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. 2024 Oct 16;19(10):e0311858. doi: 10.1371/journal.pone.0311858

Low-molecular-weight heparin in the prevention of venous thromboembolism among patients with acute intracerebral hemorrhage: A meta-analysis

Haizheng Li 1,*, Zhiguo Wu 1, Hongyu Zhang 2, Baohua Qiu 2, Yajun Wang 1
Editor: Sonu Bhaskar3
PMCID: PMC11482721  PMID: 39413073

Abstract

Objective

It remains unclear whether low-molecular-weight heparin (LMWH) is effective and safe for intracerebral hemorrhage (ICH) patients. This study presents a meta-analysis for elucidating effect of LMWH on preventing venous thromboembolism (VTE) among ICH patients.

Methods

Articles were located by systematically searching PubMed, Embase, Web of Science, Cochrane Library, China National Knowledge Infrastructure (CNKI), WANFANG DATA, VIP, and SinoMed databases. The literature was independently screened by two authors, who also extracted data and conducted a qualitative evaluation. With regard to outcomes, their risk ratios (RRs) and 95% confidence intervals (CIs) were computed, and the findings were combined using the random effects model by using Mantel-Haenszel approach.

Results

30 studies involving 2904 patients were analyzed and compared to control group. According to our findings, early low-dose LMWH, prophylaxis for VTE, was related to the markedly reduced deep vein thrombosis (DVT) (3.6% vs. 17.5%; RR, 0.25; 95% CI, 0.18–0.35; p-value<0.00001) and pulmonary embolism (PE) (0.4% vs. 3.2%; RR, 0.29; 95% CI, 0.14–0.57; p-value = 0.003), while the non-significantly increased hematoma progression (3.8% vs. 3.4%; RR, 1.06; 95% CI, 0.68–1.68; p-value = 0.79) and gastrointestinal bleeding (3.6% vs. 6.1%; RR, 0.63; 95% CI, 0.31–1.28; p-value = 0.20). Also, mortality (14.1% vs. 15.8%; RR, 0.90; 95% CI, 0.63–1.28; p-value = 0.55) did not show any significant difference in LMWH compared with control groups.

Conclusions

Our meta-analysis suggested that early low-dose of LMWH are safe and effective in ICH patients. More extensive, multicenter, high-quality randomized clinical trials (RCTs) should be conducted to validate the findings and inform clinical practice.

1. Introduction

Among patients with intracerebral hemorrhage (ICH), venous thromboembolism (VTE) presents life-threatening consequences and represents a significant global health burden. One study reported that the risks of deep vein thrombosis (DVT) and pulmonary embolism (PE) in ICH patients are 2.4% and 1.1%, respectively [1]. In line with the American Heart Association (AHA) and American Stroke Association (ASA) guidelines, intermittent pneumatic compression (IPC) should be initiated upon admission (class I; level of evidence A), while unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH) can be administered within 1–4 day after admission (class II; level of evidence B) [2]. However, the 2020 guidelines of the Heart and Stroke Foundation of Canada (HSFC) recommend starting LMWH after two days of admission (level of evidence B) [3]. Most of the guidelines that report the use of LMWH and UFH for preventing VTE among ICH patients offer weak recommendations with low-quality evidence [2–5]. However, the American Society of Hematology (ASH) 2018 guidelines provide a strong recommendation for ICH patients, based on moderate certainty of evidence [6]. In view of limited related evidence, only 16.5% of ICH patients receive prophylactic anticoagulation [7]. This is primarily because it is believed that these patients have a high risk of bleeding. Therefore, this work conducted an improved meta-analysis on recent studies (randomized or non-randomized) to elucidate the role of LMWH for VTE prevention in ICH patients. Additionally, the effect of LMWH on DVT, PE, hematoma progression, gastrointestinal bleeding, and mortality was systematically analyzed.

2. Methods

2.1 Search strategy and screening criteria

The judicious protocol describing specific objectives, search strategy, screening criteria, study quality evaluation, clinical outcomes, and statistical analysis was developed. The protocol was written according to reporting guidelines of Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA). Our protocol was registered in PROSPERO database (registration number: CRD42024525822). PubMed, Embase, Web of Science, Cochrane Library, China National Knowledge Infrastructure (CNKI), WANFANG DATA, VIP, and SinoMed databases were comprehensively searched from inception to November 2023, in addition to a systematic manual search of journal articles. S1 Table shows more details about queries. Further, studies below were included: (1) ICH patients; (2) intervention: LMWH treatment only or LMWH with mechanical treatment [Graduated Compression Stockings (GCS), Intermittent pneumatic compression (IPC)]; (3) comparison: mechanical treatment (GCS, IPC) or not; (4) primary outcomes: DVT, PE, hematoma progression; and secondary outcomes: gastrointestinal bleeding, and mortality; (5) study design: randomized clinical trials (RCTs) and cohort study; (6) publications whose full-texts could be obtained to screen and extract data. In order to remove any irrelevant and non-specific studies, studies below were excluded: (1) Studies involving patients with ICH caused by surgery, traumatic brain injury, or those with intracranial hemorrhages other than ICH (e.g., subarachnoid hemorrhage, traumatic intracerebral hemorrhage, subdural hematoma, or epidural hematoma); (2) UFH or combined antiplatelet drugs; (3) non-original studies (like review, case report, meta-analysis, or systematic review). Endnote X9 was used to exclude duplicates and screen the literature. Two authors independently selected and assessed the eligibility of English studies or those published in non-English language (namely, Chinese), and any discrepancy was resolved by a third author.

