Key points

Introduction

The reversal of antiplatelet and anticoagulant therapy and its resumption is a critical issue in the management of patients suffering from traumatic brain injury (TBI) or spinal cord injury (SCI). Although thromboprophylaxis is necessary to prevent life-threatening thromboembolism, it may also increase the risk of new bleeding or the expansion of pre-existing hematomas, both of which can have devastating consequences. An anticoagulation holiday , a temporary cessation of anticoagulant therapy, may be considered in patients with TBI to reduce the risk of hemorrhage. Preclinical evidence has demonstrated an association between plasma levels of direct oral anticoagulants (DOACs) and the volume of intracranial hemorrhage (ICH), as shown by Schaefer and colleagues, who investigated the effects of anticoagulation with dabigatran or warfarin on TBI. However, this approach increases the risk of thromboembolic events, particularly in patients with an elevated predisposition to clot formation. Balancing these competing risks requires careful consideration of the most appropriate timing for intervention, taking into account individual risk factors and the patient’s overall clinical status.

This review explores current strategies for anticoagulant and antiplatelet reversal, the risk factors for venous thromboembolism (VTE) in patients with TBI and SCI, and the pros and cons associated with both hemorrhage and thrombosis. Through this discussion, the authors aim to provide insights that can guide clinicians in making decisions about prophylaxis in these high-risk populations.

Coagulation in neurotrauma: pathophysiology

Understanding the pathophysiology of coagulation in neurotrauma is essential for managing patients with TBI and SCI. Neurotrauma can disrupt normal hemostatic processes, leading to complex coagulation abnormalities. Trauma-induced coagulopathy is a prominent feature of neurotrauma, characterized by the simultaneous presence of hypocoagulability and hypercoagulability. The systemic inflammatory response triggered by severe trauma significantly affects coagulation pathways. Trauma activates systemic inflammatory responses, releasing cytokines and tissue factors that impact coagulation. This inflammatory reaction can impair normal hemostatic mechanisms, contributing to both bleeding and clotting disorders.

Brohi and colleagues first associated acute coagulopathy in trauma with both a hypercoagulable state and a bleeding tendency. In addition, tissue trauma could result in direct endothelial injury, leading to the release of procoagulant factors as well as platelet activation. This damage promotes the exposure of tissue factor, which activates the extrinsic pathway of the coagulation cascade and leads to increased clot formation. Specific disruptions in coagulation pathways owing to neurotrauma include disseminated intravascular coagulation, where severe trauma results in widespread clotting that consumes clotting factors and platelets, leading to an increased risk of bleeding owing to the depletion of these components. Hypofibrinogenemia is another common issue, where trauma causes decreased fibrinogen levels, impairing the formation of stable blood clots; this is associated with worse outcomes. Furthermore, trauma can cause both quantitative and qualitative defects in platelets, leading to premature activation and aggregation or impaired function, which diminishes their ability to form effective clots.

In neurotrauma, coagulation could be further impaired by increased intracranial pressure (ICP), which can exacerbate bleeding tendencies by affecting cerebral perfusion and hemostatic balance. Elevated ICP disrupts normal clotting mechanisms because of changes in cerebral blood flow and pressure. TBI can lead to localized coagulopathy at the injury site, including the formation of intracranial hematomas as well as venous sinus thrombosis. Similarly, acute SCI can disrupt autonomic regulation and affect blood coagulation. Immobility associated with SCI increases the risk of VTE, whereas the inflammatory response to spinal cord damage alters coagulation pathways, with these changes potentially persisting for months after the traumatic event.

