Demand forecasting for platelet usage: From univariate time series to multivariable models.

Platelet products are both expensive and have very short shelf lives. As usage rates for platelets are highly variable, the effective management of platelet demand and supply is very important yet challenging. The primary goal of this paper is to present an efficient forecasting model for platelet demand at Canadian Blood Services (CBS). To accomplish this goal, five different demand forecasting methods, ARIMA (Auto Regressive Integrated Moving Average), Prophet, lasso regression (least absolute shrinkage and selection operator), random forest, and LSTM (Long Short-Term Memory) networks are utilized and evaluated via a rolling window method. We use a large clinical dataset for a centralized blood distribution centre for four hospitals in Hamilton, Ontario, spanning from 2010 to 2018 and consisting of daily platelet transfusions along with information such as the product specifications, the recipients' characteristics, and the recipients' laboratory test results. This study is the first to utilize different methods from statistical time series models to data-driven regression and machine learning techniques for platelet transfusion using clinical predictors and with different amounts of data. We find that the multivariable approaches have the highest accuracy in general, however, if sufficient data are available, a simpler time series approach appears to be sufficient. We also comment on the approach to choose predictors for the multivariable models.

An unsupervised learning approach to identify immunoglobulin utilization patterns using electronic health records.

BACKGROUND: Managing Canada's immunoglobulin (Ig) product resource allocation is challenging due to increasing demand, high expenditure, and global shortages. Detection of groups with high utilization rates can help with resource planning for Ig products. This study aims to uncover utilization subgroups among the Ig recipients using electronic health records (EHRs). METHODS: The study included all Ig recipients (intravenous or subcutaneous) in Calgary from 2014 to 2020, and their EHR data, including blood inventory, recipient demographics, and laboratory test results, were analyzed. Patient clusters were derived based on patient characteristics and laboratory test data using K-means clustering. Clusters were interpreted using descriptive analyses and visualization techniques. RESULTS: Among 4112 recipients, six clusters were identified. Clusters 1 and 2 comprised 408 (9.9%) and 1272 (30.9%) patients, respectively, contributing to 62.2% and 27.1% of total Ig utilization. Cluster 3 included 1253 (30.5%) patients, with 86.4% of infusions administered in an inpatient setting. Cluster 4, comprising 1034 (25.1%) patients, had a median age of 4 years, while clusters 2-6 were adults with median ages of 46-60. Cluster 5 had 62 (1.5%) patients, with 77.3% infusions occurring in emergency departments. Cluster 6 contained 83 (2.0%) patients receiving subcutaneous Ig treatments. CONCLUSION: The results identified data-driven segmentations of patients with high Ig utilization rates and patients with high risk for short-term inpatient use. Our report is the first on EHR data-driven clustering of Ig utilization patterns. The findings hold the potential to inform demand forecasting and resource allocation decisions during shortages of Ig products.

Exploring the potential harm of varied blood storage on patients undergoing cardiovascular surgery.

BACKGROUND AND OBJECTIVES: Debate exists surrounding the optimal duration of red blood cell (RBC) storage. A hypothesis emerging from previous research suggests that exposure to fresh blood may be harmful to patients undergoing cardiac surgery. This study uses a large transfusion medicine database to explore the association between in-hospital mortality and red cell storage duration. MATERIALS AND METHODS: This is an exploratory retrospective cohort study of all adult patients at Hamilton, Canada, over a 14-year period that received at least one allogeneic red cell transfusion during their hospitalization for cardiac surgery requiring bypass. The primary outcome for the study was in-hospital death. Analysis was performed using multivariate Cox regression modelling with time-dependent and time-independent covariates and stratification variables. Five models with varying definitions for short, intermediate and prolonged duration of RBC storage were tested. RESULTS: From March 2004 to December 2017, 11,205 patients met the inclusion criteria and were included in the regression analyses. No significant effect of short-duration red storage on patient mortality was observed in all statistical models, with the red cells stored for the longest duration as the reference group. When patients who received exclusively fresh (hazard ratio [HR] 1.040, 95% confidence interval [CI] 0.588-1.841, p-value = 0.893) and older aged (HR 1.038, 95% CI 0.769-1.1.402, p-value = 0.0801) RBCs were compared with those who received exclusively mid-age red cells as the reference, statistical significance was similarly not reached. CONCLUSION: Red cells stored for the shortest duration are not associated with increased risk of mortality among cardiac surgery patients.

