Publications by authors named "Philippe Bierling"

85 Publications

Methylprednisolone-induced immune thrombocytopenia.

Am J Hematol 2020 01 31;95(1):E13-E16. Epub 2019 Oct 31.

Etablissement Français du Sang, Service d'Immunologie plaquettaire, Hôpital Henri Mondor, Créteil, France.

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http://dx.doi.org/10.1002/ajh.25645DOI Listing
January 2020

Transfusion-Transmitted Hepatitis E Virus Infection in France.

Transfus Med Rev 2019 07 20;33(3):146-153. Epub 2019 Jun 20.

Etablissement Français du Sang, La Plaine St Denis, France; UMR 1098 Inserm, Etablissement Français du Sang, Université de Franche-Comté, Besançon, France. Electronic address:

There is growing concern regarding the risk of transfusion- transmitted (TT) hepatitis E. Since the first described case in 2006, several TT hepatitis E have been reported to the French hemovigilance network. We performed a retrospective analysis of all cases of TT hepatitis E reported between 2006 and 2016. Transfusion-transmitted hepatitis E with high imputability according to phylogenetic analysis occurred in 23 patients aged 8 to 88 years and involved mostly solid organ recipients (n = 9) or patients with malignant hematological diseases (n = 9, including 4 hematopoietic allograft recipients). Involved blood products were plasma (n = 7), among which 6 had undergone pathogen reduction with solvent/detergent (n = 4) or amotosalen + ultra-violet A (UVA) (n = 2 from 1 donation) treatments, red blood concentrates (n = 7), apheresis platelets concentrates (n = 3) and whole blood pooled platelets concentrates (n = 6), among which one had underwent amotosalen + UVA treatment. Median hepatitis E virus (HEV) RNA dose infused was 5.79 [4.36-10.10] log IU. HEV infection progressed to chronic hepatitis E in 14 (61%) immunocompromised patients, 2 of whom had advanced liver fibrosis at diagnosis. Chronic hepatitis E patients cleared HEV with ribavirin treatment (n = 10), after immunosuppressive drug reduction (n = 3), or spontaneously (n = 1). One additional organ transplant recipient with associated co-morbidities died with ongoing HEV infection and multiple organ failure. The other 8 (34.8%) patients with TT hepatitis E cleared HEV within 6 months with ribavirin treatment (n = 3), reduced immunosuppression (n = 1) or spontaneously (n = 4). Red cells, platelets, and plasma transfusions may be associated with TT hepatitis E that can evolve to chronic hepatitis E in immunocompromised patients. Hepatitis E virus has emerged in France as a clinically significant TT infection risk.
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http://dx.doi.org/10.1016/j.tmrv.2019.06.001DOI Listing
July 2019

A new platelet alloantigen (Efs , HPA-35bw) on glycoprotein IIIa leading to neonatal alloimmune thrombocytopenia.

Transfusion 2019 07 3;59(7):2463-2464. Epub 2019 Apr 3.

HLA-HPA Laboratory/Université Paris Est Créteil/ Inserm U955, EFS BloodCenter of Ile de France, Créteil, France.

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http://dx.doi.org/10.1111/trf.15283DOI Listing
July 2019

A novel in vivo porcine model of intervertebral disc degeneration induced by cryoinjury.

Int Orthop 2018 09 10;42(9):2263-2272. Epub 2018 May 10.

Université Paris-Est-Créteil (UPEC), Laboratoire de bio-ingénierie cellulaire, tissulaire et sanguine à visée thérapeutique (BCTSVT), INSERM/IMRB-U955, équipe n°10, groupe 5, Créteil, France.

Purpose: Degenerative disc disease involves sequential events that lead to the loss of cells, a decrease in disc matrix production, disc dehydration, and alteration of its biomechanical properties. The aim of this study was to determine whether cryoinjury of the nucleus pulposus performed through endplate perforation contributes to disc degeneration and to compare this technique with standard methods.

Method: Under general anesthesia, the lumbar discs of six pigs were exposed and randomly submitted to needle puncture of the annulus fibrosus (NeP), isolated endplate injury (EP), or cryoinjury using a 2.5-J Thompson cryoprobe applied through a single endplate perforation (EP+cryo). The remaining discs served as controls. Animals were sacrificed at two months and the harvested lumbar spines were submitted to CT scan and MRI investigations. Histologic analysis was performed to assess the degree of disc degeneration.

Results: CT scan showed that decrease in average disc height was more important after cryoinjury (49.3%) than after endplate perforation (16.9%) (P < 0.0001) or needle puncture (19.4%) (P < 0.0001). On MRI, the dehydration ratio was significantly more important after EP+cryo (60%) than after NP (40%) or EP (30%) (P < 0.0001). After cryoinjury, the histologic score developed for this study was significantly higher than after needle puncture or endplate perforation (P < 0.0001).

Conclusions: Imaging and histological analysis showed that disc cryoinjury applied through endplate perforation was superior to the classical NeP and EP models to induce experimental disc degeneration. This model appears suitable for testing safety and efficacy of novel treatments of intervertebral disc degeneration.
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http://dx.doi.org/10.1007/s00264-018-3971-2DOI Listing
September 2018

High immunogenicity of red blood cell antigens restricted to the population of African descent in a cohort of sickle cell disease patients.

Transfusion 2018 06 29;58(6):1527-1535. Epub 2018 Apr 29.

Etablissement Français du Sang (EFS)-Ile de France, Créteil.

Background: Sickle cell disease (SCD) patients undergo multiple red blood cell (RBC) transfusions and are regularly exposed to low-prevalence (LP) antigens specific to individuals of African descent. This study evaluated the prevalence of antibodies against LP antigens in SCD patients and the need to identify these antibodies in everyday practice.

