J.-C. Gris

Clinical implications of clopidogrel non-response in cardiovascular patients: a systematic review and meta-analysis

Summary.  Background: Previous studies have shown an important risk of cardiovascular events in patients with clopidogrel biological non‐response, and data have shown considerable, unexplored heterogeneity. Objectives: To evaluate the magnitude of cardiovascular risk associated with clopidogrel non‐response and to explore heterogeneity. Methods: This was a systematic review and meta‐analysis of prospective studies of patients treated with clopidogrel for symptomatic atherothrombosis, evaluated by light transmission aggregometry with ADP and monitored prospectively for clinical ischemic events. Results: Fifteen studies were included, totaling 3960 patients, of whom 25% were considered to be clopidogrel non‐responders. The global relative risk (RR) for recurrent ischemic events in clopidogrel non‐responders was 3.5 [95% confidence interval (CI) 2.4–5.2, P < 0.0001]. The results of the different studies were heterogeneous (Cochran P = 0.01 and I2 = 52%). The most recent studies yielded lower RRs [global RR = 2.9 (95% CI 2.3–3.8) after 2007, and global RR = 6.6 (95% CI 3.7–11.9) before 2007, P = 0.01]. Heterogeneity was present in the group of studies in which more than 10% of patients took glycoprotein (GP)IIb–IIIa inhibitors [Cochran P = 0.003 and I2 = 70%; RR = 3.8 (95% CI 2.9–5.1)] and was absent in the other studies [Cochran P = 0.88 and I2 = 0; RR = 2.5 (95% CI 1.7–3.6)]. The RR was significantly higher in studies using higher ADP maximal aggregation cut‐offs (> 65%) for clopidogrel non‐response than in studies using lower cut‐offs [RR = 5.8 (95% CI 3.2–10.3) and RR = 2.9 (95% CI 2.2–3.7), respectively, P = 0.03]. Conclusions: The risk of ischemic events associated with clopidogrel non‐response is now more precisely defined. The risk is heterogeneous across studies, possibly because of an interaction with GPIIb–IIIa inhibitors and the use of different cut‐offs to identify non‐responders.

More on: factor V Leiden and prothrombin G20210A polymorphisms as risk factors for miscarriage during a first intended pregnancy: the matched case-control ‘NOHA First’ study

evidence of a significant interaction when measured by adenosine 5¢-diphosphate (ADP)-induced platelet aggregation or urinary11-dehydro thromboxaneB2concentrations.Webelieve our results are consistent with previous reports of enhanced platelet sensitivity to ADP and collagen in patients with least inhibition of arachidonic acid-induced platelet aggregation during aspirin therapy [2,3]. However, we also agree with Almsherqi et al. that the mechanisms of aspirin resistance remain incompletely understood and require clarification [4].

Factor V Leiden and prothrombin G20210A polymorphisms as risk factors for miscarriage during a first intended pregnancy: the matched case-control ‘NOHA first’ study: Factor V Leiden and prothrombin mutations and fetal loss

Summary.  Factor V Leiden (FVL) and prothrombin G20210A (FIIG20210A) mutations are associated with a higher risk of miscarriage: we sought to understand whether this association differs by clinical time of unexplained miscarriage, and by ethnic origin, among women with no previous thrombotic episode, during the first intended pregnancy. We performed a case–control study nested in a cohort of 32 683 women. We analyzed 3496 pairs of women matched for classical confounding factors. The FVL and FIIG20210A mutations were associated with an increased risk of miscarriage in Caucasian women [odds ratio (OR) 3.19, 95% confidence interval (CI) 2.37–4.30, P < 0.001 and OR 2.36, 95% CI, 1.72–3.24, P < 0.001, respectively]. Among non‐Caucasian women, the mutations were rare and the associations with risk of miscarriage less clear. FVL and FIIG20210A mutations were independent risk factors for miscarriages only for women with related clinical signs occurring from the 10th week of gestation on (OR 3.46, 95% CI 2.53–4.72, P < 0.001 and OR 2.60, 95% CI 1.86–3.64, P < 0.001, respectively). These results indicate that FVL and FIIG20210A mutations are associated with a significant risk of spontaneous abortion which clinical signs occur from the 10th week on of the first intended pregnancy.

Addition of enoxaparin to aspirin for the secondary prevention of placental vascular complications in women with severe pre-eclampsia. The pilot randomised controlled NOH-PE trial.

Administration of heparin in the secondary prevention of placental vascular complications is still experimental. In women with a previous severe pre-eclampsia, we investigated the effectiveness of enoxaparin, a low-molecular-weight heparin, in preventing these complications. Between January 2000 and January 2010, 224 women from the NOHA First cohort, with previous severe pre-eclampsia but no foetal loss during their first pregnancy and negative for antiphospholipid antibodies, were randomised to either a prophylactic daily dose of enoxaparin starting from the positive pregnancy test (n=112), or no enoxaparin (n=112). The primary outcome was a composite of at least one of the following: pre-eclampsia, abruptio placentae, birthweight ≤ 5th percentile, or foetal loss after 20 weeks. Enoxaparin was associated with a lower frequency of primary outcome: 8.9% (n=10/112) vs. 25 % (28/112), p=0.004, hazard ratio = 0.32, 95% confidence interval (0.16-0.66), p=0.002. Enoxaparin was safe, with no obvious side-effect, no thrombocytopenia nor major bleeding event excess. This pilot study shows that enoxaparin given early during the second pregnancy decreases the occurrence of placental vascular complications in women with a previous severe pre-eclampsia during their first pregnancy.

