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

In close cooperation with Prof. Dr. Martin Dichgans and PD Dr. Steffen Tiedt from the Department of Neurology and the Institute for Stroke and Dementia Research (ISD) and the Institute of Neuroradiology led by Prof. Dr. Thomas Liebig, the research group analyzed clots,that were removed from stroke patients as part of a mechanical thrombectomy. This procedure for reopening blocked cerebral vessels enabled 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. The researchers chose cerebral arteries for this study 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 being able to reliably examine 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 could be characterized with unprecedented resolution. In addition, mouse models and in-vitro experiments were used to functionally confirm the observed mechanisms.

The researchers discovered that certain monocytes - so-called non-classical monocytes - attract neutrophils, which in the low-oxygen environment of the thrombus convert into a form that produces blood clot-dissolving enzymes, in particular the urokinase receptor (PLAUR). The authors call this process "immunothrombolysis".

"Our results show that immune cells not only cause damage, but can also help to dissolve thrombi again," says Dr. Kami Pekayvaz, first author of the study and Clinician Scientist at the Medical Clinic I of the LMU Hospital. "This finding opens up completely new therapeutic possibilities."

What is particularly interesting is that if a certain signaling pathway in the neutrophils is artificially activated - the so-called HIF1a signaling pathway - the cells develop increased thrombus-dissolving properties. When the mechanism was blocked, the thrombi dissolved significantly less easily in affected mice.

"Although current drugs for thrombolysis work quickly, they increase the risk of dangerous bleeding," explains Prof. Dr. Konstantin Stark, who is the last author of the study together with PD Dr. Leo Nicolai and Senior Consultant at the Medical Clinic I of the LMU Hospital. "If we succeed in specifically controlling the body's own immune system to dissolve thrombi, this could be a gentler form of treatment."

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