2.2 Data collection

Data pertaining to the study design, type of intracerebral hemorrhage, treatment option, dosage, time of onset of treatment, duration of treatment, methods of diagnosis of DVT/PE/hematoma progression, follow-up period, event number, and study participant number were obtained by two investigators. Any disagreement in the data extraction was resolved by adjudicating with the third investigator.

2.3 Quality evaluation

Qualitative evaluation of RCTs and non-randomized trials (non-RCTs) was conducted by two investigators using the revised Cochrane risk-of-bias tool (RoB 2) and the Newcastle-Ottawa Scale (high quality 7≤to≤9, moderate quality 4≤to≤6, and low quality <4), respectively. Any conflict in the quality assessment was interceded by a third author.

2.4 Endpoints

The primary study endpoints were asymptomatic and symptomatic DVT (diagnosed by clinical symptoms, Doppler ultrasound, venography, and magnetic resonance imaging), PE (diagnosed by clinical symptoms and computed tomography pulmonary angiography), and hematoma progression (diagnosed by clinical symptoms and computed tomography, defined as a ≥33% increase in hematoma volume). The secondary study endpoints were gastrointestinal bleeding and mortality.

2.5 Statistical analysis

Review Manager V.5.3 software (Cochrane Collaboration, London, UK) and stata (StataCorp. 2017. Stata Statistical Software: Release 14; StataCorp LLC, College Station, Texas, USA) were employed for data analysis. Continuous variables were described as means (standard deviations), while categorical variables were described as numbers (percentages). We used Mantel-Haenszel approach-based random-effects model for combining results. Effect size was determined by calculating risk ratio (RR) and 95% confidence intervals (CI). To evaluate heterogeneities among the studies, the Mantel-Haenszel method was employed, with p-value = 0.10 indicating statistical significance. Furthermore, Higgins’ I2 statistic was employed to compare the extent of heterogeneity (low heterogeneity ≤30%, moderate heterogeneity 30%< to ≤50%, high heterogeneity >50%). For primary endpoints, at least ten studies were conducted for DVT, PE, and hematoma progression. Small-study effects were detected by assessing Egger’s test and funnel plot. The trim-and-fill approach was applied to provide an estimate of the treatment effect adjusted for selection bias. Additionally, subgroup analyses based on study design, ICH type, and ICH treatment type (operation or not) were performed. Lastly, the differences among the subgroups were examined in a random-effects model.

3. Results

3.1 Study screening

Fig 1 exhibits our study screening procedure. There were altogether 13451 records obtained from databases search of citations; in addition, three more articles were found in additional sources. When duplicates were carefully eliminated, 10954 records were acquired and subsequently evaluated. After that, these articles were examined by title- and abstract-reading, with only 52 articles being retained for further study. The full-text of these selected 52 articles was assessed, among which, 30 were finally enrolled for the meta-analysis, while the remaining 22 were excluded. Table 1 summarizes the designs of these 30 qualified articles. The remaining 22 articles were excluded because of the following reasons: patients with traumatic ICH (one study) [8]; patients with subarachnoid hemorrhage (two studies) [9, 10]; patients with ICH due to surgery (three studies) [11–13]; use of UFH (four studies) [14–17]; use of antiplatelet drugs (two studies) [18, 19]; lack of control group (five studies) [20–24]; patients with DVT during admission (one study) [25]; contradictory content (four studies) [26–29].

Fig 1. Flowchart showing the study inclusion and exclusion procedure.

Fig 1

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Table 1. Features of enrolled articles.

