Publications by authors named "Masja de Haas"

108 Publications

Are fetal bilirubin levels associated with the need for neonatal exchange transfusions in hemolytic disease of the fetus and newborn?

Am J Obstet Gynecol MFM 2021 Feb 17:100332. Epub 2021 Feb 17.

Department of Pediatrics, Division of Neonatology, Leiden University Medical Center, Leiden.

Background: Fetal bilirubin is routinely measured at our center when taking a pretransfusion blood sample at intrauterine transfusions in hemolytic disease of the fetus and newborn. However, the clinical value of fetal bilirubin assessment is not well known, and the information is rarely used. We speculated that there could be a role for this measurement in predicting the need for neonatal exchange transfusion.

Objective: To evaluate the predictive value of fetal bilirubin for exchange transfusions in severe hemolytic disease of the fetus and newborn.

Study Design: In this observational study 186 infants with Rh alloantibody mediated hemolytic disease of the fetus and newborn treated with one or more intrauterine transfusions at the Leiden University Medical Center between 2006 and June 2020 were included. Antenatal and postnatal factors were compared between infants with and without exchange transfusion treatment. The primary outcome was the fetal bilirubin level before the last intrauterine transfusion in relation to the need for exchange transfusion.

Results: In a multivariate logistic regression analysis, the fetal bilirubin level before the last intrauterine transfusions (odds ratio of 1.32; 95% confidence interval 1.09-1.61 per 1 mg/dL) and the total number of IUTs (odds ratio 0.63; 95% confidence interval 0.44-0.91 per intrauterine transfusion) were independently associated with the need for exchange transfusion. The area under the curve was determined at 0.71. A Youden index was calculated of 0.43. The corresponding fetal bilirubin level was 5 mg/dL and had a sensitivity of 79% and a specificity of 64%.

Conclusion: A high fetal bilirubin level before the last intrauterine transfusion was associated with a high likelihood of neonatal exchange transfusion.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ajogmf.2021.100332DOI Listing
February 2021

Reduction of anti-K-mediated hemolytic disease of newborns after the introduction of a matched transfusion policy: A nation-wide policy change evaluation study in the Netherlands.

Transfusion 2021 Feb 2. Epub 2021 Feb 2.

Department of Immunohematology Diagnostics, Sanquin Diagnostic Services, Amsterdam, The Netherlands.

Background: During pregnancy, maternal red blood cell (RBC) antibodies can lead to life-threatening fetal hemolysis and anemia. Women can become immunized by a pregnancy or an unmatched transfusion. Our aim was to quantify the effect of a nationwide K-matched transfusion policy for women of childbearing age potential to prevent K-immunization in pregnancy.

Study Design And Methods: In this nation-wide policy change evaluation study we determined the occurrence of RBC antibodies before and after introduction of a K-matched transfusion policy and evaluated the cause K alloimmunization 10 years after introduction of this measure. K-matched transfusion for females under 45 years of age is advised in the Dutch transfusion guideline since 2004. We used laboratory data from pregnancies with RBC antibodies identified in the period 1999-2018 obtained as part of a population-based screening program in the Netherlands.

Results: Tests of 36 286 pregnancies produced a positive antibody screening result which concerned anti-K in 1550 pregnancies. The occurrence of anti-K decreased from 67.9 to 20.2 per 100 000 pregnancies. The relative risk reduction was 0.70 which largely exceeded the relative risk reduction of 0.27 for antibodies against RBC antigens for which no preventive matching is required. The number of pregnancies at risk for anti-K-mediated disease decreased from 9.7 to 4.2 per 100 000 pregnancies.

Conclusions: A K-matched transfusion policy is associated with a major decrease in a number of pregnant women with anti-K and pregnancies at risk for anti-K-mediated disease. A relatively simple measure is now shown to impact prevention of hemolytic disease in the fetus and newborn.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/trf.16276DOI Listing
February 2021

Biological stratification of clinical disease courses in childhood immune thrombocytopenia.

J Thromb Haemost 2021 Jan 1. Epub 2021 Jan 1.

Department of Immunohematology Diagnostics, Sanquin Diagnostic Services, Amsterdam, The Netherlands.

Background: In childhood immune thrombocytopenia (ITP), an autoimmune bleeding disorder, there is a need for better prediction of individual disease courses and treatment outcomes.

Objective: To predict the response to intravenous Immunoglobulins (IVIg) and ITP disease course using genetic and immune markers.

Methods: Children aged below seven years with newly diagnosed ITP (N = 147) from the TIKI study were included, which randomized children to an IVIg or observation group. A total of 46 variables were available: clinical characteristics, targeted genotyping, lymphocyte immune phenotyping, and platelet autoantibodies.

Results: In the treatment arm, 48/80 children (60%) showed a complete response (platelets ≥100 x 10 /L) that lasted for at least one month (complete sustained response; CSR) and 32 exhibited no or a temporary response (absence of a sustained response; ASR). For a biological risk score, five variables were selected by regularized logistic regression that predicted ASR vs CSR: 1) hemoglobin; 2) platelet count; 3) genetic polymorphisms of FcγRIIc; 4) the presence of IgG anti-platelet antibodies; and 5) preceding vaccination. The ASR sensitivity was 0.91 (95% CI, 0.80 - 1.00) and specificity was 0.67 (95% CI, 0.53 - 0.80). In the 67 patients of the observation arm, this biological score was also associated with recovery during one-year follow-up. The addition of the biological score to a predefined clinical score further improved the discrimination of favorable ITP disease courses.

Conclusions: The prediction of disease courses and IVIg treatment responses in ITP is improved by using both clinical and biological stratification.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/jth.15232DOI Listing
January 2021

A clinical prediction score for transient versus persistent childhood immune thrombocytopenia.

J Thromb Haemost 2021 01 27;19(1):121-130. Epub 2020 Nov 27.

Department of Immunohematology Diagnostics, Sanquin Diagnostic Services, Amsterdam, the Netherlands.

