In this retrospective observational study, we evaluated age-based differences in the impact of coagulopathy on the functional and survival outcomes in 1036 patients with isolated TBI. After adjusting for potential confounders, we found a lower impact of coagulopathy on GOS-E scores and in-hospital mortality in the elderly group compared with the non-elderly group. Notably, the impact of coagulopathy on GOS-E scores decreased steadily with increasing age after the age of 65 years.
The presence of coagulopathy upon ED admission has been reported to be a strong predictor of patient outcomes and overall TBI prognosis [3, 16]. Specifically, compared with patients without coagulopathy, patients with coagulopathy have a nine- and thirty-times higher risk of mortality and unfavorable functional outcome, respectively [2, 17]. TBI is likely to induce coagulopathy through independent mechanisms in the absence of tissue hypoperfusion, shock, or hemodilution . The course of TBI-induced coagulopathy and the subsequent increase in intracranial hemorrhage has been reported to reflect the rapid progression from hypercoagulable and hyperfibrinolysis states to a hypocoagulable state within a few hours after head injury until the clotting factors are consumed [19, 20]. The mechanism underlying the initial post-TBI hypercoagulable and hyperfibrinolysis state has been reported to involve extensive TF release by the damaged brain into circulation, which results in coagulation pathway activation and the subsequent consumption of coagulation factors [2, 21]. Further, alternative proposed mechanisms include the release of endogenous tissue-type plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA) from contusional brain tissue  or the depletion of alpha-2-plasmin inhibitor . Plasmin, which is the major effector for fibrin clot lysis, is converted from plasminogen by both tPA and uPA. Although the aforementioned mechanisms could render patients with TBI prone to have bleeding tendencies, they are probably an oversimplification of a much more complex series of events that occur either simultaneously or sequentially after TBI.
Although there was no between-group difference in the ISS and RTS scores, there was a higher proportion of patients with coagulopathy upon arrival and lower impact of coagulopathy on outcomes in the elderly group compared with the non-elderly group. We excluded patients with a history of taking anti-coagulants or anti-platelet agents; however, the various physiologic derangements and coexisting diseases in elderly patients might affect their coagulation function. Moreover, they are various modifications of the blood coagulation system that accompany the aging process. The plasma levels of some factors (such as fibrinogen, factor VII, and factor VIII) have been reported to increase with aging [24, 25]. Further, increased TF expression and availability, which could augment factor VII, have been reported in elderly patients . These age-related changes could induce the hypercoagulable state and secondary hyperfibrinolysis [24, 25]. Therefore, the risk for coagulopathy, which was determined using the aforementioned markers, could be lower in elderly patients. However, since these procoagulant proteins are normally present in plasma in large excessive amount, the pathophysiologic significance of the relatively small aging-related changes remains unclear.
There have been reports of aging-related cerebral atrophy and diffuse gray matter loss, which indicates that elderly patients might have a smaller brain volume compared with non-elderly patients . Therefore, geriatric patients are generally less likely to present neurological signs resulting from increased intracranial hemorrhage given their brain volume reduction, even in those with severe intracranial injury [28, 29].
Although TBI-induced coagulopathy manifests as disseminated intracranial hemorrhage and delayed intracranial (intracerebral) hematoma , the lower impact of TIC-induced intracranial hemorrhage on outcomes in elderly patients could be attributed to the increased intracranial pressure reserve given the brain volume reduction. There is a need for further studies to assess the effect of intracranial hemorrhage in atrophic brains in critical conditions.
Our findings could potentially influence the treatment strategy in elderly patients with TBI presenting with coagulopathy. Early intervention for coagulopathy in patients with TBI has been reported to be independently associated with favorable survival and neurological outcomes . Although the administration of adequate blood product amounts is the most common intervention for TIC, there have been reports warning against the excessive use of blood products given the potential risk of adverse events caused by blood transfusion . Larger transfusion amounts have been reported to be associated with mortality in trauma patients even after adjusting for injury severity ; further, this effect might be even more pronounced in geriatric patients. Our findings indicate a potential risk of employing a blood transfusion strategy based on coagulation function in geriatric TBI patients. Specifically, the disadvantage of blood transfusion might outweigh its benefit and the limited effect of coagulopathy on outcomes among elderly patients might mislead clinicians.
Several limitations should be considered in the interpretations of our findings. First, since this was a two-center retrospective observational cohort study, there are inevitable limitations regarding residual confounding and limited generalizability. Second, there is a considerable risk of type II error given the limited sample size. Third, more than half of our patients suffered multifocal intracranial hemorrhage, which impeded us from performing sub-group analysis based on the brain injury pattern. Finally, we did not use specific devices for monitoring blood clotting function, such as thromboelastography (functional fibrinogen by TEG, Haemonetics Corporation, Braintree, MA) or thromboelastometry (ROTEM, FIBTEM, TEM International GmbH, Munich, Germany) [33–35]. Therefore, we could only identify coagulopathy based on basic laboratory abnormalities. Nonetheless, to the best of our knowledge, this is the first study to evaluate age-related differences in the impact of coagulopathy on the outcomes. Our findings indicate the need for a different age-based interpretation regarding the presence of TIC in patients with TBI. There is a need for further research to confirm our results and develop an age-related therapeutic strategy.