Study Design Country Type of ICH Participants Operation Treatment Control Dosage Time of onset of treatment Duration of treatment DVT diagnosis PE diagnosis Hematoma progression diagnosis Follow-up duration
Zhao 2020 RCT China Unspecified ICH 70 Yes LMWH IPC+GCS 4000IU QD Post operation 3rd day ≤10 days Clinical NR NR 14 days
Ni 2018 Cohort study China Spontaneous ICH 104 No LMWH (enoxaparin)+IPC IPC 0.4ml QD Admission 4th day 7 days NE NE CT 7 days
Yu 2015 RCT China Unspecified ICH 103 No LMWH No LMWH 4000IU QD NR 14 days Doppler CT NR 14 days
Yin 2019 RCT China Unspecified ICH 86 No LMWH+IPC+GCS IPC+GCS 4000IU QD Admission 3rd day 5 days Doppler NR CT 14 days
Tang 2015 RCT China Hypertensive ICH 40 No LMWH (nadroparin) No LMWH 5000IU QD Post-ICH 3rd/4th day 15 days Doppler CTA CT 15 days
Mo 2021 RCT China Unspecified ICH 80 No LMWH+IPC IPC 57IU/kg QD NR 14 days NR NR NR 14 days
Xu 2019 RCT China Unspecified ICH 30 No LMWH No LMWH 0.4ml NR NR Clinical NE NE NR
Qian 2012 RCT China Hypertensive ICH 60 No LMWH (nadroparin)+GCS No LMWH 0.4ml QD NR 14 days Doppler NR CT 14 days
Feng 2021 RCT China Unspecified ICH 150 Yes LMWH (nadroparin)+IPC IPC 4100IU QD Post operation 3rd day 10 days Doppler NR NR 10 days
Li 2011 RCT China Hypertensive ICH 60 Yes LMWH (nadroparin)+GCS GCS 1025IU/10kg Q12H Post operation 3rd day 10 days Doppler NE CT 10 days
Jiang 2014 RCT China Hypertensive ICH 82 Yes LMWH+IPC IPC 4100IU QD Post operation 3rd day 14 days Doppler/MRI/Venography NR NR 21 days
Liu 2008 RCT China Hypertensive ICH 60 Yes LMWH (nadroparin)+GCS No LMWH 3500IU QD NR 14 days Doppler NR NR 14 days
Xia 2018 RCT China Hypertensive ICH 102 Yes LMWH No LMWH 9500/4750IU QD NR NR Clinical NR NR NR
Yang 2018 RCT China Hypertensive ICH 100 Yes LMWH+IPC No LMWH 0.2ml QD Post operation 3rd day ≤14 days Doppler NE NE 14 days
Wang 2015 RCT China Hypertensive ICH 106 Yes LMWH+IPC+GCS IPC+GCS 4100IU QD Post operation 3rd day Until TEG normal Doppler NE NE 3 months
Yang 2010 RCT China Hypertensive ICH 99 Yes LMWH No LMWH NR Post operation 4th day 14 days Doppler NR CT 14 days
Qin 2018 RCT China Hypertensive ICH 98 Yes LMWH (nadroparin)+IPC IPC 57IU/kg QD Post operation 3rd day 14 days Doppler/MRI/Venography NR CT 21 days
Guan 2019 RCT China Hypertensive ICH 92 Yes LMWH (nadroparin)+IPC IPC 0.4ml QD Post operation 3rd day 14 days Doppler CTA CT 6 months
Zhang 2017 Cohort study China Unspecified ICH 150 No LMWH+IPC+GCS IPC+GCS 4000IU QD Admission 3rd day NR Doppler NE CT 14 days
Chen 2019 Cohort study China Unspecified ICH 120 No LMWH No LMWH 0.4ml Admission 3rd day 14 days NR NR NR 14 days
Gu 2014 Cohort study China Spontaneous ICH 94 No LMWH (nadroparin) IPC 0.4ml QD Admission 4th day 10 days Doppler NE CT 14 days
Wu 2022 Cohort study China Spontaneous ICH 91 Yes LMWH (enoxaparin)+IPC IPC 4000IU QD Post operation 4th day 7–14 days Doppler NR CT 28 days
Sun 2017 Cohort study China Hypertensive ICH 100 Yes LMWH+IPC IPC 4100IU QD Post operation 3rd day 4 days Clinical NE NE 4 days
Lu 2021 Cohort study China Unspecified ICH 82 Yes LMWH+IPC IPC 4100IU QD Post operation 3rd day 14 days NR NE NE 21 days
Yu 2022 RCT China Unspecified ICH 42 Yes LMWH No LMWH 3000IU QD Admission 4th day 7d days NR NE NE 7 days
Sui 2022 RCT China Unspecified ICH 50 Yes LMWH+IPC IPC 4100IU QD Post operation 0 day 14d days Clinical NE NE 14 days
Paciaroni 2020 RCT Italy Spontaneous ICH 73 No LMWH (enoxaparin) No LMWH 0.4 ml NR (10±1) days Doppler CTA CT 90 days
Song 2021 Cohort study China Hypertensive ICH 98 No LMWH+IPC+GCS IPC+GCS 4000IU QD NR 5 days NR NR NR 5 days
Tetri 2008 Cohort study Finland Spontaneous ICH 407 No LMWH (enoxaparin) No LMWH 20mg QD Post-ICH 2nd day 8 (5–12) days NR NR CT 3 months
Orken 2009 RCT Türkiye Spontaneous ICH 75 No LMWH (enoxaparin) GCS 40mg QD Admission 3rd day NR Doppler CTA CT 21 days
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3.2 Study quality

Fig 2 and Table 2 outline quality data for those 30 included articles. Among the 21 RCTs, two were rated as high risk of overall bias since they used clinical diagnosis to measure the outcome. Also, most articles showed certain concerns in overall bias. Among the nine non-RCTs, eight were adjudged to be high quality, only one was of moderate quality.

Fig 2. Quality assessment of randomized controlled trials.

Fig 2

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Table 2. Quality evaluation of non-randomized controlled trials.

Selection Comparability Outcome
Study Representativeness of the exposed cohort Selection of the non exposed cohort Ascertainment of exposure Demonstration that outcome of interest was not present at start of study Comparability of cohorts on the basis of the design or analysis Assessment of outcome Was follow-up long enough for outcomes to occur Adequacy of follow up of cohorts Total scores
Chen 2019 ★ ★ ★ ★ ★★ ☆ ★ ☆ 7
Zhang 2017 ★ ★ ★ ★ ★★ ★ ★ ☆ 8
Gu 2014 ★ ★ ★ ★ ★★ ★ ★ ☆ 8
Wu 2022 ★ ★ ★ ★ ★★ ★ ★ ☆ 8
Sun 2017 ★ ★ ★ ★ ★★ ☆ ★ ☆ 7
Lu 2021 ★ ★ ★ ★ ★★ ☆ ★ ☆ 7
Tetri 2008 ★ ★ ★ ★ ☆☆ ★ ★ ☆ 6
Song 2021 ★ ★ ★ ★ ★★ ☆ ★ ☆ 7
Ni 2018 ★ ★ ★ ★ ★★ ★ ★ ☆ 8
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3.3 Study outcomes

