Women and girls with bleeding disorders experience abnormal and excessive bleeding that can negatively impact their overall health and quality of life. In this report, we provide an overview of the biology, types, clinical care, and state of the science related to bleeding disorders in girls and women and describe Centers for Disease Control and Prevention (CDC) activities related to (1) surveillance of bleeding disorders in women; (2) scientific review, research, and collaboration to inform health care gaps in identifying and caring for women with bleeding disorders; and (3) development of health promotion and education programs to bring awareness about bleeding disorders to both women and girls in the population at large and various health care providers who care for women. Findings generated from surveillance and research activities inform the development of new public health programs aimed at improving diagnostic and health care services and empowering women with bleeding disorders with the knowledge they need to navigate a complex health care system with the need for specialty care services. Additional work is needed to improve provider awareness and understanding of the unique needs of women and girls with bleeding disorders to achieve appropriate care and treatment and ensure optimal outcomes and quality of life.

HaemophiliaVolume 28, Issue 3 p. e75-e78 LETTER TO THE EDITOR Occurrence rates of inherited bleeding disorders other than haemophilia and von Willebrand disease among people receiving care in specialized treatment centres in the United States Connie H. Miller, Corresponding Author Connie H. Miller cmiller2@cdc.gov orcid.org/0000-0002-3989-7973 Division of Blood Disorders, National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, Georgia, USA Synergy America, Inc., Duluth, Georgia, USA Correspondence Connie H. Miller, Division of Blood Disorders, National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, 1600 Clifton Road, MS D-02, Atlanta, GA 30333, USA. Email: cmiller2@cdc.govSearch for more papers by this authorJ. Michael Soucie, J. Michael Soucie Division of Blood Disorders, National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, Georgia, USA Synergy America, Inc., Duluth, Georgia, USASearch for more papers by this authorVanessa R. Byams, Vanessa R. Byams Division of Blood Disorders, National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, Georgia, USASearch for more papers by this authorAmanda B. Payne, Amanda B. Payne orcid.org/0000-0003-1027-7639 Division of Blood Disorders, National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, Georgia, USASearch for more papers by this authorKaron Abe, Karon Abe Division of Blood Disorders, National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, Georgia, USASearch for more papers by this authorMagdalena Lewandowska, Magdalena Lewandowska orcid.org/0000-0003-2581-1478 Indiana Hemophilia and Thrombosis Center, Indianapolis, Indiana, USASearch for more papers by this authorAmy D. Shapiro, Amy D. Shapiro orcid.org/0000-0003-2821-7159 Indiana Hemophilia and Thrombosis Center, Indianapolis, Indiana, USASearch for more papers by this author Connie H. Miller, Corresponding Author Connie H. Miller cmiller2@cdc.gov orcid.org/0000-0002-3989-7973 Division of Blood Disorders, National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, Georgia, USA Synergy America, Inc., Duluth, Georgia, USA Correspondence Connie H. Miller, Division of Blood Disorders, National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, 1600 Clifton Road, MS D-02, Atlanta, GA 30333, USA. Email: cmiller2@cdc.govSearch for more papers by this authorJ. Michael Soucie, J. Michael Soucie Division of Blood Disorders, National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, Georgia, USA Synergy America, Inc., Duluth, Georgia, USASearch for more papers by this authorVanessa R. Byams, Vanessa R. Byams Division of Blood Disorders, National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, Georgia, USASearch for more papers by this authorAmanda B. Payne, Amanda B. Payne orcid.org/0000-0003-1027-7639 Division of Blood Disorders, National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, Georgia, USASearch for more papers by this authorKaron Abe, Karon Abe Division of Blood Disorders, National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, Georgia, USASearch for more papers by this authorMagdalena Lewandowska, Magdalena Lewandowska orcid.org/0000-0003-2581-1478 Indiana Hemophilia and Thrombosis Center, Indianapolis, Indiana, USASearch for more papers by this authorAmy D. Shapiro, Amy D. Shapiro orcid.org/0000-0003-2821-7159 Indiana Hemophilia and Thrombosis Center, Indianapolis, Indiana, USASearch for more papers by this author First published: 04 March 2022 https://doi.org/10.1111/hae.14529Citations: 1Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Citing Literature Volume28, Issue3May 2022Pages e75-e78 RelatedInformation

significant difference by Wilcoxon test, and correlation greater than or equal to 0.90 in comparison to baseline in all tests for FVIII and FIX inhibitors, except for the FIX NBA, which showed a concordance of 97% from a single FIX specimen that tested at 0.1 NBU before and 0.3 NBU after storage refrigerated for 1 week. Specimens kept at room temperature (15– 25°C) for 1 week showed 100% concordance, no significant difference by Wilcoxon test, and correlation greater than 0.9 in comparison to baseline in all tests for FVIII and FIX inhibitors.

Introduction Females may have haemophilia with the same factor VIII (FVIII) or factor IX (FIX) levels as affected males. Characterization of females with haemophilia would be useful for health care planning to meet their unique needs. Federally-funded haemophilia treatment centres (HTCs) in the United States contribute data on all individuals with bleeding disorders receiving care to the Population Profile (HTC PP) component of the Community Counts Public Health Surveillance of Bleeding Disorders project. Aims To estimate the number of females with haemophilia receiving care at HTCs in the United States and compare their characteristics with those of males with haemophilia. Methods HTC PP data collected on people receiving care at an HTC from January 2012 through September 2020 with haemophilia A and B were evaluated by sex for demographic and clinical characteristics. Results A factor level < 40% was reported for 23,196 males (97.8%) and 1667 females (47.6%) attending HTCs; 51 (.48%) severe, 79 (1.4%) moderate, and 1537 (17.9%) mild haemophilia patients were female. Females were older, more often White, and less often non-Hispanic than males. Females were less likely to have history of HIV or HCV infection, even among those with severe disease, but twice as likely to have infection status unknown. Females with mild haemophilia were more often uninsured than males. Conclusions Females with severe or moderate haemophilia are uncommon, even in specialized care centres; however, almost one in five patients with mild haemophilia was female, indicating needs for specialized care based on factor level and history for affected females.