Study Design And Methods: Plasma from 211 SCD patients was tested with RBCs expressing the following LP antigens: RH10 (V), RH20 (VS), RH23 (D ), RH30 (Go ), KEL6 (Js ), and MNS6 (He).

Results: Nine LP antibodies were found in eight patients (3.8%): five anti-RH23, two anti-RH30, and two anti-MNS6. The exposure risk, calculated for each LP antigen, was below 3% per RBC unit, for all antigens tested. Thus, in this cohort of transfused SCD patients, the prevalence of LP antibodies was similar to that of antibodies against antigens of the FY, JK, and MNS blood group systems. These findings also reveal the occurrence of anti-RH23 in SCD patients. No anti-RH20 or anti-KEL6 were found, despite the high frequency of mismatch situations.

Conclusion: These results highlight the immunogenicity of these LP antigens, and the evanescence of antibodies against LP antigens. They also highlight the importance of appropriate pretransfusion testing for patients frequently transfused, who are likely to be exposed to multiple types of blood group antigens.
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http://dx.doi.org/10.1111/trf.14633DOI Listing
June 2018

Systematic detection of portal or splenic vein thrombosis after splenectomy for immune cytopenia.

Am J Hematol 2018 07;93(7):E170-E172

Service de Médecine Interne, Centre de référence des cytopénies auto-immunes de l'adulte, Hôpital Henri Mondor, Assistance Publique-Hôpitaux de Paris, Université Paris Est Créteil, Créteil, France.

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http://dx.doi.org/10.1002/ajh.25120DOI Listing
July 2018

Anti-CD20 Antibody Prevents Red Blood Cell Alloimmunization in a Mouse Model.

J Immunol 2017 12 20;199(11):3771-3780. Epub 2017 Oct 20.

Etablissement Français du Sang, 94000 Créteil, France;

Alloimmunization against RBCs can cause life-threatening delayed hemolytic transfusion reactions. Anti-CD20 Ab has recently been used to prevent alloimmunization. However, its effects remain unclear, particularly in lymphoid organs. We investigated the impact of murine anti-CD20 Ab in the blood and spleen. We assessed protocols for preventing primary alloimmunization and for abolishing established alloimmunization. Prophylactic protocols prevented alloimmunization. However, anti-CD20 treatment could only limit the further amplification of established alloimmunization. Residual B cell subtype distribution was disrupted in the spleen, but adoptive transfer studies indicated that these cells were neither plasma nor memory cells. Anti-CD20 Ab had a major effect on alloreactive CD4 T cells, increasing the expansion of this population and its CD40 expression, while lowering its CD134 expression, thereby confirming its role in alloimmunization. In conclusion, this study shows that anti-CD20 immunotherapy can prevent RBC Ab development. However, this immunotherapy is limited by the increase in alloreactive CD4 T lymphocytes. Nevertheless, treatment with anti-CD20 Abs should be considered for patients requiring transfusion with a very high risk of alloimmunization and life-threatening complications.
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http://dx.doi.org/10.4049/jimmunol.1700754DOI Listing
December 2017

Clinical severity in adult warm autoimmune hemolytic anemia and its relationship to antibody specificity.

Haematologica 2018 01 12;103(1):e35-e38. Epub 2017 Oct 12.

Etablissement Français du Sang, Île-de-France, Hôpital Henri-Mondor, Créteil; INSERM U955 équipe 2: Transfusion et Maladies du Globule Rouge; IMRB (Institut Mondor de Recherche Biomédicale), Créteil; laboratoire d'Excellence GR-Ex, F75739 Paris, France.

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http://dx.doi.org/10.3324/haematol.2017.175976DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5777213PMC
January 2018

Severe hemolysis after plasma transfusion in a neonate with necrotizing enterocolitis, Clostridium perfringens infection, and red blood cell T-polyagglutination.

Transfusion 2017 11 22;57(11):2571-2577. Epub 2017 Jun 22.

Etablissement Français du Sang (EFS) Ile-de-France, Paris.

Background: Red blood cell (RBC) Thomsen-Friedenreich antigen exposure (T activation) in infants with necrotizing enterocolitis (NEC) has occasionally been associated with posttransfusional intravascular hemolysis thought to be due to anti-T antibodies in the donor plasma.

Study Design And Methods: We describe an infant with NEC and Clostridium perfringens infection complicated by severe hemolysis after plasma transfusion. After this case, infants with confirmed NEC were prospectively evaluated for T activation. We checked for hemolysis in patients with T activation receiving plasma-containing blood products.

Results: The infant had received 80 mL of fresh-frozen plasma (FFP). His RBCs displayed strong T activation, and agglutination was observed with four of six ABO-compatible FFP units. A direct antiglobulin test was negative. IgM-class anti-T antibodies were present in small amounts (titer of 8) in the transfused FFP. Anti-T antibodies from the blood donor were not hemolytic in vitro. In the prospective study, T activation was observed in three of 28 infants with NEC (11%). One infant presented moderate T activation and two infants presented very strong T activation but only moderate decreases in sialic acid expression on the RBC membrane. These three infants presented no signs of hemolysis after transfusion with unwashed blood products or FFP.

Conclusion: Anti-T antibodies are unlikely to be the etiologic factor for the hemolytic reactions observed in infants with NEC and T activation. Massive RBC desialylation and the direct action of bacterial toxins are more probable causes. Strict avoidance of plasma-containing blood products does not seem justified in these infants.
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http://dx.doi.org/10.1111/trf.14196DOI Listing
November 2017

Red blood cells for transfusion in patients with sepsis: respective roles of unit age and exposure to recipient plasma.