Immunoglobulin utilization in Canada: a comparative analysis of provincial guidelines and a scoping review of the literature.

BACKGROUND: Canada has high immunoglobulin (IG) product utilization, raising concerns about appropriate utilization, cost and risk of shortages. Currently, there is no national set of standardized IG guidelines, and considerable variations exist among the existing provincial guidelines. The aims of this study were: (1) to compare the existing Canadian provincial guidelines on the use of IG products to identify their consistencies and differences and (2) to examine the existing research in Canada on IG supply and utilization following the establishment of IG guidelines to understand the scope of research and pinpoint the gaps. METHODS: A comparative analysis accounted for the differences across provincial IG guidelines. We highlighted similarities and differences in recommendations for medical conditions. A scoping review of citations from MEDLINE, PubMed, Scopus and Embase databases was conducted for studies published from January 01, 2014, to April 12, 2023. RESULTS: While provincial guidelines represented a considerable overlap in the medical conditions delineated and relatively uniform dose calculations, numerous differences were observed, including in recommendation categories, provision of pediatric dosing, and divergent recommendations for identical conditions based on patient demographics. The scoping review identified 29 studies that focused on the use of IG in Canada. The themes of the studies included: IVIG utilization and audits, the switch from IVIG to SCIG, patient satisfaction with IVIG and/or SCIG, the economic impact of self-administered SCIG versus clinically administered IVIG therapy, and the efficacy and cost-effectiveness of alternative medications to IG treatment. CONCLUSION: The differences in guidelines across provinces and the factors influencing IVIG/SCIG use, patient satisfaction, and cost savings are highlighted. Future research may focus on clarifying costs and comparative effectiveness, exploring factors influencing guideline adherence, and evaluating the impact of updated guidelines on IG use and patient outcomes.

A retrospective analysis of haemolytic reactions to intravenous immunoglobulin using data from the Transfusion-Transmitted Injuries Surveillance System (Ontario).

BACKGROUND AND OBJECTIVES: Haemolysis can occur following intravenous immunoglobulin (IVIG) infusion. Haemovigilance data were analysed using a novel approach for including two control groups with no haemolysis to IVIG. Objectives included a summary of all reactions to IVIG, rate estimates and analysis of haemolytic reactions including risk factors. MATERIALS AND METHODS: Canadian haemovigilance data from Ontario (2013-2021), IVIG distribution and transfusion data from the blood supplier, and data from a large local transfusion registry were used. An 'other-reactions' control group included patients with IVIG reactions that were not haemolytic, and registry patients with no-reaction were the 'no-reaction controls'. Descriptive analysis and two logistic regression models for the different control groups were performed. RESULTS: One thousand one hundred and seventy reactions were included. Most common were febrile non haemolytic (26.1%), minor allergic (24.5%) and IVIG headache (15.3%) followed by haemolytic 10.9% (128/1170). Haemolytic reaction rates decreased over time: rates since 2020 estimated between 1.5 and 2.9/1000 kg IVIG used. The regression model for other-reaction controls identified two risk factors for haemolysis: non-O blood group recipients compared with group O recipients (p value = 0.0106) and IVIG dose per 10 g increase (OR 1.359; 95% CI 1.225-1.506). The model using no-reaction controls gave similar results and also showed no pre-medication was associated with a higher risk of haemolysis (OR 29.084; 95% CI 1.989-425.312). CONCLUSION: The frequency of haemolytic reactions has decreased over time. We confirmed non-O blood group recipients and IVIG dose as risk factors for haemolysis and raise the hypothesis that no pre-medication may increase the risk of haemolysis.

Laboratory and demographic predictors of functional assay positive status in suspected heparin-induced thrombocytopenia: A multicenter retrospective cohort study.