Altogether 30 articles (RCTs and non-RCTs) and 2904 patients were analyzed. Amongst these studies, 13 involved hypertensive ICH patients, 6 included spontaneous ICH cases, while 11 involved unspecified ICH patients. Also, 16 studies enrolled patients after ICH operation. Thromboprophylaxis was initiated on the 3rd to 4th day after hospitalization or ICH operation and continued for 14 days in most studies. In the majority of included studies, the dosing regimen of LMWH was generally 0.4 ml daily (enoxaparin 4000 IU per day, nadroparin 4100 IU per day).

There was no obvious heterogeneity for the effect of LMWH on DVT among 29 studies involving 2800 patients (I2 = 15%; p-value = 0.24). In comparison with control group, LMWH group showed the significantly reduced DVT (3.7% vs. 17.5%; RR, 0.25; 95% CI, 0.18–0.35; p-value<0.00001) (Fig 3). Meanwhile, asymmetry could be seen from funnel plot of DVT (Egger’s test, p-value = 0.001) (Fig 4). The Filled meta-analysis performed by trim-and-fill method involved 29 articles, which conformed to initial analysis. S1–S3 Figs summaries the subgroup analysis results.

Fig 3. Effect of LMWH on DVT.

Fig 3

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Fig 4. Funnel plot illustrating the role of LMWH in DVT.

Fig 4

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The effect of LMWH on PE, investigated based on 17 studies that involved 1807 patients, suggested the absence of obvious heterogeneity across those enrolled articles (I2 = 0%; p-value = 1.00). LMWH group demonstrated significantly reduced PE in comparison with control group (0.4% vs. 3.2%; RR, 0.29; 95% CI, 0.14–0.57; p-value = 0.0003) (Fig 5). The funnel plot analysis of PE showed an asymmetrical shape (Egger’s test, p-value = 0.001) (Fig 6). The Filled meta-analysis performed by trim-and-fill method involved 17 articles, which conformed to initial analysis. S4–S6 Figs summarizes the subgroup analyses.

Fig 5. Effect of LMWH on PE.

Fig 5

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Fig 6. Funnel plot illustrating the role of LMWH in PE.

Fig 6

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The effect of LMWH on hematoma progression was evaluated from 18 studies with 1819 patients and obvious heterogeneity was not found across diverse studies (I2 = 0%; p-value = 0.84). Further, in comparison with control group, LMWH group exhibited the non-significant increase in hematoma progression (3.8% vs. 3.4%; RR, 1.06; 95% CI, 0.68–1.68; p-value = 0.79) (Fig 7). Asymmetry was observed from funnel plot of hematoma progression (Egger’s test, p-value = 0.03) (Fig 8). The Filled meta-analysis performed by trim-and-fill method involved 18 articles, which conformed to initial analysis. S7–S9 Figs displays the subgroup analyses.

Fig 7. Effect of LMWH on hematoma progression.

Fig 7

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Fig 8. Funnel plot illustrating the role of LMWH in hematoma progression.

Fig 8

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The meta-analysis of six studies with 530 patients on the effect of LMWH on gastrointestinal bleeding indicated the absence of obvious heterogeneity across our enrolled articles (I2 = 0%; p-value = 0.60). The LMWH group showed a non-significant rise in gastrointestinal bleeding (3.6% vs. 6.1%; RR, 0.63; 95% CI, 0.31–1.28; p-value = 0.20) in comparison with control group (Fig 9). Subgroup analyses were summarized in S10–S12 Figs.

Fig 9. Effect of LMWH on gastrointestinal bleeding.

Fig 9

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This work summarized the effect of LMWH on mortality in four articles involving 674 patients, and obvious heterogeneity was not observed across these articles (I2 = 0%; p-value = 0.66). Further, mortality did not show any significant difference in LMWH versus control groups (14.1% vs. 15.8%; RR, 0.90; 95% CI, 0.63–1.28; p-value = 0.55) (Fig 10). The subgroup analyses were summarized in S13–S15 Figs.

Fig 10. Effect of LMWH on mortality.

Fig 10

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4. Discussion

The clinical management of ICH patients, who develop DVT, is inconsistent due to the use of anticoagulant agents that may cause hematoma progression among the patients. Therefore, effective prophylaxis of VTE is needed in ICH patients. Generally, most of the guidelines provide weak recommendations with low quality evidence about using low-dose LMWH for ICH patients to prevent VTE [2–5]. Our findings demonstrate that in ICH patients, LMWH prophylaxis for VTE is related to the markedly reduced DVT and PE and the non-significantly increased hematoma progression, and gastrointestinal bleeding. One of the limitations of anticoagulant agents in ICH patients is the increased risk of mortality. However, our data showed that mortality did not exhibit any significant difference between the LMWH and control groups.

