The stakes of this question are enormous. Antithrombotic drugs, including anticoagulants and antiplatelet agents, are prescribed to millions of people for atrial fibrillation, venous thromboembolism, and cardiovascular disease, and they dramatically increase the risk and severity of intracranial hemorrhage. Compared with patients who bleed while not taking these medications, those on antithrombotics face higher rates of hematoma expansion, worse functional outcomes, and greater mortality. Hematoma expansion is the central villain in this story: every additional milliliter of blood within the brain parenchyma carries roughly a five percent increased risk of death or dependency, and approximately a third of patients who present within six hours of symptom onset will experience significant growth of their hemorrhage. Rapid reversal of anticoagulation is therefore one of the most consequential decisions in emergency neurology.

The guideline panel, an interdisciplinary task force of ten specialists spanning neurocritical care, trauma surgery, hematology, nursing, and pharmacy, framed five clinical questions using the Population, Intervention, Comparator, Outcome framework. Three questions updated prior recommendations while two were entirely new. The panelists independently rated outcomes by importance, elevating mortality, functional outcome, and thrombosis to critical status, and applied the Grading of Recommendations, Assessment, Development, and Evaluation methodology to synthesize evidence from randomized trials and observational cohorts. Notably, the panel included a public member recruited through the Anticoagulation Forum to represent the patient and family perspective, and all members were vetted for conflicts of interest before voting.

The most consequential recommendation concerns the showdown between andexanet alfa and prothrombin complex concentrate. Andexanet alfa is an inactive recombinant decoy form of human factor Xa that sponges up factor Xa inhibitors and restores thrombin generation. It was not commercially available when the 2016 guideline was written, and its subsequent rise was propelled largely by the ANNEXA-4 trial, a single-arm study of 352 patients in which 82 percent achieved excellent or good hemostasis. But the new analysis, drawing on 21 studies encompassing 4,938 patients, tells a more sobering story. The sole randomized trial, ANNEXA-I, compared andexanet alfa against usual care in factor Xa inhibitor-associated intracerebral hemorrhage and found no significant mortality benefit: 27.8 percent of andexanet recipients died versus 25.5 percent of those receiving usual care. Andexanet did improve hemostatic efficacy, with 67 percent achieving the composite hemostasis endpoint compared with 53.1 percent under usual care, and it produced less very large hematoma expansion. Yet hemostasis is a surrogate outcome, and the panel prioritized patient-centered endpoints instead.

What tipped the scales decisively was thrombosis. Meta-analysis revealed a significant increase in thrombotic events with andexanet alfa, with a relative risk of 1.37 overall, and in the spontaneous hemorrhage subgroup the risk nearly doubled at a relative risk of 1.99. These events were predominantly arterial, most commonly acute ischemic strokes identified on neuroimaging, and even small asymptomatic infarcts may erode long-term functional recovery. Andexanet alfa appears prothrombotic through two distinct mechanisms: reversal of anticoagulation itself, and direct inhibition of tissue factor pathway inhibitor. These findings contributed to the United States Food and Drug Administration declining AstraZeneca’s application for full approval, and the manufacturer voluntarily withdrew the drug from the US market as of December 2025, though it remains available internationally. The panel therefore issued a conditional recommendation favoring four-factor prothrombin complex concentrate over andexanet alfa for both spontaneous and traumatic factor Xa inhibitor-associated hemorrhage, the latter based on very low certainty evidence.

The guideline also delivers a nuanced verdict on platelet transfusion, long a reflexive response to bleeding on antiplatelet drugs like aspirin and clopidogrel. For patients with spontaneous intraparenchymal hemorrhage who do not require surgery, the panel recommends against platelet transfusion, a position anchored by the PATCH trial, a high-quality randomized study showing that transfusion offered no benefit in mortality, functional outcome, or thrombosis, and in fact was associated with worse functional outcomes. The picture flips for surgical patients: a single randomized trial from China found that aspirin users undergoing craniotomy for basal ganglia hemorrhage who received perioperative platelet transfusion had lower mortality, reduced postoperative hemorrhage, and better six-month functional outcomes. The panel accordingly suggests platelet transfusion for aspirin-treated patients requiring neurosurgery, while explicitly limiting this recommendation to aspirin because no data exist for P2Y12 inhibitors in this setting. For traumatic intracranial hemorrhage, where ten retrospective studies produced contradictory and confounded results, the panel declined to make any recommendation at all.

