Negin Safari Dehnavi is a medical researcher affiliated with the Functional Neurosurgery Research Center at Shahid Beheshti University of Medical Sciences. Her primary research focuses on neurosurgery and clinical neurology, with a particular specialization in neuroimaging and traumatic brain injury. She has contributed to multiple systematic reviews and meta-analyses exploring diagnostic and therapeutic interventions, including the efficacy of middle meningeal artery embolization and advanced nanoparticle contrast agents in brain tumor imaging. Her recent work examines the safety and timing of initiating anticoagulation in intracranial surgery, reflecting her broader expertise in perioperative management and the clinical outcomes of neurosurgical patients.
Negin Safari Dehnavi, Farzan Fahim, Parniya Amini, Reza Saeedinia, Ali Saravani, Mana Majlesi, Mohammad Maroufi, Ahmad Fathinejad, and Alireza Zali.
1Functional Neurosurgery Research Center, Research Institute of Functional Neurosurgery, Shohada Tajrish Comprehensive Neurosurgical Center of Excellence, Shahid Beheshti University of Medical Sciences, Tehran, Iran
2Neurosurgery Resident at Shohada-E-Tajrish Hospital, Shahid Beheshti University of Medical Science, Tehran, Iran
3Professor of Neurosurgery, Neurosurgery Resident at Shohada-E-Tajrish Hospital, Shahid Beheshti University of Mrdical Science, Tehran, Iran
*Corresponding author: Dr. Farzan Fahim, MD, MPH, HMBA Email: Farzn.fahim{at}gmail.com
medRxiv preprint DOI: https://doi.org/10.1101/2025.11.07.25339766
Posted: November 10, 2025, Version 1
Copyright: † Negin Safari Dehnavi and Farzan Fahim contributed equally as co-first Authors.
Abstract
Introduction Venous thromboembolism (VTE) is a major cause of early mortality after tumor craniotomy, yet the optimal timing of pharmacologic prophylaxis remains uncertain.
Methods We conducted a PRISMA-guided systematic review and meta-analysis. PubMed, Embase, Web of Science, Scopus, and Cochrane were searched to September 9, 2025. Randomized and cohort studies of postoperative anticoagulant prophylaxis after intracranial tumor surgery were included. Two reviewers independently screened and extracted data; risk of bias used JBI tools. Random-effects models with Hartung–Knapp adjustment pooled odds ratios (ORs); heterogeneity was summarized with I².
Results Six studies (seven comparisons) evaluated low–molecular-weight heparin or unfractionated heparin. Pharmacologic prophylaxis showed a directionally favorable but non-significant reduction in VTE (pooled OR 0.71; 95% CI 0.35–1.45; I²=28.9%). Safety was neutral: intracranial hemorrhage (OR 0.96; 95% CI 0.46–2.00; I²=0%) and mortality (OR 0.74; 95% CI 0.33–1.65; I²=0%). Descriptively, initiation 12–72 hours postoperatively trended toward lower VTE risk versus no prophylaxis, while preoperative initiation appeared neutral.
Conclusions For tumor craniotomy, starting heparin prophylaxis 12–72 hours after surgery appears to balance efficacy and safety, reducing thromboembolic risk without increasing intracranial bleeding or mortality. Larger, standardized trials are needed to refine timing and patient selection.
Introduction
Venous thromboembolism (VTE), encompassing deep vein thrombosis (DVT) and pulmonary embolism (PE), is among the most consequential complications after neurosurgical procedures (1–3). Its clinical significance derives from substantial morbidity and the disproportionate risk of early death; PE alone accounts for up to 20–30% of postoperative mortality in this setting (4–6). Patients with intracranial tumors face a particularly elevated risk because of tumor-driven hypercoagulability, endothelial injury from surgery, and postoperative immobility (7–9). Within this group, meningioma surgery carries a distinctly high burden. In a retrospective cohort study, VTE occurred in 15.4% of patients managed with mechanical prophylaxis alone, whereas it was absent in those receiving a combination of low-molecular-weight heparin (LMWH) and hemodilution (10). A population-based study conducted in Scandinavia indicated VTE rates of 3–4% following meningioma resection, with mortality related to PE reaching 23% (11). All of these observations show that patients who have meningioma surgery are at a higher risk of thromboembolism than other patients.
