# B cell responses in heparin-induced thrombocytopenia

> **NIH NIH R01** · VERSITI BLOOD HEALTH, INC. · 2020 · $549,400

## Abstract

ABSTRACT
Heparin-induced thrombocytopenia (HIT) is the most common drug-induced immune thrombocytopenia and
can have devastating consequences for an affected patient. Antibodies that recognize the platelet alpha-
granule protein, platelet factor 4 (PF4), in a complex with heparin (“HIT antibodies”) are central to HIT
pathogenesis. The kinetics of HIT antibody production, characterized by rapid onset and apparent lack of
immunologic memory, suggest T-cell independence, but IgG antibodies typical of HIT argue for T cell
involvement. These ambiguous features of the HIT antibody response have confounded efforts to characterize
HIT immune- pathogenesis. There are three subsets of mature B cells, follicular (FO), marginal zone (MZ) and
B1 B cells. Each subset has a distinct role in the humoral immune response and is regulated differently.
Signals generated through the B cell receptor (BCR) are required for B cell development, function and
establishment of self-tolerance and dysregulation of BCR signaling can lead to autoimmunity. In previous
studies under this grant, we showed in a mouse model that MZ B cells play a critical role in HIT antibody
production, that breakdown of immunologic tolerance appears to be involved in HIT antibody production in
mice and humans, and that T helper cells control heparin-induced production of HIT antibodies in mice. We
also identified important signaling molecules and pathways that are critical for BCR-mediated B-cell function
and tolerance. Based on these findings, we hypothesize that PF4/heparin-specific B cells originate from the
distinct MZ B cell subset in human HIT patients and that activation and proliferation of pathogenic B cells is
controlled by T cells and the major tolerance mechanism, anergy. To test this hypothesis, three specific aims
are proposed. Specifically, we will 1) define the cellular source and molecular properties of anti-PF4/heparin
antibodies in human HIT, 2) investigate mechanisms by which T cells help PF4/heparin-specific MZ B cells,
and 3) characterize molecular mechanism(s) that regulate PF4/heparin antibody production. Defining the
cellular and molecular mechanisms responsible for HIT antibody production will provide new clues to the
pathogenesis of HIT, suggest novel tools for HIT diagnosis, prophylaxis and treatment and may contribute to
the understanding of other autoimmune diseases relevant to transfusion medicine.

## Key facts

- **NIH application ID:** 9846233
- **Project number:** 5R01HL130724-04
- **Recipient organization:** VERSITI BLOOD HEALTH, INC.
- **Principal Investigator:** DEMIN WANG
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $549,400
- **Award type:** 5
- **Project period:** 2017-01-01 → 2020-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9846233

## Citation

> US National Institutes of Health, RePORTER application 9846233, B cell responses in heparin-induced thrombocytopenia (5R01HL130724-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9846233. Licensed CC0.

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