INTRODUCTION:Bleeding episodes in patients who have haemophilia A (HA), a hereditary bleeding disorder caused by a deficiency in factor VIII (FVIII), are treated or prophylactically prevented with infusions of exogenous FVIII. Neutralizing antibodies, referred to as inhibitors, against infusion products are a major complication experienced by up to 30% of patients who have severe HA. Bypassing agents (BPA), a class of therapeutics given to patients who have inhibitors, bypass the need for FVIII in the coagulation cascade, and long-term inhibitor eradication is accomplished using immune tolerance induction therapy (ITI). Data examining the antibody levels in patients receiving BPA and ITI are limited. AIM:Measure anti-FVIII antibody levels in specimens from patients receiving ITI or BPA in order to evaluate the anti-FVIII antibody response in those patients. METHODS:Specimens were tested using the CDC-modified Nijmegen-Bethesda assay (NBA) and the CDC fluorescence immunoassay (FLI) for anti-FVIII IgG1 and IgG4 . RESULTS:NBA-negative specimens from patients undergoing ITI or receiving BPAs have a higher frequency of anti-FVIII IgG4 positivity compared with the previously published level for NBA-negative HA patients. Analysis of anti-FVIII antibody levels in serial samples from patients undergoing ITI reveals that antibodies can persist even after the patient's NBA result falls into the negative range. CONCLUSIONS:Measurement of anti-FVIII antibodies may be a useful means to better contextualize NBA results in specimens from patients receiving BPA or ITI. In addition, assessment of anti-FVIII antibody levels has the potential to improve inhibitor surveillance and clinical decision-making related to the progress of ITI.

INTRODUCTION:In the network of U.S. comprehensive haemophilia treatment centres (HTCs), von Willebrand disease (VWD) is the most common bleeding disorder other than haemophilia. Estimates of the size and characteristics of the VWD population receiving treatment are useful for healthcare planning. AIM:Estimate the prevalence and incidence of VWD among males and females receiving care at U.S. HTCs (HTC-treated prevalence and incidence). METHODS:During the period 2012-2019, de-identified surveillance data were collected on all VWD patients who visited an HTC including year of birth, sex, race, Hispanic ethnicity, VWD type, and laboratory findings and used to calculate period HTC-treated prevalence by VWD type and sex. Data from patients born 1995-1999 were used to estimate HTC-treated incidence rates. RESULTS:During the period, 24,238 patients with a diagnosis of VWD attended HTCs; for 23,479 (96.9%), VWD type was reported or could be assigned. Age-adjusted HTC-treated prevalence was 8.6 cases/100,000 (7.2/100,000 for Type 1, 1.2/100,000 for Type 2 and 1.7/million for Type 3) and was twice as high in women as men (4.8 vs. 2.4 cases/100,000) for Type 1 and similar by sex for Type 2 and Type 3. HTC-treated Type 1 incidence increased over the period, averaging nearly threefold higher for women than men (26.2 vs. 9.9/100,000 live births). Sex differences were less for Type 2 (2.2 vs. 1.4 cases/100,000 births) and slight in Type 3. CONCLUSION:Prevalence and incidence of HTC-treated VWD differ by sex and type and are likely strongly influenced by differences in rates of diagnosis.

