There is insufficient evidence to support an evidence-based recommendation for routine use of viscoelastic testing (VET) or routine reversal of coagulopathy in patients with penetrating traumatic brain injury (pTBI).

In the absence of direct scientific evidence, EXPERT CONSENSUS concluded that:

• VET may be used to guide the correction of coagulopathy. (88% consensus)
• In patients with pTBI, coagulopathy should be corrected to minimize the risk of worsening of intracranial hemorrhage. (100% consensus)

No evidence or expert opinion supported distinct recommendations based on patient gender, age, wounding mechanism, or military vs. civilian context.

Coagulopathy in traumatic brain injury is a well-recognized and common phenomenon with scientific literature demonstrating that TBI-induced coagulopathy follows a distinct pathological pathway.1 TBI-induced coagulopathy is associated with worse outcomes in both blunt and penetrating TBI and in both military and civilian populations2-7, and has been reported in as many 45-64% of patients with pTBI.4,6-8 Though various theories have been advanced as to the cause of this phenomenon such as the release of thromboplastin from injured brain tissue, TBI-induced coagulopathy remains poorly understood. A variety of independent risk factors for the development of coagulopathy have been described and include penetrating mechanism9, low GCS score6,7,10, effacement of cisterns/cerebral edema6,7, transfusion requirement6 and subarachnoid hemorrhage.7 Given the known morbidity of coagulopathy in patients with TBI from a variety of mechanisms, an attempt to reverse coagulopathy with plasma, prothrombin complex concentrates, vitamin K, or other agents is widely considered standard of care.

Traditional evaluation of coagulopathy has relied on platelet count, the international normalized ratio (INR), partial thromboplastin time (PTT) and prothrombin time (PT). There is a large body of data that has described the coagulopathy associated with TBI based on these "conventional" clotting assays.7,8,10-12 There is an increasing body of evidence that viscoelastic testing (VET) via thromboelastography (TEG) and rotational thromboelastometry (ROTEM) may be more accurate for detecting and characterizing coagulopathy in patients with trauma.13-15

The previous pTBI guidelines did not endeavor to provide any recommendations for the use of VET or the reversal of coagulopathy.

Use of Viscoelastic Testing - No studies were identified that met criteria for inclusion in the guidelines evidence tables. Routine viscoelastic testing (VET) has been widely utilized in mixed populations of patients with both blunt and penetrating TBI to define and detect coagulopathy.4,9,16-20 However, few studies have specifically examined the issue of use of VET to define coagulopathy in patients with pTBI. We identified one study, Folkerson, et al., that examined determination of coagulopathy by use of rapid thromboelastography (rTEG)4. These authors defined coagulopathy as activated clotting time (ACT) greater than 128 seconds, K-Time (KT) greater than 2.5 minutes, angle less than 56 degrees, maximum amplitude less than 55mm, and LY-30 greater than 3.0%, or platelet count 150,000/uL or less. There were no outcomes or associations reported from rTEG use.1 Ninety-nine patients had pTBI. Coagulopathy was associated with early mortality (aOR [adjusted odds ratio] 3.99, 95% confidence interval [CI], 1.37 to 11.72) after controlling for age, gender, Glasgow Coma Scale score, blood pressure, and base excess in this study.1 Another study compared blunt to pTBI patients, and pTBI were found to be more coagulopathic as compared to those with blunt mechanisms of injury by a variety of TEG parameters.9

Benefits and Harms of Correction of Coagulopathy - The data on correction of coagulopathy in patients with pTBI as measured by VET is extremely limited. On one small case series was identified and included for completeness, (N=3) that examined rates of hemorrhage cessation with reversal of coagulopathy with recombinant activated Factor VII in addition to standard reversal agents that specifically looked at patients with penetrating TBI. The authors reported a 100% rate of hemorrhage cessation in a series of three patients, however all progressed to brain death and two underwent organ donation. Hematologic parameters were reported before and after administration of recombinant activated Factor VII (Table).21 Additional products, however, were given prior to treatment with recombinant activated Factor VII (e.g., fresh frozen plasma, cryoprecipitate, platelets, red blood cells). This study provides very low strength of evidence that cessation of refractory hemorrhage may be achieved with the use of recombinant activated Factor VII, although clinical outcomes were uniformly poor.