According to the results of our meta-analysis, LMWH was initiated on the 3rd to 4th day after admission or operation and continued for 14 days in most studies. The dosing regimen of LMWH was generally 0.4 ml daily (enoxaparin 4000 IU per day, nadroparin 4100 IU per day). Consequently, early administration of low-dose LMWH is both effective and safe in ICH patients. This information may assist doctors in making clinical decisions. To further support these findings, we analyzed three subgroups, which strengthened our findings. Because we believed that whether ICH patients accept surgical treatment may affect the outcome, so we performed a subgroup analysis. In a previous meta-analysis on 4 articles, applying heparin for preventing VTE is related to the markedly reduced PE [30]. The present data is in good agreement with a recent meta-analysis that includes 28 studies and 3697 patients and demonstrates that heparin is effective and safe among ICH patients [31]. A study with 68 ICH patients suggests that heparin initiation on day two is correlated with the more markedly reduced PE than on day four or day ten [14]. However, more investigations are warranted for determining the best way to prevent VTE among ICH patients.

Although our meta-analysis offers valuable information on LMWH in preventing venous thromboembolism among ICH patients, there are certain limitations, e.g., small sample size, inclusion of non-randomized studies, concerns about overall bias, relatively short follow-up duration, and lack of long-term outcomes. Hence, additional large, multicenter, high-quality RCTs are necessary to validate the findings and inform clinical practice.

Supporting information

S1 Checklist. PRISMA 2020 checklist.

(DOCX)

pone.0311858.s001.docx (24.1KB, docx)
S1 File. ALL studies identified in the literature search.

(XLSX)

pone.0311858.s002.xlsx (1MB, xlsx)
S1 Table. Search details.

(DOCX)

pone.0311858.s003.docx (16KB, docx)
S2 Table. List of articles included in the meta-analysis.

(DOCX)

pone.0311858.s004.docx (20.5KB, docx)
S3 Table. Summary of outcomes in enrolled study.

(DOCX)

pone.0311858.s005.docx (21.9KB, docx)
S4 Table. Quality assessment of randomized controlled trials.

(DOCX)

pone.0311858.s006.docx (18.2KB, docx)
S1 Fig. Subgroup analysis stratified by study design: Effect of LMWH on DVT.

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pone.0311858.s007.tif (1.8MB, tif)
S2 Fig. Subgroup analysis stratified by ICH type: Effect of LMWH on DVT.

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pone.0311858.s008.tif (2MB, tif)
S3 Fig. Subgroup analysis stratified by ICH treatment type: Effect of LMWH on DVT.

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pone.0311858.s009.tif (1.8MB, tif)
S4 Fig. Subgroup analysis stratified by study design: Effect of LMWH on PE.

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pone.0311858.s010.tif (1.4MB, tif)
S5 Fig. Subgroup analysis stratified by ICH type: Effect of LMWH on PE.

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pone.0311858.s011.tif (1.6MB, tif)
S6 Fig. Subgroup analysis stratified by ICH treatment type: Effect of LMWH on PE.

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pone.0311858.s012.tif (1.4MB, tif)
S7 Fig. Subgroup analysis stratified by study design: Role of LMWH in hematoma progression.

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pone.0311858.s013.tif (1.5MB, tif)
S8 Fig. Subgroup analysis stratified by ICH type: Effect of LMWH on hematoma progression.

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pone.0311858.s014.tif (1.7MB, tif)
S9 Fig. Subgroup analysis stratified by ICH treatment type: Effect of LMWH on hematoma progression.

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pone.0311858.s015.tif (1.5MB, tif)
S10 Fig. Subgroup analysis stratified by study design: Effect of LMWH on gastrointestinal bleeding.

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pone.0311858.s016.tif (961.3KB, tif)
S11 Fig. Subgroup analysis stratified by ICH type: Effect of LMWH on gastrointestinal bleeding.

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pone.0311858.s017.tif (1.1MB, tif)
S12 Fig. Subgroup analysis stratified by ICH treatment type: Effect of LMWH on gastrointestinal bleeding.

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pone.0311858.s018.tif (983.7KB, tif)
S13 Fig. Subgroup analysis based on study design: Effect of LMWH on mortality.

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pone.0311858.s019.tif (833KB, tif)
S14 Fig. Subgroup analysis based on ICH type: Effect of LMWH on mortality.

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pone.0311858.s020.tif (978.2KB, tif)
S15 Fig. Subgroup analysis based on ICH treatment type: Effect of LMWH on mortality.

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pone.0311858.s021.tif (828.2KB, tif)

Data Availability

All relevant data are within the manuscript and its Supporting information files. We confirm our submission contains all raw data required to replicate the results of our study.

Funding Statement

The author(s) received no specific funding for this work.

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Decision Letter 0

Sonu Bhaskar

24 Jul 2024

PONE-D-24-20586Low-molecular-weight heparin in the prevention of venous thromboembolism among patients with acute intracerebral hemorrhage: A meta-analysisPLOS ONE

Dear Dr. Li,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

==============================

ACADEMIC EDITOR:

Thank you for submitting your work to PLOS One. Based on careful review of your work and taking into account feedback from the reviewers, I would like to invite you to address the concerns raised and submit a revised version.

Whilst the study addresses an important clinical issue concerning the prevention of venous thromboembolism (VTE) in patients with acute intracerebral hemorrhage (ICH), which is a significant cause of morbidity and mortality; there are some issues that merit consideration.  By providing a meta-analysis, the manuscript seeks to provide evidence regarding the effectiveness and safety of low-molecular-weight heparin (LMWH) in this patient population.  The analysis includes 30 studies and 2904 patients.

