Françoise Boehlen

The association between circulating antibodies against domain I of beta2-glycoprotein I and thrombosis: an international multicenter study

Summary.  Background: Diagnosis of the antiphospholipid syndrome (APS) is difficult as a result of limited specificity of existing assays for detecting clinically relevant antiphospholipid antibodies. Anti‐beta2‐glycoprotein I (beta2GPI) antibodies play a central role in the disease process of APS. Objectives: We have investigated the relation between antiphospholipid antibodies with specificity for domain I of beta2GPI and thrombosis/pregnancy morbidity in an international multicenter study. Patients/methods: Four hundred and seventy‐seven patients derived from nine different centres met the inclusion criterion of having anti‐beta2GPI antibodies in their plasma/serum. Clinical data and results of tests for lupus anticoagulant, anti‐cardiolipin antibodies and anti‐beta2GPI antibodies were established at the different centres of inclusion. After being re‐tested for the presence of IgG and/or IgM anti‐beta2GPI antibodies, the samples were tested for the presence of IgG‐directed against domain I of beta2GPI and results were correlated with the thrombotic and obstetric history. Results: Re‐testing for the presence of anti‐beta2GPI antibodies resulted in inclusion of 442/477 patients. IgG class anti‐domain I antibodies were present in plasma of 243/442 patients (55%). 201/243 (83%) had a history of thrombosis. This resulted in an odds ratio of 3.5 (2.3–5.4, 95% confidence interval) for thrombosis. Anti‐domain I IgG antibodies were also significantly correlated with obstetric complications [odds ratio: 2.4 (1.4–4.3, 95% confidence interval)]. Conclusion: In this multicenter study, the detection of IgG antibodies that are directed against domain I of beta2GPI proved to be more strongly associated with thrombosis and obstetric complications than those detected using the standard anti‐beta2GPI antibody assay.

TAFI antigen and D-dimer levels during normal pregnancy and at delivery

We have investigated whether the levels of thrombin‐activatable fibrinolysis inhibitor (TAFI) were correlated with d‐dimer levels during pregnancy and at delivery. From the 10th week of pregnancy to delivery, 519 samples from 144 women (mean age 29·3 ± 5, range 19–43) were obtained. We confirm the gradual increase of d‐dimer levels, and provide reference intervals for d‐dimer measurements throughout normal pregnancy. TAFI levels increased moderately during pregnancy but no inverse correlation with d‐dimer levels was observed.

Platelet count at term pregnancy: a reappraisal of the threshold ☆

Objective To assess the safety of a new platelet count threshold for the definition of maternal thrombocytopenia late in pregnancy. Methods A platelet count was performed in 6770 pregnant women late in pregnancy and in 6103 of their newborns as well as in a control group of 287 age-matched nonpregnant healthy women. Results The prevalence of maternal thrombocytopenia (platelet count less than 150 × 109/L) was 11.6%. The mean platelet counts (248 compared with 213 × 109/L) and 2.5th percentile (164 compared with 116 × 109/L) were significantly higher in healthy nonpregnant women than in pregnant women. Among thrombocytopenic pregnant women, 621 (79%) had platelet counts between 116 and 149 × 109/L; none (0%; 95% confidence interval 0, 0.6) had complications related to thrombocytopenia, and none of their newborns had severe thrombocytopenia (platelet count less than 20 × 109/L). Conclusion In healthy pregnant women, a platelet count over 115 × 109/L late in pregnancy does not require further investigation during pregnancy and may be considered a safe threshold.

Fibrinogen and the Risk of Thrombosis

Fibrinogen contributes to thrombosis risk in different ways. Indeed, various mutations in the fibrinogen genes predispose to thrombosis. At the same time, high levels of fibrinogen are also associated with thrombotic complications. Although the underlying causative mechanisms are not clear, this most likely involves the associated inflammatory and hypercoagulable states. In the last few years, particular attention has focused on the polymorphisms of fibrinogen genes involved in increased fibrinogen levels or fibrinogen qualitative changes. The association between dysfibrinogenemia and risk of thrombosis is well known, and some mechanisms have been clearly identified. Paradoxically, some patients with either hypofibrinogenemia or afibrinogenemia may also suffer from severe thromboembolic complications. The management of these patients is particularly challenging because they are not only at risk of thrombosis but also of bleeding. This review discusses the various quantitative and qualitative defects of fibrinogen associated with thrombosis, the tests that may predict the thrombotic risk, as well as some preventive or therapeutic approaches.