Heparin-induced thrombocytopenia (HIT) is an antibody-mediated immune response against platelet factor 4 (PF4) bound to heparin anticoagulants. A priori identification of patients at-risk for HIT remains elusive and a number of risk factors have been identified, but these associations and their effect sizes have limited validation in large cohorts of suspected HIT patients. The aim of this study was to investigate existing anti-PF4/heparin antibody thresholds and model the relationship of demographic variables and anti-PF4/heparin antibody levels with functional assay positivity across multiple institutions in the absence of detailed clinical data. In a large collection of suspected HIT patients (n = 8904), we tested for associations between laboratory and demographic variables and functional assay positive status as well as anti-PF4/heparin antibody levels. We also tested for correlation between IgG-specific and polyspecific (IgG/IgA/IgM) anti-PF4/heparin antibody values and their ability to predict functional assay positive status using area under the receiver operating characteristic (AUROC). Logistic regression identified increasing anti-PF4/heparin antibody OD levels (OR = 51.84 [37.27-74.34], p < 2.0 × 10-16) and female sex (OR = 1.47 [1.19-1.82], p = 3.5 × 10-4) as risk factors for positive functional assay in the largest cohort with consistent effect sizes in two other cohorts. In a subset of 1175 patients, polyspecific and IgG-specific anti-PF4/heparin antibody values were heterogeneous (mean coefficient of variation = 31.9 %), but strongly correlated (rho = 0.878; p < 2 × 10-16) with similar prediction of functional assay positivity (polyspecific AUROC = 0.976 and IgG-specific AUROC = 0.980). Thus, we recapitulate previously identified risk factors of functional assay positivity, providing precise effect sizes in a large observational population of suspected HIT patients. Our data reinforce the necessity of functional assay confirmation and suggest that, despite heterogeneity, polyspecific and IgG-specific anti-PF4/heparin antibody assays predict functional assay positive status similarly, even in the absence of 4Ts scores and detailed clinical data.

An evaluation of the clinical impacts of 7-day platelets.

BACKGROUND: In August 2017, Canadian Blood Services extended the shelf-life of platelet concentrates from 5 to 7 days. The clinical impacts of this policy change remain unclear. STUDY DESIGN AND METHODS: We used a before-after retrospective design of platelet-transfused adult inpatients in Hamilton, ON, Canada. Data were captured for 18 months before (Period 1: February 2016-July 2017) and 18 months after (Period 2: September 2017-February 2019) 7-day platelet implementation. Primary outcome was absolute platelet count increment (ACI) in univariate and multivariate analyses adjusted for confounders. Data were obtained from our institution's transfusion database, Ontario's Transfusion Transmitted Injuries Surveillance System, and the blood supplier. RESULTS: Overall, 1360 patients with single dose platelet transfusions were included in Period 1 and 1211 patients in Period 2. Median age at admission was 66 years, and approximately 40% of patients underwent cardiac surgery. Using a non-inferiority margin of -10 × 109 /L, platelets transfused during the 7-day storage period were non-inferior to those transfused in the 5-day storage period [mean count difference - 4.63 × 109 /L (95% CI -7.40 to -1.87, p = 0.0001)]. However, platelet ACIs following transfusion consistently trended lower in the 7-day group for all patients and subgroups. No differences in secondary clinical outcomes were observed. Platelet expiry reduced from 8.1 to 6.3% (p < 0.0001). CONCLUSION: Platelet transfusions following 7-day storage policy were non-inferior to transfusions in the 5-day policy period, although reduced ACIs were observed. There were no increases in adverse clinical outcomes.

KEL1 negative red cell transfusions for females of current or future child-bearing potential: A clinical impact and feasibility study.

