Abnormal coagulation and platelet function in patients with severe traumatic brain injury

Traumatic brain injury (TBI) is associated with a high mortality and severe long-term morbidity in survivors. TBI often affects previously healthy young persons, and represents one of the most common causes of death among younger patients. The outcome in general trauma patients has improved over the recent decades. Unfortunately, lesser improvements have been achieved in the treatment of TBI. The pathophysiology of TBI is complicated, and changes in the haemostatic system are important parts of the complex response that occurs following TBI. Development of socalled secondary brain injuries with bleeding complications follow the trauma and contributes to the adverse outcome.

In the present thesis patients with severe isolated TBI were studied, with a focus on abnormalities in coagulation and platelet function. Cerebrovenous blood samples were collected repeatedly and compared to samples from the arterial circulation, in order to investigate the pathophysiological processes within the damaged brain. In agreement with previous studies, we observed that changes in the haemostatic system developed in hours to days following TBI. Intracerebral inflammation was also present in the TBI patients, which may modify coagulation responses to injury. Signs of “platelet dysfunction”, with a decreased platelet response to arachidonic acid, was observed in the patients, and over time a bleeding tendency developed. This “platelet dysfunction” was associated with bleeding complications. We also investigated circulating microparticles (MPs) released from platelets, endothelial cells and leukocytes using flow-cytometry. We found that activation of platelets took place when blood passed the injured brain, as there was a transcranial gradient in platelet MPs exposing the platelet activation marker P-selectin. We also found that endothelial derived MPs exposing tissue factor were generated in the injured brain and released into the circulation, whereas leukocyte derived MPs exposing tissue factor seemed to accumulate in the brain. In order to identify new brain specific markers of injury we assessed circulating MPs exposing antigens from brain tissue (from astrocytes and neurons) using flow cytometry. These MPs were higher in plasma from TBI patients compared to healthy controls, but there was a considerable variability between individuals, and also with-in the patients over time. More research is needed before MPs derived from brain tissue can be used as biomarkers in TBI. Monitoring of coagulation and platelet function in TBI may provide information regarding which patients that will develop bleeding complications and need hemostatic (procoagulant) treatment. Solid evidence that this improves patient outcome is, however, lacking at present.

List of scientific papers

I. Coagulation abnormalities associated with severe isolated traumatic brain injury : cerebral arteriovenous differences in coagulation and inflammatory markers. Nekludov M, Antovic J, Bredbacka S, Blombäck M., J.Neurotrauma. 2007, 24(1): 174−80
https://doi.org/10.1089/neu.2006.0173

II. Platelet dysfunction in patients with severe traumatic brain injury. Nekludov M, Bellander B-M, Blombäck M, Wallen H., J.Neurotrauma. 2007, 24 (11): 1699−706.
https://doi.org/10.1089/neu.2007.0322

III. Formation of microparticles in the injured brain of patients with severe isolated traumatic brain Injury. Nekludov M, Mobarrez F, Gryth D, Bellander B-M, Wallen H. J.Neurotrauma 2014, 31(23): 1927−33
https://doi.org/10.1089/neu.2013.3168

IV. Brain-derived microparticles in patients with severe isolated traumatic brain injury, Nekludov M, Bellander B-M, Gryth D, Wallen H, Mobarrez F. [Manuscript]