We look forward to receiving revised version of your work. 

Major comments:

1. While the study attempts to address heterogeneity, the inclusion of both randomized controlled trials (RCTs) and non-randomized studies could introduce variability and affect the robustness of the conclusions (Page 5, Lines 84-87).

2. The study focuses primarily on short-term outcomes, which may not fully capture the long-term safety and efficacy of LMWH in ICH patients (Page 9, Lines 188-190), thereby limiting the overall scope of this work.

3. The inclusion of non-randomized studies and concerns about overall bias in some studies need to be addressed more thoroughly (Page 5, Lines 84-87).

4. While the protocol is registered in PROSPERO, additional details about deviations from the original protocol should be clearly stated (Page 4, Lines 58-59).

5. The exclusion criteria are appropriately detailed, but the justification for excluding specific types of studies (e.g., those involving other types of intracranial hemorrhage) could be better explained (Page 4, Lines 67-73).

6.  The relatively short follow-up period in some included studies may limit the ability to observe long-term outcomes (Page 9, Lines 188-190).

7. The manuscript does not provide detailed practical recommendations for implementing LMWH treatment in clinical practice (Page 10, Lines 181-185).

8. The study does not compare the effectiveness of LMWH with other potential thromboprophylactic agents or methods, which could provide a more comprehensive clinical perspective (Page 3, Lines 52-53).

9. There are a few typographical errors that need correction, such as "meta -analysis " instead of "meta-analysis" (Page 1, Line 1).

10.  Ensure consistency in the use of abbreviations and terms throughout the manuscript, such as "RCT" vs. "non-RCT" (Page 5, Lines 84-85).

11. Some references are not up-to-date, and more recent studies could be included to support the findings (Page 10, Lines 198-307).

Minor comments:

12. Abstract:

Line 1: Correct "meta -analysis " to "meta-analysis."

Line 15: Clarify the definition of "early low-dose" in the context of LMWH treatment.

13. Introduction:

Page 1, Line 2: Rephrase "life-threatening consequences, representing a significant global health burden" for clarity.

Page 2, Line 3: Provide more context on the current limitations of existing guidelines for LMWH use in ICH patients.

14. Methods:

Page 4, Line 55: Clarify the inclusion criteria for studies and justify the exclusion of non-original studies.

Page 4, Line 67: Explain the rationale for excluding studies involving other types of intracranial hemorrhage.

15. Results:

Page 7, Line 106: Elaborate on the reasons for excluding 22 articles after full-text assessment. These should also be included in the PRISMA diagram. 

Page 8, Line 132: Provide more detail on the methods used to assess heterogeneity and the implications of the findings.

16. Discussion:

Page 9, Line 164: Discuss the clinical implications of the findings in more detail, including potential changes to clinical practice guidelines.

Page 10, Line 188: Address the limitations of the study more thoroughly, including the potential impact of short follow-up duration and inclusion of non-randomized studies.

17. Conclusion:

Page 10, Line 190: Emphasize the need for large, multicentric, and high-quality RCTs to validate the findings and inform clinical practice.

==============================

Please submit your revised manuscript by Sep 07 2024 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

  • A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.

  • A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.

  • An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Sonu Bhaskar, MD PhD

Academic Editor

PLOS ONE

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Additional Editor Comments:

See above

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Partly

Reviewer #2: Yes

**********

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: No

**********

4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: No

**********

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Li and colleagues conducted a LMWH-focused meta-analysis to quantify LMWH’s safety and efficacy after an acute non-traumatic ICH. They manually reviewed 109,054 abstracts and 52 full-text articles to identify and analyze 30 prospective intervention trials (randomized and non-randomized). The key finding is that LMW is a safe (no rise in hematoma expansion / rebleed) and efficacious (reduced VTE) when initiated in the first 4 days of either hospitalization or surgical intervention.

Overall the study is well-done and well-reported. I have no major concerns about the overall scientific soundness of the work.

The introduction and discussion needs to be a bit better about conveying the purpose and unique value proposition of the present study compared to past meta-analyses. For example, the authors cite some discrepancies in guidelines by ASA (LMWH/UFH within 1-4 days) and HSFC (LMWH after 2 days). But this study doesn’t help in this regard because looked at any patient who got LMWH within 4 days. Also, they cite the low general quality of evidence. But compared to prior meta-analyses looking at either LMWH or UFH (Chi et al – reference #30), how does an LMWH-focused meta-analysis raise the level of evidence?

Reviewer #2: The authors present a comprehensive systematic review and meta-analysis on a critical issue of LMWH use in patients with ICH for VTE prophylaxis. The analysis was performed using PRISMA standards, and its protocol was provisionally registered in a PROSPERO. The paper is clear and contains essential findings. It may be accepted after clarification of a few issues.

Abstract

-Please clarify the search strategy and inclusion criteria in the Methods section.

Methods section

Search strategy and screening criteria

-Please state what designs of the studies were eligible for, including (RCT and cohort).

-Please clarify the type of ICH in the inclusion criteria to distinguish it from posttraumatic and postoperational.

-Please clarify if any automatic tools were used to screen titles and abstracts and exclude duplications.