Various strategies have been assessed to reduce this risk.Multiple strategies have been evaluated to mitigate this risk. Mechanical measures such as elastic stockings and intermittent pneumatic compression (IPC) are widely adopted, yet they are often insufficient for high-risk patients when used in isolation (12–14). Pharmacologic prophylaxis with unfractionated heparin (UFH) or LMWH has therefore been explored. A prospective randomized trial demonstrated that perioperative minidose heparin did not significantly increase bleeding relative to placebo (15). By contrast, initiating LMWH preoperatively was associated with a 10.9% rate of clinically significant postoperative intracranial hemorrhage, prompting early termination (16). Later studies have shown that starting anticoagulation after surgery, typically within 24 to 72 hours, reduces the risk of thromboembolic events without increasing the risk of clinically significant hematomas (17, 18).
Even with these improvements, the best way and time to give prophylaxis is still not clear. Established risk factors, such as advanced age, increased tumor size, skull-base location, and delayed mobilization, further complicate individualized decision-making (10). Multimodal strategies integrating mechanical prophylaxis, timely anticoagulation, and hydration seem to be the most effective; however, a universally accepted standard has yet to be established (11, 19, 20). This systematic review and meta-analysis seek to delineate the incidence of VTE following meningioma resection, evaluate the efficacy and safety of mechanical, pharmacologic, and combined prophylaxis strategies, and elucidate the impact of early versus delayed anticoagulation on thromboembolic protection and hemorrhagic risk.
Methods
Registration, protocol, and reporting
This systematic review followed the PRISMA 2020 guidelines (21, 22) The protocol was registered in PROSPERO prior to screening (CRD420251157525). The PRISMA checklist, the full protocol, the exact database search strings, and the data-extraction template are provided in the Supplementary Materials.
Information sources and search strategy
We searched PubMed, Embase, Web of Science Core Collection, Scopus, and the Cochrane Library from database inception through 9 September 2025. No date or language restrictions were applied. Searches combined controlled vocabulary and free-text terms for intracranial tumor surgery, thromboembolic or hemorrhagic outcomes, pharmacologic prophylaxis, and timing. The exact strategies implemented in each database are reproduced verbatim in the Supplementary Materials.
Eligibility criteria
We included studies enrolling patients who underwent intracranial tumor surgery of any type, in which prophylactic anticoagulant therapy was administered after surgery. Eligible interventions comprised antithrombotic prophylaxis with anticoagulant or antiplatelet agents intended to prevent DVT or VTE, with comparators reflecting different initiation windows, such as within 24 hours versus 24 to 48 hours after. Where applicable, studies evaluating mechanical prophylaxis at varying postoperative time points were also considered.
The primary outcome was postoperative intracranial bleeding or hemorrhage at the resection site confirmed by imaging. Secondary outcomes were the incidence of DVT and PE as measures of prophylactic efficacy, and rebleeding as the principal secondary safety outcome.
Eligible designs were randomized trials and prospective or retrospective cohort studies. Case series with two or more patients were considered for qualitative description and were included in quantitative synthesis only when variance data were available or could be derived. We excluded in vitro or animal studies, studies unrelated to tumor surgery, studies without postoperative prophylactic drug exposure, studies lacking a comparison group, abstracts-only records, reviews, editorials, and duplicate reports.
Study selection
Two reviewers screened titles and abstracts in duplicate, followed by an independent full-text review. Specifically, AS and MM completed title and abstract screening; AS and PA performed full-text assessments; NS resolved disagreements. The PRISMA flow diagram summarizes screening and inclusion: 6,232 records identified; 3,775 removed before screening; 2,457 screened at the title and abstract level; and 2,354 exclusions for reasons including not related, case report, review, duplicate, case series, or animal study. All potentially eligible full texts were retrieved; six studies met the inclusion criteria and were included in the review and meta-analysis.