Essentials There is a need for improved tools to predict persistent and chronic immune thrombocytopenia (ITP). We developed and validated a clinical prediction model for recovery from newly diagnosed ITP. The Childhood ITP Recovery Score predicts transient vs. persistent ITP and response to intravenous immunoglobulins. The score may serve as a useful tool for clinicians to individualize patient care. ABSTRACT: Background Childhood immune thrombocytopenia (ITP) is an autoimmune bleeding disorder. The prognosis (transient, persistent, or chronic ITP) remains difficult to predict. The morbidity is most pronounced in children with persistent and chronic ITP. Clinical characteristics are associated with ITP outcomes, but there are no validated multivariate prediction models. Objective Development and external validatation of the Childhood ITP Recovery Score to predict transient versus persistent ITP in children with newly diagnosed ITP. Methods Patients with a diagnosis platelet count ≤ 20 × 10 /L and age below 16 years were included from two prospective multicenter studies (NOPHO ITP study, N = 377 [development cohort]; TIKI trial, N = 194 [external validation]). The primary outcome was transient ITP (complete recovery with platelets ≥100 × 10 /L 3 months after diagnosis) versus persistent ITP. Age, sex, mucosal bleeding, preceding infection/vaccination, insidious onset, and diagnosis platelet count were used as predictors. Results In external validation, the score predicted transient versus persistent ITP at 3 months follow-up with an area under the receiver operating characteristic curve of 0.71. In patients predicted to have a high chance of recovery, we observed 85%, 90%, and 95% recovered 3, 6, and 12 months after the diagnosis. For patients predicted to have a low chance of recovery, this was 32%, 46%, and 71%. The score also predicted cessation of bleeding symptoms and the response to intravenous immunoglobulins (IVIg). Conclusion The Childhood ITP Recovery Score predicts prognosis and may be useful to individualize clinical management. In future research, the additional predictive value of biomarkers can be compared to this score. A risk calculator is available (http://www.itprecoveryscore.org).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/jth.15125DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7839442PMC
January 2021

Evolution and Utility of Antiplatelet Autoantibody Testing in Patients with Immune Thrombocytopenia.

Transfus Med Rev 2020 10 16;34(4):258-269. Epub 2020 Sep 16.

Department of Immunohematology Diagnostics, Sanquin Diagnostic Services, Amsterdam, the Netherlands; Sanquin Research, Center for Clinical Transfusion Research, Leiden, the Netherlands; Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, the Netherlands.

To this day, immune thrombocytopenia (ITP) remains a clinical diagnosis made by exclusion of other causes for thrombocytopenia. Reliable detection of platelet autoantibodies would support the clinical diagnosis, but the lack of specificity and sensitivity of the available methods for platelet autoantibody testing limits their value in the diagnostic workup of thrombocytopenia. The introduction of methods for glycoprotein-specific autoantibody detection has improved the specificity of testing and is acceptable for ruling in ITP but not ruling it out as a diagnosis. The sensitivity of these assays varies widely, even between studies using comparable assays. A review of the relevant literature combined with our own laboratory's experience of testing large number of serum and platelet samples makes it clear that this variation can be explained by variations in the characteristics of the tests, including in the glycoprotein-specific monoclonal antibodies, the glycoproteins that are tested, the platelet numbers used in the assay and the cutoff levels for positive and negative results, as well as differences in the tested patient populations. In our opinion, further standardization and optimization of the direct autoantibody detection methods to increase sensitivity without compromising specificity seem possible but will still likely be insufficient to distinguish the often very weak specific autoantibody signals from background signals. Further developments of autoantibody detection methods will therefore be necessary to increase sensitivity to a level acceptable to provide laboratory confirmation of a diagnosis of ITP.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.tmrv.2020.09.003DOI Listing
October 2020

Treatment-associated hemolysis in Kawasaki disease: association with blood-group antibody titers in IVIG products.

Blood Adv 2020 07;4(14):3416-3426

Department of Blood Cell Research, Sanquin Research and Landsteiner Laboratory, Amsterdam University Medical Center (UMC), University of Amsterdam, Amsterdam, The Netherlands.

Hemolytic anemia resulting from IV Immunoglobulin (IVIG) treatment can be a serious complication, especially for those with underlying conditions with a high level of inflammation and after administration of high IVIG dosages, such as Kawasaki disease (KD), a multisystem vasculitis affecting young children. This hemolysis is caused by antibodies against blood groups A and B, but the precise mechanism for hemolysis is not known. We performed a single center, partly retrospective, partly prospective study of a cohort of 581 patients who received IVIG for treatment of KD from 2006 to 2013. Factors associated with hemolysis were identified through univariable and multivariable logistic regression. Six IVIG preparations were assayed for their hemolytic effect with serological and cellular assays to clarify the mechanism of red cell destruction. During the study period, a sudden increase in the incidence of hemolysis was observed, which coincided with the introduction of new IVIG preparations in North America that contained relatively high titers of anti-A and anti-B. These blood-group-specific antibodies were of the immunoglobulin G2 (IgG2) subclass and resulted in phagocytosis by monocyte-derived macrophages in an FcγRIIa-dependent manner. Phagocytosis was increased in the presence of proinflammatory mediators that mimicked the inflammatory state of KD. An increased frequency of severe hemolysis following IVIG administration was caused by ABO blood-group-specific IgG2 antibodies leading to FcγRIIa-dependent clearance of erythrocytes. This increase in adverse events necessitates a reconsideration of the criteria for maximum titer (1:64) of anti-A and anti-B in IVIG preparations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/bloodadvances.2020002253DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7391134PMC
July 2020

HIP (HPA-screening in pregnancy) study: protocol of a nationwide, prospective and observational study to assess incidence and natural history of fetal/neonatal alloimmune thrombocytopenia and identifying pregnancies at risk.

BMJ Open 2020 07 20;10(7):e034071. Epub 2020 Jul 20.

Department of Immunohaematology Diagnostics, Sanquin, Amsterdam, The Netherlands.

Introduction: Fetal and neonatal alloimmune thrombocytopenia (FNAIT) may lead to severe fetal or neonatal bleeding and/or perinatal death. Maternal alloantibodies, targeted against fetal human platelet antigens (HPAs), can result thrombocytopenia and bleeding complications. In pregnancies with known immunisation, fetal bleeding can be prevented by weekly maternal intravenous immunoglobulin infusions. Without population-based screening, immunisation is only detected after birth of an affected infant. Affected cases that might have been prevented, when timely identified through population-based screening. Implementation is hampered by the lack of knowledge on incidence, natural history and identification of pregnancies at high risk of bleeding. We designed a study aimed to obtain this missing knowledge.

