# Adrien Jacobs - Undergraduate Research Supplement 5R01-HL151730

> **NIH NIH R01** · DUKE UNIVERSITY · 2024 · $11,978

## Abstract

ABSTRACT
Heparin induced thrombocytopenia (HIT) is a severe thrombotic disorder initiated by ultralarge immune
complexes (ULICs) containing IgG antibody to a multivalent antigen composed of platelet factor 4 (PF4) and
heparin (H). Even today, patients with HIT remain at risk for death, amputation, recurrent thromboembolism and
bleeding while receiving maximally tolerated doses of anti-Xa or anti-thrombin agents. Thus, there is an unmet
need for a deeper insight into the pathobiology of thrombosis in HIT that will lead to targeted novel non-
anticoagulant interventions to supplement contemporary therapy. Our published and pilot data demonstrate that
activation of the complement pathway fulfills this gap. Specifically, we show that HIT ULICs: 1) interact with and
bind activated complement components 2) generate soluble complement components via the classical pathway,
3) deposit C3 on platelets, neutrophils, monocytes and endothelial cells (ECs), 4) initiate cellular activation
leading to neutrophil degranulation, monocyte tissue factor (TF) and procoagulant activity 5) activate
complement in the presence of direct thrombin inhibitors, 6) trigger complement-mediated cellular activation
upstream of C5 and 7) promote significant complement deposition in a murine thrombosis model. Based on
these findings, we hypothesize that complement activation by HIT ULICs contributes to the prothrombotic state
in HIT through EC injury mediated by soluble and surface expressed complement receptors (CRs) and dual
amplification of FcγRs and CRs on cells expressing FcγRs. In the aims that follow, we will address the following
questions related to complement in HIT: 1) Does complement stabilize HIT ULICs, prevent disassembly and
amplify procoagulant responses by ECs that lack FcγRs? In this aim, we will test the hypothesis that complement
stabilizes ULIC assembly and promotes EC injury and impairs complement regulatory function, leading to release
of vWF multimers that amplify ULIC formation and complement activation. 2) Does complement amplify
procoagulant responses by FcγR expressing cells and serve as a biomarker of incipient disease? In this aim,
we will test the hypothesis that complement-coated ULICS amplify FcγRIIA signaling by promoting cooperativity
of complement and FcγR receptors. In this aim, we will examine effects of ULIC composition on cellular activation,
identify CRs involved in binding HIT ULICs, examine effects of HIT ULICs on soluble and cellular complement
regulatory mechanisms and characterize complement activation in patients with and without symptomatic anti-
PF4/heparin antibodies. 3) Can Complement inhibition serve as a therapeutic strategy for HIT? In this aim, we
will use microfluidic assays and murine thrombosis models to test the hypothesis that the net effects of
complement activation by HIT ULICs contributes to macrovascular thrombosis and its modulation can reduce
need for antithrombotic therapy in HIT. Together, these studies will provi...

## Key facts

- **NIH application ID:** 10908895
- **Project number:** 3R01HL151730-04S1
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Gowthami M Arepally
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $11,978
- **Award type:** 3
- **Project period:** 2020-12-15 → 2024-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10908895

## Citation

> US National Institutes of Health, RePORTER application 10908895, Adrien Jacobs - Undergraduate Research Supplement 5R01-HL151730 (3R01HL151730-04S1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10908895. Licensed CC0.

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