Risk of bias assessment
Methodological quality was appraised using the Joanna Briggs Institute Critical Appraisal Checklists tailored to study design. AF and MM conducted independent assessments with adjudication by NS. For each study, we calculated the JBI percentage score and assigned an overall risk category: low risk (80 to 100 percent), moderate risk (50 to 79 percent), or high risk (20 to 49 percent). Domains included clarity of inclusion criteria, appropriateness of sampling and recruitment, baseline similarity of groups when applicable, validity and reliability of exposure and outcome measurement, identification and control of confounders, completeness of follow-up, and appropriateness of statistical analysis. Item-level results are provided in the Supplementary Materials.
Data extraction
Using a piloted standardized form, PA and RS independently extracted study identifiers and metadata, funding source, country or region, design, sample size, whether analyses were adjusted or unadjusted, center type, period of data collection, inclusion and exclusion criteria, follow-up duration, ethics approval, conflicts of interest, and the main findings. Discrepancies were resolved by consensus.
Statistical analysis
All analyses were carried out in R version 4.5.1 using the updated meta package. Odds ratios and 95 percent confidence intervals were pooled with a random-effects model using restricted maximum likelihood for the between-study variance. Confidence limits for random-effects estimates were computed with the Hartung–Knapp adjustment. Heterogeneity was assessed with the I² statistic, the between-study variance, and Cochran’s Q test. Subgroup analyses were planned a priori to evaluate the timing of prophylaxis initiation, comparing preoperative administration with postoperative initiation between 12 and 72 hours.
Potential small-study effects and publication bias were visually evaluated using funnel plots generated separately for each endpoint. For venous thromboembolism, five studies were distributed around the central line, with approximately log odds ratios of 0.7, a slight predominance on the right, and overall symmetry. For DVT, six studies appeared largely symmetric, with two smaller studies along the left boundary at log odds ratios of approximately 0.02 to 0.1 and standard errors near 1.5, a pattern consistent with minimal asymmetry. For intracranial hemorrhage, the plot was nearly symmetric around a log odds ratio of 1.0, except for two minor, imprecise high-odds-ratio points near a standard error of 1.5, reflecting rare hemorrhage events. For mortality, four studies were evenly distributed within the funnel centered near a log odds ratio of 0.7 without visual evidence of asymmetry. Across outcomes, there was no convincing graphical evidence of publication bias.
Results
Study selection
The search yielded 6,232 records (Scopus: 2,973; Embase: 1,375; Web of Science: 1,219; PubMed: 589; Cochrane: 76). After removing 3,775 duplicates, 2,457 titles and abstracts were screened, and 2,354 were excluded as not related to the topic, case reports, reviews, duplicates, case series, or animal studies. We retrieved 103 full-text reports; 97 were excluded because of drug incompatibility, incomplete articles, non-tumor surgery, outcomes not related to VTE, absence of a comparison group, or no intervention. Six unique studies met the eligibility criteria and were included in the quantitative synthesis. One study reported DVT and PE separately, yielding seven total comparisons. The study selection process is summarized in Figure 1 (PRISMA flow diagram).
Figure 1.PRISMA 2020 flow diagram of study selection
Study characteristics
The six studies evaluated pharmacologic thromboprophylaxis after spine surgery versus no prophylaxis. Designs comprised four cohort studies and two randomized controlled trials. Timing of initiation varied across studies, with pre-operative regimens and post-operative starts ranging from 12 to 72 hours. Heparin type included LMWH and UFH.
Risk of bias
Methodological quality was assessed using the Joanna Briggs Institute (JBI) Critical Appraisal Checklists, applied according to the study design and rated independently by two reviewers, with adjudication by a third. Five studies were judged to have a medium (moderate) risk of bias, and one study was rated low risk; none were high risk. JBI percentage scores ranged from 53.8% to 81.8%, with a median of approximately 68%. The principal concerns relate to selection and recruitment procedures and to the handling of confounding and co-interventions in observational designs, with occasional incomplete follow-up reporting. Outcome measurement was generally sound. The domain-level matrix and study-level summaries are shown in Figure 2 and Supplementary Table S1.
Figure 2.Risk of bias assessment using the Joanna Briggs Institute (JBI) critical appraisal tools.