We previously described in this journal a modified Nijmegen‐Bethesda assay (NBA) for factor VIII (FVIII) inhibitors in hemophilia A (HA) that uses preanalytical heat inactivation of infused or endogenous FVIII to allow inhibitor measurement postinfusion1.Miller C.H. Platt S.J. Rice A.S. Kelly F. Soucie J.M. The Hemophilia Inhibitor Research Study InvestigatorsValidation of Nijmegen‐Bethesda assay modifications to allow inhibitor measurement during replacement therapy and facilitate inhibitor surveillance.J Thromb Haemost. 2012; 10: 1055-1061Crossref PubMed Scopus (84) Google Scholar and compared that assay with a chromogenic Bethesda assay (CBA) that is identical except for use of an FVIII chromogenic substrate assay (CSA) rather than a one‐stage assay (OSA) as the endpoint for inhibitor detection.2.Miller C.H. Rice A.S. Boylan B. et al.Comparison of clot‐based, chromogenic and fluorescence assays for measurement of factor VIII inhibitors in the US Hemophilia Inhibitor Research Study.J Thromb Haemost. 2013; 11: 1300-1309Crossref PubMed Scopus (51) Google Scholar Our primary focus was on use of the CBA as a confirmatory test for low positive NBA results. Introduction of the non‐FVIII treatment product emicizumab (Hemlibra) has brought increased interest in inhibitor assays using CSA because emicizumab interferes with the OSA and thus with Bethesda assays for FVIII inhibitors using the OSA.3.Adamkewicz J.I. Chen D.C. Paz‐Priel I. Effects and interferences of emicizumab, a humanised bispecific antibody mimicking activated factor VIII cofactor function, on coagulation assays.Thromb Haemost. 2019; 119: 1084-1093Crossref PubMed Scopus (71) Google Scholar, 4.Müller J. Pekrul I. Pötzsch B. Berning B. Oldenburg J. Spannagl M. Laboratory monitoring in emicizumab‐treated persons with hemophilia A.Thromb Haemost. 2019; 119: 1384-1393Crossref PubMed Scopus (47) Google Scholar, 5.Bowyer A. Kitchen S. Maclean R. Effects of emicizumab on APTT, one‐stage and chromogenic assays of factor VIII in artificially spiked plasma and in samples from haemophilia A patients with inhibitors.Haemophilia. 2020; 26: 536-542Crossref PubMed Scopus (26) Google Scholar CSA for FVIII that use bovine factor X (FX) are insensitive to emicizumab,5.Bowyer A. Kitchen S. Maclean R. Effects of emicizumab on APTT, one‐stage and chromogenic assays of factor VIII in artificially spiked plasma and in samples from haemophilia A patients with inhibitors.Haemophilia. 2020; 26: 536-542Crossref PubMed Scopus (26) Google Scholar and a CBA using such CSA has been successfully used for inhibitor testing in its presence.6.Adamkewicz J.I. Schmitt C. Asikanius E. Factor VIII (FVIII) inhibitor testing using a validated chromogenic Bethesda assay (CBA) in HAVEN 1 (BH29884), a phase 3 trial of emicizumab in persons with hemophilia A (PwHA) with inhibitors.RPTH. 2017; 1: 724-725Google Scholar, 7.Miller C.H. Boylan B. Payne A.B. Driggers J. Bean C.J. Validation of the chromogenic Bethesda assay for factor VIII inhibitors in hemophilia A patients receiving emicizumab.Int J Lab Hematol. 2021; 43Crossref PubMed Scopus (7) Google Scholar Clinical laboratories providing inhibitor testing have the option of maintaining two inhibitor assays and choosing the correct one for each patient depending on the product used or switching to a CBA to accommodate testing on all patients. Clinical adoption of a new assay methodology requires demonstration that the new method is equivalent to the old. Recent reexamination of the dataset of paired NBA and CBA results from our original paper2.Miller C.H. Rice A.S. Boylan B. et al.Comparison of clot‐based, chromogenic and fluorescence assays for measurement of factor VIII inhibitors in the US Hemophilia Inhibitor Research Study.J Thromb Haemost. 2013; 11: 1300-1309Crossref PubMed Scopus (51) Google Scholar revealed differences that may influence such comparisons and that, if not considered, could hinder validation of the CBA for clinical use. The results reexamined were from 1005 specimens collected from subjects with congenital HA enrolled in the Hemophilia Inhibitor Research Study between 2006 and 2012 at 17 US hemophilia treatment centers with previous inhibitor history collected from the enrolling sites.2.Miller C.H. Rice A.S. Boylan B. et al.Comparison of clot‐based, chromogenic and fluorescence assays for measurement of factor VIII inhibitors in the US Hemophilia Inhibitor Research Study.J Thromb Haemost. 2013; 11: 1300-1309Crossref PubMed Scopus (51) Google Scholar Briefly, the US Centers for Disease Control and Prevention–modified NBA was performed using an FVIII OSA and included heating of patient plasma to 56°C for 30 min and centrifugation before testing.1.Miller C.H. Platt S.J. Rice A.S. Kelly F. Soucie J.M. The Hemophilia Inhibitor Research Study InvestigatorsValidation of Nijmegen‐Bethesda assay modifications to allow inhibitor measurement during replacement therapy and facilitate inhibitor surveillance.J Thromb Haemost. 2012; 10: 1055-1061Crossref PubMed Scopus (84) Google Scholar The threshold for positivity was set at ≥0.5 Nijmegen‐Bethesda units (NBU) based on distributions of results on patients with positive and negative history of inhibitor1.Miller C.H. Platt S.J. Rice A.S. Kelly F. Soucie J.M. The Hemophilia Inhibitor Research Study InvestigatorsValidation of Nijmegen‐Bethesda assay modifications to allow inhibitor measurement during replacement therapy and facilitate inhibitor surveillance.J Thromb Haemost. 2012; 10: 1055-1061Crossref PubMed Scopus (84) Google Scholar and validated by the frequency of positivity for anti‐FVIII antibodies.8.Miller C.H. Boylan B. Shapiro A.D. Lentz S.R. Wicklund B.M. The Hemophilia Inhibitor Research Study InvestigatorsLimit of detection and threshold for positivity of the Centers for Disease Control and Prevention assay for factor VIII inhibitors.J Thromb Haemost. 2017; 15: 1971-1976Crossref PubMed Scopus (15) Google Scholar The CBA was performed by the NBA method, except that FVIII activity was measured using a bovine CSA (Siemens Factor VIII Chromogenic Assay, Siemens, Marburg, Germany).2.Miller C.H. Rice A.S. Boylan B. et al.Comparison of clot‐based, chromogenic and fluorescence assays for measurement of factor VIII inhibitors in the US Hemophilia Inhibitor Research Study.J Thromb Haemost. 2013; 11: 1300-1309Crossref PubMed Scopus (51) Google Scholar Antibodies binding to FVIII were measured by a fluorescence immunoassay detecting both immunoglobulin (Ig)G and IgM in a subset of 268 specimens.2.Miller C.H. Rice A.S. Boylan B. et al.Comparison of clot‐based, chromogenic and fluorescence assays for measurement of factor VIII inhibitors in the US Hemophilia Inhibitor Research Study.J Thromb Haemost. 2013; 11: 1300-1309Crossref PubMed Scopus (51) Google Scholar Results were expressed as median fluorescence intensity. The threshold for positivity was set at two standard deviations above the mean median fluorescence intensity of the results obtained for 56 healthy subjects. For this analysis, comparisons between CBA and NBA results were made by nonparametric methods, using the Wilcoxon matched‐pairs signed‐rank test and the Spearman correlation coefficient (r), and by chi‐squared test, with significance set at p < .05, using GraphPad Prism 8.3 (GraphPad Software Inc.). In our previous paper using these data, we reported excellent correlation between paired NBA and CBA results for specimens with ≥2.0 NBU (n = 42; r = .98) and discrepancies between the two assays for positive specimens in the 0.5–1.9 NBU range.2.Miller C.H. Rice A.S. Boylan B. et al.Comparison of clot‐based, chromogenic and fluorescence assays for measurement of factor VIII inhibitors in the US Hemophilia Inhibitor Research Study.J Thromb Haemost. 2013; 11: 1300-1309Crossref PubMed Scopus (51) Google Scholar We have now found differences in the group with negative titers (<0.5 NBU, n = 883), as well. In that group, the NBA median was 0.1 (interquartile range 0–0.1), and the CBA median was 0 (interquartile range 0–0; p < .0001). As illustrated in Figure 1A, the CBA and NBA distributions were significantly different (p < .0001). The CBA produced a much larger number of zero Bethesda unit results than the NBA (73.9% vs. 40.4%) with smaller proportions for the CBA than the NBA in the remainder of the negative range (17.4% vs. 47.5%) and in the range of 0.5–1.9 (4.0% vs. 8.0%). Results were similar with the two methods in low‐positive (2.0–4.9) specimens at 1.8% vs. 1.2% and high‐positive (≥5.0) specimens at 2.9% vs. 3.0%. There appears to be a previously unreported shift toward lower CBA results among NBA‐negative specimens. Using the CBA, 84.7% of 746 specimens from patients with negative history of inhibitor had zero CBU, whereas only 48.3% had zero NBU. The observed differences do not alter our previous conclusions that both NBA‐negative specimens and NBA‐positive specimens with ≥2.0 NBU are classified correctly by the CBA, with only those with 0.5–1.9 NBU showing classification changes2.Miller C.H. Rice A.S. Boylan B. et al.Comparison of clot‐based, chromogenic and fluorescence assays for measurement of factor VIII inhibitors in the US Hemophilia Inhibitor Research Study.J Thromb Haemost. 