Transfusion 2017 08 31;57(8):1898-1904. Epub 2017 May 31.

Etablissement Français du Sang Ile-de-France, site Henri-Mondor.

Background: Red blood cell (RBC) storage in blood banks is not exempt from cellular injury. Alterations not observed on RBCs freshly isolated from units can rapidly appear in circulation. The transfusion of old blood units, even if this is a controversial issue, could therefore have adverse effects on the recipient. We wanted to determine the respective effects of storage duration and recipient plasma on RBCs for transfusion into patients with severe sepsis.

Study Design And Methods: Eleven stored RBC units were sampled at various time points, approximately Days 3 to 8 (referred to as fresh RBCs) and Days 38 to 42 (old RBCs) and tested in coincubation experiments with plasma obtained from 13 patients with severe sepsis and 17 healthy donors as controls. RBCs were tested after 24 or 48 hours at 37°C for the detection of senescence markers (phosphatidylserine exposure, calcium influx, and reactive oxygen species detection and decrease in size) with or without exposure to plasma.

Results: We confirmed that a 42-day refrigerated storage of RBCs alone (without any incubation in plasma) had no significant effect on RBCs and no senescence marker detected. By contrast, ex vivo exposure to plasma samples altered both fresh and old RBCs, with a much larger effect for old RBCs, regardless of the plasma used (sepsis vs. control).

Conclusion: We show that the main factor affecting the senescence of RBCs for transfusion into patients with severe sepsis is the age of the stored units rather than the clinical status of the recipient.
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http://dx.doi.org/10.1111/trf.14170DOI Listing
August 2017

Long-term complications of splenectomy in adult immune thrombocytopenia.

Medicine (Baltimore) 2016 Nov;95(48):e5098

Centre de Référence des Cytopénies Auto-immunes de l'adulte, Hôpital Henri Mondor, Assistance Publique-Hôpitaux de Paris, Université Paris Est Créteil, Créteil, France Département de Santé Publique, Assistance Publique-Hôpitaux de Paris, Université Paris Est Créteil, Créteil, France.

The recent large decrease in splenectomy use for chronic immune thrombocytopenia (ITP) is partly due to still-unsolved questions about long-term safety. We performed the first single-center exposed/unexposed cohort study evaluating the long-term incidence of splenectomy complications in patients with primary ITP. Overall, 83 patients who underwent splenectomy more than 10 years ago (exposed) were matched with 83 nonsplenectomized patients (unexposed) on the date of ITP diagnosis ±5 years, age and gender. After a median follow-up of 192 months (range 0.5-528), 43 patients (52%) achieved overall response after splenectomy. Splenectomized patients experienced more venous thromboembolism (VTE) than controls (n = 13 vs n = 2, P = 0.005). On multivariate analysis, splenectomy was an independent risk factor of VTE (hazard ratio = 4.006, P = 0.032 [95% confidence interval: 1.13-14.21]). Splenectomized patients presented more severe infections on long-term follow-up: all required hospitalization, and 5/26 (19%) infections led to severe sepsis or septic shock and to death for 3 cases (none in controls). However, the incidence of malignancy was similar in both groups, as was cardiovascular risk, which appeared to be related more to ITP than splenectomy. Finally, splenectomy did not significantly decrease overall survival. Despite the risk of thrombosis and severe sepsis, splenectomy remains an effective and curative treatment for ITP.
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http://dx.doi.org/10.1097/MD.0000000000005098DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5134764PMC
November 2016

Seasonal variations of incident primary immune thrombocytopenia in adults: An ecological study.

Eur J Intern Med 2017 Jan 7;37:e26-e28. Epub 2016 Oct 7.

Service de Médecine Interne, CHU Henri-Mondor, Assistance publique-Hôpitaux de Paris, centre de référence des cytopénies auto-immunes de l'adulte, Université Paris-Est-Créteil, Créteil F-94000, France.

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http://dx.doi.org/10.1016/j.ejim.2016.09.025DOI Listing
January 2017

Evidence of benefits from using fresh and cryopreserved blood to transfuse patients with acute sickle cell disease.

Transfusion 2016 07 17;56(7):1730-8. Epub 2016 May 17.

Etablissement Français du Sang, Île-de-France, Hôpital Henri-Mondor.

Background: The transfusion of red blood cell (RBC) concentrates is the main treatment for acute vaso-occlusive symptoms in sickle cell disease (SCD). Units of packed RBCs (pRBCs) must retain optimal characteristics for transfusion throughout the storage period. Transfused RBCs interact with the plasma and the endothelium that lines blood vessels and may be the target of immune-hematologic conflict if the patient produces antibodies against RBCs. Questions remain concerning the benefit-risk balance of RBC transfusions, in particular about the shelf-life of the units.

Study Design And Methods: Plasma samples from 33 hemoglobin SS patients with SCD who had severe acute-phase symptoms or were in steady-state were put in contact with 10 fresh-stored and older stored samples from the same 10 RBC units. The factors affecting RBC survival (phosphatidylserine exposure, cytosolic calcium influx, cell size reduction) were analyzed.

Results: We show that the effects of plasma samples from patients with SCD on pRBCs depend on the clinical condition of the patients and the duration of red cell storage. Signs of RBC senescence were correlated with the clinical status of the patient from whom the plasma sample was obtained. A decrease in RBC size and an increase in phosphatidylserine exposure were correlated with the duration of RBC storage. The behavior of cryopreserved pRBCs was similar to that of fresh refrigerated RBCs when challenged with patient plasma samples.