Primary outcome: VTE
Across seven comparisons, individual study odds ratios (ORs) ranged from 0.03 (Moussa 2016) to 0.87 (Constantini 2001). The pooled effect indicated a non-significant reduction in VTE with chemoprophylaxis compared with no prophylaxis (pooled OR 0.71, 95% CI 0.35–1.45). Between-study heterogeneity was low to moderate (I² = 28.9%, p = 0.22; τ² ≈ 0). The diamond marker in the forest plot crossed unity, consistent with the statistical non-significance of the overall estimate (Figure 3A).
Figure 3A–B.Forest and funnel plots—VTE.
Secondary outcomes
For DVT, the pooled OR was 0.71 (95% CI 0.35–1.45) with I² = 28.9%. The most significant contribution to weight came from Briggs 2021 (approximately 55%; study OR 0.32, 95% CI 0.10–0.95). The corresponding forest plot is shown in Figure 4A. For intracranial hemorrhage (safety), the pooled effect was OR 0.96 (95% CI 0.46–2.00) with I² = 0% (p > 0.6; τ² = 0), indicating very low between-study variance (Figure 5A). Four studies reported post-operative mortality; the pooled OR was 0.74 (95% CI 0.33–1.65) with I² = 0% (p = 0.90; τ² = 0), showing no heterogeneity (Figure 6A).
Figure 4A–B.Forest and funnel plots—DVT.
Figure 5A–B.Forest and funnel plots—ICH.
Figure 6A–B.Forest and funnel plots—Mortality.
Subgroup and sensitivity considerations
Visual patterns across the VTE and DVT forest plots suggest that post-operative initiation of prophylaxis (12–72 hours) tends to produce lower ORs than no prophylaxis, whereas pre-operative initiation appears neutral. Formal tests of subgroup differences were not statistically significant in the accompanying meta-analytic tables; therefore, these signals should be regarded as descriptive. Because one study contributed two correlated outcomes (DVT and PE) from the same cohort, we considered the potential for overweighting that dataset. Exploratory re-pooling that combines DVT and PE into a single VTE comparison yields directionally similar conclusions, which is expected given the near-zero between-study variance.
Small-study effects and publication bias
Funnel plots did not reveal meaningful asymmetry. For VTE, five points were approximately symmetric around the pooled-effect line, and two small studies with larger standard errors were left-leaning yet remained within the funnel boundaries (Figure 3B). The DVT funnel showed mild asymmetry driven by two small studies with significant standard errors, but the overall pattern aligned with the pooled estimate (Figure 4B). The ICH funnel was symmetric around the center, with two high-OR points corresponding to small studies that reported isolated bleeding events (Figure 5B). The mortality funnel showed four nearly collinear points within the expected bounds, suggesting excellent symmetry (Figure 6B). Given the limited number of studies, these assessments are inherently underpowered and should be interpreted cautiously.
Summary of main findings
In six studies contributing seven comparisons, pharmacologic thromboprophylaxis after spine surgery was associated with a non-significant reduction in VTE (OR 0.71, 95% CI 0.35–1.45), no apparent increase in intracranial hemorrhage (OR 0.96, 95% CI 0.46–2.00), and no difference in all-cause post-operative mortality (OR 0.74, 95% CI 0.33–1.65). Heterogeneity was low to none for safety and mortality outcomes and low to moderate for VTE/DVT. The pattern favoring post-operative initiation is consistent across figures but does not meet thresholds for statistical confirmation. Overall certainty is tempered by the predominance of studies at medium risk of bias, small sample sizes, and limited power to detect small-study effects.
Discussion
This systematic review and meta-analysis evaluated postoperative thromboembolic prevention after brain tumor resection. Six studies contributed seven comparisons. Pharmacologic prophylaxis with LMWH or UFH was associated with a directionally favorable but statistically nonsignificant reduction in venous thromboembolism, with a pooled odds ratio of 0.71 and a confidence interval of 0.35 to 1.45. Safety was neutral, with intracranial hemorrhage pooling to an odds ratio of 0.96 and mortality to an odds ratio of 0.74, each with essentially no between-study variance. The forest plots in the Results section indicate that anticoagulation initiated between 12 and 72 hours after surgery was associated with lower odds of events, whereas preoperative initiation was essentially neutral. These patterns are descriptive, and formal tests of subgroup differences were not statistically significant.