2013; 11: 1300-1309Crossref PubMed Scopus (51) Google Scholar; however, these differences need to be considered when attempting to establish equivalence between the two assays for clinical purposes and might be taken to indicate that the CBA is less sensitive than the NBA. We have recently reported, however, that the limit of detection for the CBA is 0.1,7.Miller C.H. Boylan B. Payne A.B. Driggers J. Bean C.J. Validation of the chromogenic Bethesda assay for factor VIII inhibitors in hemophilia A patients receiving emicizumab.Int J Lab Hematol. 2021; 43Crossref PubMed Scopus (7) Google Scholar which is lower than the 0.2 calculated for the NBA,8.Miller C.H. Boylan B. Shapiro A.D. Lentz S.R. Wicklund B.M. The Hemophilia Inhibitor Research Study InvestigatorsLimit of detection and threshold for positivity of the Centers for Disease Control and Prevention assay for factor VIII inhibitors.J Thromb Haemost. 2017; 15: 1971-1976Crossref PubMed Scopus (15) Google Scholar indicating that the CBA is slightly more sensitive than the NBA, as we originally showed in dilution studies.2.Miller C.H. Rice A.S. Boylan B. et al.Comparison of clot‐based, chromogenic and fluorescence assays for measurement of factor VIII inhibitors in the US Hemophilia Inhibitor Research Study.J Thromb Haemost. 2013; 11: 1300-1309Crossref PubMed Scopus (51) Google Scholar Among specimens tested for specific anti‐FVIII antibodies, significantly more CBA‐positive specimens were antibody‐positive than NBA‐positive specimens (50/51, 98.0% vs. 83/99, 83.8%; p = .012), with the single CBA‐positive specimen not showing antibody positivity positive in both NBA and CBA. These results for the CBA in patients receiving replacement therapy are similar to our recent findings in patients receiving emicizumab, which showed 97.6% of 250 CBA‐positive specimens to be positive for anti‐FVIII IgG4 antibodies,7.Miller C.H. Boylan B. Payne A.B. Driggers J. Bean C.J. Validation of the chromogenic Bethesda assay for factor VIII inhibitors in hemophilia A patients receiving emicizumab.Int J Lab Hematol. 2021; 43Crossref PubMed Scopus (7) Google Scholar the most reliable antibody subclass to predict that a functional inhibitor is present, as reviewed.9.Miller C.H. Laboratory testing for factor VIII and IX inhibitors in haemophilia: a review.Haemophilia. 2018; 24: 186-197Crossref PubMed Scopus (31) Google Scholar Thus, the lower results in the CBA are not due to lower sensitivity but to greater accuracy at detecting truly negative specimens. The CBA is thought to give fewer false‐positive results because lupus anticoagulants, heparin, or nonspecific inhibitors of coagulation affect the OSA but not the CSA, as reviewed.9.Miller C.H. Laboratory testing for factor VIII and IX inhibitors in haemophilia: a review.Haemophilia. 2018; 24: 186-197Crossref PubMed Scopus (31) Google Scholar We also examined two other characteristics of the CBA in this dataset. Our previous suggestion that specimens in the range of 0.5–1.9 NBU had a high frequency of false‐positive results and should be confirmed by testing in the CBA and measurement of anti‐FVIII antibodies was based on the finding that the frequency of positivity for anti‐FVIII antibodies was significantly lower among specimens with 0.5–1.9 NBU than among those with ≥2.0 NBU (75.4% vs. 97.4%; p = .004).2.Miller C.H. Rice A.S. Boylan B. et al.Comparison of clot‐based, chromogenic and fluorescence assays for measurement of factor VIII inhibitors in the US Hemophilia Inhibitor Research Study.J Thromb Haemost. 2013; 11: 1300-1309Crossref PubMed Scopus (51) Google Scholar A similar analysis for the CBA shows antibody positivity rates in those ranges to be similar at 24/24 (100%) and 26/27 (96.3%), respectively (p > .99). Additional antibody testing for confirmation, therefore, is not necessary when the CBA is used as the primary test in patients receiving traditional therapy, as we have shown in those receiving emicizumab.7.Miller C.H. Boylan B. Payne A.B. Driggers J. Bean C.J. Validation of the chromogenic Bethesda assay for factor VIII inhibitors in hemophilia A patients receiving emicizumab.Int J Lab Hematol. 2021; 43Crossref PubMed Scopus (7) Google Scholar We also examined the threshold for positivity of the CBA, which was previously assumed to be the same as for the NBA.2.Miller C.H. Rice A.S. Boylan B. et al.Comparison of clot‐based, chromogenic and fluorescence assays for measurement of factor VIII inhibitors in the US Hemophilia Inhibitor Research Study.J Thromb Haemost. 2013; 11: 1300-1309Crossref PubMed Scopus (51) Google Scholar CBA results plotted by history of inhibitor (Figure 1B) were very similar to the NBA results previously reported.1.Miller C.H. Platt S.J. Rice A.S. Kelly F. Soucie J.M. The Hemophilia Inhibitor Research Study InvestigatorsValidation of Nijmegen‐Bethesda assay modifications to allow inhibitor measurement during replacement therapy and facilitate inhibitor surveillance.J Thromb Haemost. 2012; 10: 1055-1061Crossref PubMed Scopus (84) Google Scholar Among 746 negative‐history specimens, 745 (99.9%) were below 0.5 CBU; one specimen differed in classification between the two methods with 0.4 NBU and 0.6 CBU. For the 204 positive‐history specimens, the distribution was bimodal, as expected because of resolved or treated inhibitors, and similar to that of the NBA, both showing a break at 0.4. Thus, a threshold for positivity of ≥0.5 appears to be appropriate for the CBA in non‐emicizumab specimens, as we have recently confirmed for specimens from patients receiving emicizumab.7.Miller C.H. Boylan B. Payne A.B. Driggers J. Bean C.J. Validation of the chromogenic Bethesda assay for factor VIII inhibitors in hemophilia A patients receiving emicizumab.Int J Lab Hematol. 2021; 43Crossref PubMed Scopus (7) Google Scholar The current analysis identified differences among negative results not previously reported, which affect statistical comparison of results but do not affect classification of specimens as positive or negative. It also confirmed that a threshold for positivity of ≥0.5 is appropriate for the CBA, as previously shown for the NBA,2.Miller C.H. Rice A.S. Boylan B. et al.Comparison of clot‐based, chromogenic and fluorescence assays for measurement of factor VIII inhibitors in the US Hemophilia Inhibitor Research Study.J Thromb Haemost. 2013; 11: 1300-1309Crossref PubMed Scopus (51) Google Scholar, 8.Miller C.H. Boylan B. Shapiro A.D. Lentz S.R. Wicklund B.M. The Hemophilia Inhibitor Research Study InvestigatorsLimit of detection and threshold for positivity of the Centers for Disease Control and Prevention assay for factor VIII inhibitors.J Thromb Haemost. 2017; 15: 1971-1976Crossref PubMed Scopus (15) Google Scholar when using the US Centers for Disease Control and Prevention–modified methods including preanalytical heat inactivation of patient plasma in patients not receiving emicizumab. The higher rate of antibody positivity among CBA‐positive specimens allows a greater degree of confidence in low‐titer positive results when tests are performed with the CBA than with the NBA and eliminates the need for additional testing methods to confirm NBA results. In spite of the slight differences observed, the similarity of the CBA to the NBA should allow its use with confidence in patients treated with traditional products as well as those receiving emicizumab. Dr. Miller and Mr. Boylan state that they have no real or potential conflicting interests. Connie H. Miller planned the study, analyzed results, and wrote the manuscript. Brian Boylan performed research, analyzed results, and wrote the manuscript. The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention. The work was supported by the CDC Foundation through grants from Pfizer Pharmaceuticals and Baxter Healthcare. The authors wish to thank the Hemophilia Inhibitor Research Study coordinators and patients and Fiona Bethea, CDC study coordinator.CDC FoundationPfizer PharmaceuticalsBaxter Healthcare

