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

Abstract

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 with positive functional assay as the outcome in a large discovery cohort of patients divided into three 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 (alpha=5x10-8) were investigated in a replication cohort (alpha=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 IgG level (odds ratio [OR] 16.53[95% confidence interval 13.83-19.74], p=1.51x10-209) and female sex (OR 1.15[1.01-1.32], p=0.034). 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[0.682-0.828], p=7.80x10-9) and in the replication cohort (OR 0.467 [0.228-0.954], p=0.0367). 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 was a risk factor for HIT (O blood group OR 1.42 [1.26-1.61], p=3.09x10-8). Meta-analyses indicated that the ABO association was independent of PF4/heparin IgG levels and was stronger when functional assay-positive cases were compared to antibody-positive (functional assay-negative) controls than to antibody-negative controls. Sequencing and fine-mapping of ABO demonstrated that rs8176719 was the causal 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.

ABO blood group antigens and differential glycan expression: Perspective on the evolution of common human enzyme deficiencies

“…Although an SNP at the ABO locus was one of the 38 significant loci identified, its statistical association was not significant after Bonferroni correction for multiple testing. GWAS studies have also found significant findings relating to the ABO gene locus, including an association with heparin-induced thrombocytopenia (HIT) ( Karnes et al., 2022 ).…”

Platelet factor 4 triggers thrombo‐inflammation by bridging innate and adaptive immunity

“…However, large genome-wide association studies did not show any major genetic risk factors other than blood group O. 10,11 Diagnostic laboratory testing is discussed later in this review; treatment recommendations are summarized in the 2018 guidelines of the American Society of Hematology. 12 Vaccination against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) represents a biomedical breakthrough against the Covid-19 pandemic that has prevented millions of fatalities.…”

“…Females are at slightly higher risk than males, and some genetic polymorphisms within FcγRIIa and related signaling proteins also increase risk. However, large genome‐wide association studies did not show any major genetic risk factors other than blood group O 10,11 . Diagnostic laboratory testing is discussed later in this review; treatment recommendations are summarized in the 2018 guidelines of the American Society of Hematology 12 …”

Association of Metal Cations with the Anti-PF4/Heparin Antibody Response in Heparin-Induced Thrombocytopenia

“…Factors in uencing the risk of HIT have been of great interesting in the eld, as treatment for HIT is only actionable after the manifestation of symptoms [8]. Studies have shown genetic polymorphisms alter HIT risk [9][10][11][12][13] with the most con dent association seen in HIT associated thrombosis [14]. Other factors such as clinical setting [15], heparin formulation [16], gender [17,18], and anti-PF4/heparin antibody titers [18] have shown associations with HIT, but many risk factors show only modest increases in chances for progression to full-blown HIT.…”