# Elucidating the Role of Inherited Complement System Defects in the Molecular Pathophysiology of Sepsis and Purpura Fulminans

> **NIH NIH R21** · BETH ISRAEL DEACONESS MEDICAL CENTER · 2021 · $131,250

## Abstract

PROJECT SUMMARY
Purpura fulminans (PF) is a rare but devastating complication of sepsis in which patients
develop a highly thrombotic subtype of disseminated intravascular coagulation (DIC), leading to
dismemberment, end organ damage, and death. PF can be triggered by a range of bacterial
infections and is distinguished by extremely high levels of circulating cytokines and failure of key
anti-inflammatory pathways which cause a marked upregulation of procoagulant tissue factor
(TF) expression by activated monocytes. Because PF represents an extreme disease phenotype,
leveraging our findings in this disorder could yield key insights into the broader problem of septic
DIC. However, at present almost nothing is known about the molecular pathophysiology and
genetic predisposition underlying PF. Utilizing germline whole exome sequencing (WES) and a
targeted gene discovery approach, we have found a significant enrichment in rare, deleterious
coding variants in the complement systems of patients with PF compared to unselected patients
with sepsis (P<0.0001). Intriguingly, we also found that these variants may be associated with
increased mortality in unselected sepsis patients despite the absence of overt PF. We
hypothesize that complement system defects lead to heightened systemic inflammation and
procoagulant activity, resulting in the development of coagulopathy. In Aim 1 of this project, we
will follow up on our preliminary results by performing WES on clinically well-annotated
specimens in the NHLBI BioLINCC repository from septic patients without overt PF. We will
correlate complement mutational status to plasma biomarkers of thrombosis and inflammation
after adjusting for age, sex, ethnicity, and comorbidities in order to understand if complement
system defects are associated with worsened thrombo-inflammation in sepsis. In Aim 2, we will
functionally characterize a novel class of rare PF-associated variants in complement receptors 3
and 4 (CR3/4) with respect to their impact on monocyte-driven inflammation and thrombosis.
The proposed work will provide important new insights into the relationship between innate
immunity and dysregulated coagulation and generate a foundational WES dataset with
biological correlates for studying the widespread problem of coagulopathy in sepsis.

## Key facts

- **NIH application ID:** 10246412
- **Project number:** 5R21HL153655-02
- **Recipient organization:** BETH ISRAEL DEACONESS MEDICAL CENTER
- **Principal Investigator:** Pavan Bendapudi
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $131,250
- **Award type:** 5
- **Project period:** 2020-09-01 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10246412

## Citation

> US National Institutes of Health, RePORTER application 10246412, Elucidating the Role of Inherited Complement System Defects in the Molecular Pathophysiology of Sepsis and Purpura Fulminans (5R21HL153655-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10246412. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*