Thrombocytopenia detected during pregnancy addresses the issue of its mechanism and of the possible occurrence of neonatal thrombocytopenia. To further investigate these issues, 50 women referred to ...us because of thrombocytopenia detected during pregnancy (platelet count, <150 × 109/L), were extensively studied, as well as their offspring. Among these thrombocytopenic women, we used the threshold of 70 × 109/L to differentiate between mild and severe thrombocytopenia. Whatever the severity of thrombocytopenia, we found biological features of an autoimmune disorder in 48% of the women, and chronic thrombocytopenia in 55%. A familial thrombocytopenia was evidenced in 1 case. These 50 women gave birth to 63 neonates, among whom 24 were thrombocytopenic, either at birth or during the first week of life. Neonatal thrombocytopenia could only be predicted in multiparous women, on the basis of previous neonatal thrombocytopenia in older siblings, and/or when maternal platelet life span study, performed before pregnancy, had evidenced an autoimmune thrombocytopenia (AITP)-like profile. These results suggest that, in case of pregnancy-associated thrombocytopenia, familial and immunological studies, combined with postdelivery iterative platelet counts, should be performed to properly characterize the thrombocytopenia. Moreover, the platelet count of the neonate should be carefully assessed at birth and during the following days, a platelet life span study should be performed after delivery in the mother, because these two parameters are likely to bring valuable information regarding the forthcoming pregnancies and the risk of neonatal thrombocytopenia.
Lung transplantation (LT) is accompanied by pro-inflammatory cytokine release, which correlates with the graft outcome (1–3). Extracorporeal cytokine adsorption therapy (ECAT) by Cytosorb® ...(CytoSorbents Corporation, Monmouth Junction, United States), a porous polymer beads adsorption cartridge, removes hydrophobic substances of molecular weight ≤60 kDa from the blood. ECAT is a promising therapy in hyperinflammatory situations (4–8), but has never been evaluated in LT. We evaluate for the first time ECAT on both circulating and membrane phagocyte-expressed inflammation biomarkers in the postoperative course of LT.We conducted a prospective study at Bichat-Claude Bernard Hospital (Paris, France). Consecutive patients undergoing LT and admitted to the intensive care unit (ICU) postoperatively with extracorporeal membrane oxygenation (ECMO) were assessed. Cytosorb® cartridge was integrated into a bypass of the ECMO circuit at ICU admission. ECAT was performed during 24 h with the same cartridge. Blood samples were collected before cartridge placement (T0), after 24 h of ECAT (T1), and 24 h after cartridge removal (T2). We studied the evolution of membrane activation markers of neutrophils (CD66b and CD11b) and monocytes (CD14 and HLA-DR) by flow cytometry (Becton-Dickinson, FACS Lyric), the quantification of plasma levels of IL-6 and IL-8 by Luminex assay (Procartaplex®, Thermofisher) and L-lactate (Radiometer ABL90), and coagulation factors (factors II, V, VII, X, C protein, antithrombin III, and fibrinogen. Clinical data and outcomes are expressed in median (IQR). The study was approved by the French National Ethics Committee “Comité de Protection des Personnes Sud-Est II” (2017-A02625-48).Six patients were transplanted for fibrosis (n = 4), chronic obstructive pulmonary disease (COPD) (n = 1) and silicosis (n = 1). At T2, neutrophil activation markers CD66b and CD11b expressions were significantly decreased as well as L-lactate levels (Figure 1). A downward trend was observed for monocyte activation markers (CD14 and HLA-DR), IL-6 and IL-8. No rebound effect was observed for any of these markers 24 h after cartridge removal. Coagulation markers were not altered. However, we observed one case of cartridge clotting after 12 h of treatment, without any consequences on the ECMO circuit. At T0, T1 and T2, norepinephrine doses were 0.75 (0.3–1.1), 0.25 (0.04–0.58) and 0.25 (0.03–1.15) μg/kg/min and PaO2/FiO2 ratio were 77 (74–118), 93 (88–107) and 79 (72–98) mmHg, respectively. Compared with a “control” cohort of 27 transplant patients over the same study period, the ICU length of stay and in hospital were longer for patients with ECAT, respectively of 64 (46–69) vs 41 (33–53) and 121 (82–146) vs 45 (38–63) days. However, at 1 year after LT, patients with ECAT were all alive, whereas the survival rate for patients in the “control” cohort without ECAT was 70.4%.We present the first pilot study on the feasibility and efficacy of ECAT after LT. The decrease in neutrophil and monocyte activation markers has never been reported before and suggests a possible indirect immunomodulatory effect of ECAT on phagocyte activation. The decreased plasma IL-6 and IL-8 concentrations was not significant. However, the three patients with elevated IL-6 and/or IL-8 levels at T0 experienced a dramatic decrease at T1. Cytosorb® appears to be a safe and promising device to fight post-LT inflammation, and should be re-evaluated in a larger study.