BACKGROUND: Anti-K is an alloantibody stimulated in response to the KEL1 antigen and may cause hemolytic disease of the fetus and newborn (HDFN). Provision of KEL1 negative blood to females of child-bearing potential was not our practice. We assessed the impact of our policy and assessed feasibility of a KEL1 negative transfusion policy. STUDY DESIGN AND METHODS: This is a cohort study spanning Jan 1, 2007-Jun 30, 2017 in Hamilton, Canada. Data were obtained via our institution's transfusion database. Chart reviews of females age ≤45 with anti-K were performed; data on RBC KEL1 phenotype were obtained from the blood supplier when needed to ascertain the cause of alloimmunization. Descriptive analysis of hospital KEL1 negative inventory demand and supply was performed. RESULTS: From Jan 2007-Jun 2017, 8.6% of all RBC units transfused were provided to females age ≤45. There were 111 females with detectable anti-K. Median age at time of antibody detection was 34 years (interquartile range 27-40) and 28 of 111 (25.2%) patients may have been alloimmunized by transfusion. Of 49 pregnancies, seven had complications due to anti-K. We estimated that our existing RBC inventory (with 16% units known to be KEL1 negative in 2017) is sufficient to meet demand and support a KEL1 negative transfusion policy for females age ≤45. CONCLUSION: Transfusion was responsible for alloimmunization in 25% of females with anti-K over 10 years. Analysis of supply and demand can be used to inform feasibility of a KEL1 negative transfusion policy.

A positive blood culture is associated with a lower haemoglobin increment in hospitalized patients after red blood cell transfusion.

BACKGROUND AND OBJECTIVES: Abundant clinical evidence supports the safety of red blood cell (RBC) concentrates for transfusion irrespective of storage age, but still, less is known about how recipient characteristics may affect post-transfusion RBC recovery and function. Septic patients are frequently transfused. We hypothesized that the recipient environment in patients with septicaemia would blunt the increase in post-transfusion blood haemoglobin (Hb). The main objective was to compare the post-transfusion Hb increment in hospitalized patients with or without a positive blood culture. MATERIALS AND METHODS: A retrospective cohort study using data from the Transfusion Research, Utilization, Surveillance, and Tracking database (TRUST) was performed. All adult non-trauma in-patients transfused between 2010 and 2017 with ≥1 RBC unit, and for whom both pre- and post-transfusion complete blood count and pre-transfusion blood culture data were available were included. A general linear model with binary blood culture positivity was fit for continuous Hb increment after transfusion and was adjusted for patient demographic parameters and transfusion-related covariates. RESULTS: Among 210,263 admitted patients, 6252 were transfused: 596 had positive cultures, and 5656 had negative blood cultures. A modelled Hb deficit of 1.50 g/L in blood culture-positive patients was found. All covariates had a significant effect on Hb increment, except for the age of the transfused RBC. CONCLUSION: Recipient blood culture positivity was associated with a statistically significant but modestly lower post-transfusion Hb increment in hospitalized patients. In isolation, the effect is unlikely to be clinically significant, but it could become so in combination with other recipient characteristics.

A cross-sectional study of haemolytic disease of the newborn in Uganda.

BACKGROUND AND OBJECTIVES: Haemolytic disease of the newborn (HDN) is an immune haemolytic anaemia from maternal alloantibodies. Rh immunoglobulin (RhIg) prophylaxis can prevent alloimmunization to the D antigen. However, RhIg is not universally available in Uganda. ABO incompatibility also causes HDN. We determined the prevalence of HDN among newborn infants with jaundice in Uganda. MATERIALS AND METHODS: We conducted a prospective cross-sectional study at Kawempe National Referral Hospital, Kampala, Uganda. Infants aged 0-14 days with neonatal jaundice (or total bilirubin >50 µmol/L) were enrolled. Clinical evaluation and laboratory testing, including ABO, RhD typing and maternal antibody screen, were performed. RESULTS: A total of 466 babies were enrolled. The mean (SD) age was 3.4 (1.5) days. Of newborn babies with jaundice, 17.2% (80/466) had HDN. Babies with HDN had lower haemoglobin (SD); 15.7 (2.7) compared with those without HDN; 16.4 (2.4) g/dL, p = 0.016; and a higher bilirubin (interquartile range); 241 (200-318) compared with those without HDN; 219 (191-263) µmol/L, p < 0.001. One baby had anti-D HDN, while 46/466 had HDN from an ABO incompatibility (anti-A 43.5% and anti-B 56.5%); 82% of babies with HDN also had suspected neonatal sepsis or birth asphyxia. About 79.2% (57/72) of mothers did not have ABO/Rh blood group performed antenatally. All infants with HDN survived except one. CONCLUSION: Among newborn infants with jaundice, HDN is not rare. The majority is due to ABO HDN affecting group A and group B babies equally. Ensuring routine ABO/Rh grouping for all pregnant women is an area for improvement.