Quality evaluation

-Due to the presence of different approaches for interpretation of the NOS score, please clarify your own.

Endpoints

-Please clarify the definitions of all outcomes. What is the difference between hematoma expansion and rebleeding?

-According to the analysis of the risk of selection bias, I can suggest that GI bleeding and hematoma expansion/rebleeding were not considered primary outcomes. Please clarify and divide outcomes into primary and secondary. Please note that all primary outcomes need a separate analysis for publication bias, as you already performed for DVT, PE, and hematoma expansion/rebleeding.

Statistical analysis

-Do you mean p<0.01 for heterogeneity?

-Please clarify a threshold for I2 that represents heterogeneity.

-Please clarify whether under treatment type you mean surgery or not surgery.

-Please consider subgroup analysis for the LMWH initiation time, which is crucial for ICH.

-Also, it is interesting to look at the effect of LMWH in terms of different comparators (IPC alone, IPC + ESC, no prophylaxis).

Results

Study screening

-What do you mean by the use of heparin in the excluded studies? Unfractionated heparin? Please consider that you do not have such an exclusion criterion in the methods section.

Study outcomes

-You stated about the non-significant increase in GI bleeding; however, the forest plot favors LMWH. Please check this statement.

Discussion

-Please discuss the clinical relevance of your findings in the context of the lack of influence of LMWH on mortality.

Figure 1

Please design a flowchart in accordance with the PRISMA standard and describe what other sources were used to find 3 records (reference list of relevant papers? authors' archive?)

Supplementary

-Please check your query. Using #1 for Pubmed, I found 60280 results that significantly exceed the stated 13451.

**********

6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: Yes: Kirill Lobastov

**********

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

PLoS One. 2024 Oct 16;19(10):e0311858. doi: 10.1371/journal.pone.0311858.r002

Author response to Decision Letter 0

10 Aug 2024

Thank you for your letter and for your comments concerning our manuscript. Our respond to editor and reviewer comments are detailed in rebutter letter.

Attachment

Submitted filename: rebuttal letter.docx

pone.0311858.s022.docx (28.1KB, docx)

Decision Letter 1

Sonu Bhaskar

22 Sep 2024

PONE-D-24-20586R1Low-molecular-weight heparin in the prevention of venous thromboembolism among patients with acute intracerebral hemorrhage: A meta-analysisPLOS ONE

Dear Dr. Li,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Please submit your revised manuscript by Nov 06 2024 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

  • A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.

  • A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.

  • An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Sonu Bhaskar, MD PhD

Academic Editor

PLOS ONE

Journal Requirements:

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

Additional Editor Comments:

Thank you for submitting the revised version of your manuscript. While there have been improvements, there are still a few issues that need to be addressed before the manuscript can be considered further. I kindly invite you to respond to the reviewers' remaining queries and submit a revised version of your manuscript for further evaluation.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: (No Response)

Reviewer #3: (No Response)

Reviewer #4: (No Response)

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Partly

Reviewer #3: Yes

Reviewer #4: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #3: Yes

Reviewer #4: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #3: Yes

Reviewer #4: No

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #3: Yes

Reviewer #4: No

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: (No Response)

Reviewer #3: The Authors present the results of a meta-analysis related to a frequently encountered clinical problem: is it safe to use prophylactic LMWH for thrombosis prevention in spontaneous ICH? And how long after ICH should LMWH be started?

Comments to the Authors:

1. The meta-analysis inclusion criteria only states: studies reporting patients with ICH. It should be corrected to spontaneous ICH as other ICH types are listed in the exclusion criteria.

2. Hematoma expansion and rebleeding are basically the same. I would recommend using the term “hematoma progression” instead. Also correct in Table 1.

3. In the Results section: four studies were excluded due to heparin use. I’m guessing you mean unfractionated heparin. Also correct in Figure 1.

4. Please elaborate why did you include 11 studies with unspecified ICH if your primary focus was on spontaneous ICH.

5. The risk of GI bleeding was non-significantly lower in the LMWH group based on the reported numbers and Forest plot. Please correct in the Results section.

Reviewer #4: The authors conducted a meta-analysis to evaluate the effectiveness of low molecular weight heparin (LMWH) in on preventing venous thromboembolism (VTE) among ICH patients. While the authors should be commended for conducting a thorough analysis, it is my humble opinion that this manuscript will benefit immensely from copyediting to address the numerous grammatical errors and improve overall clarity.

The search strategy (the actual terms used to conduct the search) utilized by the authors is not clearly communicated. Moreover, the search strategy seems to miss ICH, which is the primary patient population for which this research was conducted. The authors only mentioned that ICH was added later in the manuscript. Given that a systematic review should be reproducible, it is advised that the authors employ the service of a librarian to improve their systematic search and make it more reproducible.

Given that the studies evaluating most of the adverse outcomes are few, it will be advisable to evaluate a composite outcome of any major bleeding.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #3: No

Reviewer #4: No

**********

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

PLoS One. 2024 Oct 16;19(10):e0311858. doi: 10.1371/journal.pone.0311858.r004

Author response to Decision Letter 1

24 Sep 2024

Thank you for your letter and for your comments. Those comments are all valuable and very helpful for revising and improving our paper, as well as the important guiding significance to our researches. We have studied comments carefully and have made correction which we hope meet with approval. We tried our best to improve the manuscript and made some changes in the manuscript. We appreciate for your warm work earnestly, and hope that the correction will meet with approval. Once again, thank you very much for your comments and suggestions. I appreciate your time and look forward to hearing from you soon.