Background/Objectives
Tools for prognostication of neurologic outcome of adult patients under venoarterial ECMO (VA-ECMO) have not been thoroughly investigated. We aimed to determine whether early ...standard electroencephalography (
std
EEG) can be used for prognostication in adults under VA-ECMO.
Methods
Prospective single-center observational study conducted in two intensive care units of a university hospital, Paris, France. Early
std
EEG was performed on consecutive adult patients treated with VA-ECMO for refractory cardiogenic shock or refractory cardiac arrest. The association between
std
EEG findings and unfavorable outcome was investigated. The primary endpoint was 28-day mortality. The secondary endpoint was severe disability or death at 90 days, defined by a score of 4–6 on the modified Rankin scale.
Results
A total of 122 patients were included, of whom 35 (29%) received cardiopulmonary resuscitation before VA-ECMO cannulation. Main
std
EEG findings included low background frequency ≤ 4 Hz (
n
= 27, 22%) and background abnormalities, i.e., a discontinuous (
n
= 20, 17%) and/or an unreactive background (
n
= 12, 10%). Background abnormalities displayed better performances for prediction of unfavorable outcomes, as compared to clinical parameters at time of recording. An unreactive
std
EEG background in combination with a background frequency ≤ 4 Hz had a false positive rate of 0% for prediction of unfavorable outcome at 28 days and 90 days, with sensitivities of 8% and 6%, respectively. After adjustment for confounders, a lower background frequency was independently associated with unfavorable outcome at 28 days (adjusted odds ratio per 1-Hz increment, 95% CI 0.71, 0.52–0.97), whereas no such independent association was observed at 90 days.
Conclusion
Standard EEG abnormalities recorded at time of VA-ECMO initiation are predictive of unfavorable outcomes. However, the low sensitivity of these parameters highlights the need for a multimodal evaluation for improving management of care and prognostication.
Summary
Acquired factor V inhibitor (AFVI) is an extremely rare disorder that may cause severe bleeding. To identify factors associated with bleeding risk in AFVI patients, a national, multicentre, ...retrospective study was made including all AFVI patients followed in 21 centres in France between 1988 and 2015. All patients had an isolated factor V (FV) deficiency <50% associated with inhibitor activity. Patients with constitutional FV deficiency and other causes of acquired coagulation FV deficiencies were excluded. The primary outcome was incident bleeding and factors associated with the primary outcome were identified. Thirty‐eight (74 36–100 years, 42·1% females) patients with AFVI were analysed. Bleeding was reported in 18 (47·4%) patients at diagnosis and in three (7·9%) during follow‐up (7 0·2–48.7 months). At diagnosis, FV was <10% in 31 (81·6%) patients. Bleeding at diagnosis was associated with a prolonged prothrombin time that strongly correlated with the AFVI level measured in plasma {r = 0·63, 95% confidence interval (CI) 0·36–0·80, P < 0·05}. Bleeding onset during follow‐up was associated with a slow AFVI clearance (P < 0·001). The corresponding receiver operating characteristics curve showed that AFVI clearance was predictive of bleeding onset with an AFVI clearance of seven months with a sensitivity of 100% (95% CI: 29–100) and a specificity of 86% (95% CI: 57–98, P = 0·02). Kaplan–Meier analysis showed that AFVI clearance >7 months increased the risk of bleeding by 8 (95% CI: 0·67–97, P = 0·075). Prothrombin time at diagnosis and time for clearance of FV inhibitor during follow‐up are both associated with bleeding in patients with AFVI.
