Jens Kjeldsen-Kragh

Reconsidering fetal and neonatal alloimmune thrombocytopenia with a focus on screening and prevention

Uncertainty regarding the pathophysiology of fetal and neonatal alloimmune thrombocytopenia (FNAIT) has hampered the decision regarding how to identify, follow-up and treat the women and children with this potentially serious condition. Since knowledge of the condition is derived mainly from retrospective studies, understanding of the natural history of this condition remains incomplete. General screening programs for FNAIT have still not been introduced, mainly because of a lack of reliable risk factors and effective treatment. Now, several prospective screening studies involving up to 100,000 pregnant women have been published and the results have changed the understanding of the pathophysiology of FNAIT and, thereby, the approach toward diagnostics, prevention and treatment in a more appropriate way.

In HPA 1a-immunized women the decrease in anti-HPA 1a antibody level during pregnancy is not associated with anti-idiotypic antibodies

A large screening and intervention study, aimed at reducing morbidity and mortality associated with severe anti-HPA 1a antibody induced neonatal alloimmune thrombocytopenia (NAIT), has recently been carried out in Norway.[1][1] Recently, it was shown that the anti-HPA 1a levels surprisingly

True risk of fetal/neonatal alloimmune thrombocytopenia in subsequent pregnancies: a prospective observational follow-up study

To assess neonatal platelet counts by comparing alloimmunised pregnancies from a Norwegian screening and intervention study with subsequent pregnancies from the same women.

3′,4′-Dimethoxyflavone and valproic acid promotes the proliferation of human hematopoietic stem cells

IntroductionHuman hematopoietic stem cells (HSCs) have been clinically used for transplantation and gene and cellular therapy for more than 4 decades. However, this use is limited because of the challenges in the ex vivo culturing of HSCs. The major hurdle is to amplify these cells without losing their self-renewing property.MethodsIn our study, we tested 3′,4′-dimethoxyflavone (3′4′-DMF) and valproic acid (VPA) on the ex vivo expansion of HSCs under both normoxic (20% O2) and hypoxic (1% O2) conditions. 3′4′-DMF is a widely used anticancer drug that acts as a competitive antagonist of the aryl hydrocarbon receptor. VPA is a potent inhibitor of histone deacetylase and is used in the treatment of neurologic disorders.ResultsCulturing HSCs (from mobilized peripheral blood) under normoxia, with 3′4′-DMF and VPA, highly preserved the CD34 positivity (3′4′-DMF, 22.1%, VPA, 20.3%) after 1 week and strongly enhanced the CD34+ cells (3′4′-DMF, 27.8 fold; VPA, 34.1 fold) compared with the control cultures (11.6% and 14.4 fold). Addition of 3′4′-DMF and VPA also resulted in more primary colonies and replating efficiency compared with control cultures. Although no significant effect was observed on the enhancement of CD34+ cells under hypoxia, the number of primary colonies was significantly higher than the control cultures.ConclusionsBased on these findings, this study presents, for the first time, in vitro evidence for a new and relevant effect of 3′4′-DMF on human HSCs. In addition, the results suggest a potential clinical use of 3′4′-DMF and VPA in HSC therapy.

The pathophysiology of FNAIT cannot be deduced from highly selected retrospective data.

To the editor: Today there is no consensus regarding the optimal method for determining the fetal status when the mother has alloantibodies against fetal platelets. Therefore, it was with great interest we read the article by Bertrand et al[1][1] recently published in Blood . However, we feel that

Determination of fetal RHD type in plasma of RhD negative pregnant women

Abstract Alloimmunization against the RhD antigen is the most common cause of hemolytic disease of the fetus and newborn. Antenatal anti-D prophylaxis in addition to postnatal anti-D prophylaxis reduces the number of RhD-immunizations compared to only postnatal administration. Cell-free fetal DNA released from the apoptotic trophoblastic placental cells into the maternal circulation can be used to determine the fetal RHD type in a blood sample from an RhD negative mother. Based on this typing, antenatal anti-D prophylaxis can be recommended only to RhD negative women carrying an RhD positive fetus, since only these women are at risk of developing anti-D. The objective was to establish and validate a method for non-invasive fetal RHD typing. The fetal RHD genotype was studied in 373 samples from RhD negative pregnant women (median gestational week 24). DNA extracted from plasma was analyzed for the presence/absence of RHD exon 7 and 10 in a real-time PCR. The RHD genotype of the fetus was compared with the serological RhD type of the newborn. In 234 samples, the fetal RHD test was positive and in 127 samples negative. There was one false positive and no false negative results. In 12 samples, the fetal RHD type could not be determined, in all of them due to a maternal RHD gene. This method gives a reliable detection of fetal RHD positivity in plasma from RhD negative pregnant women. Antenatal anti-D prophylaxis based on the predicted fetal RhD type will avoid unnecessary treatment of pregnant women carrying an RhD negative fetus.

Author response to: Cost-effectiveness analysis of screening for neonatal alloimmune thrombocytopenia was based on invalid assumption

Sir, We appreciate Atle Fretheim’s1 interest in our paper about cost-effectiveness of antenatal screening for neonatal alloimmune thrombocytopenia (NAIT).2 We are surprised, however, that Atle Fretheim is able to conclude without any reservation that ‘the key variable in the cost-effectiveness analysis is not valid’ and that ‘the comparison is clearly not valid’. We fully acknowledge that there is uncertainty regarding the effectiveness of the screening and intervention programme and the other parameters used for the costeffectiveness analysis (CEA). In the paper describing the outcome of the screening programme,3 we have explained that a randomised controlled trial (RCT) could not be carried out for both ethical and practical reasons, and therefore, we chose to compare our results with other previously published studies on NAIT.3,4 The data presented in Blood2 were not useful for the CEA because a CEA requires data on disability as well as fatality, and the CEA was therefore based on data from a large review of the literature that explored the morbidity and mortality of NAIT-related intracranial haemorrhage (ICH), including both prospective and retrospective studies. We agree that this data source was not optimal, and better data would have been preferred, but we were unable to identify other sources. In the CEA, we carried out both one-way sensitivity analyses and probabilistic sensitivity analyses to deal with these uncertainties. Moreover, we explicitly discuss these limitations in the paper.2 Even though the risk of fatality and disability were considerably lower with screening than without in the base-case analysis (1.8 versus 10.2% and 1.8 versus 15.0%, respectively), these risks were allowed to be almost equal for disability or even overlapping for fatality in the sensitivity analyses (Table 1 in our paper).2 There is also uncertainty associated with even the best RCT. Uncertainty can never be eliminated, but the challenge is to estimate the magnitude of the uncertainties and to deal with them appropriately, such as performing sensitivity analyses. Policy makers make decision on the basis of the best current knowledge, not upon perfect information that is unavailable. The objective of a decision analysis is exactly to help policy makers be better informed. In retrospect, we regret that we did not apply even wider bounds in the sensitivity analyses. However, if the difference in risk of fatality and disability between screening and no screening was reduced to 0.6 and 0.9%, the cost per quality adjusted life year (QALY) would still be less than V53,000. In Norway, the Ministry of Finance has considered this value to be the limit for what can be considered cost-effective.5 In other words, screening is cost-effective with lower effectiveness than we assumed in the sensitivity analysis. In the abstract of the paper, we concluded that ‘our calculations indicate that it is possible to establish an antenatal screening programme for NAIT that is cost-effective’.2 We see no reason to change this conclusion on the basis of Atle Fretheim’s criticism.1 j