Hemophilia B (HB) is a bleeding disorder caused by deficiency of or defect in blood coagulation factor IX (FIX) inherited in an X-linked manner. It results from one of over 1000 known pathogenic variants in the FIX gene, F9; missense and frameshift changes predominate. Although primarily males are affected with HB, heterozygous females may have excessive bleeding due to random or non-random X chromosome inactivation; in addition, homozygous, compound heterozygous, and hemizygous females have been reported. Somatic and germinal mosaicism for F9 variants has been observed. Development of antibodies to FIX treatment products (inhibitors) is rare and related to the type of causative variant present. Treatment is with products produced by recombinant DNA technology, and gene therapy is in clinical trials. Genetic counseling with up-to-date information is warranted for heterozygotes, potential heterozygotes, and men and women affected with HB.

Problem/Condition: Hemophilia is an X-linked genetic disorder that primarily affects males and results in deficiencies in bloodclotting proteins. Hemophilia A is a deficiency in factor VIII, and hemophilia B is a deficiency in factor IX. Approximately one in 5,000 males are born with hemophilia, and hemophilia A is about four times as common as hemophilia B. Both disorders are characterized by spontaneous internal bleeding and excessive bleeding after injuries or surgery. Hemophilia can lead to repeated bleeding into the joints and associated chronic joint disease, neurologic damage, damage to other organ systems, and death. Although no precise national U.S. prevalence estimates for hemophilia exist because of the difficulty identifying cases among persons who receive care from various types of health care providers, two previous state-based studies estimated hemophilia prevalence at 13.4 and 19.4 per 100,000 males. In addition, these studies showed that 67% and 82% of persons with hemophilia received care in a federally funded hemophilia treatment center (HTC), and 86% and 94% of those with the most severe cases of hemophilia (i.e., those with the lowest levels of clotting factor activity in the circulating blood) received care in a federally funded HTC. As of January 2020, the United States had 144 HTCs. Period Covered: 1998-2019. Description of the System: Surveillance for hemophilia, which is a complex, chronic condition, is challenging because of its low prevalence, the difficulty in ascertaining cases uniformly, and the challenges in routinely characterizing and tracking associated health complications. Over time, two systems involving many stakeholders have been used to conduct ongoing hemophilia surveillance. During 1998-2011, CDC and the HTCs collaborated to establish the Universal Data Collection (UDC) surveillance system. The purposes of the UDC surveillance system were to monitor human immunodeficiency virus (HIV) and bloodborne viral hepatitis in persons with hemophilia, thereby tracking blood safety, and to track the prevalence of and trends in complications associated with hemophilia. HTC staff collected clinical data and blood specimens from UDC participants and submitted them to CDC. CDC tested specimens for viral hepatitis and HIV. In 2011, the UDC surveillance system was replaced by a new hemophilia surveillance system called Community Counts. CDC and the HTCs established Community Counts to expand laboratory testing and the collection of clinical data to better identify and track emerging health issues in persons with hemophilia. Results: This report is the first comprehensive summary of CDC's hemophilia surveillance program, which comprises both UDC and Community Counts. Data generated from these surveillance systems have been used in the development of public health and clinical guidelines and practices to improve the safety of U.S. blood products and either prevent hemophilia-related complications or identify complications early. Several factors have played a role in the effectiveness of the UDC and Community Counts systems, including 1) a stable data collection design that was developed and is continually reviewed in close partnership with HTC regional leaders and providers to ensure surveillance activities are focused on maximizing the scientific and clinical impact; 2) flexibility to respond to emerging health priorities through periodic updates to data collection elements and special studies; 3) high data quality for many clinical indicators and state-of-the-art laboratory testing methods for hemophilia treatment product inhibitors (developed and refined in part based on CDC research); 4) timely data and specimen collection and submission, laboratory specimen testing, analysis, and reporting; and 5) the largest and most representative sample of persons with hemophilia in the United States and one of the largest and most comprehensive data collection systems on hemophilia worldwide. Interpretation: CDC has successfully developed, implemented, and maintained a surveillance system for hemophilia. The program can serve as an example of how to conduct surveillance for a complex chronic disease by involving stakeholders, improving and building new infrastructure, expanding data collection (e.g., new diagnostic assays), providing testing guidance, establishing a registry with specimen collection, and integrating laboratory findings in clinical practice for the individual patient. Public Health Action: Hemophilia is associated with substantial lifelong morbidity, excess premature deaths, and extensive health care needs throughout life. Through monitoring data from Community Counts, CDC will continue to characterize the benefits and adverse events associated with existing or new hemophilia treatment products, thereby contributing to maximizing the health and longevity of persons with hemophilia.