Methods And Analysis: The HIP (HPA-screening in pregnancy) study is a nationwide, prospective and observational cohort study aimed to assess incidence and natural history of FNAIT as well as identifying pregnancies at high risk for developing bleeding complications. For logistic reasons, we invite rhesus D-negative or rhesus c-negative pregnant women, who take part in the Dutch population-based prenatal screening programme for erythrocyte immunisation, to participate in our study. Serological HPA-1a typing is performed and a luminex-based multiplex assay will be performed for the detection of anti-HPA-1a antibodies. Results will not be communicated to patients or caregivers. Clinical data of HPA-1a negative women and an HPA-1a positive control group will be collected after birth. Samples of HPA-1a immunised pregnancies with and without signs of bleeding will be compared with identify parameters for identification of pregnancies at high risk for bleeding complications.

Ethics And Dissemination: Ethical approval for this study has been obtained from the Medical Ethical Committee Leiden-The Hague-Delft (P16.002). Study enrolment began in March 2017. All pregnant women have to give informed consent for testing according to the protocol. Results of the study will be disseminated through congresses and publication in relevant peer-reviewed journals.

Trial Registration Number: NCT04067375.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/bmjopen-2019-034071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7375633PMC
July 2020

The association and functional relevance of genetic variation in low-to-medium-affinity Fc-gamma receptors with clinical platelet transfusion refractoriness.

J Thromb Haemost 2020 08 25;18(8):2047-2053. Epub 2020 Jun 25.

Department of Blood Cell Research, Sanquin Research and Landsteiner Laboratory, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.

Background: Inadequate responses to platelet transfusions (i.e., platelet transfusion refractoriness [PLT refractoriness]) are a serious problem. Multiple factors contribute to low yields upon platelet transfusion, among which are platelet-reactive allo-antibodies. Platelet-reactive allo-antibodies occur in up to 30% of patients receiving multiple transfusions, and presumably lead to rapid destruction of the transfused platelets via receptors for IgG, the Fc-gamma receptors (FcγRs). Genetic variation in FcγRs is associated with susceptibility to immune thrombocytopenia, in which autoantibodies against platelets cause thrombocytopenia.

Objectives: We hypothesized that genetic variation in FcγRs may also influence PLT refractoriness in allo-immunized patients and could help in identifying the patients at risk.

Patients/methods: Patients with severe PLT refractoriness for whom diagnostic testing for allo-immunization was requested in the period of 2005 to 2013 were retrospectively included. A case-control study was performed comparing patients in whom platelet-reactive antibodies were detected (n = 181) with ethnically matched healthy controls (n = 180) to determine differences in all known functional copy number variations and single nucleotide polymorphisms in FcγRs.

Results And Conclusions: None of the tested FcγR genetic variations seemed associated with the development of severe PLT refractoriness. In contrast to observations in immune thrombocytopenia, genetic variation in FcγRs does not seem to influence the chance to develop PLT refractoriness. Our results do not support determination of FcγR genetic background as a means to identify patients most at risk for PLT refractoriness.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/jth.14892DOI Listing
August 2020

Anti-platelet antibody immunoassays in childhood immune thrombocytopenia: a systematic review.

Vox Sang 2020 May 20;115(4):323-333. Epub 2020 Feb 20.

Department of Immunohematology Diagnostics, Sanquin Diagnostic Services, Amsterdam, The Netherlands.

Background: In adult immune thrombocytopenia (ITP), an acquired autoimmune bleeding disorder, anti-platelet autoantibody testing may be useful as a rule-in test. Childhood ITP has different disease characteristics, and the diagnostic and prognostic value of anti-platelet antibody testing remains uncertain.

Objective: To systematically review the diagnostic accuracy of anti-platelet autoantibody testing in childhood ITP.

Methods: PubMed and EMBASE were searched for studies evaluating immunoassays in childhood ITP. Study quality was assessed (QUADAS2), and evidence was synthesized descriptively.

Results: In total, 40 studies (1606 patients) were identified. Nine studies reported sufficient data to determine diagnostic accuracy measures. Anti-platelet IgG antibody testing showed a moderate sensitivity (0·36-0·80 platelet-associated IgG [direct test]; 0·19-0·39 circulating IgG [indirect test]). In studies that reported control data, including patients with non-immune thrombocytopenia, specificity was very good (0·80-1·00). Glycoprotein-specific immunoassays showed comparable sensitivity (three studies) and predominantly identified IgG anti-GP IIb/IIIa antibodies, with few IgG anti-GP Ib/IX antibodies. Anti-platelet IgM antibodies were identified in a substantial proportion of children (sensitivity 0·62-0·64 for direct and indirect tests).

Conclusion: The diagnostic evaluation of IgG and IgM anti-platelet antibodies may be useful as a rule-in test for ITP. In children with insufficient platelets for a direct test, indirect tests may be performed instead. A negative test does not rule out the diagnosis of ITP. Future studies should evaluate the value of anti-platelet antibody tests in thrombocytopenic children with suspected ITP.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/vox.12894DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7317748PMC
May 2020

IgG-Fc glycosylation before and after rituximab treatment in immune thrombocytopenia.

Sci Rep 2020 02 20;10(1):3051. Epub 2020 Feb 20.

Sanquin Research, Department of Experimental Immunohematology, Amsterdam, The Netherlands and Landsteiner Laboratory, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.

The interactions of antibodies with myeloid Fcγ receptors and the complement system are regulated by an Asn297-linked glycan in the Fc portion of IgG. Alterations of serum IgG-Fc glycosylation have been reported in various autoimmune diseases, and correlate with treatment response and disease activity. We hypothesized that IgG-Fc glycosylation is altered in immune thrombocytopenia (ITP) and associates with response to anti-CD20 monoclonal antibody treatment (rituximab). IgG-Fc glycosylation was analyzed by liquid chromatography-mass spectrometry. We found that IgG-Fc glycosylation was identical between refractory ITP patients (HOVON64 trial; N = 108) and healthy controls (N = 120). Two months after rituximab treatment, we observed a shift in Fc glycosylation, with a mean 1.7% reduction in galactosylation for IgG1 and IgG4 and a mean 1.5% increase for bisection in IgG1, IgG2/3 and IgG4 (adjusted p < 1.7 × 10 and p < 2 × 10, respectively). Neither baseline nor longitudinal changes in IgG-Fc glycosylation after rituximab were associated with clinical treatment response. We conclude that IgG-Fc glycosylation in refractory ITP is similar to healthy controls and does not predict treatment responses to rituximab. The observed changes two months after treatment suggest that rituximab may influence total serum IgG-Fc glycosylation. Overall, our study suggests that the pathophysiology of refractory ITP may differ from other autoimmune diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-020-59651-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7033207PMC
February 2020

Anti-platelet antibodies in childhood immune thrombocytopenia: Prevalence and prognostic implications.

