Exploring the role of extracellular vesicles in thrombosis and pregnancy complications
Imagine your body's cellular communication system has been hacked. Instead of transmitting normal messages, microscopic couriers now deliver destructive signals that trigger blood clots and pregnancy complications. This isn't science fiction—it's the reality for people living with antiphospholipid syndrome (APS), an autoimmune disorder that researchers are now understanding through the lens of extracellular vesicles (EVs).
EVs deliver harmful signals that activate blood clots and disrupt pregnancy in APS patients.
EV patterns may help identify APS patients at highest risk for specific complications.
The story of EVs in APS represents a fascinating convergence of immunology, hematology, and obstetrics—one that might finally unlock better treatments for a condition that has puzzled doctors for decades.
Antiphospholipid syndrome is a systemic autoimmune disorder characterized by two main problems: persistent thrombosis (blood clots in arteries or veins) and/or obstetric complications (including recurrent pregnancy loss). Underlying these clinical manifestations is the presence of antiphospholipid antibodies (aPL)—a group of autoantibodies that mistakenly target the body's own proteins and phospholipids 1 .
Extracellular vesicles are submicron particles continuously released from nearly all cell types under both physiological and pathological conditions. In healthy individuals, approximately 10 billion EVs circulate in every milliliter of plasma 1 .
Research has revealed that women with obstetric APS show distinct patterns of EVs. A 2025 study found that APS-affected women with pregnancy complications had significantly lower levels of resting endothelial cell-derived EVs 2 .
aPL antibodies bind to target cells (endothelial cells, platelets, monocytes) 4 .
Activated cells release EVs with distinct compositions that propagate the disease state 1 .
Pathogenic EVs activate more cells, producing more vesicles and amplifying the disease process 1 .
A compelling 2025 study published in the International Journal of Molecular Sciences set out to determine whether specific EV profiles could be linked to particular clinical manifestations of APS 2 .
The research team enrolled:
Creating a robust framework for comparison of EV profiles and clinical manifestations.
The findings revealed striking differences between APS patients and healthy individuals, providing the most detailed picture to date of how EVs reflect disease activity:
| EV Type | Healthy Controls (%) | APS Patients (%) | p Value |
|---|---|---|---|
| reEVs | 0.44 | 1.88 | 0.01 |
| aeEVs | 0.00 | 0.30 | <0.01 |
| opEVs | 12.75 | 22.70 | <0.01 |
| ppEVs | 1.09 | 1.50 | 0.156 |
The discovery that women with obstetric APS had significantly lower reEVs provides a particularly important clue. This pattern suggests that the capacity to maintain healthy, resting endothelial cells may be compromised in these patients, potentially contributing to their pregnancy complications 2 .
A groundbreaking 2024 study applied deep proteomic analysis to EVs from patients with obstetric APS (OAPS), creating an unprecedented view of the molecular machinery inside these vesicles 3 .
Using advanced 4D-data-independent acquisition mass spectrometry (4D-DIA-MS), researchers analyzed both large and small EVs from serum samples. The results were striking: they identified 4,270 proteins in large EVs and 3,328 proteins in small EVs—a depth of coverage that dramatically exceeds conventional plasma proteomics 3 .
Proteins identified in large EVs
| Protein | EV Type | Change in OAPS | Potential Significance |
|---|---|---|---|
| Von Willebrand Factor (VWF) | Large EVs | Increased | Contributes to hypercoagulability and thrombosis risk |
| Insulin Receptor (INSR) | Both large and small EVs | Altered | Suggests metabolic dysfunction in OAPS |
| Novel EV Proteins | Both types | Multiple alterations | Reveals previously unknown disease mechanisms |
EV proteins largely originate from cellular organelles and plasma membranes rather than representing typical secreted proteins. This means they provide a unique window into cellular changes happening throughout the body—a "tissue leakage" effect that could help researchers understand how APS affects various organs 3 .
Studying extracellular vesicles in antiphospholipid syndrome requires specialized reagents and methodologies. Here are the key tools enabling discoveries in this field:
| Tool Category | Specific Examples | Purpose and Function |
|---|---|---|
| EV Isolation Methods | Ultracentrifugation, Density-gradient centrifugation, Size-exclusion chromatography | Separate EVs from other plasma components based on physical properties |
| EV Characterization | Nanoparticle tracking analysis (NTA), Transmission electron microscopy (TEM), Western blot | Determine EV size, concentration, and identity |
| Surface Marker Detection | CD146, CD42a, CD41, CD31, CD62P antibodies | Identify cellular origins of EVs using flow cytometry |
| Proteomic Analysis | 4D-data-independent acquisition mass spectrometry (4D-DIA-MS), Tandem mass tag (TMT) labeling | Identify and quantify protein cargo in EVs |
| Functional Assays | Cell migration assays, Tube formation assays, Thrombosis models | Determine biological effects of EVs on target cells and systems |
| Cellular Models | Human umbilical vein endothelial cells (HUVECs), Monocytes, Platelets | Study EV mechanisms in controlled laboratory environments |
The standardization of these methods following guidelines from the International Society for Extracellular Vesicles (ISEV) has been crucial for generating comparable results across different laboratories 8 . As the field advances, these tools continue to evolve, enabling increasingly sophisticated insights into how EVs contribute to APS pathology.
The journey into the world of extracellular vesicles has transformed our understanding of antiphospholipid syndrome. These tiny messengers, once overlooked, are now recognized as central players in APS pathology—carrying prothrombotic signals, disrupting normal endothelial function, and contributing to pregnancy complications.
The potential clinical applications are substantial. EVs could serve as much-needed biomarkers to identify APS patients at highest risk for thrombosis or obstetric complications, allowing for personalized prevention strategies 2 6 . They might also monitor treatment response or help classify disease subtypes based on their specific molecular signatures.
Understanding EVs opens new therapeutic possibilities. If we can decipher how pathogenic EVs form, what messages they carry, and how they target specific cells, we might develop interventions to:
The study of extracellular vesicles in antiphospholipid syndrome represents a powerful example of how exploring fundamental biological processes can reveal unexpected insights into human disease.
As research continues, these silent messengers may yet tell their most important stories—leading us to better diagnostics, treatments, and ultimately, improved lives for people with APS.