Abstract Background Calibrated Automated Thrombography (CAT) has been widely used to assess in vitro thrombin generation as an informative intermediary phenotype of coagulation. Interlaboratory ...exercises have documented a worrisome poor reproducibility. There are some data on the normalisation with an appropriate external reference plasma (RP). This multicentre study of the French-speaking CAT Club aimed at providing further evidence for the usefulness of such a normalisation. Materials and Methods Lyophilised aliquots of a RP along with 3 plasmas (P1 = normal; P2 = hypo-; P3 = hypercoagulable) were sent to 34 laboratories (corresponding to 38 instruments). CAT was studied using 1 and 5 pM tissue factor and other dedicated reagents. Normalisation with the local RP in use in the laboratory could also be performed. Interlaboratory CVs were calculated for each plasma before and after normalisation. Results Regarding endogenous thrombin potential, a good discrimination between the 3 plasmas was achieved in all laboratories but there was no overlap after normalisation only. CVs were generally not reduced with the use of local RP but were generally improved with normalisation using the external RP, often becoming lower than 10%. Regarding P2 however, the benefit of normalisation was poor, and there were analytical difficulties as well, some laboratories being unable to get a useable signal. Conclusions We confirm that normalisation of CAT results with a suitable external RP is useful in “real life” practice as it often permits an acceptable level of interlaboratory variability. In case of frank hypocoagulability, further improvements are required to get reliable, potentially clinically relevant results.
HIV patients exposed to abacavir have an increased risk of myocardial infarction, with contradictory results in the literature. The aim of our study was to determine whether abacavir has a direct ...effect on platelet activation and aggregation using platelets from healthy donors and from HIV-infected patients under therapy with an undetectable viral load.
Platelet-rich plasma (PRP) or whole blood from healthy donors was treated with abacavir (5 or 10 μg/mL) or its active metabolite carbovir diphosphate. Experiments were also performed using blood of HIV-infected patients (n = 10) with an undetectable viral load. Platelet aggregation was performed on PRP by turbidimetry and under high shear conditions at 4000 s
. Platelet procoagulant potential was analysed by measuring thrombin generation by thrombinography.
Abacavir and carbovir diphosphate significantly increased the aggregation of platelets from healthy donors induced by collagen at 2 μg/mL (P = 0.002), but not at 0.5 μg/mL. No effect of abacavir or carbovir diphosphate was observed on platelet aggregation induced by other physiological agonists or by high shear stress, or on thrombin generation. Pretreatment of blood from HIV-infected patients with abacavir produced similar results.
Our results suggest that abacavir does not significantly influence platelet activation in vitro when incubated with platelets from healthy donors or from HIV-infected patients. It is, however, not excluded that a synergistic effect with other drugs could promote platelet activation and thereby play a role in the pathogenesis of myocardial infarction.
Myeloproliferative neoplasms (MPN) are associated with an increased risk of arterial and venous thrombosis. Besides clinical factors (previous history of thrombosis, age > 60 years, cardiovascular ...risk factors), procoagulant phenotype, proadhesive properties of the endothelium and secretion of inflammatory cytokines, contribute to the pathogenesis of thrombosis in MPN. Pegylated interferon alpha (IFN) has obviously a great therapeutic efficacy on hematopoietic cell proliferation but its other biological effects particularly on hemostasis and inflammation have not been determined.