J Thromb Haemost 2020 05 12;18(5):1210-1220. Epub 2020 Apr 12.

Laboratory for Platelet and Leukocyte Serology, Department of Immunohematology Diagnostics, Sanquin Diagnostic Services, Amsterdam, the Netherlands.

Background: Anti-platelet antibody testing may be useful for the diagnosis and management of childhood immune thrombocytopenia (ITP).

Objectives: Here we aimed to assess the prevalence and prognostic significance of anti-platelet glycoprotein-specific IgM and IgG antibodies.

Methods: Children with newly diagnosed ITP were included at diagnosis and randomized to an intravenous immunoglobulins (IVIg) or careful observation group (TIKI trial). In this well-defined and longitudinally followed cohort (N = 179), anti-platelet glycoprotein-specific IgM and IgG antibodies were determined by monoclonal antibody-immobilization of platelet antigens.

Results: The dominant circulating anti-platelet antibody class in childhood ITP was IgM (62% of patients); but IgG antibodies were also found (10%). Children without IgM platelet antibodies were older and more often female. There was weak evidence for an association between IgM anti-GP IIb/IIIa antibodies and an increased bleeding severity (P = .03). The IgM and IgG anti-platelet responses partially overlapped, and reactivity was frequently directed against multiple glycoproteins. During 1-year follow-up, children with IgM antibodies in the observation group displayed a faster platelet recovery compared to children without, also after adjustment for age and preceding infections (P = 7.1 × 10 ). The small group of patients with detectable IgG anti-platelet antibodies exhibited an almost complete response to IVIg treatment (N = 12; P = .02), suggesting that IVIg was particularly efficacious in these children.

Conclusions: Testing for circulating anti-platelet antibodies may be helpful for the clinical prognostication and the guidance of treatment decisions in newly diagnosed childhood ITP. Our data suggest that the development of even more sensitive tests may further improve the clinical value of antibody testing.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/jth.14762DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7318215PMC
May 2020

Suppression of compensatory erythropoiesis in hemolytic disease of the fetus and newborn due to intrauterine transfusions.

Am J Obstet Gynecol 2020 07 21;223(1):119.e1-119.e10. Epub 2020 Jan 21.

Center for Clinical Transfusion Research, Sanquin Research, Leiden, the Netherlands; Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, the Netherlands; Department of Immunohematology Diagnostics, Sanquin, Amsterdam, the Netherlands.

Background: Infants with severe hemolytic disease of the fetus and newborn often require 1 or multiple intrauterine transfusions to treat fetal anemia. Intrauterine transfusions may have an inhibiting effect on fetal and neonatal erythropoiesis.

Objective: To quantify the effect of 1 or multiple intrauterine transfusions on the fetal erythropoiesis by assessing the fetal reticulocyte counts in a population with severe hemolytic disease of the fetus and newborn.

Study Design: This was an observational cohort study in infants admitted to the Leiden University Medical Center who received 1 or multiple intrauterine transfusions for hemolytic disease of the fetus and newborn caused by (Rh)D or Kell antibodies and were born between January 2005 and December 2018.

Results: A total of 235 patients were included, of whom 189 were patients with D-mediated hemolytic disease of the fetus and newborn and 46 with Kell-mediated hemolytic disease of the fetus and newborn. Absolute fetal reticulocyte count in D-mediated hemolytic disease of the fetus and newborn declined exponentially over the course of consecutive intrauterine transfusions, with a 62% decline after 1 intrauterine transfusion (95% confidence interval, 56-67). A similar exponential decline was observed in Kell-mediated hemolytic disease of the fetus and newborn, with 32% (95% confidence interval, 19-45) decline after 1 intrauterine transfusion. This decline was not associated with the varying gestational age at the time of the first intrauterine transfusion or the total number of intrauterine transfusions. The number of red blood cell transfusions for postnatal anemia was greater for infants with D and Kell-mediated hemolytic disease of the fetus and newborn with >2 intrauterine transfusions (median of 3 [interquartile range, 2-3] vs 2 [interquartile range, 1-3], P=.035, in D-mediated disease and median of 2 [interquartile range, 1-2] vs 1 [interquartile range, 1-1], P<.001, in Kell-mediated disease). Infants born after >2 intrauterine transfusions less often required exchange transfusion in D-mediated hemolytic disease of the fetus and newborn (19/89 [21%] vs 31/100 [31%], P=.039), compared with infants with 1-2 intrauterine transfusions.

Conclusion: Treatment with intrauterine transfusions causes an exponential decrease in fetal reticulocyte counts in both D- and Kell-mediated hemolytic disease of the fetus and newborn. Suppression of the compensatory erythropoiesis leads to prolonged postnatal anemia and an increased requirement of red blood cell transfusions after birth.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ajog.2020.01.028DOI Listing
July 2020

Knowledge, attitude and practices of obstetric care providers towards maternal red-blood-cell immunization during pregnancy.

Vox Sang 2020 Apr 29;115(3):211-220. Epub 2019 Dec 29.

Department of Clinical Transfusion Research, Sanquin Research, Leiden, The Netherlands.

Background And Objectives: A successful routine RBC alloantibody screening programme should not lead to unnecessary emotional burden during pregnancy due to inadequate counselling on the risk of severe haemolytic disease of the foetus and the newborn (HDFN). Rareness of this disease may result in insufficient knowledge and subsequent inadequate information transfer to women, diagnosed with RBC antibodies. We investigated the current knowledge, views and experiences of Dutch obstetric care providers regarding RBC alloimmunization during pregnancy.

Materials And Methods: We performed a quantitative cross-sectional study, using a structured digital questionnaire to measure knowledge, attitude and practices (KAP) regarding maternal RBC alloimmunization among Dutch obstetric care providers in 2016.