Accuracy of International Classification of Diseases, 10th Revision Codes for Identifying Sepsis: A Systematic Review and Meta-Analysis.

Administrative databases are increasingly used in research studies to capture clinical outcomes such as sepsis. This systematic review and meta-analysis examines the accuracy of International Classification of Diseases, 10th revision (ICD-10), codes for identifying sepsis in adult and pediatric patients. DATA SOURCES: We searched MEDLINE, EMBASE, Web of Science, CENTRAL, Epistemonikos, and McMaster Superfilters from inception to September 7, 2021. STUDY SELECTION: We included studies that validated the accuracy of sepsis ICD-10 codes against any reference standard. DATA EXTRACTION: Three authors, working in duplicate, independently extracted data. We conducted meta-analysis using a random effects model to pool sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). We evaluated individual study risk of bias using the Quality Assessment of Diagnostic Accuracy Studies tool and assessed certainty in pooled diagnostic effect measures using the Grading of Recommendations Assessment, Development, and Evaluation framework. DATA SYNTHESIS: Thirteen eligible studies were included in the qualitative synthesis and the meta-analysis. Eleven studies used manual chart review as the reference standard, and four studies used registry databases. Only one study evaluated pediatric patients exclusively. Compared with the reference standard of detailed chart review and/or registry databases, the pooled sensitivity for sepsis ICD-10 codes was 35% (95% CI, 22-48, low certainty), whereas the pooled specificity was 98% (95% CI: 98-99, low certainty). The PPV for ICD-10 codes ranged from 9.8% to 100% (median, 72.0%; interquartile range [IQR], 50.0-84.7%). NPV ranged from 54.7% to 99.1% (median, 95.9%; interquartile range, 85.5-98.3%). CONCLUSIONS: Sepsis is undercoded in administrative databases. Future research is needed to explore if greater consistency in ICD-10 code definitions and enhanced quality measures for ICD-10 coders can improve the coding accuracy of sepsis in large databases.

A data-informed system to manage scarce blood product allocation in a randomized controlled trial of convalescent plasma.

BACKGROUND: Equitable allocation of scarce blood products needed for a randomized controlled trial (RCT) is a complex decision-making process within the blood supply chain. Strategies to improve resource allocation in this setting are lacking. METHODS: We designed a custom-made, computerized system to manage the inventory and allocation of COVID-19 convalescent plasma (CCP) in a multi-site RCT, CONCOR-1. A hub-and-spoke distribution model enabled real-time inventory monitoring and assignment for randomization. A live CCP inventory system using REDCap was programmed for spoke sites to reserve, assign, and order CCP from hospital hubs. A data-driven mixed-integer programming model with supply and demand forecasting was developed to guide the equitable allocation of CCP at hubs across Canada (excluding Québec). RESULTS: 18/38 hospital study sites were hubs with a median of 2 spoke sites per hub. A total of 394.5 500-ml doses of CCP were distributed; 349.5 (88.6%) doses were transfused; 9.5 (2.4%) were wasted due to mechanical damage sustained to the blood bags; 35.5 (9.0%) were unused at the end of the trial. Due to supply shortages, 53/394.5 (13.4%) doses were imported from Héma-Québec to Canadian Blood Services (CBS), and 125 (31.7%) were transferred between CBS regional distribution centers to meet demand. 137/349.5 (39.2%) and 212.5 (60.8%) doses were transfused at hubs and spoke sites, respectively. The mean percentages of total unmet demand were similar across the hubs, indicating equitable allocation, using our model. CONCLUSION: Computerized tools can provide efficient and immediate solutions for equitable allocation decisions of scarce blood products in RCTs.

A data-driven approach to determine daily platelet order quantities at hospitals.