Conclusion: The key points of this study are that the clinical condition of patients with SCD can negatively affect the integrity of pRBCs for transfusion, and those effects increase with longer storage. Also, cryopreserved pRBCs behave similarly to fresh RBCs when challenged with plasma samples from patients with SCD in acute phase. Our data provide the first evidence that fresh RBCs stored for short periods may be of greater benefit to patients with SCD than RBCs that have been refrigerated for longer periods, particularly for those who have acute symptoms of SCD.
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http://dx.doi.org/10.1111/trf.13636DOI Listing
July 2016

Anti-HI can cause a severe delayed hemolytic transfusion reaction with hyperhemolysis in sickle cell disease patients.

Transfusion 2016 07 3;56(7):1828-33. Epub 2016 May 3.

Établissement Français du Sang, Ile de France, Hôpital Henri Mondor.

Background: Delayed hemolytic transfusion reaction (DHTR) is a life-threatening condition in sickle cell disease (SCD) patients that is frequently complicated by hyperhemolysis. Antibodies resulting from antigen disparity between donors of European ancestry and patients of African ancestry are common, but situations involving antibodies not classically of clinical significance are also encountered. Anti-HI is generally considered to be an innocuous naturally occurring antibody.

Study Design And Methods: We describe two cases of hyperhemolysis with anti-HI and provide details of the reported cases.

Results: Both SCD patients were polyimmunized and belonged to blood group B. They developed anti-HI that was reactive at 37°C, after the transfusion of group O red blood cell units matched for all known and produced antibodies classically considered to be clinically significant. Both patients developed DHTR with hyperhemolysis. In the first case, a pregnant woman, a second transfusion was unavoidable and the patient died from cardiac arrest. The state of the second patient improved without the need for further transfusion.

Conclusion: Three other cases of DHTR with anti-HI have been described in the literature in SCD patients. The two additional cases reported here definitively demonstrate that anti-HI is dangerous in SCD patients. As a result, ABO-identical matching (including A1 status) must be considered in SCD patients with anti-HI.
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http://dx.doi.org/10.1111/trf.13611DOI Listing
July 2016

Fatal transfusion-transmitted infection due to Citrobacter koseri.

Transfusion 2016 Jun 4;56(6):1311-1313. Epub 2016 Apr 4.

EFS Ile de France, Ivry sur Seine, France.

Background: Transfusion-transmitted bacterial infection (TTBI) is still one of the most feared complications of blood transfusion.

Case Report: We report a fatal case involving an 8-year-old child with congenital dyskeratosis complicated by severe aplastic anemia who was regularly transfused with platelet (PLT) concentrates for 5 years. The patient received an apheresis PLT concentrate (APC) on Day 0 due to thrombocytopenia complicated by mucocutaneous hemorrhage. Thirty minutes after the start of the transfusion, bradycardia and dyspnea appeared, quickly followed by chills, nausea, vomiting, headache, and hyperthermia. TTBI was suspected and the patient was immediately treated with intravascular antibiotherapy. On Day 3, the patient developed severe acute respiratory distress syndrome leading to death on Day 7. Patient blood cultures and APC cultures were both positive for Citrobacter koseri.

Results: The donor was a 19-year-old woman. She had previously given blood. No infectious symptom was reported during the medical interviews before and after the donation and no postdonation information was received. On the day of the donation (Day -2), her white blood cell count was 5.83 × 10 /L. She came back on Day 8 to undergo additional tests. The cultures from blood, stool, urine, the skin of the inside of the elbow at the point of needle insertion, and ear samples were all negative for C. koseri. However, a nasal sample was positive for C. koseri.

Conclusion: The isolates from the donor's blood cultures, the APC bag, the attached tube, and the donor's nasal sample all gave identical profiles; they were thus identified as the same strain and the TTBI was confirmed.
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http://dx.doi.org/10.1111/trf.13589DOI Listing
June 2016

Autologous bone marrow stromal cells are promising candidates for cell therapy approaches to treat bone degeneration in sickle cell disease.

Stem Cell Res 2015 Nov 8;15(3):584-594. Epub 2015 Oct 8.

Université Paris-Est, Faculté de médecine, Laboratoire de "Bioingénierie cellulaire, tissulaire et sanguine", EA3952, Créteil, France; Etablissement Français du Sang d'Ile-de-France, Unité d'Ingénierie et de Thérapie Cellulaire, Créteil, France. Electronic address:

Osteonecrosis of the femoral head is a frequent complication in adult patients with sickle cell disease (SCD). To delay hip arthroplasty, core decompression combined with concentrated total bone marrow (BM) treatment is currently performed in the early stages of the osteonecrosis. Cell therapy efficacy depends on the quantity of implanted BM stromal cells. For this reason, expanded bone marrow stromal cells (BMSCs, also known as bone marrow derived mesenchymal stem cells) can be used to improve osteonecrosis treatment in SCD patients. In this study, we quantitatively and qualitatively evaluated the function of BMSCs isolated from a large number of SCD patients with osteonecrosis (SCD-ON) compared with control groups (patients with osteonecrosis not related to SCD (ON) and normal donors (N)). BM total nuclear cells and colony-forming efficiency values (CFE) were significantly higher in SCD-ON patients than in age and sex-matched controls. The BMSCs from SCD-ON patients were similar to BMSCs from the control groups in terms of their phenotypic and functional properties. SCD-ON patients have a higher frequency of BMSCs that retain their bone regeneration potential. Our findings suggest that BMSCs isolated from SCD-ON patients can be used clinically in cell therapy approaches. This work provides important preclinical data that is necessary for the clinical application of expanded BMSCs in advanced therapies and medical products.
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http://dx.doi.org/10.1016/j.scr.2015.09.016DOI Listing
November 2015

Fetal and neonatal alloimmune thrombocytopenia: predictive factors of intracranial hemorrhage.