Desmopressin, a vasopressin analog that releases factor VIII and von Willebrand factor and may enhance platelet procoagulant activity, fared no better. The 2016 guideline had suggested considering a single dose for antiplatelet-associated hemorrhage, but the new analysis, including the DASH phase 2 feasibility trial and nine observational studies, found no effect on hematoma expansion, mortality, or functional outcome, with all confidence intervals crossing unity. The panel made no recommendation, while emphasizing the urgent need for adequately powered randomized trials of a treatment that remains biologically plausible for a condition with no proven therapy. Similarly, the panel could not issue guidance on whether to reverse anticoagulation in patients with very small intraparenchymal hemorrhages, a genuinely difficult clinical dilemma, since no studies directly address it. The decision hinges on factors such as time from onset to imaging, hemorrhage location, the specific anticoagulant and timing of the last dose, and imaging markers like the CT spot sign that predict expansion.

One genuinely new recommendation embraces technology over therapeutics. Viscoelastic hemostatic assays, including thromboelastography and rotational thromboelastometry, are point-of-care whole blood tests that render real-time coagulation dynamics rather than static snapshots. The panel suggests using these assays to guide treatment of coagulopathy in traumatic intracranial hemorrhage when available, a conditional recommendation resting on very low certainty evidence but supported by a mortality signal in the severe traumatic brain injury subgroup of one randomized trial, with a relative risk of 0.59. Because the tests carry minimal inherent risk compared with medications or transfusions, the panel judged the balance favorable even with sparse data, though it acknowledged that treatment protocols vary widely between centers and that standardized algorithms remain lacking.

The panel was candid about the limitations pervading this literature. Observational studies comparing andexanet with prothrombin complex concentrate are vulnerable to selection bias, since patients assigned to usual care were often treated later, had higher blood pressures, or were perceived as having better prognoses, patterns that could artificially favor andexanet. Formulations of prothrombin complex concentrate differ in factor content, some contain heparin, and none carries a labeled indication for factor Xa inhibitor reversal, while optimal dosing, historically 50 units per kilogram, was never established on robust data. The panel also advised against combining andexanet alfa with prothrombin complex concentrate unless benefit clearly outweighs the prothrombotic risk, and flagged a practical pitfall: patients transferred between hospitals may arrive without documentation of reversal agents already given.

Perhaps the most telling conclusion is what the guideline could not say. Not a single strong recommendation emerged from the entire exercise, a reflection of how thin the evidence remains for one of the most feared complications of modern cardiovascular medicine. The panel laid out a research agenda calling for randomized trials of platelet transfusion in traumatic hemorrhage, adequately powered studies of desmopressin, direct comparisons of reversal versus observation in small hemorrhages, and standardized viscoelastic assay protocols. Until those trials arrive, clinicians now have a clearer, more skeptical map of the territory: favor prothrombin complex concentrate over andexanet, withhold platelets from non-surgical patients, give them to aspirin users heading for the operating room, and let real-time coagulation testing steer trauma resuscitation. In a field where overtreatment has proven as dangerous as undertreatment, knowing what not to do may be the guideline’s most valuable contribution.

