Hemophilia A Research Program

Overview

This study longitudinally observes the intergenerational (mother-child) continuum in hemophilia A from pregnancy through early childhood. Because the study follows mother-child pairs, the study includes both a maternal cohort and a pediatric cohort. Each cohort has a primary goal: for the mother with a severe hemophilia genotype, the overarching primary goal is to understand the risks for pregnancy-associated bleeding and postpartum hemorrhage (PPH); for the child, the overarching primary goal is to understand the risks, timing, and circumstances of development of anti-FVIII antibodies. From a longitudinal perspective, risks for both bleeding in the mother and anti-FVIII antibody development in the child are expected to be influenced over time by genetic and environmental factors that begin early in (or before) pregnancy. Enrollment of blood relatives is offered to improve power to better understand inherited contributions to bleeding and inhibitor development in the mother-baby pairs.

HARP is a longitudinal observational, decentralized and multisite (with one hybrid site), national prospective cohort study in hemophilia A. Participants will be treated by their HCPs, with no limitations on medical decision-making. Hemophilia A is an inherited X-linked bleeding disorder caused by deficiency in coagulation factor VIII (FVIII). Severe hemophilia A is defined by a FVIII level \< 0.01 IU/dL (or \< 1%). A significant complication of hemophilia A is the development of immune responses to FVIII, also known as inhibitors. In pregnancy, mothers who have a hemophilia-causing genotype are at high-risk for postpartum hemorrhage (PPH). Genetics, other health factors, and environment are all thought to contribute to immune responses and bleeding risks. This study seeks to better understand factors involved in inhibitor development and bleeding beginning before birth. To accomplish the goal of following 50 mother-child pairs with a child affected by severe hemophilia A from pregnancy through at least the first 2 years of life, we expect to enroll approximately 120 pregnant mothers with a pregnancy at-risk of being affected by severe hemophilia A. The biological father, first- and second-degree blood relatives of the child, and other relatives whose data or samples may be informative for the planned genetic studies of hemophilia and inhibitors may be invited to participate in the study and provide data and samples in order to improve power of the study to robustly investigate the heritable causes of bleeding and inhibitors. Based on incidence and prevalence calculations of hemophilia by the Centers for Disease Control and Prevention, approximately 150 males are born with severe hemophilia A in the United States annually. Because one-third of these patients should not have a prior family history, a conservative estimate for new babies with severe hemophilia A born into a family known to have hemophilia would be 100 males annually. HARP will open 1-2 U.S. fixed sites, with most participants expected to enroll in the decentralized study. The HARP study design will enable maternal and neonatal/early life sample and data collection for a continuous picture of hemophilia A phenotypes and immunological development. The duration of participation in HARP for each mother-child pair will be from enrollment during pregnancy until the child is at least 2 years old. Mother-child pairs will complete the study when the child reaches 50 cumulative FVIII EDs without an inhibitor or HARP ends, whichever comes first. The expected range of duration of participation for any one mother-child pair will range from 2.2 years up to 5 years, with many participants expected to be followed for \< 3 years. The primary biological sample type collected in HARP is longitudinal blood samples. Blood samples will be collected at the time of a clinical sample whenever possible to minimize the number of procedures for both mother and child. Leftover clinical blood samples and biological specimens will be used to supplement research samples whenever possible; this will improve the breadth of samples available for research and help to minimize blood volumes taken. Other sources of biological samples (hair, saliva, buccal, urine, stool, cervix, vagina, skin flora, chorionic villus, amniotic fluid, umbilical cord blood, umbilical cord, placental tissue) may be collected for research. Samples that are normally collected by any invasive medical procedure other than blood sampling (e.g., cervical sampling, amniotic fluid) will only be collected at the time of an otherwise clinically indicated collection procedure. Maternal blood samples will be obtained at enrollment and at specified times during pregnancy, during the hospital admission for childbirth, and until the 6+ weeks PP (non-pregnant baseline) last sample is drawn. If the hemophilia A genotype-positive mother receives treatment for hemophilia, samples will be timed with treatment monitoring whenever possible. At the time of delivery, cord blood and placental tissues will be sampled. For the pediatric participants, an extra research sample will be collected during standard newborn screening, and a neonatal research blood draw will be requested in the first days of life if one is not ordered for clinical purposes. The study blood sampling schema is designed to ensure a minimum of two pre-FVIII exposure blood samples for all infants regardless of timing of the first FVIII ED. Thereafter, pediatric blood sampling will follow a time- and event-based sampling protocol for the duration of the study. Briefly, one to two research blood samples will be collected around specified EDs. If no research blood sample has been collected for 3 months, a research blood draw will be requested. This time-based schema allows sampling to coincide at least twice annually with other early life immunologic events. Two additional blood samples to enable cellular immunology studies will be collected between ED 20 and 50 or between ages 18 and 24 months, whichever comes first. If the child is reported by the laboratory to have a positive first-time clinical FVIII inhibitor test result, a sample will be requested to be drawn within 2-6 weeks of the inhibitor-positive blood draw for confirmatory testing. HARP will follow NIH guidance to cap the total pediatric blood volumes drawn to the weight- and time-based maximum volumes recommended (see Appendix 12.2 of the protocol). HARP will additionally follow European Union guidance to cap daily blood volumes drawn for research in the neonatal period (see Appendix 12.2 of the protocol). Maternal participants will have a clinical genotype sent to the HARP Central Laboratory at the beginning of the study if a clinical genotype is not already established. All pediatric participants will have clinical hemophilia A genotyping and FVIII inhibitor testing performed via the HARP Central Laboratory. All other clinical tests will be performed locally. Data will be collected longitudinally throughout the study, including medical records, electronic health record data, photographs and imaging data, and patient-reported outcomes (PROs) using questionnaires and diaries. Race, ethnicity, and social determinants of health are implicated in both maternal hemorrhage and childhood immune status, and these data will be gathered. Questionnaires will be administered to the hemophilia A genotype-positive mother to capture bleeding, other medical conditions and events, and PRO and well-being measures including measures of QOL. Tools will be adapted from existing questionnaires (e.g., PROMIS-29, ISTH-BAT, interim bleeding score, self-BAT, PBAC, PHQ-8, PhenX Toolkit, infant feeding). Hemophilia A genotype-positive mothers will be provided with a study diary to track bleeding, medical events, treatments, efficacy, and other basic medical information (e.g., other medications, other new diagnoses) for themselves and their child, including immunologic events such as illnesses, infections, and immunizations for the child. Blood relative participants will answer questionnaires, release medical records, and have biological samples collected. The primary sample type is expected to be blood, other samples such as cheek swabs may also be collected. The study will perform data analyses, immunologic, coagulation, genomics and other -omics research investigating the study hypotheses. Data and samples collected throughout the study will be saved in a shareable resource to support future research.