Results: About 10% of obstetric care providers completed the questionnaire. A sufficient level of knowledge was found in 7% of all participants (N = 329). Knowledge about RhD immunisation and prophylaxis was sufficient in 60% of the responders. Knowledge gaps were found concerning the relevance of non-RhD RBC antibodies, the indications for giving extra RhD prophylaxis and the interpretation of laboratory test results. Healthcare providers estimated their own level of knowledge 'sufficient' (primary/secondary care) to 'good' (tertiary care), and all participants considered their professional role important within the screening programme.

Conclusion: Dutch obstetric care providers showed a lack of knowledge regarding maternal RBC immunization. Awareness of the lack of knowledge is necessary to help obstetric care providers to be careful in giving information and even to decide to contact the expert centre before counselling the patient.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/vox.12883DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7187211PMC
April 2020

Diagnostic value of laboratory monitoring to predict severe hemolytic disease of the fetus and newborn in non-D and non-K-alloimmunized pregnancies.

Transfusion 2020 02 23;60(2):391-399. Epub 2019 Dec 23.

Center of Clinical Transfusion Research, Sanquin Research and Leiden University Medical Center, Leiden, The Netherlands.

Background: Pregnant women are routinely screened for red blood cell (RBC) antibodies early in pregnancy. If RBC-alloantibodies are detected, repeated laboratory testing is advised to timely identify pregnancies at high risk for severe hemolytic disease of the fetus and newborn (HDFN). We assessed for RBC alloantibodies, other than anti-D or anti-K, cut-offs for the titer and the antibody dependent cellular cytotoxicity (ADCC) test to select high-risk cases. To advise on test repeat intervals, and to avoid unnecessary testing, we evaluated the chance for exceeding the cut-offs for Rh antibodies other than anti-D, Jk, Fy, and S/s antibodies.

Study Design And Methods: Diagnostic value of antibody titer and ADCC test was determined with data from a prospective index-cohort study, conducted in 2002-2004. Laboratory test outcomes were from a recent observational cohort (2015-2016).

Results: A titer cut-off of ≥16 showed a sensitivity of 100% (95% CI:73-100%) and a positive predictive value (PPV) of 17% (95% CI:14%-20%). The percentage of pregnancies reaching a titer above the cut-off of ≥16 varied from 0% for anti-Jk /Jk (n = 38) to 36% for anti-c (n = 97). The ADCC test showed no cut-off with a 100% sensitivity. However, in cases with a titer ≥16 and an ADCC test ≥30% a PPV of 38% was obtained to detect severe HDFN.

Conclusion: A titer cut-off of ≥16 is adequate to detect all cases at risk for severe HDFN; the ADCC test may add a more accurate risk estimation. Repeated testing is recommended in pregnancies with anti-c. In pregnancies with other Rh antibodies a repeated test in the third trimester is recommended.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/trf.15631DOI Listing
February 2020

Necrotizing enterocolitis in haemolytic disease of the newborn: a retrospective cohort study.

Vox Sang 2020 Feb 19;115(2):196-201. Epub 2019 Dec 19.

Department of Pediatrics, Division of Neonatology, Leiden University Medical Center, Leiden, The Netherlands.

Background And Objectives: Necrotizing enterocolitis (NEC) is a common and often severe gastrointestinal emergency in newborn infants. While usually affecting (very) premature infants, an association between NEC and haemolytic disease of the foetus and newborn (HDFN) has been suggested. HDFN may be an additional risk factor to develop NEC. The objective of this study was to evaluate the occurrence of NEC in infants affected with moderate to severe HDFN in a large single centre cohort as compared to a broad population of infants without HDFN.

Materials And Methods: Retrospective cohort study of medical records of neonates with and without HDFN, with a gestational age at birth ≥30 weeks and ≤38 weeks, and admitted to the Leiden University Medical Center between January 2000 and December 2016.

Results: A total of 3284 patient records of infants born in the study period were reviewed and 317 cases of HDFN were identified. The incidence of NEC was significantly higher among infants with HDFN compared to infants without HDFN: 4/317 affected infants (1·3%) vs. 11/2967 affected infants (0·4%, relative risk 3·40, 95% confidence interval: 1·09-10·63).

Conclusions: We observed a higher incidence of NEC in an overall late preterm to near term population of infants with moderate to severe HDFN, compared to infants born without HDFN. The clinician taking care of an HDFN-affected infant should be cautious of this higher risk.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/vox.12862DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7028041PMC
February 2020

Genetic Variation in Low-To-Medium-Affinity Fcγ Receptors: Functional Consequences, Disease Associations, and Opportunities for Personalized Medicine.

Front Immunol 2019 3;10:2237. Epub 2019 Oct 3.

Sanquin Research and Landsteiner Laboratory, Department of Blood Cell Research, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands.

Fc-gamma receptors (FcγR) are the cellular receptors for Immunoglobulin G (IgG). Upon binding of complexed IgG, FcγRs can trigger various cellular immune effector functions, thereby linking the adaptive and innate immune systems. In humans, six classic FcγRs are known: one high-affinity receptor (FcγRI) and five low-to-medium-affinity FcγRs (FcγRIIA, -B and -C, FcγRIIIA and -B). In this review we describe the five genes encoding the low-to-medium -affinity FcγRs (, and , including well-characterized functionally relevant single nucleotide polymorphisms (SNPs), haplotypes as well as copy number variants (CNVs), which occur in distinct copy number regions across the locus. The evolution of the locus is also discussed. Importantly, we recommend a consistent nomenclature of genetic variants in the locus. Next, we focus on the relevance of genetic variation in the locus in auto-immune and auto-inflammatory diseases, highlighting pathophysiological insights that are informed by genetic association studies. Finally, we illustrate how specific FcγR variants relate to variation in treatment responses and prognosis amongst autoimmune diseases, cancer and transplant immunology, suggesting novel opportunities for personalized medicine.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2019.02237DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6786274PMC
October 2020

Anti-glycoprotein Ibα autoantibodies do not impair circulating thrombopoietin levels in immune thrombocytopenia patients.

Haematologica 2020 04 11;105(4):e172-e174. Epub 2019 Jul 11.