Subject of Research: Guideline-based reversal of antithrombotic medications in adults with acute intracranial hemorrhage

Article Title: Treatment of Antithrombotic-Associated Intracranial Hemorrhage in Adults: A Focused Guideline Update from the Neurocritical Care Society and the Society of Critical Care Medicine

Article References: Vallejo, M. C., Kennedy, L. S., Dengler, B., Barthol, C., Belley-Cote, E. P., Burns, J. D., Chau, V. K., Cordonnier, C., Cuker, A., Honarmand, K., Mahmoud, S. H., Wilcox, M. E., & Kumar, M. A. (2026). Treatment of Antithrombotic-Associated Intracranial Hemorrhage in Adults: A Focused Guideline Update from the Neurocritical Care Society and the Society of Critical Care Medicine. Neurocritical Care. https://doi.org/10.1007/s12028-026-02601-4

Image Credits: AI Generated

DOI: 10.1007/s12028-026-02601-4

Keywords: intracranial hemorrhage, antithrombotic reversal, andexanet alfa, prothrombin complex concentrate, platelet transfusion, desmopressin, factor Xa inhibitors, antiplatelet agents, viscoelastic hemostatic assays, GRADE methodology, neurocritical care, clinical guideline

The review, led by Ali Msheik of Hamad Medical Corporation in Doha, Qatar, together with colleagues in trauma surgery, neurocritical care, and medical ethics, synthesized all available systematic reviews of viscoelastic hemostatic assays in neurocritical illness. These assays, which include thromboelastography known as TEG, TEG Platelet Mapping, and rotational thromboelastometry known as ROTEM, differ fundamentally from standard coagulation tests. Instead of isolating plasma and timing a single clotting reaction, they measure the actual physical behavior of clot formation in whole blood: how quickly the clot initiates, how strongly it propagates, how firm the final clot becomes, and how readily fibrinolysis breaks it down. In principle, this gives clinicians a real-time picture of hemostasis that standard tests cannot capture.

To assess the accumulated evidence, the researchers followed PRISMA 2020 reporting guidelines, the Joanna Briggs Institute manual for umbrella reviews, and MOOSE recommendations, searching PubMed, Embase, Scopus, the Cochrane Library, and Web of Science from database inception to January 2026. Two physician reviewers with experience in neurocritical care independently screened records, extracted data, and appraised methodological quality. The screening funnel was dramatic: of 272 records identified, 199 were screened after duplicate removal, and only four systematic reviews survived full-text assessment. The authors emphasized that this narrowing reflects the strict restriction to review-level evidence with reproducible methods and extractable neuro-specific data, not a post hoc reshaping of the question.

Those four reviews encompassed 73 study occurrences representing 63 unique primary studies, spanning traumatic brain injury, subarachnoid hemorrhage, and mixed populations with ischemic stroke and coronary artery disease. A corrected covered area analysis quantified how much the underlying evidence overlapped, finding only slight overall redundancy at 5.3 percent. Within traumatic brain injury, however, the two dedicated reviews shared 12 primary studies, a corrected covered area of 29.4 percent, while the subarachnoid hemorrhage and antiplatelet therapy reviews shared no studies with other clusters. This low overall overlap means the field is not merely recycling the same small trials, an encouraging sign for the maturity of the evidence base even as quality concerns remain.

The methodological appraisal revealed uneven rigor. Using AMSTAR-2, a validated tool for assessing systematic reviews, only one review, a 2021 meta-analysis of thromboelastography in traumatic brain injury by Cannon and colleagues, achieved moderate confidence, supported by a registered protocol, a comprehensive search, duplicate screening, and structured bias assessment. The remaining reviews earned low or critically low confidence ratings owing to absent protocols, incomplete reporting of excluded studies, and limited transparency. When the authors then applied GRADE criteria to rate certainty in individual outcomes, most estimates in traumatic brain injury and subarachnoid hemorrhage fell to low or very low certainty, a consequence of predominantly observational designs, inconsistent definitions, and imprecise effects.