Toll-like receptor 2 mediates the activation of human monocytes and endothelial cells by antiphospholipid antibodies

The presence of antiphospholipid antibodies (aPLAs) is associated with arterial or venous thrombosis and/or recurrent fetal loss. The proposed pathogenic mechanisms for aPLA effects include the inflammatory activation of monocytes and endothelial cells. Toll-like receptors (TLRs) are candidate signaling intermediates. The aim of this study was to investigate the relative contribution of TLR2 and TLR4 in cell activation by aPLAs. Of 32 patient-derived aPLAs, 19 induced an inflammatory activation of human monocytes and umbilical vein endothelial cells (HUVECs). In HUVECs, inflammatory responses to these aPLAs were increased by TNF pretreatment, which increases the expression of TLR2 but not TLR4. Anti-TLR2 but not anti-TLR4 antibodies reduced the aPLA-induced activation of monocytes and HUVECs. aPLAs activated TLR2-expressing human embryonic kidney 293 (HEK293) cells but not TLR4-expressing cells. Binding studies demonstrated an interaction between aPLAs and TLR2 but not TLR4. A role for CD14, a coreceptor for TLR2 and TLR4, can be inferred by observations that anti-CD14 antibodies reduced responses to aPLAs in monocytes, and that responses in HEK293 cells expressing TLR2 and CD14 were greater than in HEK293 cells expressing TLR2 alone. Our results demonstrate a role for TLR2 and CD14 in human endothelial cell and monocyte activation by aPLAs.

Eculizumab in acute recurrence of thrombotic microangiopathy after renal transplantation

Renal thrombotic microangiopathy (TMA) is a severe complication of systemic lupus erythematosus (SLE), which is associated with the presence of antiphospholipid (aPL) antibodies. In its most fulminant form, TMA leads to a rapid and irreversible end‐stage renal failure. Eculizumab, an anti‐C5 monoclonal antibody, is a novel therapy of choice for patients with paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome. Here, we report the case of a 27‐year‐old woman, known for SLE and end‐stage renal disease due to fulminant TMA. Both aPL antibodies and antinucleosome antibodies were positive. The patient underwent a living‐related kidney transplantation with immediate production of urine. Although serum creatinine was remaining high, a graft biopsy, performed on day 6, demonstrated a TMA recurrence. Despite a treatment with plasma exchange, the situation got worse and dialysis was started. Eculizumab treatment was subsequently administered and renal function improved rapidly. Three months after transplantation, serum creatinine was at 100 μmol/L, without proteinuria. This case illustrates the benefit of eculizumab therapy in a fulminant recurrence of TMA after kidney transplantation, resistant to classical therapy.

D‐dimer levels during delivery and the postpartum

Summary.  Background: D‐dimer (DD) measurement has proved to be very useful to exclude venous thromboembolism (VTE) in outpatients. However, during pregnancy, the progressive increase as well as the interindividual variations of DD means that in this instance they are of poor value to rule out VTE. Only a few studies have reported measurements of DD levels in the postpartum. Objectives: To measure DD sequentially in the puerperium in order to determine when DD levels return to values obtained in non‐pregnant women and can again be used in the exclusion of VTE. Patients and methods: After uncomplicated pregnancies, 150 women delivering at term either vaginally (n = 100) or by cesarean section (n = 50) were included. DD levels were measured immediately following delivery and next at days 1, 3, 10, 30 and 45. Results: There was a marked elevation of DD at delivery, especially when instrumental. All DD measurements were above 500 ng mL−1 at delivery, at day 1 and at day 3 postpartum. A sharp decrease in DD was observed between day 1 and day 3, followed by a slight increase at day 10. At day 30 and day 45, respectively, 79% and 93% of women in the vaginal delivery group and 70% and 83% in the cesarean group had levels below 500 ng mL−1. Bleeding, breastfeeding and heparin prophylaxis did not modify DD levels significantly. Conclusion: Using the Vidas DD new assay, our study provides reference intervals for DD in the postpartum period. Using a cut‐off at 500 ng mL−1, DD measurement for ruling out VTE was found to be useful again 4 weeks after delivery.

ANKRD26 -related thrombocytopenia and myeloid malignancies

To the editor: Since the discovery that mutations in the 5′ untranslated region (UTR) of ANKRD26 are responsible for an autosomal-dominant form of thrombocytopenia ( ANKRD26 -RT),[1][1] 21 affected families were reported.[2][2] A study analyzing this series of patients suggested that ANKRD26 -RT

Anti-protein S antibodies following a varicella infection: detection, characterization and influence on thrombin generation

Summary.  Postinfectious purpura fulminans is a rare disease. Varicella is one of the precipitating conditions and we recently observed such a case. The 4‐year‐old child was found to have a severe transient protein S deficiency. By enzyme‐linked immunosorbent assay and surface plasmon resonance we first demonstrated that anti‐protein S antibodies were present and also transient. Next we characterized the epitopes against which these antibodies were directed and found that they predominantly recognized the N‐terminal part of protein S. Finally we showed by thrombography a transient dramatic hypercoagulable state as a result of thrombin being unregulated by the dynamic protein C inhibitory system: in vitro thrombin generation, in response to a low concentration of tissue factor, was almost insensitive to activated protein C up to 25 nmol L−1 on day 4 while it was normally sensitive on day 42. For the first time, we demonstrated a temporal relationship between protein S deficiency, antibodies to protein S and hypercoagulability, thus supporting the pathogenic role of these antibodies.

Not all statins interfere with clopidogrel during antiplatelet therapy

Background Clopidogrel and statins are frequently coadministered in patients with ischemic heart diseases. Recent reports suggested that clopidogrels effectiveness in inhibiting adenosine diphosphate (ADP)‐induced platelets aggregation is attenuated by co‐administration of certain statins. The objective of the present study was to define which statin might interfere with the antiaggregation property of clopidogrel.