Sanquin Research, Department of Experimental Immunohematology and Landsteiner Laboratory, Amsterdam UMC, University of Amsterdam, Amsterdam

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3324/haematol.2019.228908DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7109722PMC
April 2020

Transient and chronic childhood immune thrombocytopenia are distinctly affected by Fc-γ receptor polymorphisms.

Blood Adv 2019 07;3(13):2003-2012

Department of Immunohematology Diagnostics, Sanquin Diagnostic Services, Amsterdam, The Netherlands.

In childhood immune thrombocytopenia (ITP), anti-platelet autoantibodies mediate platelet clearance through Fc-γ receptor (FcγR)-bearing phagocytes. In 75% to 90% of patients, the disease has a transient, self-limiting character. Here we characterized how polymorphisms of FcγR genes affect disease susceptibility, response to intravenous immunoglobulin (IVIg) treatment, and long-term recovery from childhood ITP. Genotyping of the locus was performed in 180 children with newly diagnosed ITP, 22 children with chronic ITP, and 180 healthy control children by multiplex ligation-dependent probe amplification. Children with newly diagnosed ITP were randomly assigned to a single administration of IVIg or observation, and followed for 1 year (Treatment With or Without IVIg for Kids With ITP [TIKI] trial). We defined transient ITP as a complete recovery (≥100 × 10/L) 3 months after diagnosis, including both self-limiting disease/IVIg responders and chronic ITP as absence of a complete recovery at 12 months. ITP susceptibility, as well as spontaneous recovery and response to IVIg, was associated with the genetic variants *ORF and *27W and the promoter variant 2B.4. These variants were overrepresented in patients with transient (N = 131), but not chronic (N = 43), disease. The presence of *ORF predisposed to transient ITP with an odds ratio of 4.7 (95% confidence interval, 1.9-14.3). Chronic ITP was associated with a deletion of (copy number region 1) with an odds ratio of 6.2 (95% confidence interval, 1.8-24.7). Taken together, susceptibility to transient and chronic ITP is distinctly affected by polymorphic variants of genes. Our data suggest that genotyping of the locus may be useful for prognosis and guidance of treatment decisions in newly diagnosed childhood ITP.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/bloodadvances.2019000068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6616256PMC
July 2019

Complement C3 inhibition by compstatin Cp40 prevents intra- and extravascular hemolysis of red blood cells.

Haematologica 2020 31;105(2):e57-e60. Epub 2020 Jan 31.

Sanquin Research, Department of Immunopathology, Amsterdam and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3324/haematol.2019.216028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7012486PMC
January 2020

Predicting anaemia and transfusion dependency in severe alloimmune haemolytic disease of the fetus and newborn in the first 3 months after birth.

Br J Haematol 2019 08 29;186(4):565-573. Epub 2019 May 29.

Department of Paediatrics, Division of Neonatology, Leiden University Medical Centre, Leiden, the Netherlands.

Infants with haemolytic disease of the fetus and newborn (HDFN) often require erythrocyte transfusions in the first 3 months of life. We aimed to evaluate the incidence, timing and potential predictors of transfusion-dependent anaemia. An observational cohort of 298 term and near-term infants with severe HDFN treated with or without intrauterine transfusion (IUT) was evaluated. Transfusions were administered to 88% (169/193) of infants with IUT and 60% (63/105) without IUT. The following potential predictors were associated with less anaemia: K compared to D immunisation [odds ratio (OR) 0·13, 95% confidence interval (CI): 0·03-0·55], higher reticulocyte count at birth [per 10 parts per thousand (‰) higher, OR 0·99, CI: 0·97-1·00] and exchange transfusion (OR 0·11, 95% CI: 0·03-0·50). Without IUT, these variables were: lower reticulocyte count at birth (per 10‰ lower, OR 1·02, 95% CI: 1·00-1·03), lower maximum bilirubin after birth (per 10 μmol/l lower, OR 1·01, 95% CI: 1·01-1·02) and exchange transfusion (OR 0·07, 95% CI: 0·01-0·20). In conclusion, potential predictors for anaemia in infants with severe HDFN varied between infants treated with and without IUT and are useful for selecting subgroups of infants at increased risk of anaemia.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/bjh.15962DOI Listing
August 2019

Neonatal Alloimmune Neutropenia.

Transfus Med Hemother 2018 Oct 24;45(5):311-316. Epub 2018 Sep 24.

Immunohematology Diagnostic Services, Sanquin Diagnostic Services, Amsterdam, the Netherlands.

Neonatal alloimmune neutropenia (NAIN, NAIN or NIN) is a neutrophil blood group antagonism, analogous to hemolytic disease of the fetus and newborn (HDFN) and fetal/neonatal alloimmune thrombocytopenia (FNAIT). A limited number of prospective screening studies showed that granulocyte-specific antibodies were detectable in 0.35-1.1% of random postnatal maternal samples and that the incidence of NAIN was below 0.1%. Symptoms vary from none to mild skin infections, omphalitis or more severe infections like pneumonia, sepsis, and meningitis. Treatment of neonatal infection with antibiotics and granulocyte-colony stimulating factor is advised.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000492949DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6489100PMC
October 2018

Plasma thrombopoietin levels as additional tool in clinical management of thrombocytopenic neonates.

Platelets 2020 13;31(1):62-67. Epub 2019 Feb 13.

Department of Immunohematology Diagnostic Services Amsterdam, Sanquin Diagnostic Services, Amsterdam, The Netherlands.

Plasma thrombopoietin (Tpo) levels distinguish thrombocytopenia resulting from increased platelet destruction or decreased platelet production. We investigated whether measuring plasma Tpo levels in thrombocytopenic newborns is of diagnostic value to establish the underlying mechanism of thrombocytopenia.Tpo levels were measured with in-house developed ELISA in samples referred to our center because of thrombocytopenia noticed in the first 10 days of life. Clinical data were collected.Plasma Tpo levels <128 AU/ml were found in the majority (92%) of 121 newborns with immune-mediated thrombocytopenia ( = 104) and thrombocytopenia due to bacterial infections ( = 7); increased plasma Tpo levels (≥128 AU/ml) were found in thrombocytopenic newborns with severe asphyxia ( = 24). Highly increased plasma Tpo levels (>200 AU/ml) were found in thrombocytopenic neonates with congenital viral infections ( = 22) or amegakaryocytosis ( = 6). A plasma Tpo level <128 AU/ml excludes (negative predictive value 96%, 95% CI 90-99) severe asphyxia, congenital viral infections and amegakaryocytosis as the cause for thrombocytopenia in newborns.Increased plasma Tpo levels indicate that thrombocytopenia in newborns, as a result of various nonimmune disorders, is often caused by (temporary) bone marrow suppression/failure. Measurement of plasma Tpo levels provides the clinician with an additional tool to decide on the differential diagnosis, the necessity for subsequent diagnostics and treatment in neonates with thrombocytopenia.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/09537104.2019.1572877DOI Listing
April 2020

International Society of Blood Transfusion Working Party on Red Cell Immunogenetics and Blood Group Terminology: Report of the Dubai, Copenhagen and Toronto meetings.