The aim of the study was to determine whether IFN impacts the biological profile including endothelial and platelet markers compared to MPN patients treated by hydroxyurea (HU) and non-treated (NT) patients.
Patients with polycythemia vera (PV) or essential thrombocythemia (ET) treated with IFN or HU or without any cytostatic drug were included. Platelet membrane glycoproteins and platelet activation were measured by flow cytometry. We evaluated shear-induced platelet aggregation (SIPA) at 4000 sec-1 that mimics stenotic arteries. We measured coagulation proteins by their activity and endothelial parameters (von Willebrand factor (VWF) antigen and activity, soluble thrombomodulin). Thrombin generation was measured in platelet poor plasma and platelet rich plasma. Platelet accumulation on immobilized collagen was measured using whole blood perfused at 1500 sec-1 in flow chambers. Statistical analysis was performed by ANOVA to compare the 3 groups of patients (p<0.05) and post-test Newman-Keuls to compare groups side-by-side (p<0.01).
Eighty-eight patients were included: 28 treated by IFN (20 PV and 8 ET), 38 treated by HU (27 PV and 11 ET) and 22 NT (6 PV and 16 ET). All patients were treated with aspirin 75 or 100 mg/day. Prior history of thrombosis occurred in 25.7% of ET and in 31.5% of PV. During the follow up (> 6months), only 1 arterial and 2 venous thrombosis were observed.
Hematological parameters and JAK2 V617F status was in the expected range in ET and PV patients.
Surprisingly, we observed some significant effect of IFN on 1) platelets with a decreased GPVI expression compared to HU- and non-treated patients and increased levels of SIPA at 4000 sec-1. 2) endothelial cells with significantly increased levels of Willebrand antigen and activity. 3) coagulation parameters with decreased protein S activity and increased levels of factor VIII:C and fibrinogen (table 1). All the other parameters tested were similar in the 3 groups of patients.
We had the opportunity to test 10 patients at least 6 months after IFN discontinuation. IFN was stopped for side effects in 6 patients, for complete molecular response in 2 and for normalization of hematological parameters in 2 others. GPVI expression, SIPA, VWF activity and antigen, protein S activity, FVIIIC and fibrinogen returned to levels similar to those of non-treated patients and were significantly different from the levels in IFN-treated patients (table 2). These results indicate that IFN was responsible for these biological modifications.
In conclusion, these unexpected data showing an increase of procoagulant and inflammatory markers in IFN-treated MPN patients could be considered as a part of IFN biological activity. Though minimal, these alterations could require more intensive preventive anticoagulation than aspirin in patients with heterozygous FV Leiden or FII G20210A mutation.
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No relevant conflicts of interest to declare.
The goal of this study was to identify differences in shear-induced platelet aggregation (SIPA) between patients who did or did not experience subacute stent thrombosis (SAT).
Despite dual ...antiplatelet therapy, SAT after coronary stenting occurs in approximately 1% of patients. There is no accepted platelet function test to identify patients at risk.
We analyzed platelet aggregation in 10 patients who had experienced SAT (cases), 22 stented patients without SAT (controls), and 17 healthy volunteers (normals). All patients except normals were treated with both aspirin and clopidogrel.
Shear-induced platelet aggregation was higher in cases than in controls at both shear rates of 200 s(-1) (40.9 +/- 12.2% vs. 18.2 +/- 18%, p = 0.013) and 4,000 s(-1) (57.4 +/- 16.4% vs. 23.4 +/- 21.2%, p = 0.009). Moreover, SIPA in cases was significantly higher than in normals both at 200 s(-1) (p = 0.013) and 4,000(-1) (p = 0.009).
Shear-induced platelet aggregation is increased in patients experiencing SAT compared with controls receiving dual antiplatelet therapy and to normals receiving no antiplatelet therapy, which suggests increased intrinsic patient-related platelet reactivity in patients with SAT. The predictive value of SIPA for SAT requires prospective investigation.
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