Transfusion 2016 Jan 7;56(1):59-66; quiz 58. Epub 2015 Sep 7.

Platelet Immunology, Institut National de la Transfusion Sanguine, Paris, France.

Background: In Caucasians, fetal/neonatal alloimmune thrombocytopenia (FNAIT) is most frequently caused by maternal alloimmunization against the human platelet antigen HPA-1a. The most serious complication of severe FNAIT is intracranial hemorrhage (ICH). ICH mainly occurs in utero; therefore, there is a need to identify noninvasive predictive factors of ICH to facilitate early identification of this condition and to determine response to maternal therapy.

Study Design And Methods: We studied gynecologic and immunogenetic variables of severe cases of anti-HPA-1a FNAIT within three groups: Group I, FNAIT without ICH; Group II, FNAIT with ICH; and Group III, suspected FNAIT cases without detectable maternal anti-HPA-1a alloantibodies.

Results: ICH was associated with a poor outcome because it led to death in 59% of cases. Multigravida (two or more pregnancies) was overrepresented in Group II, consistent with the high concentrations of maternal HPA-1a alloantibody and the frequent detection of a strong newborn-specific HLA class I antibody response at delivery. The proportion of HLA-DRB4*01:01P (*01:01 or *01:03) women was similar in Groups I and II, but this allele was overrepresented in Group III, in which FNAIT was less severe than in the other two groups. Finally, antenatal intravenous immunoglobulin therapy tended to be more effective in HLA-DRB3*01:01(+)/HLA-DRB4*01:01P(+) women than for HLA-DRB3*01:01(+)/HLA-DRB4*01:01P(-) women.

Conclusion: The number of gestations is a predictive factor of ICH in anti-HPA-1a-alloimmunized women. Maternal immunogenetic variables should be investigated in the context of maternal immunization and may predict response to maternal therapy in subsequent pregnancies.
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http://dx.doi.org/10.1111/trf.13274DOI Listing
January 2016

Donor Immunization Against Human Leukocyte Class II Antigens is a Risk Factor for Graft-versus-Host Disease.

Biol Blood Marrow Transplant 2016 Feb 11;22(2):292-299. Epub 2015 Nov 11.

Department of Hematology, AP-HP, Hôpital Henri Mondor, DHU Virus-Immunity-Cancer, Créteil, France; IMRB, University Paris Est Créteil, INSERM U955, Créteil, France; Center for Clinical Investigation in Biotherapy, Créteil, France. Electronic address:

The sensitization to HLA antigens is caused mainly by pregnancy and transfusions; however, anti-HLA antibodies also may be detected in nulliparous females and nontransfused males, and thus specifically in hematopoietic stem cell transplantation (HSCT) donors. In such cases, the impact on HSCT outcome is known only for platelet transfusion refractoriness. This study addresses the impact on graft-versus-host disease (GVHD) of anti-HLA antibodies detected in voluntary unrelated donors. Among 100 donor/recipient (D/R) pairs, 33 and 82 showed at least 1 HLA class I and class II mismatch, respectively. Because class II mismatches were more frequent, we focused our detection on anti-class II antibodies, using the Luminex assay. Among 82 HLA class II mismatched D/R pairs, 26 donors (32%) had at least 1 anti-HLA class II antibody detected in peripheral blood. Recipients of a graft from an anti-class II immunized donor had a higher cumulative incidence for a first episode of either acute or chronic GVHD (2- year cumulative incidence, 88% versus 67%; P = .03), which was confirmed in multivariate analysis (hazard ratio, 1.7; P = .04). In particular, according to the National Institutes of Health classification scheme, the cumulative incidence of chronic GVHD was higher in recipients of immunized donors (multivariate hazard ratio, 2.5; P = .02). Identifying specificities of anti-class II antibodies revealed that 13 of 26 alloimmunized donors had recipient-specific antibodies, directed mainly against mismatched HLA-DPB1 alleles. Donor-derived anti-HLA antibodies could be detected in recipients up to at least 6 months post-HSCT, supporting their association with chronic GVHD. Donor immunization against foreign HLA antigens is a new parameter to predict the occurrence of GVHD after HSCT from HLA-mismatched unrelated donors.
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http://dx.doi.org/10.1016/j.bbmt.2015.09.027DOI Listing
February 2016

Red blood cell alloimmunization is influenced by the delay between Toll-like receptor agonist injection and transfusion.

Haematologica 2016 Feb 1;101(2):209-18. Epub 2015 Oct 1.

Établissement Français du Sang, Créteil, France Institut Mondor de Recherche Biomédicale, lnserm U955, Equipe 2, Créteil, France Laboratory of Excellence GR-Ex, Paris, France

Murine models of red blood cell transfusion show that inflammation associated with viruses or methylated DNA promotes red blood cell alloimmunization. In vaccination studies, the intensity of antigen-specific responses depends on the delay between antigen and adjuvant administration, with a short delay limiting immune responses. In mouse models of alloimmunization, the delay between the injection of Toll-like receptor agonists and transfusion is usually short. In this study, we hypothesized that the timing of Toll-like receptor 3 agonist administration affects red blood cell alloimmunization. Poly(I:C), a Toll-like receptor 3 agonist, was administered to B10BR mice at various time points before the transfusion of HEL-expressing red blood cells. For each time point, we measured the activation of splenic HEL-presenting dendritic cells, HEL-specific CD4(+) T cells and anti-HEL antibodies in serum. The phenotype of activated immune cells depended on the delay between transfusion and Toll-like receptor-dependent inflammation. The production of anti-HEL antibodies was highest when transfusion occurred 7 days after agonist injection. The proportion of HEL-presenting CD8α(+) dendritic cells producing interleukin-12 was highest in mice injected with poly(I:C) 3 days before transfusion. Although the number of early-induced HEL-specific CD4(+) T cells was similar between groups, a high proportion of these cells expressed CD134, CD40 and CD44 in mice injected with poly(I:C) 7 days before transfusion. This study clearly shows that the delay between transfusion and Toll-like receptor-induced inflammation influences the immune response to transfused red blood cells.
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http://dx.doi.org/10.3324/haematol.2015.134171DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4938341PMC
February 2016

Cutaneous rash and dapsone-induced hypersensitivity syndrome a common manifestation in adult immune thrombocytopenia. Presentation and outcome in 16 cases.

