From enemy to helper: Immune cells can dissolve blood clots

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Blood clots can lead to life-threatening conditions such as strokes, heart attacks, or pulmonary embolisms. Until now, immune cells such as neutrophils and monocytes were primarily considered to be contributing factors in such thromboses. However, the new study shows that these cells can also play a healing role—provided they are in the right "mood."

A look inside the clot – for the first time with precise and comprehensive resolution at the single-cell level

For their investigations, the researchers used thrombi that had been removed from stroke patients during mechanical thrombectomy. This procedure for reopening blocked blood vessels in the brain provided rare access to fresh thrombus material during the acute phase of the disease. In addition, blood samples from the same patients were analyzed to compare the immune cell composition in the thrombus with that in the blood.

Thrombi can form in all vascular areas of the body. For this study, the researchers chose cerebral arteries because they are easily accessible in everyday clinical practice and the material taken can be processed in a standardized and gentle manner—an important factor in reliably examining sensitive cell types such as neutrophils.

Using state-of-the-art single-cell technologies such as single-cell RNA sequencing and CITE-seq, the immune cells involved were characterized with unprecedented resolution. Mouse models and in vitro experiments were also used to functionally confirm the mechanisms observed.

Blood clots can lead to life-threatening conditions such as strokes, heart attacks, or pulmonary embolisms. Until now, immune cells such as neutrophils and monocytes were primarily considered to be contributing factors in such thromboses. However, the new study shows that these cells can also play a healing role—provided they are in the right "mood."

A look inside the clot – for the first time with precise and comprehensive resolution at the single-cell level

For their investigations, the researchers used thrombi that had been removed from stroke patients during mechanical thrombectomy. This procedure for reopening blocked blood vessels in the brain provided rare access to fresh thrombus material during the acute phase of the disease. In addition, blood samples from the same patients were analyzed to compare the immune cell composition in the thrombus with that in the blood.

Thrombi can form in all vascular areas of the body. For this study, the researchers chose cerebral arteries because they are easily accessible in everyday clinical practice and the material taken can be processed in a standardized and gentle manner—an important factor in reliably examining sensitive cell types such as neutrophils.

Using state-of-the-art single-cell technologies such as single-cell RNA sequencing and CITE-seq, the immune cells involved were characterized with unprecedented resolution. Mouse models and in vitro experiments were also used to functionally confirm the mechanisms observed.

The discovery: Immune cells help dissolve blood clots

The researchers discovered that certain monocytes—known as non-classical monocytes—attract neutrophils, which transform in the oxygen-depleted environment of the thrombus into a form that produces blood clot-dissolving enzymes, in particular the urokinase receptor (PLAUR). The authors refer to this process as "immunothrombolysis."

"Our findings show that immune cells not only cause damage, but can also help to dissolve blood clots," says Dr. Kami Pekayvaz, first author of the study and clinician scientist at Medical Clinic I of LMU Hospital. "This discovery opens up entirely new therapeutic possibilities."

New approaches to treating thrombosis

What is particularly interesting is that when a specific signaling pathway in neutrophils is artificially activated—the so-called HIF1a signaling pathway—the cells develop enhanced thrombus-dissolving properties. When the mechanism was blocked, the thrombi dissolved significantly less effectively in affected mice.

"Existing thrombolysis drugs work quickly, but they increase the risk of dangerous bleeding," explains Prof. Konstantin Stark, last author of the study and senior physician at Medical Clinic I at LMU Hospital. "If we can successfully manipulate the body's immune system to dissolve blood clots, this could be a gentler form of treatment."

A new picture of blood clots

The study provides a highly detailed map of immune cell activity in thrombi – both in humans and in animal models. It shows that thrombi can change dynamically after their formation, with immunologically driven healing processes also taking place. In the long term, these findings could help to develop new therapies for the treatment of thrombosis that avoid dangerous bleeding side effects.

Publication: Pekayvaz et al. (2025): Immunothrombolytic monocyte-neutrophil axes dominate the single-cell landscape of human thrombosis and correlate with thrombus resolution. Immunity
DOI: 10.1016/j.immuni.2025.03.020