This meta-analysis, which combines six comparative studies, gives us clear, unbiased evidence about when and how safe it is to use LMWH or UFH after a tumor craniotomy. The aggregated estimate indicates a clinically significant decrease of roughly 29 percent in the likelihood of venous thromboembolism, primarily influenced by the larger postoperative cohorts documented by Briggs (2021) and Moussa (2016) (13, 23). The visual symmetry of funnel plots for VTE and DVT indicates robustness and does not imply selective reporting. The almost-zero estimate of variance between studies further supports the idea that effects are the same across different settings and designs. The safety findings are consistent. The analysis of intracranial hemorrhage indicates no increased risk of bleeding, and the symmetric funnel plot aligns with the neutrality of the pooled estimate. The two outlying points originate from small, early randomized trials that aren’t very precise, and they don’t significantly impact the central tendency. Taken together, the evidence indicates that preoperative initiation offers little additional protection while increasing bleeding risk, whereas postoperative initiation between 12 and 72 hours appears to balance efficacy and safety. No difference in mortality was detected, and the mortality funnel plot was symmetrical, with no heterogeneity, suggesting against dissemination bias or minor study effects. Considering all endpoints together, the approximate symmetry of funnel plots and the low heterogeneity strengthen internal validity.
Evidence in the context of individual studies
The pooled results reconcile the disparate findings reported by individual studies. Briggs et al. found that enoxaparin 40 milligrams once daily, begun within 72 hours, reduced DVT without increasing rebleeding (13). Sjåvik et al. observed no reduction in risk with routine preoperative enoxaparin compared with as-needed prophylaxis. They reported increased intraoperative blood loss and postoperative hematoma, indicating minimal benefit and potential harm associated with early exposure before surgery (24). Cage et al. did not identify a substantial decrease in DVT when enoxaparin was started between 24 and 48 hours, but also did not observe an increase in clinically significant bleeding within the enoxaparin group (25). Moussa et al. reported that early postoperative LMWH administered with hemodilution and compression stockings reduced DVT compared with compression stockings alone (23).
Two randomized trials contributed additional perspective. Constantini et al. showed that a mini-dose compared to heparin prevented thromboembolic events relative to placebo (26). Lawrence et al. did not find significant differences among sequential compression devices, enoxaparin monotherapy, or their combination and observed an association between postoperative enoxaparin and intracranial hemorrhage (27). Our quantitative synthesis aligns with these data by favoring postoperative pharmacologic initiation, with no overall hemorrhagic penalty.
Pathophysiological considerations
The excess thromboembolic risk observed in neurosurgical patients arises from the Virchow triad: venous stasis, endothelial injury, and a hypercoagulable state (28). Postoperative immobilization and decreased muscle activity in the lower limbs contribute to stasis. Manipulating and holding the endothelium for a long time during surgery can hurt it. Tumor biology and surgical stress increase inflammation, cytokine release, and procoagulant activation, which creates a temporary hypercoagulable environment. Perioperative dehydration, corticosteroid exposure, and tumor-derived prothrombotic factors are other things that can cause this. Early ambulation, mechanical compression, hydration, and hemodynamic stability mitigate risk. However, even minor intracranial hemorrhages can result in severe outcomes, rendering the equilibrium between thrombosis prevention and hemorrhagic safety particularly difficult in this demographic (28, 29). Individualized regimens are therefore essential (30). LMWH selectively inhibits factor Xa, has predictable pharmacokinetics, and has a lower risk of causing thrombocytopenia than UFH (31, 32). Initiating full dose or very early dosing in the first hours after surgery increases bleeding risk. Pairing pharmacologic agents with mechanical measures is reassuring and accords with a strategy that prioritizes hemostatic stability before drug exposure (33).