Am J Hematol 2015 Oct 1;90(10):E201-2. Epub 2015 Sep 1.

Service De Médecine Interne, Centre De Référence Des Cytopénies auto-Immunes De L'adulte, Hôpital Henri Mondor, Assistance Publique Hôpitaux De Paris, Université Paris Est Créteil, Créteil, France.

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http://dx.doi.org/10.1002/ajh.24068DOI Listing
October 2015

Vincristine efficacy and safety in treating immune thrombocytopenia: a retrospective study of 35 patients.

Eur J Haematol 2016 Mar 9;96(3):269-75. Epub 2015 Jun 9.

Hôpital Jean-Verdier, Service de Médecine Interne, Université Paris 13, Assistance Publique-hôpitaux de Paris (AP-HP), Bondy Cedex, France.

Although vincristine (VCR) is sometimes prescribed for newly diagnosed immune thrombocytopenia (ITP), its efficacy in refractory ITP and sustained efficacy has yet to be demonstrated. We describe our clinical experience and recommend vincristine's correct place in ITP management. This retrospective study analysed data from 35 patients with newly diagnosed (ND), persistent (P) or chronic (C) ITP treated with VCR. The initial response rate, defined as >30 × 10(9) platelets/L, reached 86% after a median of 7 [interquartile range (IQR) 6-13] days. In ND and P ITP, even when previous therapies were inefficient, initial response was 87.5%, suggesting that this treatment could be used particularly in rescue. Median survival time, without failure or relapse, was 15 months (Kaplan-Meier curve). Predictive factors (univariate analysis) of an initial and long-term response were a small number of prior treatments received. However, at 2 yr, only seven patients had sustained response. Eight (23%) patients experienced adverse events: neuropathy for seven and bowel obstruction for one. Vincristine efficacy in ITP was confirmed, and it could be a good strategy for treating resistant ITP, especially in emergencies. In this era of new therapeutics, VCR deserves to remain on the list of ITP treatments because of its initial efficacy, safety and low cost.
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http://dx.doi.org/10.1111/ejh.12586DOI Listing
March 2016

Development of a simple procedure for the treatment of femoral head osteonecrosis with intra-osseous injection of bone marrow mesenchymal stromal cells: study of their biodistribution in the early time points after injection.

Stem Cell Res Ther 2015 Apr 13;6:68. Epub 2015 Apr 13.

Université Paris-Est, Faculté de médecine, Laboratoire de "Bioingénierie cellulaire, tissulaire et sanguine", EA3952, 5 rue Gustave Eiffel, 94000, Créteil, France.

Introduction: Osteonecrosis of the femoral head (ONFH) is a degenerative disease progressing to a femoral head (FH) collapse. Injection of osteoprogenitor cells like bone marrow mesenchymal stromal cells (BMSCs) into the FH appears to be a good therapeutic treatment. However, safety and efficacy of BMSCs to treat bone defect are the main preclinical data required for clinical application. Efficacy and the lack of risk of cell transformation after amplification of BMSCs have been extensively described. The main objectives of this study were to develop a simple and usable procedure for clinicians and control its feasibility by evaluating the biodistribution of BMSCs after injection into the FH in a large animal model. The impact of this approach was evaluated on one natural pig ONFH.

Methods: BMSCs were directly injected in the pig FH, and then the biodistribution of grafted cells was detected by quantitative real-time polymerase chain reaction, cytometry, or a combination of classic histology analysis and in situ hybridization (ISH). BMSC efficacy on bone regeneration was evaluated by magnetic resonance imaging (MRI) and histology.

Results: After 30-minute and 24-hour follow-up, grafted cells were detected at the injection site and no BMSCs were detected in filter organs or body fluids. The combination of classic histology analysis and ISH showed a good homogeneity of cell distribution in FH. Local delivery of BMSCs onto a bone scaffold associated with bone formation in vivo confirmed the preferential tropism of BMSCs to the bone tissue as well as their efficacy to form bone. Treatment of a natural pig ONFH by autologous BMSCs indicated a beginning of bone healing as early as 2 weeks with a complete healing after 9 weeks. At this stage, MRI and histological analysis were similar to those of a normal FH.

Conclusions: Intra-osseous injection of BMSCs in FH seems to be a good strategy for ONFH treatment as the safety concerning the biodistribution of BMSCs is ensured. Moreover, the efficacy of BMSCs in natural ONFH seems to indicate that this is a promising approach. Altogether, these results constitute the preclinical data necessary for the setup of a clinical application with expanded BMSCs in the context of advanced therapy medicinal products.
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http://dx.doi.org/10.1186/s13287-015-0036-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4448288PMC
April 2015

Phenotypic differences of CD4(+) T cells in response to red blood cell immunization in transfused sickle cell disease patients.

Eur J Immunol 2015 Jun 15;45(6):1868-79. Epub 2015 Apr 15.

Etablissement Français du Sang, Créteil, France.

