# Thrombosis and Antiphospholipid Antibodies

> **NIH VA I01** · MICHAEL E DEBAKEY VA MEDICAL CENTER · 2024 · —

## Abstract

β2-glycoprotein I (β2-Gp1) is a cardiolipin-binding protein first identified in 1961. It is a 50
 kDa glycoprotein with a plasma concentration of 1−4 µM. The physiological function of β2-Gp1
 is not known even though it is conserved evolutionarily from invertebrates to humans.
 Anticardiolipin antibodies are associated with arterial, venous, microvascular thrombosis or
with recurrent midtrimester abortion due to placental vascular insufficiency. These antibodies are
not specific towards cardiolipin, but to conformational epitopes on proteins bound to cardiolipin.
The most common protein antigen is β2-Gp1. High titers of these antibodies are associated with
thrombosis and recurrent midtrimester abortion due to placental thrombosis. While a large number
of hypotheses have been put forward, the precise mechanism of thrombosis is not known because
the physiological function of β2-Gp1 is not known.
Mitochondria are organelles that maintain energy supply in cells. Cardiolipin is a universal
component of mitochondrial membrane. Its unique physicochemical properties play an important
role in the structural organization and function. Recent investigations have shown mitochondria
are released during tissue injury and are also present in the extracellular space as an intact
organelle or enclosed in vesicle. Extracellular mitochondrial DNA resembles bacterial DNA and
present as damage-associated molecular patterns (DAMP), which provoke a proinflammatory
response.
Our studies propose a novel function for evolutionarily conserved β2-Gp1 as a regulator of
extracellular mitochondria levels in circulation and how antiβ2-Gp1 antibodies may lead to a
procoagulant state. We show that β2-Gp1 binds to circulating cardiolipin-expressing extracellular
mitochondria in a concentration-dependent manner. In vitro, β2-Gp1 promotes mitochondrial
uptake and clearance by macrophages and endothelial cells. In vivo, β2-Gp1-deficient mice have
increased circulating extracellular mitochondria. We also demonstrate defective clearance due to
impaired phagocytosis of infused mitochondria from the circulation in β2-Gp1-deficient mice. We
posit that the evolutionarily conserved β2-Gp1 mediates the clearance of circulating
cardiolipin-expressing extracellular mitochondria. Our goals in the current proposal are to
expand these studies, delving further into the role of β2-Gp1 in the clearance of circulating
mitochondria, and to investigate how β2-Gp1 antibodies predispose to thrombosis. These specific
aims of this proposal are (1) To further define the role of β2-Gp1 in the clearance of
extracellular mitochondria. We will test the hypothesis that β2-Gp1 promotes clearance of
cardiolipin-expressing mitochondria by macrophages and/or endothelial cells. (2) To
determine the effect of engulfed exogenous mitochondria on macrophage and endothelial
functions. (3) To determine the role of antiβ2-Gp1 antibodies in thrombosis seen in
antiphospholipid syndrome. We will test the hypothesis that the up...

## Key facts

- **NIH application ID:** 10702059
- **Project number:** 1I01BX005939-01A2
- **Recipient organization:** MICHAEL E DEBAKEY VA MEDICAL CENTER
- **Principal Investigator:** Perumal Thiagarajan
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2023-10-01 → 2027-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10702059

## Citation

> US National Institutes of Health, RePORTER application 10702059, Thrombosis and Antiphospholipid Antibodies (1I01BX005939-01A2). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10702059. Licensed CC0.

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