Vox Sang 2019 Jan 12;114(1):95-102. Epub 2018 Nov 12.

Rabin Medical Center, Petach Tiqva, Israel.

Background And Objectives: The International Society of Blood Transfusion (ISBT) Working Party for Red Cell Immunogenetics and Blood Group Terminology meets in association with the ISBT congress and has met three times since the last report: at the international meetings held in Dubai, United Arab Emirates, September 2016 and Toronto, Canada, June 2018; and at a regional congress in Copenhagen, Denmark, June 2017 for an interim session.

Methods: As in previous meetings, matters pertaining to blood group antigen nomenclature and classification were discussed. New blood group antigens were approved and named according to the serologic and molecular evidence presented.

Results And Conclusions: Fifteen new blood group antigens were added to eight blood group systems. One antigen was made obsolete based on additional data. Consequently, the current total of blood group antigens recognized by the ISBT is 360, of which 322 are clustered within 36 blood groups systems. The remaining 38 antigens are currently unassigned to a known system. Clinically significant blood group antigens continue to be discovered, through serology/sequencing and/or recombinant or genomic technologies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/vox.12717DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6342652PMC
January 2019

Anti-HLA antibodies with complementary and synergistic interaction geometries promote classical complement activation on platelets.

Haematologica 2019 02 27;104(2):403-416. Epub 2018 Sep 27.

Department of Immunohaematology and Blood Transfusion, Leiden University Medical Center

High titers of HLA antibodies are associated with platelet refractoriness, causing poor platelet increments after transfusions in a subset of patients with HLA antibodies. Currently, we do not know the biological mechanisms that explain the variability in clinical responses in HLA alloimmunized patients receiving platelet transfusions. Previously we showed that a subset of anti-HLA IgG-antibodies induces FcγRIIa-dependent platelet activation and enhanced phagocytosis. Here, we investigated whether anti-HLA IgG can induce complement activation on platelets. We found that a subset of anti-HLA IgG induced complement activation via the classical pathway, causing C4b and C3b deposition and formation of the membrane-attack complex. This resulted in permeabilization of platelet membranes and increased calcium influx. Complement activation also caused enhanced α-granule release, as measured by CD62P surface exposure. Blocking studies revealed that platelet activation was caused by FcγRIIa-dependent signaling as well as HLA antibody induced complement activation. Synergistic complement activation employing combinations of monoclonal IgGs suggested that assembly of oligomeric IgG complexes strongly promoted complement activation through binding of IgGs to different antigenic determinants on HLA. In agreement with this, we observed that preventing anti-HLA-IgG hexamer formation using an IgG-Fc:Fc blocking peptide, completely inhibited C3b and C4b deposition. Our results show that HLA antibodies can induce complement activation on platelets including membrane attack complex formation, pore formation and calcium influx. We propose that these events can contribute to fast platelet clearance in patients refractory to platelet transfusions with HLA alloantibodies, who may benefit from functional-platelet matching and treatment with complement inhibitors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3324/haematol.2018.201665DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6355480PMC
February 2019

The near disappearance of fetal hydrops in relation to current state-of-the-art management of red cell alloimmunization.

Prenat Diagn 2018 11 27;38(12):943-950. Epub 2018 Sep 27.

Department of Obstetrics, Leiden University Medical Center, Leiden, The Netherlands.

Objective: In this study, we aim to evaluate trends in the condition of fetuses and neonates with hemolytic disease at the time of first intrauterine transfusion (IUT) and at birth, in relation to routine first-trimester antibody screening, referral guidelines, and centralization of fetal therapy.

Method: We conducted a 30-year cohort study including all women and fetuses treated with IUT for red cell alloimmunization at the Dutch national referral center for fetal therapy.

Results: Six hundred forty-five fetuses received 1852 transfusions between 1 January 1987 and 31 December 2016. After the introduction of routine first-trimester antibody screening, the hydrops rate declined from 39% to 15% (OR 0.284, 95% CI, 0.19-0.42, P < 0.001). In the last time cohort, only one fetus presented with severe hydrops (OR 0.482, 95% CI, 0.38-0.62, P < 0.001). Infants are born less often <32 weeks (OR 0.572, 95% CI, 0.39-0.83, P = 0.004) and with higher neonatal hemoglobin (P < 0.001). Neonatal hemoglobin was positively independently associated with gestational age at birth, fetal hemoglobin, and additional intraperitoneal transfusion at last IUT.

Conclusion: Severe alloimmune hydrops, a formerly often lethal condition, has practically disappeared, most likely as a result of the introduction of routine early alloantibody screening, use of national guidelines, and pooling of expertise in national reference laboratories and a referral center for fetal therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/pd.5355DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6282502PMC
November 2018

Predicting anti-Kell-mediated hemolytic disease of the fetus and newborn: diagnostic accuracy of laboratory management.

Am J Obstet Gynecol 2018 10 29;219(4):393.e1-393.e8. Epub 2018 Jul 29.

Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands; Department of Immunohematology Diagnostics, Sanquin Diagnostic Services, Amsterdam, The Netherlands; Department of Clinical Transfusion Research, Sanquin Research, Amsterdam, The Netherlands.

Background: There is controversy on critical cut-off values of laboratory testing to select pregnancies at increased risk for anti-Kell-mediated hemolytic disease of the fetus and newborn. Without early detection and treatment, anti-Kell-mediated hemolytic disease of the fetus and newborn may result in progressive fetal anemia, fetal hydrops, asphyxia, and perinatal death.