Alloimmunization against red blood cells (RBCs) is the main immunological risk associated with transfusion in patients with sickle cell disease (SCD). However, about 50-70% of SCD patients never get immunized despite frequent transfusion. In murine models, CD4(+) T cells play a key role in RBC alloimmunization. We therefore explored and compared the CD4(+) T-cell phenotypes and functions between a group of SCD patients (n = 11) who never became immunized despite a high transfusion regimen and a group of SCD patients (n = 10) who had become immunized (at least against Kidd antigen b) after a low transfusion regimen. We studied markers of CD4(+) T-cell function, including TLR, that directly control lymphocyte function, and their spontaneous cytokine production. We also tested responders for the cytokine profile in response to Kidd antigen b peptides. Low TLR2/TLR3 expression and, unexpectedly, strong expression of CD40 on CD4(+) T cells were associated with the nonresponder status, whereas spontaneous expression of IL-10 by CD4(+) T cells and weak Tbet expression were associated with the responder status. A Th17 profile was predominant in responders when stimulated by Jb(k) . These findings implicate CD4(+) T cells in alloimmunization in humans and suggest that they may be exploited to differentiate responders from nonresponders.
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http://dx.doi.org/10.1002/eji.201445187DOI Listing
June 2015

Red blood cell Thomsen-Friedenreich antigen expression and galectin-3 plasma concentrations in Streptococcus pneumoniae-associated hemolytic uremic syndrome and hemolytic anemia.

Transfusion 2015 Jun 30;55(6 Pt 2):1563-71. Epub 2014 Dec 30.

Etablissement Français du Sang Ile de France, Villejuif, France.

Background: Pneumococcal hemolytic uremic syndrome (P-HUS) is a rare but severe complication of invasive pneumococcal disease (IPD) in young children. Consensual biologic diagnosis criteria are currently lacking.

Study Design And Methods: A prospective study was conducted on 10 children with culture-confirmed IPD. Five presented with full-blown P-HUS, three had an incomplete form with hemolytic anemia and mild or no uremia (P-HA), and two had neither HUS nor HA. Thomsen-Friedenreich (T), Th, and Tk cryptantigens and sialic acid expression were determined on red blood cells (RBCs) with peanut (PNA), Glycine soja (SBA), Bandeiraea simplicifolia II, and Maackia amurensis lectins. Plasma concentrations of the major endogenous T-antigen-binding protein, galectin-3 (Gal-3), were analyzed.

Results: We found that RBCs strongly reacted with PNA and SBA lectins in all P-HUS and P-HA patients. Three P-HUS and three P-HA patients showed also concomitant Tk activation. Direct antiglobulin test (DAT) was positive in three P-HUS (one with anti-C3d and two with anti-IgG) and two P-HA patients (one with anti-C3d and one with anti-IgG). RBCs derived from the two uncomplicated IPD patients reacted with PNA but not with SBA lectin. Gal-3 plasma concentrations were increased in all P-HUS patients.

Conclusions: The results indicate high levels of neuraminidase activity and desialylation in both P-HUS and P-HA patients. T-antigen activation is more sensitive than DAT for P-HUS diagnosis. Combining PNA and SBA lectins is needed to improve the specificity of T-antigen activation. High concentrations of Gal-3 in P-HUS patients suggest that Gal-3 may contribute to the pathogenesis of P-HUS.
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http://dx.doi.org/10.1111/trf.12981DOI Listing
June 2015

Bone-Forming Capacity and Biodistribution of Bone Marrow-Derived Stromal Cells Directly Loaded Into Scaffolds: A Novel and Easy Approach for Clinical Application of Bone Regeneration.

Cell Transplant 2015 28;24(10):1945-55. Epub 2014 Oct 28.

Université Paris-Est Créteil, Faculté de médecine, Laboratoire de "Bioingénierie Cellulaire, Tissulaire et Sanguine," Créteil, France.

In the context of clinical applications of bone regeneration, cell seeding into scaffolds needs to be safe and easy. Moreover, cell density also plays a crucial role in the development of efficient bone tissue engineering constructs. The aim of this study was to develop and evaluate a simple and rapid cell seeding procedure on hydroxyapatite/β-tricalcium phosphate (HA/βTCP), as well as define optimal cell density and control the biodistribution of grafted cells. To this end, human bone marrow-derived stromal cells (hBMSCs) were seeded on HA/βTCP scaffolds, and we have compared bone formation using an ectopic model. Our results demonstrated a significantly higher bone-forming capacity of hBMSCs directly loaded on HA/βTCP during surgery compared to hBMSCs preseeded for 7 days in vitro on HA/βTCP before ectopic implantation. The extent of new bone formation increases with increasing hBMSC densities quantitatively, qualitatively, and in frequency. Also, this study showed that grafted hBMSCs remained confined to the implantation site and did not spread toward other tissues, such as liver, spleen, lungs, heart, and kidneys. In conclusion, direct cell loading into a scaffold during surgery is more efficient for bone regeneration, as well as quick and safe. Therefore direct cell loading is suitable for clinical requirements and cell production control, making it a promising approach for orthopedic applications. Moreover, our results have provided evidence that the formation of a mature bone organ containing hematopoietic islets needs a sufficiently high local density of grafted hBMSCs, which should guide the optimal dose of cells for clinical use.
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http://dx.doi.org/10.3727/096368914X685276DOI Listing
August 2016

Safety and efficacy of rituximab in adult immune thrombocytopenia: results from a prospective registry including 248 patients.

Blood 2014 Nov 7;124(22):3228-36. Epub 2014 Oct 7.

Service de Médecine Interne, Centre de Référence Labellisé des Cytopénies Auto-Immunes de l'Adulte and.