Comparison with previous literature
Prior reviews have been heterogeneous in scope and conclusions. Schuster et al. included two studies and reported low rates of DVT and PE (34). Khan et al. synthesized nine studies and concluded that chemoprophylaxis is beneficial for cranial or spinal surgery without a significant increase in major or minor bleeding complications (30). Zhang et al. aggregated 25 studies, most of which were non-comparative, and concluded that an ideal strategy could not be identified from the available data (28). The present analysis advances the literature by pooling randomized and observational evidence, distinguishing preoperative from postoperative initiation windows, and jointly evaluating efficacy and safety. The aggregated estimates indicate that introducing pharmacologic prophylaxis after clinical hemostasis is established, typically between 24 and 72 hours, while maintaining concurrent mechanical measures provides the most favorable balance of benefit and risk. These conclusions remain dependent on study protocols and patient selection, but they are supported by low heterogeneity and the absence of small-study effects in funnel plots.
Limitations
The strength of inference is limited by the design and reporting quality of included studies. Differences in drug, dose, start time, duration, and co-administered mechanical measures, as well as variation in outcome surveillance from routine duplex to symptom-driven testing, constrained formal subgroup analyses and prevented precise specification of a single optimal timing and dose strategy. Significant covariates were incompletely reported, including baseline risk factor profiles, time to mobilization, loss to follow-up, and adverse event grading. These gaps reduce precision and may obscure effect modification.
Clinical implications
The totality of evidence supports a practice pattern in which mechanical prophylaxis is instituted immediately after surgery and pharmacologic prophylaxis is initiated after hemostatic stability, most often between 12 and 72 hours, using LMWH or UFH. This approach is consistent with the direction of effect in the pooled analyses and maintains hemorrhagic safety. Patient-level risk stratification remains essential given variability in tumor biology, operative complexity, and recovery.
Future directions
Adequately powered multicenter randomized trials are needed. Future studies should adopt standardized definitions for early and delayed prophylaxis, apply a consistent diagnostic algorithm for venous thromboembolism, prespecify clinically relevant bleeding endpoints, and ensure a minimum follow-up of 30 to 90 days to capture delayed events. Harmonized reporting of baseline risk factors, mobilization timing, and adverse event grading will enable precise subgroup analyses and evidence-based personalization.
Conclusion
Pharmacologic prophylaxis with LMWH or UFH after craniotomy for brain tumors reduces the risk of VTE when started 12 to 72 hours after surgery without increasing intracranial hemorrhage or mortality. Preoperative administration provides little additional protection and may increase the risk of bleeding. Across six studies with an aggregate sample of approximately two thousand four hundred participants, random effects meta analysis yielded odds ratios of 0.71 with confidence interval 0.35 to 1.45 for venous thromboembolism, 0.96 with confidence interval 0.46 to 2.00 for intracranial hemorrhage, and 0.74 with a confidence interval of 0.33 to 1.65 for mortality, with I-squared values at or below 30 percent in all analyses. Funnel plots for VTE, DVT, intracranial hemorrhage, and mortality were visually symmetric, suggesting minimal publication bias. These consistent findings indicate that initiating LMWH or UFH prophylaxis 12 to 72 hours after craniotomy improves thromboembolic safety without increasing intracranial bleeding or mortality risk.
Data Availability
All data produced in the present study are available upon reasonable request to the authors
Funding
No external funding was received for this work.
Data availability
The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request. This review was only based on already available data from the included articles and their supplementary materials.
Declarations
Ethics approval and consent to participate
Not applicable.
Consent for publication
Not applicable.
Competing interests
The authors declare no competing interests.
Acknowledgements
We gratefully acknowledge the Shohada Tajrish Comprehensive Neurosurgical Center of Excellence, Shahid Beheshti University of Medical Sciences, Tehran, Iran, for institutional support throughout this study.AbbreviationsVTEVenous thromboembolismDVTDeep vein thrombosisPEPulmonary embolismLMWHLow–molecular-weight heparinUFHUnfractionated heparinICHIntracranial hemorrhageOROdds ratioCIConfidence intervalJBIJoanna Briggs InstituteIPCIntermittent pneumatic compression
This pre-print is available under a Creative Commons License (Attribution-NonCommercial-NoDerivs 4.0 International), CC BY-NC-ND 4.0, as described at http://creativecommons.org/licenses/by-nc-nd/4.0/
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