Objective: We aimed to determine the value of repeated anti-Kell titer determination and biological activity measurement using the antibody-dependent cellular cytotoxicity test determination in the management of pregnancies at risk for anti-Kell-mediated hemolytic disease of the fetus and newborn.

Study Design: This was a retrospective cohort study of pregnancies with anti-Kell and a Kell-positive fetus, identified from January 1999 through April 2015. Laboratory test results and clinical outcome were collected from the Dutch nationwide screening program and the national reference center for fetal therapy in The Netherlands, the Leiden University Medical Center. Diagnostic accuracy was measured (receiver operating characteristic curves, sensitivity, specificity, positive and negative predictive values) for anti-Kell titers and antibody-dependent cellular cytotoxicity test. The relationship between the titer and antibody-dependent cellular cytotoxicity measurements and the 2 foregoing measurements were computed with a Pearson product-moment correlation coefficient.

Results: In a 16-year unselected cohort, representing screening results of 3.2 million pregnancies resulting in live births in The Netherlands, we identified 1026 Kell-immunized pregnancies. In all, 93 pregnant women had anti-Kell and a Kell-positive child, without other red cell alloantibodies. In all, 49 children (53%) needed intrauterine or postnatal transfusion therapy. The first anti-Kell titer showed already a high diagnostic accuracy with an area under the curve of 91%. The optimal cut-off point for the titer was 4 (sensitivity 100%; 95% confidence interval, 91-100), specificity 27% (95% confidence interval, 15-43), and positive predictive value 60% (49-71%). The antibody-dependent cellular cytotoxicity test was not informative to select high-risk pregnancies. Linear regression showed no significant change during pregnancy, when antibody titer and antibody-dependent cellular cytotoxicity test results were compared with every 2 foregoing measurements (P < .0001).

Conclusion: Early determination of the anti-Kell titer is sufficient to select pregnancies at increased risk for hemolytic disease of the fetus and newborn with need for transfusion therapy. If the Kell status of the fetus is known to be positive, a titer of ≥4 can be used to target intensive clinical monitoring.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ajog.2018.07.020DOI Listing
October 2018

Intravenous immunoglobulin vs observation in childhood immune thrombocytopenia: a randomized controlled trial.

Blood 2018 08 26;132(9):883-891. Epub 2018 Jun 26.

Department of Pediatric Hematology, University Medical Center Utrecht, Utrecht, The Netherlands.

Management of children with newly diagnosed immune thrombocytopenia (ITP) consists of careful observation or immunomodulatory treatment. Observational studies suggest a lower risk for chronic ITP in children after intravenous immunoglobulin (IVIg) treatment. In this multicenter randomized trial, children aged 3 months to 16 years with newly diagnosed ITP, platelet counts 20 × 10/L or less, and mild to moderate bleeding were randomly assigned to receive either a single infusion of 0.8 g/kg IVIg or careful observation. Primary outcome was development of chronic ITP, which at the time of study initiation was defined as a platelet count lower than 150 × 10/L after 6 months. Two hundred six children were allocated to receive IVIg (n = 102) or careful observation (n = 104). Chronic ITP occurred in 18.6% of the patients in the IVIg group and 28.9% in the observation group (relative risk [RR], 0.64; 95% confidence interval [CI], 0.38-1.08). Platelet counts lower than 100 × 10/L at 12 months (current definition of chronic ITP) were observed in 10% of children in the IVIg group and 12% in the observation group (RR, 0.83; 95% CI, 0.38-1.84). Complete response rates in the first 3 months were significantly higher in the IVIg group. Immunoglobulin G Fc receptor IIb genetic variations were associated with early complete response in both groups. Grade 4 to 5 bleeding occurred in 9% of the patients in the observation group vs 1% in the IVIg group. This trial was registered at www.trialregister.nl as NTR 1563.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood-2018-02-830844DOI Listing
August 2018

Postponing Early intrauterine Transfusion with Intravenous immunoglobulin Treatment; the PETIT study on severe hemolytic disease of the fetus and newborn.

Am J Obstet Gynecol 2018 09 11;219(3):291.e1-291.e9. Epub 2018 Jun 11.

Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands; Center for Clinical Transfusion Research, Sanquin Research, Leiden University Medical Center, Leiden, The Netherlands; Immunohematology Diagnostic Services, Sanquin Blood Supply, Amsterdam, The Netherlands.

Background: Intrauterine transfusion for severe alloimmunization in pregnancy performed <20 weeks' gestation is associated with a higher fetal death rate. Intravenous immunoglobulins may prevent hemolysis and could therefore be a noninvasive alternative for early transfusions.

Objective: We evaluated whether maternal treatment with intravenous immunoglobulins defers the development of severe fetal anemia and its consequences in a retrospective cohort to which 12 fetal therapy centers contributed.

Study Design: We included consecutive pregnancies of alloimmunized women with a history of severe hemolytic disease and by propensity analysis compared index pregnancies treated with intravenous immunoglobulins (n = 24) with pregnancies managed without intravenous immunoglobulins (n = 28).

Results: In index pregnancies with intravenous immunoglobulin treatment, fetal anemia developed on average 15 days later compared to previous pregnancies (8% less often <20 weeks' gestation). In pregnancies without intravenous immunoglobulin treatment anemia developed 9 days earlier compared to previous pregnancies (10% more <20 weeks), an adjusted 4-day between-group difference in favor of the immunoglobulin group (95% confidence interval, -10 to +18; P = .564). In the subcohort in which immunoglobulin treatment was started <13 weeks, anemia developed 25 days later and 31% less <20 weeks' gestation (54% compared to 23%) than in the previous pregnancy. Fetal hydrops occurred in 4% of immunoglobulin-treated pregnancies and in 24% of those without intravenous immunoglobulin treatment (odds ratio, 0.03; 95% confidence interval, 0-0.5; P = .011). Exchange transfusions were given to 9% of neonates born from pregnancies with and in 37% without immunoglobulin treatment (odds ratio, 0.1; 95% confidence interval, 0-0.5; P = .009).

Conclusion: Intravenous immunoglobulin treatment in mothers pregnant with a fetus at risk for hemolytic disease seems to have a potential clinically relevant, beneficial effect on the course and severity of the disease. Confirmation in a multicenter randomized trial is needed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ajog.2018.06.007DOI Listing
September 2018