We conducted a prospective multicenter registry of 248 adult patients with immune thrombocytopenia (ITP) treated with rituximab to assess safety. We also assessed response and predictive factors of sustained response. In total, 173 patients received 4 infusions of 375 mg/m(2) and 72 received 2 fixed 1-g infusions 2 weeks apart. The choice of the rituximab regimen was based on the physician's preference and not patient characteristics. Overall, 38 patients showed minor intolerance to rituximab infusions; infusions had to be stopped for only 3 patients. Seven showed infection (n = 11 cases), with an incidence of 2.3 infections/100 patient-years. Three patients died of infection 12 to 14 months after rituximab infusions, but the role of rituximab was questionable. In total, 152 patients (61%) showed an overall initial response (platelet count ≥30 × 10(9)/L and ≥2 baseline value). At a median follow-up of 24 months, 96 patients (39%) showed a lasting response. On multivariate analysis, the probability of sustained response at 1 year was significantly associated with ITP duration <1 year (P = .02) and previous transient complete response to corticosteroids (P = .05). The pattern of response was similar with the 2 rituximab regimens. With its benefit/risk ratio, rituximab used off-label may remain a valid option for treating persistent or chronic ITP in adults. This trial was registered at www.clinicaltrials.gov as #NC1101295.
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http://dx.doi.org/10.1182/blood-2014-06-582346DOI Listing
November 2014

Quality control of extracorporeal photochemotherapy: Proliferation assay using CFSE validated according to ISO 15189:2007 standards.

Cytometry B Clin Cytom 2015 Jan 16;88(1):30-9. Epub 2014 Sep 16.

Faculté des sciences pharmaceutiques et biologiques, Université Paris-Descartes, Paris, France; Etablissement Français du Sang, Unité d'Ingénierie et de Thérapie Cellulaire, Créteil, France.

Background: For the last 40 years, the technique of extracorporeal photopheresis (ECP) has constantly developed. Among irradiation systems, those called "off-line" allow the validation of the quality of the cell therapy product. The inhibition of the proliferation of lymphocytes after ultraviolet irradiation (UVA) is usually verified by the tritiated thymidine assay as in vitro proliferation assay. The document presented here describes the results obtained while performing the setting up of an alternative proliferation assay using flow cytometry according to ISO 15189:2007 Standard.

Methods: Cells samples taken before and after UVA irradiation were labeled with CarboxyFluorescein Succinimidyl Ester (CFSE) and then cultured with phytohemagglutinin-A (PHA). After 3 days, an analysis of the CFSE staining was realized by flow cytometry. In order to validate the shift in the method used according to Standard, the following tests were performed: 1) comparison with the reference method, 2) robustness test, 3) reagents stability.

Results: Comparison method demonstrated that the sensitivity of the CFSE test is 100%, the specificity is 89%, and the concordance is almost complete. The CFSE test is robust regarding parameters like cell concentration or PHA concentration. PHA and CFSE are stable for 6 months and one year, respectively.

Conclusion: Validation of this alternative test, according to the ISO 15189:2007 Standard, has demonstrated good concordance with reference method. The results of the robustness and stability of reagents are appropriate for its routine use. Thus, the benefits of alternative technique make it a wise choice for the quality control of ECP in a cell therapy laboratory.
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http://dx.doi.org/10.1002/cyto.b.21188DOI Listing
January 2015

Profound symptomatic hypogammaglobulinemia: a rare late complication after rituximab treatment for immune thrombocytopenia. Report of 3 cases and systematic review of the literature.

Autoimmun Rev 2014 Oct 27;13(10):1055-63. Epub 2014 Aug 27.

Service de Médecine Interne, Centre de référence des cytopénies auto-immunes de l'adulte, Hôpital Henri Mondor, Assistance Publique Hôpitaux de Paris, Université Paris Est Créteil, Créteil, France.

Introduction: B-cell depletion with rituximab (RTX) is widely used to treat autoimmune diseases, especially as second-line therapy for immune thrombocytopenia (ITP). The incidence of RTX-induced hypogammaglobulinemia is unknown because of heterogeneous follow-up and confounding factors such as concomitant immunosuppressive treatments in most patients. We describe 3 cases and attempted to determine the incidence of RTX-induced hypogammaglobulinemia by a systematic review of the literature.

Methods: We retrospectively analyzed 189 ITP patients receiving RTX in 3 referral centers in France and conducted a systematic review of 32 studies (results published 2001-2014) reporting the use of RTX for ITP, particularly searching for symptomatic secondary hypogammaglobulinemia. We also searched for case reports of hypogammaglobulinemia after RTX initiation for ITP.

Results: Of the 189 patients, 3 showed symptomatic hypogammaglobulinemia more than 2years after RTX infusion (initial immunoglobulin level was normal). All 3 presented recurrent severe infections. In 2, the outcome suggested common variable immunodeficiency. In patient 3, the peripheral blood lacked CD19(+)CD20(+) B cells and the bone-marrow B-cell precursor level was impaired. Among 1245 ITP patients in the literature who received RTX for ITP, gammaglobulin level was monitored before and after RTX initiation for 351 (28%). For 192 (55%), dosages were available and we identified 21 patients with secondary hypogammaglobulinemia, usually not symptomatic, 14 of whom had received concomitant dexamethasone. Finally, we found 4 case reports of ITP and symptomatic hypogammaglobulinemia possibly related to RTX according to the authors.

Conclusions: This large analysis led us to recommend monitoring serum immunoglobulin level before and repeatedly after RTX initiation for ITP. Physicians should be aware of hypogammaglobulinemia as a rare but severe complication of RTX.
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http://dx.doi.org/10.1016/j.autrev.2014.08.036DOI Listing
October 2014