# Investigating the Role of Heme-Induced Complement Activation in SCD Pregnancy

> **NIH NIH K99** · EMORY UNIVERSITY · 2024 · $101,183

## Abstract

Project Summary/Abstract
Though pregnancy in all cases harbors risk of complications, pregnancy in sickle cell disease (SCD) is associated
with an exceptionally high risk of complications including preterm delivery, deep vein thrombosis, intrauterine
growth restriction, preeclampsia, and intrauterine death. Women with SCD also experience higher cesarean and
maternal death rates. Though the mechanistic drivers of poor pregnancy outcomes specific to SCD are not well
defined, similar complications in non-SCD pregnancy are often attributed to inflammatory dysregulation and
impaired vascular maintenance. These conditions are significantly elevated at baseline in SCD and highly likely
to be exacerbated as pregnancy proceeds.
One principal driver of such vascular impairment and inflammatory dysregulation in SCD is chronic intravascular
hemolysis producing not only anemic conditions but additional release of toxic biproducts including heme. This
circulating heme is detrimental to a number of vascular signaling pathways and is known to overstimulate the
complement system, an innate immune responder whose activity is elevated at baseline in SCD. Under normal
circumstances, well-regulated complement activation is essential to homeostasis and healthy gestation, but
when overstimulated, complement activity acts to promote robust pro-inflammatory responses and local tissue
degradation.
In non-SCD pregnancy, complement over-activation continues to be associated with poor outcomes including
early pregnancy loss, fetal growth restriction, hypertensive disorders, and preterm birth. It is further known to
cause damage to trophoblast and decidual cells in the placenta. It is our belief that this heme-induced
overstimulation of the complement system is at the forefront of the placental insufficiency and poor pregnancy
outcomes seen in SCD. We additionally believe these outcomes can be ameliorated both indirectly through heme
sequestration and directly through complement modulation.
Using a well-established pre-clinical mouse model of SCD we will examine these hypotheses through the
following aims. Aim 1 (K99) Characterize the effects of SCD and heme-induced complement activation on
pregnancy outcomes in the humanized Townes mouse model of SCD and Aim 2 (R00) Determine if heme-
and/or complement- modulation can improve pregnancy outcomes in the humanized Townes mouse
model of SCD. Though poor pregnancy outcomes in SCD continue to be documented, there remains limited
studies aimed at identifying underlying physiological drivers. Successful completion of these aims will provide a
framework for therapeutic investigation moving forward and could establish heme-induced complement
modulation as a viable candidate for further preclinical assessment with the ultimate goal of improving outcomes.

## Key facts

- **NIH application ID:** 10949887
- **Project number:** 1K99HL175098-01
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** CHRISTOPHER CHAMBLISS
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $101,183
- **Award type:** 1
- **Project period:** 2024-09-01 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10949887

## Citation

> US National Institutes of Health, RePORTER application 10949887, Investigating the Role of Heme-Induced Complement Activation in SCD Pregnancy (1K99HL175098-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10949887. Licensed CC0.

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