properties of FVIII. Antibodies directed against the B domain belong to this latter category. Here, we characterized B domain-specific human monoclonal Abs (mAbs) at the molecular level. A series of human mAbs directed against FVIII was produced upon immunization of transgenic XenoMouse mice with human recombinant FVIII (rFVIII). Selection of the hybridoma with epitope specificity for the B domain was performed by differential recognition of full-length and B domain-deleted rFVIII. None of the anti-B domain mAbs demonstrated inhibitory activity against FVIII. Three of the mAbs recognized linear epitopes: mAb 25H3 bound to the (1014)HIDGPSLLIEN(1024) sequence; mAbs 8E3 and 22B6 shared the same epitope, composed of residues (1534)KWNEANR(1540). The corresponding soluble peptides inhibited the binding of their respective mAbs to FVIII. mAbs 8E3 and 22B6 displaced the binding of FVIII to vonWillebrand factor. Moreover, some of them (in particular mAbs 4G6 and 8E3) were able to compete for binding to the B domain with the anti-FVIII Abs from hemophilia A patients without inhibitor or with low Bethesda titers. Further investigation will allow to better characterize their clinical relevance.

Challenges of the management of severe hemophilia A with inhibitors: two case reports emphasizing the potential interest of a high-purity human Factor VIII/von Willebrand factor concentrate and individually tailored prophylaxis guided by thrombin-generation test.

Severe hemophilia A is an X-linked bleeding disorder. Immune tolerance induction (ITI) is the best strategy of treatment when patients develop inhibitors. The objective is to illustrate the benefit of a high-purity human factor VIII/von Willebrand factor (VWF) concentrate (Octanate) in the management of ITI. We also wanted to raise the potential interest of laboratory assays such as thrombin-generation test (TGT) and epitope mapping. Two patients were treated during ITI, first with a recombinant FVIII and then with plasma-derived factor VIII without success, and, finally, with Octanate. Bypassing agents were used based on the results of TGT. Epitope mapping was performed during ITI therapy. These observations suggest the potential contribution of Octanate in the management of ITI in difficult cases. The use of bypassing agents can be necessary in prophylaxis or to treat bleedings, and may be guided by TGT results. Epitope mapping is used to describe the inhibitor. This article shows a decrease of the inhibitor directed against the C2 domain after initiation of Octanate. A high-purity human factor VIII/von Willebrand factor concentrate (Octanate) may be a valuable therapeutical option for ITI therapy. TGT and epitope mapping could be of help in the management of ITI.

Antiphospholipid antibodies are associated with positive screening for common mental disorders in women with previous pregnancy loss. The NOHA-PSY observational study

Abstract Objectives: Case reports describe neuropsychiatric manifestations associated with antiphospholipid antibodies (aPlAbs). In patients sharing the same symptoms fulfilling the antiphospholipid syndrome (APS) clinical criteria, the prevalence of common mental disorders has, however, never been studied. Methods: We observed women with three consecutive abortions before the 10th week of gestation or one foetal loss at or beyond the 10th week. We compared the prevalence of common psychiatric disorders detected through screening using the Mini International Neuropsychiatric Interview, 10 years after inclusion, in women with APS (n = 506), women negative for aPlAbs but carrying the F5rs6025 or F2rs1799963 thrombogenic polymorphism (n = 269), and women with negative thrombophilia screening results as controls (n = 764). Results: Similar prevalence values were obtained for controls and women bearing one of the two thrombogenic polymorphisms. Women with APS more frequently had mood disorders (relative risk (RR) 1.57 (1.262–1.953), P = .0001) and anxiety (RR 1.645 (1.366–1.979), P < .0001). Within the APS group, lupus anticoagulant (LA) and anti-β2GP1 IgG, or triple positivity, were strong risk factors for mood disorders. Conclusions: Women with obstetric APS have a higher risk of positive screening for common mental disorders than women without APS.

Clinical value of automated fibrin generation markers in patients with septic shock: a SepsiCoag ancillary study

An ancillary analysis to the SepsiCoag multicentric prospective observational study on patients entering an intensive care unit with septic shock evaluated the prognostic potential of fibrin generation markers (FGMs) tested at inclusion in the study, on survival at day 30. After centralization of samples, three automated FGMs were compared: D‐dimers (DDi), fibrin/fibrinogen degradation products (FDP) and fibrin monomers (FM). FM was the single FGM that was significantly higher in non‐surviving patients, area under the receiver‐operator characteristic curve (AUCROC): 0·617, P < 0·0001. Significantly higher International Society on Thrombosis and Haemostasis Disseminated Intravascular Coagulation (ISTH DIC) scores were calculated in non‐survivors using each of the three FGMs. A dose‐effect relationship was observed between ISTH DIC scores and non‐survival, with highest significance obtained using FM as the FGM. An overt DIC diagnosis using the ISTH DIC score calculated using FM was a predictor of non‐survival at day 30, independently from overt DIC diagnosis based on scores calculated using FDP or DDi. The AUCROC values testing the ability of the ISTH DIC score to predict non‐survival were 0·650, 0·624 and 0·602 using FM, DDi and FDP, respectively, as the FGM. In patients with septic shock, among the commercially‐available automated assays, automated FM is the FGM best related with late prognosis.