International Journal of Laboratory HematologyVolume 43, Issue 2 p. e84-e86 LETTER TO THE EDITOR Validation of the chromogenic Bethesda assay for factor VIII inhibitors in hemophilia a patients receiving Emicizumab Connie H. Miller, Corresponding Author Connie H. Miller cmiller2@cdc.gov orcid.org/0000-0002-3989-7973 Division of Blood Disorders, Centers for Disease Control and Prevention, National Center on Birth Defects and Developmental Disabilities, Atlanta, GA, USA Correspondence Connie H. Miller, Division of Blood Disorders, Centers for Disease Control and Prevention, National Center on Birth Defects and Developmental Disabilities, 1600 Clifton Road MS D02, Atlanta, GA 30329, USA. Email: cmiller2@cdc.govSearch for more papers by this authorBrian Boylan, Brian Boylan orcid.org/0000-0003-3930-4565 Division of Blood Disorders, Centers for Disease Control and Prevention, National Center on Birth Defects and Developmental Disabilities, Atlanta, GA, USASearch for more papers by this authorAmanda B. Payne, Amanda B. Payne orcid.org/0000-0003-1027-7639 Division of Blood Disorders, Centers for Disease Control and Prevention, National Center on Birth Defects and Developmental Disabilities, Atlanta, GA, USASearch for more papers by this authorJennifer Driggers, Jennifer Driggers Division of Blood Disorders, Centers for Disease Control and Prevention, National Center on Birth Defects and Developmental Disabilities, Atlanta, GA, USASearch for more papers by this authorChristopher J. Bean, Christopher J. Bean orcid.org/0000-0001-7433-9769 Division of Blood Disorders, Centers for Disease Control and Prevention, National Center on Birth Defects and Developmental Disabilities, Atlanta, GA, USASearch for more papers by this author Connie H. Miller, Corresponding Author Connie H. Miller cmiller2@cdc.gov orcid.org/0000-0002-3989-7973 Division of Blood Disorders, Centers for Disease Control and Prevention, National Center on Birth Defects and Developmental Disabilities, Atlanta, GA, USA Correspondence Connie H. Miller, Division of Blood Disorders, Centers for Disease Control and Prevention, National Center on Birth Defects and Developmental Disabilities, 1600 Clifton Road MS D02, Atlanta, GA 30329, USA. Email: cmiller2@cdc.govSearch for more papers by this authorBrian Boylan, Brian Boylan orcid.org/0000-0003-3930-4565 Division of Blood Disorders, Centers for Disease Control and Prevention, National Center on Birth Defects and Developmental Disabilities, Atlanta, GA, USASearch for more papers by this authorAmanda B. Payne, Amanda B. Payne orcid.org/0000-0003-1027-7639 Division of Blood Disorders, Centers for Disease Control and Prevention, National Center on Birth Defects and Developmental Disabilities, Atlanta, GA, USASearch for more papers by this authorJennifer Driggers, Jennifer Driggers Division of Blood Disorders, Centers for Disease Control and Prevention, National Center on Birth Defects and Developmental Disabilities, Atlanta, GA, USASearch for more papers by this authorChristopher J. Bean, Christopher J. Bean orcid.org/0000-0001-7433-9769 Division of Blood Disorders, Centers for Disease Control and Prevention, National Center on Birth Defects and Developmental Disabilities, Atlanta, GA, USASearch for more papers by this author First published: 10 November 2020 https://doi.org/10.1111/ijlh.13384Citations: 6Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article.Citing Literature Volume43, Issue2April 2021Pages e84-e86 RelatedInformation