Assessment of hemostatic status in neurotrauma

In the management of neurotrauma, assessment of hemostatic status is essential due to the complex interplay between hemorrhagic and thromboembolic risks. Targeted coagulopathy management seems to reduce mortality in TBI as shown by the CRASH-2 trial. ^, Correction of coagulopathy may act to reduce intracerebral bleeding; decrease cerebral ischemia due to reduced depth and duration of hemorrhagic shock; and/or reduce cerebral inflammation via cross-talk mechanisms. Because trauma-induced coagulopathy involves both the depletion of coagulation factors and platelet dysfunction, it necessitates the use of advanced diagnostic tools, such as viscoelastic hemostatic assays (VHAs). These tools provide real-time assessments of coagulation status at the point of care, crucial for determining the appropriate timing for anticoagulant therapy, deciding on the need for reversal agents, and managing bleeding risks effectively ( Table 1 ). VHAs are considered more reliable and comprehensive than traditional tests because they evaluate both soluble coagulation factors and platelets, as well as their interactions. VHAs provide a more integrated view of the coagulation process, reflecting how these components interact in real time.

For example, international normalized ratio (INR) is extremely sensitive for the effect of vitamin K antagonists but correlates poorly with DOAC activity. Where conventional coagulation tests (CCTs) lack sensitivity for residual DOAC effect, VHA abnormalities have been shown to correlate significantly with dabigatran, rivaroxaban, and apixaban activity. The main drawback is that activated clotting time, the only measure associated with the presence of factor Xa inhibitors, is insensitive in the case of low concentrations of these drugs. Specifically, dabigatran and rivaroxaban showed a significant dose-dependent correlation with clotting time at ROTEM-EXTEM, whereas dabigatran, apixaban, and rivaroxaban concentrations were strongly correlated with the reaction time R on the thromboelastography (TEG) kaolin test.

Although the ITACTIC study found no overall difference in mortality between CCTs and VHAs in the general trauma population, subgroup analysis of patients with severe TBI suggested a trend toward favoring the use of VHAs. Indeed, for TBI, VHA measures seemed to be more reliable predictors of outcome than CCT. In an observational cohort study, rapid TEG parameters alone did not successfully identify patients at risk for hematoma expansion, but the composite score, which integrates rapid-TEG parameters, showed a notable association with the progression of bleeding. Furthermore, large-scale, powered studies are needed to confirm these findings.

VHAs may improve outcomes by facilitating the prompt identification of hemostatic disturbances among patients with TBI treated with antithrombotic agents. An algorithm combining TEG and platelet mapping has been recently proposed to guide clinicians in the reversal of antiplatelet agents for ICH associated with mild and moderate TBI. Based on the degree of arachidonic acid or adenosine diphosphate receptor (ADP) site inhibition and the need for neurosurgical intervention (including external ventricular drain placement), patients might not receive reversal treatment or might be treated with 1-deamino-8- d -arginine vasopressin (DDAVP) and/or platelet transfusion. Study patients were compared with a cohort of historical controls. The study demonstrated that a TEG-Platelet Mapping algorithm can effectively reduce the need for platelet transfusions in this population. Importantly, this approach did not lead to a clinically significant increase in adverse outcomes, including clinical deterioration, delays in neurosurgical intervention, delayed platelet transfusion, or death.

As prophylactic antifibrinolytic therapy has been shown to reduce perioperative blood loss in elective spinal surgery, VHAs may have a role in optimizing drug dosage and timing also in traumatic spine injury undergoing neurosurgical treatment.

Direct oral anticoagulants and reversal treatment

An increasing number of patients are prescribed anticoagulant therapy for management of atrial fibrillation or deep venous thrombosis (DVT), or for cardiovascular prevention. Managing anticoagulation therapy presents unique challenges in the aging population owing to age-related modifications in coagulation ^, and the increased prevalence of medical comorbidities.

Traditional anticoagulants, like warfarin, require regular monitoring and dose adjustments. DOACs offer several advantages in this context, providing a more predictable pharmacokinetic profile (eliminating the need for routine monitoring of coagulation levels), a fixed dosing regimen (encouraging improved adherence to therapy), and a favorable safety profile. In addition, DOACs present a lower risk of major bleeding events in certain populations. Zeeshan and colleagues did raise concerns regarding a potentially increased risk for hematoma progression in patients on DOACs undergoing neurosurgical interventions for mild and moderate TBI, as compared with those receiving vitamin K antagonists. However, this increased risk was not observed among patients with severe TBI.

