# B cell responses in heparin-induced thrombocytopenia

> **NIH NIH R01** · VERSITI BLOOD HEALTH, INC. · 2021 · $645,343

## Abstract

ABSTRACT
Heparin-induced thrombocytopenia (HIT) is the most common drug-induced immune thrombocytopenia and can
lead to catastrophic thrombosis in an affected patient. Antibodies that recognize the platelet alpha-granule
protein, platelet factor 4 (PF4), in a complex with heparin are central to HIT pathogenesis. Human B cells have
extensive heterogeneity. Innate-like B cells, such as B1 and marginal zone (MZ) B cells, later germinal center
(GC) B cells, different types of memory B cells, and extrafollicular plasmablasts all play an importance and unique
role in the development of humoral immunity. Rapid onset of HIT antibody production and apparent lack of
immunologic memory suggest T-cell independence whereas IgG antibodies typical of HIT argue for T cell
involvement. The profound heterogeneity of human B cells and the ambiguous features of the HIT antibody
response have confounded efforts to identify the pathogenic B cells and characterize the atypical immune
response in HIT patients. In a mouse model, we have demonstrated that MZ B cells play a critical role in HIT
antibody production. In the immediate past grant period, we discovered that in mice, breakdown of immunologic
tolerance was involved in HIT antibody production and T helper cells and regulatory T cells could mediate the
production of PF4/heparin-specific HIT antibodies. We also identified several novel pathways controlling B cell
tolerance that was critical for controlling production of autoantibodies. Importantly, from HIT human patients, we
cloned PF4/heparin-specific and platelet-activating antibodies possessing a unique RKH- or Y5-motif in the
heavy chain complementarity determining region 3 (HCDR3) region that contributes the most to affinity and
specificity of antigen binding. We found that a higher percentage of PF4/heparin-specific B cells, compared to
the control B cells, exhibited extrafollicular B-cell features and an atypical memory B cell (atyMB) phenotype.
Based on these findings, we hypothesize that PF4/heparin-specific B cells undergo extrafollicular response to
follow a distinct differentiation path from activated naïve B cells first into atyMBs and then into plasmablasts in
HIT patients. To test this hypothesis, we will (1) study the characteristics of PF4/heparin-specific B cells in HIT
patients through integrative analysis of phenotypical, transcriptional and epigenetic responses of these B cells
and (2) investigate the origin and developmental trajectory of PF4/heparin-specific B cells that produce platelet-
activating antibodies in HIT patients. The proposed studies will identify the key features of PF4/heparin-specific
B cells and their correlation with disease progression and severity and will discover the evolution of PF4/heparin-
specific B-cell response. Completion of the proposed studies will provide novel insights into the molecular
pathogenesis of HIT and guide future diagnosis, prevention and treatment of this potentially devastating disease.

## Key facts

- **NIH application ID:** 10298227
- **Project number:** 2R01HL130724-05
- **Recipient organization:** VERSITI BLOOD HEALTH, INC.
- **Principal Investigator:** DEMIN WANG
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $645,343
- **Award type:** 2
- **Project period:** 2017-01-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10298227

## Citation

> US National Institutes of Health, RePORTER application 10298227, B cell responses in heparin-induced thrombocytopenia (2R01HL130724-05). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10298227. Licensed CC0.

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