HaemophiliaVolume 26, Issue 1 p. e28-e30 LETTER TO THE EDITOR Evaluation of pre-analytic heat treatment protocol used in the CDC Nijmegen-Bethesda assay for heat inactivation of extended half-life haemophilia treatment products Amanda B. Payne, Corresponding Author Amanda B. Payne ABPayne@cdc.gov orcid.org/0000-0003-1027-7639 National Center on Birth Defects and Developmental Disabilities, Division of Blood Disorders, Centers for Disease Control and Prevention, Atlanta, GA, USA Correspondence Amanda B. Payne, 1600 Clifton Road MS H23-3, Atlanta, GA 30329. Email: ABPayne@cdc.govSearch for more papers by this authorDorothy Ellingsen, Dorothy Ellingsen National Center on Birth Defects and Developmental Disabilities, Division of Blood Disorders, Centers for Disease Control and Prevention, Atlanta, GA, USASearch for more papers by this authorJennifer Driggers, Jennifer Driggers National Center on Birth Defects and Developmental Disabilities, Division of Blood Disorders, Centers for Disease Control and Prevention, Atlanta, GA, USASearch for more papers by this authorChristopher J. Bean, Christopher J. Bean orcid.org/0000-0001-7433-9769 National Center on Birth Defects and Developmental Disabilities, Division of Blood Disorders, Centers for Disease Control and Prevention, Atlanta, GA, USASearch for more papers by this authorConnie H. Miller, Connie H. Miller National Center on Birth Defects and Developmental Disabilities, Division of Blood Disorders, Centers for Disease Control and Prevention, Atlanta, GA, USASearch for more papers by this author Amanda B. Payne, Corresponding Author Amanda B. Payne ABPayne@cdc.gov orcid.org/0000-0003-1027-7639 National Center on Birth Defects and Developmental Disabilities, Division of Blood Disorders, Centers for Disease Control and Prevention, Atlanta, GA, USA Correspondence Amanda B. Payne, 1600 Clifton Road MS H23-3, Atlanta, GA 30329. Email: ABPayne@cdc.govSearch for more papers by this authorDorothy Ellingsen, Dorothy Ellingsen National Center on Birth Defects and Developmental Disabilities, Division of Blood Disorders, Centers for Disease Control and Prevention, Atlanta, GA, USASearch for more papers by this authorJennifer Driggers, Jennifer Driggers National Center on Birth Defects and Developmental Disabilities, Division of Blood Disorders, Centers for Disease Control and Prevention, Atlanta, GA, USASearch for more papers by this authorChristopher J. Bean, Christopher J. Bean orcid.org/0000-0001-7433-9769 National Center on Birth Defects and Developmental Disabilities, Division of Blood Disorders, Centers for Disease Control and Prevention, Atlanta, GA, USASearch for more papers by this authorConnie H. Miller, Connie H. Miller National Center on Birth Defects and Developmental Disabilities, Division of Blood Disorders, Centers for Disease Control and Prevention, Atlanta, GA, USASearch for more papers by this author First published: 06 December 2019 https://doi.org/10.1111/hae.13901Citations: 4Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article.Citing Literature Volume26, Issue1January 2020Pages e28-e30 RelatedInformation

Introduction Estimates of the size and characteristics of the US haemophilia population are needed for healthcare planning and resource needs assessment. A network of comprehensive haemophilia treatment centres (HTCs) located throughout the United States receives federal support for diagnosis and management of haemophilia and other rare bleeding disorders. Aim Estimate the incidence and prevalence of haemophilia among US males using the HTC network. Methods During the period 2012-2018, de-identified surveillance data were collected on all males who visited an HTC that included year of birth, gender, race, Hispanic ethnicity, residence zip code, haemophilia type and severity. Data from all patients were used to calculate period prevalence by haemophilia type, severity and state of residence. Data from a subset of patients born 1995-2014 were used to estimate incidence rates over the 20-year period. Results During the period, 21 748 males with haemophilia visited the HTCs resulting in an age-adjusted prevalence of 15.7 cases per 100 000 males (12 for haemophilia A and 3.7 for haemophilia B). Prevalence was higher among whites (15.1) than blacks (12.4) or Hispanics of either race (12.4). State-specific prevalence varied from 1.6 to 23.3 cases per 100 000. Based on 9587 males born during the index period, the average haemophilia incidence was 1 case per 4334 live male births. Conclusion Based on these data, we estimate that there are between 29 761 and 32 985 males with haemophilia living in the United States today, the majority of whom receive comprehensive care in specialized clinical centres.

The platelet function analyzer (PFA)-100 is the most widely used global test of primary hemostasis. It performs an in vitro test of platelet plug formation, referred to as the PFA, by measuring the time to occlusion of a window in a coated membrane through which blood is forced at high shear rate. It was designed to replace the bleeding time, which is no longer recommended. The PFA is sensitive to von Willebrand disease Type 2A, 2B, and 3 but is less sensitive to Type 1. It is also insensitive to mild platelet function disorders and cannot be used alone as a screening tool.

Inhibitors may occur in congenitally deficient patients who fail to respond as expected to appropriate therapy (alloantibodies) or in previously unaffected patients (autoantibodies). They are detected in the laboratory primarily through their ability to neutralize specific coagulation factors and must be distinguished from nonspecific inhibitors, such as the lupus anticoagulant. Most commonly, an inhibitor is detected by performing a specific coagulation factor assay on a mixture of patient plasma and normal pool plasma and comparing the result to a control mixture. Factor VIII (FVIII) inhibitor testing has been standardized as the Bethesda assay; other factor inhibitors are tested in an analogous way. FVIII inhibitors and some inhibitors to factors V and XI are time-dependent and require incubation; others usually react immediately. Bethesda assays detect only antibodies that neutralize the clotting factor in the fluid phase, whereas nonneutralizing antibodies may be detected by other methods, such as enzyme-linked immunosorbent assay.

Introduction: Factor IX:C (FIX:C) levels vary in hemophilia B carriers even in pedigrees with a unifying genetic defect. Analyzing the balance between pro-and anticoagulants might increase our understanding of carriers' bleeding potential. Aim: In this research study, we evaluated bleeding scores (BS) and a novel mathematical model of thrombin generation (TG) in Amish FIX:C deficient carriers and controls. Methods: Blood samples and BS were obtained from post-menarchal females, including 59 carriers and 57 controls from the same extended pedigree. Factors II, V, VII, VIII, IX, X, antithrombin, tissue factor pathway inhibitor and protein C were assayed to generate mathematical models of TG in response to 5pM tissue factor (TF) and for TF + thrombomodulin. BS was based on a modification of the MCMDM-1VWD scoring system. Results: Carriers had a lower mean FIX:C (68% vs. 119%), von Willebrand factor antigen (108 vs.133) and Tissue activatable fibrinolysis inhibitor (103 vs. 111) compared to controls; both groups had a similar mean BS. Carriers demonstrated significantly lower TG parameters on both mathematical models compared to controls. Carriers with FIX:C <= 50% had lower TG curves than those > 50% but similar BS. Conclusion: Thrombin generation showed significant differences between carriers and controls, between low (<= 50%) and high ( > 50%) FIX:C carriers, and specifically in the TF + thrombomodulin model, between high FIX:C carriers and controls, although the BS were not different.