We found one study (n=89) that looked at the reversal of coagulopathy as measured by CCAs in patients with pTBI.6 In this study, mortality rates were significantly higher in coagulopathic patients (73% vs. 25%; p < 0.001), but for the small percentage of patients coagulopathic on admission (n=40) who were alive at 24 hours (n=25), normalization of the coagulation profile was not associated with statistically significant survival advantage (75% vs 38%; P=0.29).

The risks of coagulopathy reversal are limited and consist of allergic reactions, transfusion reactions, and a slight increased risk of thromboembolic complications, depending on the agent used. These therapies are typically well tolerated and considered standard of care for reversal of coagulopathy in a variety of patient populations.

Use of VET and Reversal of Coagulopathy - The data that addresses diagnosis and detection with VET and reversal of coagulopathy is limited. However, upon extrapolation of data from mixed populations of brain injury, a likely supportive role for VET in the management of the patient with pTBI exists. VET's ability to detect different defects in the coagulation profile such as fibrinogen deficiency, platelet dysfunction, and hyperfibrinolysis make it an attractive tool for more precision resuscitation and reversal of coagulopathy. Whether or not physicians should be reverse coagulopathy in patients with pTBI cannot be guided exclusively by data at this time, but rather must be consider from related populations of blunt TBI or mixed mechanisms wherein worse outcomes occur in a coagulopathic patients. Correction of coagulopathy is also considered standard of care prior to neurosurgical intervention and to minimize the risk of progression of injury. The therapies used to reverse coagulopathy, when successful, are typically well tolerated and pose little inherent additional risk to critically ill patients.

With few exceptions, reversal of coagulopathy - whether iatrogenic or metabolic - is appropriate for pTBI patients and is considered a standard of care. Neurosurgeons typically require correction of deranged coagulation profiles before it is considered safe to proceed with neurological surgery. Given that complex vascular injuries are a defining characteristic of pTBI, intraoperative hemorrhage is already a substantial concern when operating on pTBI patients and the additional challenge inherent to coagulopathy is undesirable in this context. Although it is unclear whether reversal of coagulopathy following pTBI results in improved outcomes, there is little downside to the use of typical agents other than their expense and resource allocation issues. Some of our panelists shared the opinion that the results of VET do not necessarily align with the patient's clinical picture however - patients who clinically manifest coagulopathy can have relatively normal VET parameters and vice versa.

The management of coagulopathy in patients with pTBI remains a challenging area of clinical practice, underpinned by limited direct evidence and a reliance on extrapolations from broader traumatic brain injury (TBI) populations. Given the emerging role of viscoelastic testing (VET) in detecting and characterizing coagulopathy, prospective studies focusing on pTBI populations are important. Research should aim to compare the efficacy of VET with traditional coagulation assays in predicting hemorrhagic complications, need for surgical interventions, and patient outcomes. Studies should identify specific VET parameters that are most predictive of adverse outcomes in pTBI and evaluate the cost-effectiveness of implementing VET in routine clinical practice for pTBI management. There is also a need for RCTs that compare different coagulopathy correction strategies (including plasma, prothrombin complex concentrates, vitamin K, and other agents) in terms of efficacy, safety, and impact on clinical outcomes and explore the timing and thresholds for intervention to optimize patient outcomes. Understanding the underlying mechanisms of coagulopathy in pTBI could lead to the development of novel therapeutic targets. The exploration of biomarkers that could predict the development of coagulopathy or response to treatment should also be explored.

Studies that examine the trajectory of recovery and identify factors associated with better functional outcomes and quality of life and those which develop and validate prognostic models would guide better clinical decision-making. Given the heterogeneity of the pTBI population, comparative effectiveness research also has promise for assessing the effectiveness of VET and coagulopathy correction strategies across different patient subgroups defined by age, gender, mechanism of injury, and other relevant factors and explore differences in management strategies and outcomes between military and civilian populations, and investigate the impact of pre-existing comorbidities and concurrent injuries on the management and outcomes of coagulopathy in pTBI. Addressing these research priorities requires a multidisciplinary approach, leveraging advances in technology, biomarker discovery, and therapeutic interventions. Ultimately, the goal of future research is to develop more robust evidence-based guidelines that can be tailored to individual patient characteristics, improving outcomes for those affected by pTBI and coagulopathy.