Within those constraints, the prognostic signal was remarkably consistent. Across two reviews covering 32 unique studies in traumatic brain injury, viscoelastic assays repeatedly identified clinically relevant coagulation disturbances. Abnormal clot strength and disturbed fibrinolytic activity were associated with mortality across 18 observational studies, with radiographic hemorrhage progression in 14 studies, and with the need for neurosurgical intervention in nine, though confounding and heterogeneous outcome definitions limited those latter findings. In subarachnoid hemorrhage, a single review of 19 primary studies found that hypercoagulable profiles, particularly increased clot firmness, were consistently linked to delayed cerebral ischemia in six studies and to early brain injury severity in four. These associations make biological sense: dysregulated clot formation and breakdown plausibly contribute to secondary brain injury, hemorrhage expansion, and delayed ischemia after aneurysm rupture.

The therapeutic story was different. No review provided convincing evidence that viscoelastic-guided interventions improved outcomes in traumatic brain injury or subarachnoid hemorrhage, meaning the assays currently function as crystal balls rather than steering wheels in these conditions. The one bright spot came from mixed ischemic populations: moderate-certainty evidence from a meta-analysis of ten studies, including randomized trials, suggested that TEG-guided antiplatelet therapy in patients with ischemic stroke and coronary artery disease was associated with fewer composite ischemic and bleeding events than standard care. Mortality effects, however, remained uncertain because reporting was sparse and inconsistent, and because the population blended cardiac and cerebrovascular patients, the finding cannot be directly transferred to pure stroke care without further validation.

The authors are explicit about what this means for practice. Viscoelastic assays, they conclude, may be most appropriately used as adjunctive diagnostic and prognostic tools in neurocritical care rather than as standalone guides for transfusion or hemostatic treatment decisions in brain trauma and aneurysmal hemorrhage. The finding challenges a seductive assumption, one that has driven adoption in trauma and cardiac surgery, that simply identifying a coagulation disturbance and acting on it automatically improves outcomes. In the neurocritical setting, the leap from detection to benefit has not yet been demonstrated in rigorous trials, and current clinical guidelines accordingly do not recommend routine viscoelastic testing in these populations.

Several structural obstacles help explain the gap between prognostic promise and therapeutic proof. Included studies frequently came from single centers using institution-specific protocols, with inconsistent assay platforms, variable clinical cutoffs, and differing transfusion and antiplatelet practices. Without harmonized thresholds and standardized definitions of what counts as an actionable abnormality, clinicians cannot translate an abnormal tracing into a uniform treatment decision, and trialists cannot pool results meaningfully. These limitations reduce generalizability and complicate the interpretation of every association reported to date.

The research agenda that follows is clear. The authors call for large prospective neuro-specific cohorts using standardized viscoelastic thresholds, randomized trials testing VHA-guided transfusion or reversal strategies specifically in traumatic brain injury and subarachnoid hemorrhage, harmonization of assay parameters and clinical definitions, mechanistic studies linking viscoelastic abnormalities to neurovascular pathophysiology, and targeted evaluation of TEG-guided antiplatelet therapy in stroke populations alone. Until that work is done, the review suggests, clinicians and policymakers should read abnormal viscoelastic findings as important prognostic information, valuable for risk stratification and communication, while resisting the temptation to build treatment algorithms on evidence that has yet to bear their weight. For a technology that has already transformed hemostasis management in trauma and cardiac surgery, neurocritical care remains the unfinished frontier.

Subject of Research: Viscoelastic hemostatic assays for prognosis and treatment guidance in neurocritical illness

Article Title: The utility of viscoelastic hemostatic assays in neurocritical illness

Article References: Msheik, A., Peralta, R., Al-Rumaihi, G., Rizoli, S., Al Mokdad, Z., de Oliveira Manoel, A. L., & Al-Thani, H. (2026). The utility of viscoelastic hemostatic assays in neurocritical illness. Journal of Emergency and Disaster Medicine, 2(1), Article 10. https://doi.org/10.1007/s44467-026-00012-1

Image Credits: AI Generated

DOI: 10.1007/s44467-026-00012-1

Keywords: viscoelastic hemostatic assays, thromboelastography, ROTEM, traumatic brain injury, subarachnoid hemorrhage, ischemic stroke, coagulopathy, neurocritical care, umbrella review, antiplatelet therapy, delayed cerebral ischemia, GRADE evidence