BACKGROUND: Determining the required daily number of platelet units in hospitals is a challenging task due to the high uncertainty in daily usage and short shelf life of platelets. STUDY DESIGN AND METHODS: We developed a linear prediction model to guide the daily ordering quantity of platelet units at a hospital that orders the required units from a central supplier. The predictive model relies on historical demand data and other information from the hospital's information system. The ordering strategy is to place an order at the end of each day to bring the platelet inventory to the predicted demand for the next day. Unlike typical prediction models, the quality of the predictions is measured with respect to the resulting inventory costs of wastage and shortage. We used data from two hospitals in Hamilton, Ontario from 2015 to 2016 to train our model and evaluated its performance based on the resulting wastage and shortage rates in 2017. RESULTS: In 2017, respectively 1915 and 4305 platelet units were transfused at the two hospitals, with daily average (SD) usage of 5.2 (3.7) and 11.8 (4.4). The expiry (estimated shortage) rates were 8.67% (13.86%), and 2.28% (8.48%) at the two hospitals, respectively. Our baseline model would have reduced the expiry (shortage) rates to 2.54% (4.01%) and 0.05% (0.44%) for the two hospitals, respectively. DISCUSSION: Guiding daily ordering decisions for platelets using our proposed model could lead to a significant reduction of wastage and shortage rates at hospitals.

Plasma transfusion practices: A multicentre electronic audit.

BACKGROUND AND OBJECTIVES: Plasma is often transfused to patients with bleeding or requiring invasive procedures and with abnormal tests of coagulation. Chart audits find half of plasma transfusions unnecessary, resulting in avoidable complications and costs. This multicentre electronic audit was conducted to determine the proportion of plasma transfused without an indication and/or at a sub-therapeutic dose. METHODS: Data were extracted on adult inpatients in 2017 at five academic sites from the hospital electronic chart, laboratory information systems and the Canadian Institute for Health Information Discharge Abstract Database. Electronic criteria for plasma transfusion outside recommended indications were: (1) international normalized ratio (INR) < 1.5 with no to moderate bleeding; (2) INR ≥ 1.5, with no to mild bleeding and no planned procedures; and (3) no INR before or after plasma infusion. Sub-therapeutic dose was defined as ≤2 units transfused. RESULTS: In 1 year, 2590 patients received 6088 plasma transfusions encompassing 11,490 units of plasma occurred at the five sites. 77.7% of events were either outside indications or under-dosed. Of these, 34.8% of plasma orders had no indication identified, and 62% of these occurred in non-bleeding patients and no planned procedure with an isolated elevated INR. 70.7% of transfusions were under-dosed. Most plasma transfusions occurred in the intensive care unit or the operating room. Inter-hospital variability in peri-transfusion testing and dosing was observed. CONCLUSION: The majority of plasma transfusions are sub-optimal. Local hospital culture may be an important driver. Electronic audits, with definitions employed in this study, may be a practical alternative to costly chart audits.

Development and internal validation of a clinical prediction model for the diagnosis of immune thrombocytopenia.

BACKGROUND: Immune thrombocytopenia (ITP) is a diagnosis of exclusion that can resemble other thrombocytopenic disorders. OBJECTIVES: To develop a clinical prediction model (CPM) for the diagnosis of ITP to aid hematogists in investigating patients presenting with undifferentiated thrombocytopenia. METHODS: We designed a CPM for ITP diagnosis at the time of the initial hematology consultation using penalized logistic regression based on data from patients with thrombocytopenia enrolled in the McMaster ITP registry (n = 523) called the Predict-ITP Tool. The case definition for ITP was a platelet count less than 100 × 109 /L and a platelet count response after high-dose corticosteroids or intravenous immune globulin, defined as the achievement of a platelet count above 50 × 109 /L and at least a doubling of baseline. Internal validation was done using bootstrap resampling. Model discrimination was assessed by the c-statistic, and calibration was assessed by the calibration slope, calibration-in-the-large, and calibration plot. RESULTS: The final model included the following variables: (1) platelet count variability (based on three or more platelet count values), (2) lowest platelet count value, (3) maximum mean platelet volume, and (4) history of major bleeding (defined by the ITP bleeding scale). The optimism-corrected c-statistic was 0.83, the calibration slope was 0.88, and calibration-in-the-large for all performance measures was <0.001 with standard error <0.001, indicating good discrimination and excellent calibration. CONCLUSIONS: The Predict-ITP Tool can estimate the likelihood of ITP for a given patient with thrombocytopenia at the time of the initial hematology consultation. The tool had high predictive accuracy for the diagnosis of ITP.

