# Complement and Thrombosis in HIT

> **NIH NIH R01** · DUKE UNIVERSITY · 2022 · $599,600

## Abstract

ABSTRACT
Heparin induced thrombocytopenia (HIT) is a severe thrombotic disorder initiated by ultralarge immune
complexes (ULICs) containing IgG antibodies to a multivalent antigen composed of platelet factor 4 (PF4) and
heparin (H). Patients with HIT are at risk for death, amputation, recurrent thromboembolism and bleeding while
receiving maximally tolerated doses of factor Xa or direct thrombin inhibitors (DTIs). Thus, there is an unmet
need for 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 and bind
complement components and von Willebrand factor (vWF) multimers, 2) generate soluble complement
components via the classical pathway, 3) deposit C3 on neutrophils, monocytes and endothelial cells (ECs), 4)
trigger complement-dependent neutrophil degranulation, monocyte tissue factor (TF) and procoagulant activity
upstream of C5, 5) activate complement even in the presence of DTIs, and 6) promote complement deposition
in a murine thrombosis model of HIT. Based on these findings, we hypothesize that complement activation by
HIT ULICs contributes to the prothrombotic state in HIT through direct EC injury mediated by surface expressed
complement receptors (CRs) and by amplifying signaling by promoting cooperativity with FcRIIA on neutrophils
and monocytes. We will address the following specific aims: 1) Examine HIT ULIC-complement interactions and
effects of complement activation on ECs We will test the hypothesis that incorporation of complement enlarges
and stabilizes assembled ULICs, impairs complement regulatory function, and promotes EC injury leading to
release of vWF multimers that further amplify ULIC formation and complement activation. 2) Examine
cooperative interactions of HIT ULICs, complement and monocyte/neutrophil FcR. We will test the hypothesis
that complement-containing ULICS amplify FcRIIA signaling by promoting cooperativity with cellular CRs on
neutrophils and monocytes. We will examine the effects of ULIC composition on cell activation, identify CRs
involved in binding HIT ULICs, study soluble and cellular complement regulatory mechanisms, and characterize
complement activation in seropositive patients with and without HIT. 3) Examine complement inhibition as a
therapeutic strategy for thrombosis in HIT. We will use microfluidic assays and murine thrombosis models to
test the hypothesis that activation of the classical complement pathway by HIT ULICs promotes macrovascular
thrombosis through release of vWF from activated ECs and amplification of cellular procoagulant activity. We
will examine the efficacy of proximal and terminal complement pathway inhibition as a strategy to lower the
intensity of antithrombotic therapy needed to treat HIT. Together, these studies wil...

## Key facts

- **NIH application ID:** 10319182
- **Project number:** 5R01HL151730-02
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Gowthami M Arepally
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $599,600
- **Award type:** 5
- **Project period:** 2020-12-15 → 2024-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10319182

## Citation

> US National Institutes of Health, RePORTER application 10319182, Complement and Thrombosis in HIT (5R01HL151730-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10319182. Licensed CC0.

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