Attachment

Submitted filename: rebuttal letter (Response to Reviewers).docx

pone.0311858.s023.docx (19.7KB, docx)

Decision Letter 2

Sonu Bhaskar

26 Sep 2024

Low-molecular-weight heparin in the prevention of venous thromboembolism among patients with acute intracerebral hemorrhage: A meta-analysis

PONE-D-24-20586R2

Dear Dr. Li,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice will be generated when your article is formally accepted. Please note, if your institution has a publishing partnership with PLOS and your article meets the relevant criteria, all or part of your publication costs will be covered. Please make sure your user information is up-to-date by logging into Editorial Manager at Editorial Manager® and clicking the ‘Update My Information' link at the top of the page. If you have any questions relating to publication charges, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Sonu Bhaskar, MD PhD

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Thank you for submitting the revised version of your manuscript. After careful review, I am pleased to inform you that it has been accepted in its current form.

Reviewers' comments:

Acceptance letter

Sonu Bhaskar

7 Oct 2024

PONE-D-24-20586R2

PLOS ONE

Dear Dr. Li,

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Associated Data

    This section collects any data citations, data availability statements, or supplementary materials included in this article.

    Supplementary Materials

    S1 Checklist. PRISMA 2020 checklist.

    (DOCX)

    pone.0311858.s001.docx (24.1KB, docx)
    S1 File. ALL studies identified in the literature search.

    (XLSX)

    pone.0311858.s002.xlsx (1MB, xlsx)
    S1 Table. Search details.

    (DOCX)

    pone.0311858.s003.docx (16KB, docx)
    S2 Table. List of articles included in the meta-analysis.

    (DOCX)

    pone.0311858.s004.docx (20.5KB, docx)
    S3 Table. Summary of outcomes in enrolled study.

    (DOCX)

    pone.0311858.s005.docx (21.9KB, docx)
    S4 Table. Quality assessment of randomized controlled trials.

    (DOCX)

    pone.0311858.s006.docx (18.2KB, docx)
    S1 Fig. Subgroup analysis stratified by study design: Effect of LMWH on DVT.

    (TIF)

    pone.0311858.s007.tif (1.8MB, tif)
    S2 Fig. Subgroup analysis stratified by ICH type: Effect of LMWH on DVT.

    (TIF)

    pone.0311858.s008.tif (2MB, tif)
    S3 Fig. Subgroup analysis stratified by ICH treatment type: Effect of LMWH on DVT.

    (TIF)

    pone.0311858.s009.tif (1.8MB, tif)
    S4 Fig. Subgroup analysis stratified by study design: Effect of LMWH on PE.

    (TIF)

    pone.0311858.s010.tif (1.4MB, tif)
    S5 Fig. Subgroup analysis stratified by ICH type: Effect of LMWH on PE.

    (TIF)

    pone.0311858.s011.tif (1.6MB, tif)
    S6 Fig. Subgroup analysis stratified by ICH treatment type: Effect of LMWH on PE.

    (TIF)

    pone.0311858.s012.tif (1.4MB, tif)
    S7 Fig. Subgroup analysis stratified by study design: Role of LMWH in hematoma progression.

    (TIF)

    pone.0311858.s013.tif (1.5MB, tif)
    S8 Fig. Subgroup analysis stratified by ICH type: Effect of LMWH on hematoma progression.

    (TIF)

    pone.0311858.s014.tif (1.7MB, tif)
    S9 Fig. Subgroup analysis stratified by ICH treatment type: Effect of LMWH on hematoma progression.

    (TIF)

    pone.0311858.s015.tif (1.5MB, tif)
    S10 Fig. Subgroup analysis stratified by study design: Effect of LMWH on gastrointestinal bleeding.

    (TIF)

    pone.0311858.s016.tif (961.3KB, tif)
    S11 Fig. Subgroup analysis stratified by ICH type: Effect of LMWH on gastrointestinal bleeding.

    (TIF)

    pone.0311858.s017.tif (1.1MB, tif)
    S12 Fig. Subgroup analysis stratified by ICH treatment type: Effect of LMWH on gastrointestinal bleeding.

    (TIF)

    pone.0311858.s018.tif (983.7KB, tif)
    S13 Fig. Subgroup analysis based on study design: Effect of LMWH on mortality.

    (TIF)

    pone.0311858.s019.tif (833KB, tif)
    S14 Fig. Subgroup analysis based on ICH type: Effect of LMWH on mortality.

    (TIF)

    pone.0311858.s020.tif (978.2KB, tif)
    S15 Fig. Subgroup analysis based on ICH treatment type: Effect of LMWH on mortality.

    (TIF)

    pone.0311858.s021.tif (828.2KB, tif)
    Attachment

    Submitted filename: rebuttal letter.docx

    pone.0311858.s022.docx (28.1KB, docx)
    Attachment

    Submitted filename: rebuttal letter (Response to Reviewers).docx

    pone.0311858.s023.docx (19.7KB, docx)

    Data Availability Statement

    All relevant data are within the manuscript and its Supporting information files. We confirm our submission contains all raw data required to replicate the results of our study.

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