Genome-wide association study of platelet factor 4/heparin antibodies in heparin-induced thrombocytopenia.

Heparin, a widely used anticoagulant, carries the risk of an antibody-mediated adverse drug reaction, heparin-induced thrombocytopenia (HIT). A subset of heparin-treated patients produces detectable levels of antibodies against complexes of heparin bound to circulating platelet factor 4 (PF4). Using a genome-wide association study (GWAS) approach, we aimed to identify genetic variants associated with anti-PF4/heparin antibodies that account for the variable antibody response seen in HIT. We performed a GWAS on anti-PF4/heparin antibody levels determined via polyclonal enzyme-linked immunosorbent assays. Our discovery cohort (n = 4237) and replication cohort (n = 807) constituted patients with European ancestry and clinical suspicion of HIT, with cases confirmed via functional assay. Genome-wide significance was considered at α = 5 × 10-8. No variants were significantly associated with anti-PF4/heparin antibody levels in the discovery cohort at a genome-wide significant level. Secondary GWAS analyses included the identification of variants with suggestive associations in the discovery cohort (α = 1 × 10-4). The top variant in both cohorts was rs1555175145 (discovery ß = -0.112 [0.018], P = 2.50 × 10-5; replication ß = -0.104 [0.051], P = .041). In gene set enrichment analysis, 3 gene sets reached false discovery rate-adjusted significance (q < 0.05) in both discovery and replication cohorts: "Leukocyte Transendothelial Migration," "Innate Immune Response," and "Lyase Activity." Our results indicate that genomic variation is not significantly associated with anti-PF4/heparin antibody levels. Given our power to identify variants with moderate frequencies and effect sizes, this evidence suggests genetic variation is not a primary driver of variable antibody response in heparin-treated patients with European ancestry.

ABO O blood group as a risk factor for platelet reactivity in heparin-induced thrombocytopenia.

Heparin-induced thrombocytopenia (HIT) is an unpredictable, potentially catastrophic adverse effect resulting from an immune response to platelet factor 4 (PF4)/heparin complexes. We performed a genome-wide association study (GWAS) with positive functional assay as the outcome in a large discovery cohort of patients divided into 3 groups: (1) functional assay-positive cases (n = 1269), (2) antibody-positive (functional assay-negative) controls (n = 1131), and (3) antibody-negative controls (n = 1766). Significant associations (α = 5 × 10-8) were investigated in a replication cohort (α = 0.05) of functional assay-confirmed HIT cases (n = 177), antibody-positive (function assay-negative) controls (n = 258), and antibody-negative controls (n = 351). We observed a strong association for positive functional assay with increasing PF4/heparin immunoglobulin-G (IgG) level (odds ratio [OR], 16.53; 95% confidence interval [CI], 13.83-19.74; P = 1.51 × 10-209) and female sex (OR, 1.15; 95% CI, 1.01-1.32; P = .034). The rs8176719 C insertion variant in ABO was significantly associated with positive functional assay status in the discovery cohort (frequency = 0.41; OR, 0.751; 95% CI, 0.682-0.828; P = 7.80 × 10-9) and in the replication cohort (OR, 0.467; 95% CI, 0.228-0.954; P = .0367). The rs8176719 C insertion, which encodes all non-O blood group alleles, had a protective effect, indicating that the rs8176719 C deletion and the O blood group were risk factors for HIT (O blood group OR, 1.42; 95% CI, 1.26-1.61; P = 3.09 × 10-8). Meta-analyses indicated that the ABO association was independent of PF4/heparin IgG levels and was stronger when functional assay-positive cases were compared with antibody-positive (functional assay-negative) controls than with antibody-negative controls. Sequencing and fine-mapping of ABO demonstrated that rs8176719 was the causal single nucleotide polymorphism (SNP). Our results clarify the biology underlying HIT pathogenesis with ramifications for prediction and may have important implications for related conditions, such as vaccine-induced thrombotic thrombocytopenia.