Currently, 4 drugs are approved for clinical use. Three are anti–factor Xa inhibitors (rivaroxaban, apixaban, edoxaban), and one (dabigatran) is a direct antithrombin inhibitor. Idarucizumab, a monoclonal antibody that binds directly to dabigatran and its metabolites, neutralizing their anticoagulant effects, was approved as an antidote in 2015. The antidote is indicated for bleeding deemed uncontrolled or life-threatening despite local hemostatic measures, high risk of recurrent bleeding because of overdose, or delayed clearance of drug and need for rapid reversal to permit urgent surgical procedures. In the RE-LY trial, a 5-g idarucizumab dose was administered as 2 intravenous boluses of 2.5 g, each given over 5 to 10 minutes (with 15 minutes between doses).

Clearance of dabigatran, idarucizumab, and their complex is renally mediated and, therefore, may be impacted by renal dysfunction. Idarucizumab and dabigatran have markedly different half-lives (45 minutes vs 12–17 hours) and distribution kinetics, which may lead to a rebound effect after administering a single dose of antidote. A second dose may be necessary if bleeding continues. Dabigatran, owing to its small size, high renal clearance, high water solubility, and low plasma protein binding (around 35%), can potentially be removed by renal replacement therapy. Few studies have addressed the effectiveness of hemodialysis in removing dabigatran. ^,

Andexanet alfa (AA) is a modified recombinant inactive form of human factor Xa, which binds and sequesters factor Xa inhibitor molecules, rapidly reducing anti–factor Xa activity and restoring thrombin generation. Controversial results emerged in a recently published trial comparing the performance of AA with usual care in achieving hemostatic efficacy in patients with intracranial bleeding associated with active factor X inhibitor intake. Prothrombin complex concentrate (PCC) was administered to more than 85% of patients in the control arm. A larger proportion of patients receiving AA achieved hemostatic efficacy compared with those receiving usual care. Interestingly, the difference in the primary outcome between intervention arm and control arm was driven by the expansion of the hematoma volume, as differences for the 2 other components were not statistically significant. The main safety limitation of this study was an increased incidence of thrombotic events, including acute ischemic stroke (AIS), in the AA arm.

Three types of PCC are available. The most comprehensive is the 4-factor prothrombin complex concentrate (4F-PCC), which includes factors II, VII, IX, and X, as well as the antithrombotic proteins C and S. This type is widely used for the reversal of vitamin K antagonists, such as warfarin; examples include K-centra (available in the United States) and Beriplex (available in Europe and other regions). The second type is 3-factor prothrombin complex concentrate (3F-PCC), which contains factors II, IX, and X but lacks significant amounts of factor VII. For this reason, it is used less frequently. The third type is activated prothrombin complex concentrate (aPCC), which contains activated clotting factors, particularly factor VII, along with factors II, IX, and X. This type of PCC is typically used in patients with hemophilia who have developed inhibitors to factor VIII or IX. Even though off-label, PCC has been proposed as a reversal treatment for active factor X inhibitors owing to its favorable cost as compared with AA.

Reversal agents in neurotrauma: the state of the art

A systematic search was conducted to identify relevant studies published in the literature. The databases PubMed and Embase were used to retrieve research articles. The authors used a search strategy using specific MeSH (Medical Subject Headings) terms, including antiplatelet, reversal, oral anticoagulation, novel anticoagulant drug, andexanet, idarucizumab, thromboprophylaxis, traumatic brain injury, and spinal cord injury, along with relevant keywords to capture studies on anticoagulation, antiplatelet therapy, and their implications in TBI and SCI ( Table 2 ). The authors performed the first search on June 20, 2024. A second search was conducted on August 31, 2024 to identify articles published more recently. To ensure thorough coverage of the literature, the authors reviewed the reference lists of included studies or relevant reviews identified through the search. The authors included studies performed from January 1, 1984 to August 31, 2024.

Table 2

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