Some hemostasis variables at the end of the population distributions are risk factors for severe postpartum hemorrhages

Summary.  Background: Severe postpartum hemorrhages (PPH) represent a significant cause of maternal morbidity/mortality, but little is known about its hemostasis‐related risk factors. Among the 32 463 women enrolled in the NOHA First cohort, 317 developed severe PPH (S‐PPH group), 1269 non‐severe PPH (NS‐PPH group) and the remaining individuals were considered as control women (C group). Methods: We performed a case–control study, including 317 triplets of women allocated from the three groups that shared the same clinical characteristics as the S‐PPH group. Results: From values obtained 6–9 months after delivery, low (but not‐deficient) levels of fibrinogen, von Willebrand factor (VWF) antigen, factor (F) XI, platelet CD42b, TRAP‐induced increase of platelet CD41a and high values of serum residual prothrombin activity or closure aperture times using the collagen‐ADP cartridge on the PFA‐100® system, and blood group O, were independently associated with a significant risk of severe PPH. Being positive for at least two of these eight variables was found in 1.6%, 3.5% and 20.8% of the women from the C, the NS‐PPH and the S‐PPH groups, respectively, the odds ratio for S‐PPH in such a case being 16.4, 95%CI (6.5–41), P < 0.0001. Conclusions: Women with some hemostasis‐related variables at the low or high end of the population distributions are prone to the severe forms of PPH. Clinical trials will allow us to know if acting on these risk factors can lower the clinical severity of PPH.

Observational study of pregnant women with a previous spontaneous abortion before the 10th gestation week with and without antiphospholipid antibodies.

Summary.  Background: A clinical subtype of purely obstetrical antiphospholipid antibody (aPL‐Ab) syndrome (APS) requires three or more unexplained consecutive embryonic losses before the 10th week of gestation associated with persistently positive lupus anticoagulant (LAC), and/or anticardiolipin IgG or IgM, and/or anti‐β2‐glycoprotein I (aβ2GpI) IgG or IgM. Although this diagnostic classification of APS appeared to be the most sensitive, the APS‐associated serological criteria are still debated. Patients/methods: We prospectively observed the second pregnancy of 284 women with a previous embryonic loss, both with and without aPL‐Ab. Results: aPL‐Ab‐positive women were more prone to pregnancy loss, embryonic loss, pre‐eclampsia, placental abruption and intrauterine fetal growth restriction. Type IIa aPL‐Ab positivity (LAC present alone) was associated with the highest risk of recurrent embryonic loss and intrauterine growth restriction. Type I aPL‐Ab positivity (combinations of aPL‐Ab type positivity) was associated with the strongest risks of late complications, pre‐eclampsia and placental abruption. Finally, aβ2GpI‐M positivities were not clinically relevant in these women. Conclusion: Patients with a first unexplained pregnancy loss before the 10th week of gestation who are also positive for aPL‐Abs have a higher risk of various complications in their second pregnancy. In this study, measurement of aβ2GpI‐M had a questionable prognostic value.

Thrombophilic families with inheritably associated high levels of coagulation factors VIII, IX and XI

Summary.  We describe six families in which associated high levels of coagulation factors (F) XI, FIX and FVIII (each with a plasma concentration higher than the 95th percentile found in a control group of 500 asymptomatic individuals: respectively, 135, 145 and 155 IU dL−1) were inherited as a dominant autosomic genetic traits. In these six families, this syndrome is associated with venous thromboembolic events (Odds ratio 41 [4.9–353], P = 0.0006). It seems to predispose to idiopathic events and, as age increases, is often associated with recurrence. First thrombotic episodes occur in young patients (50% of the carriers are symptomatic at the age of 32 years) and in women, can be unmasked by hormonal treatments, mainly oral contraceptives. The association of high levels of coagulation FXI, FIX and FVIII is thus a new rare high‐risk inherited thrombophilia syndrome.

Homozygosity for the C46T polymorphism of the F12 gene is a risk factor for venous thrombosis during the first pregnancy

Summary.  Background:  A first thromboembolic event during pregnancy and puerperium is predisposed to by polymorphisms G1691A in the factor V gene (F5) (F5G1691A) and G20210A in the prothrombin gene (F2) (F2G20210A).

Recombinant human FVIIa for reducing the need for invasive second-line therapies in severe refractory postpartum hemorrhage: a multicenter, randomized, open controlled trial.

Case reports on recombinant human factor VIIa (rhuFVIIa) use in women with severe postpartum hemorrhage (PPH) showed encouraging results, but no randomized controlled trial (RCT) is available.

Simple coagulation tests improve survival prediction in patients with septic shock

Summary.  Background: Classic mortality prediction models in intensive care units (ICUs) are based on clinical scores, which do not contain any coagulation test (SAPS‐II or SOFA scores). Objectives: To determine whether coagulation tests can improve mortality prediction in patients with septic shock. Patients and methods: One hundred fifty‐eight consecutive patients with septic shock entering our institution’s ICU were investigated on the first day of admission, and deaths were registered during the first month. Results: Among all the coagulation tests performed, only the fibrinogen (Fg) plasma level, together with the SAPS‐II score and the age, were included in our simplified mortality score [area under the receiver operating curve (AUC) 0.927, standard deviation (SD) 0.030], which was more efficient than SAPS‐II and SOFA scores themselves in predicting first‐week mortality, its optimized cut‐off having a very high negative predictive value (NPV) [0.989; 95% confidence interval (CI) 0.967–1.000)]. A simplified score predicting first‐month mortality, containing the prothrombin ratio and the antithrombin activity values in addition to the age, the hemoglobin concentration, and the SAPS‐II and SOFA scores (AUC 0.889, SD 0.026), was found to be superior to the SAPS‐II and SOFA scores, the optimized cut‐off value having a high NPV (0.952; 95% CI 0.888–1.000). Conclusions: In patients admitted to an ICU with septic shock, some initial coagulation test values can help identify those who will survive in the first week and then in the first month.