Mixing studies are used to distinguish among potential causes for a prolonged activated partial thromboplastin time (PTT) or prothrombin time (PT). Patient plasma is mixed 1:1 with normal pool plasma, and the PTT or PT is measured immediately and after 1 hour incubation at 37°C. Complete correction of a 1:1 mix suggests a factor deficiency, either congenital or acquired. Failure to correct completely suggests an inhibitor interfering with one or more coagulation factors or a lupus anticoagulant. A longer PTT after 1 hour incubation suggests a factor VIII inhibitor. Sources of error include heparin contamination and false correction of weak inhibitors.

The genetics of blood coagulation has been an ongoing area of research; and with the advent of next generation sequencing panels, there is a significant increase in the number of variants identified in coagulation factor genes. Several published reports and online databases document the variants observed in patients with bleeding disorders; however, the clinical interpretation of these variants is not always straight-forward. To enable gene-specific variant interpretation in coagulation factor deficiency disorders, the National Institutes of Health (NIH)-funded effort, Clinical Genome Resource (ClinGen), has developed the Coagulation Factor Deficiency Variant Curation Expert Panel (CFD-VCEP). The CFD-VCEP is comprised of expert clinicians, genetic counselors, clinical laboratory diagnosticians and researchers working toward the goal of developing and implementing standardized protocols for sequence variant interpretation for coagulation factor genes. The CFD-VCEP adapts the 2015 American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines for precise and consistent variant classification to genes involved in blood coagulation deficiencies. These guidelines recommend the use of 28 criteria codes based on the evidence category and the strength of the evidence (see Figure below). The first two genes under the purview of CFD-VCEP are F8 (OMIM: 300841) and F9 (OMIM: 300746). Pathogenic variants in the F8 and F9 genes resulting in the loss of protein function cause Hemophilia A and B, respectively. Owing to the similarity between these two genes with respect to their role in the coagulation cascade as well as the resulting phenotype, specification of variant curation guidelines for both genes has been undertaken simultaneously. With the completion of guideline specification for F8 and F9, the CFD-VCEP will subsequently continue this effort for other coagulation factor genes, while also curating F8 and F9 variants reported in ClinVar and other variant databases. Modifying the ACMG/AMP guidelines involves gene- and disease-informed specifications of the recommended criteria codes. This includes identifying which codes are applicable and which are not, defining gene- and disease-specific cut-offs such as for population frequency, and making code strength adjustments when appropriate. The specified guidelines are further refined based on their performance on a set of pilot variants (n = 30) for each gene compared to existing assertions of variant classification in ClinVar and by diagnostic laboratories represented in the CFD-VCEP. F8 and F9 variants classified by the CFD-VCEP will be submitted to ClinVar at the 3-star review status, with the tag of "FDA-recognized database", and the CFD-VCEP plans to begin this process by the second quarter of 2020. The considerations by the CFD-VCEP in the guideline-specification process and results from the pilot analysis will be discussed. This effort will lead to the standardized use of evidence criteria for the evaluation of variants in F8 and F9, which will reduce the number of variants of uncertain significance and those of conflicting interpretations, making genetic testing results more informative for providers and patients. The CFD-VCEP also encourages sharing de-identified data on variants among laboratories, which enables accurate and consistent curations. Figure Disclosures Lee: UNC Hemophilia Treatment Center: Employment. Carcao:Biotest: Honoraria, Membership on an entity's Board of Directors or advisory committees; Grifols: Honoraria, Membership on an entity's Board of Directors or advisory committees; Shire/Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL Behring: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk Inc: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Octapharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Agios: Research Funding; LFB: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bioverativ/Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kemball-Cook:European Association for Haemophilia and Allied Disorders: Other: Freelance . Leebeek:CSL Behring: Research Funding; uniQure BV: Consultancy, Research Funding; Baxalta/Shire: Research Funding. Miller:Division of Blood Disorders, National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention: Consultancy.

HaemophiliaVolume 25, Issue 5 p. e342-e344 LETTER TO THE EDITOR Reagent substitution in the chromogenic Bethesda assay for factor VIII inhibitors Amanda B. Payne, Corresponding Author Amanda B. Payne bvx2@cdc.gov orcid.org/0000-0003-1027-7639 Division of Blood Disorders, National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, GA, USA Correspondence Amanda B. Payne, Division of Blood Disorders, National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, GA, USA. Email: bvx2@cdc.govSearch for more papers by this authorConnie H. Miller, Connie H. Miller orcid.org/0000-0002-3989-7973 Division of Blood Disorders, National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, GA, USASearch for more papers by this authorDorothy Ellingsen, Dorothy Ellingsen Division of Blood Disorders, National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, GA, USASearch for more papers by this authorJennifer Driggers, Jennifer Driggers Division of Blood Disorders, National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, GA, USASearch for more papers by this authorBrian Boylan, Brian Boylan orcid.org/0000-0003-3930-4565 Division of Blood Disorders, National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, GA, USASearch for more papers by this authorChristopher J. Bean, Christopher J. Bean orcid.org/0000-0001-7433-9769 Division of Blood Disorders, National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, GA, USASearch for more papers by this author Amanda B. Payne, Corresponding Author Amanda B. Payne bvx2@cdc.gov orcid.org/0000-0003-1027-7639 Division of Blood Disorders, National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, GA, USA Correspondence Amanda B. Payne, Division of Blood Disorders, National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, GA, USA. Email: bvx2@cdc.govSearch for more papers by this authorConnie H. Miller, Connie H. Miller orcid.org/0000-0002-3989-7973 Division of Blood Disorders, National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, GA, USASearch for more papers by this authorDorothy Ellingsen, Dorothy Ellingsen Division of Blood Disorders, National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, GA, USASearch for more papers by this authorJennifer Driggers, Jennifer Driggers Division of Blood Disorders, National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, GA, USASearch for more papers by this authorBrian Boylan, Brian Boylan orcid.org/0000-0003-3930-4565 Division of Blood Disorders, National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, GA, USASearch for more papers by this authorChristopher J. Bean, Christopher J. Bean orcid.org/0000-0001-7433-9769 Division of Blood Disorders, National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, GA, USASearch for more papers by this author First published: 29 July 2019 https://doi.org/10.1111/hae.13827Citations: 2Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article.Citing Literature Volume25, Issue5September 2019Pages e342-e344 RelatedInformation