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Brief Report

Altered coagulation profile of patients with high-grade glioma: clinical study with control group.

[version 1; peer review: 2 approved with reservations]
PUBLISHED 29 Aug 2024
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Abstract

Background

Activation of coagulation is a common phenomenon in patients with high-grade glioma, a primary malignant brain tumor.

Objective

Identify if there is an alteration in the coagulation profile in patients with high-grade glioma compared to other patients with benign brain tumors.

Methods

Sociodemographic and clinical characteristics, ECOG at admission, prothrombin time, activated partial thromboplastin time, international normalized ratio, platelet count, and blood panel results of 21 high-grade glioma patients (cases) and 42 meningioma patients (controls) from northern Peru were reviewed. Bivariate and multivariate analysis with logistic regression were performed to determine which factors are associated with glioma.

Results

Both groups had high proportions of high blood pressure (29%) and diabetes mellitus (14%). According to multivariate analysis, altered values for prothrombin time, platelet count, and ECOG score were associated with glioma (p=0.01). Furthermore, alterations in the blood panel were observed in both cases and controls but failed to reach statistical significance.

Conclusion

Patients with high-grade glioma seem to suffer more from hypercoagulable states than other patients with benign brain tumors, suggesting careful vigilance and anticoagulant treatment for these patients.

Keywords

blood coagulation, glioma, platelet count, prothrombin time, meningioma

Background

Gliomas are a class of primary brain tumors that arise from glial cells and generally have a poor prognosis.1 The malignancy of these tumors is classified into four grades, with grade four being the most malignant. High-grade gliomas (grades 3 and 4) are characterized by high mitotic activity, angiogenesis, as well as a predisposition to central necrosis, peripheral edema, rapid disease evolution, and mean survival between 12 and 17 months.13 Of these high-grade gliomas, the most common in adults are glioblastoma (grade 4), anaplastic astrocytoma, and anaplastic oligodendroglioma (both grade 3).4 The most common complication of high-grade gliomas is venous thromboembolism (VTE), with an incidence of approximately 30%.5

VTE is a common complication found in many cancers that can be triggered directly by the tumor, such as overexpression of tissue factor (TF), or indirectly through host secretion of cytokines or physical alteration of blood vessels.6,7 Approximately 50% of patients with glioblastoma have background activation of the coagulation system.8 From this information, it is likely that understanding the clotting profiles of presurgical patients would be helpful in informing treatment with anticoagulants or determining prognosis based on coagulation profile. However, the judicious use of anticoagulants is important to not increase the risk of spontaneous intracerebral hemorrhage.

Due to the aggressive nature of high-grade glioma and the risk of VTE, we set out to evaluate how the coagulation profile of these patients differs from other patients with brain cancer using a clinical study with a control group.

Methods

Study design

This is an observational, descriptive, clinical study with a control group of a convenience sample of medical records.

Sample size

Medical records of both sexes were included if they were over 18 years old and diagnosed with high-grade glioma or meningioma and treated in the Virgen de la Puerta High Complexity Hospital Oncology Service (La Esperanza, Trujillo, Peru) between 2019 and 2023. Patients with an incomplete or absent anatomopathological study, and those with autoimmune or viral diseases, a history of coagulation disorders or diseases that affect blood circulation, brain metastases, or other primary tumors as well as patients receiving treatment with anticoagulant medications, were excluded from the study.

Data collection

The medical records were reviewed to evaluate the presurgical hematological results of both controls and cases. These included hemogram (leukocytes, neutrophiles, band neutrophiles, lymphocytes, monocytes, eosinophiles, basophiles, red blood cell count, hemoglobin, and hematocrit) as well as coagulation profile (prothrombin time (PT), activated partial thromboplastin time (aPTT), international normalized ratio (INR), and platelet count (PC)). Each blood parameter was recorded as normal or abnormal.9 Additional sociodemographic and clinical characteristics were also recorded: age, sex, address, Eastern Cooperative Oncology Group (ECOG) performance status upon admission, and whether the patient had diabetes and/or high blood pressure.

Data analysis

IBM SPSS V26.0 statistical software (https://www.ibm.com/es-es/products/spss-statistics) was used for data processing. An open-source alternative to this program is PSPP (https://www.gnu.org/software/pspp/). Qualitative variables were expressed in proportions and percentages of patients. Bivariate analysis was performed to determine the relationship of the variables. The crude odds ratio (ORc) and the adjusted odds ratio (ORa) were calculated with a 95% confidence interval (CI) for each variable in its association with the presence of high-grade glioma. Those variables that showed a significant association (p < 0.05) were subjected to multivariate analysis with logistic regression.

Ethical considerations

This study was reviewed and approved by the Research Bioethics Committee of Universidad Privada Antenor Orrego (Resolution N°0563-2023-UPAO), approval date 3rd August 2023. This study complied with the 2016 Council for International Organizations of Medical Sciences (CIOMS) guidelines. Given that this study was a review of medical records routinely collected during treatment, ensured patient privacy, and did not influence treatment trajectory, the requirement for informed consent was waived by ethical approval committee. Information that personally identifies patients was eliminated from the data presented here and underlying data to protect anonymity.

Results

The sample consisted of 21 patients with high-grade glioma (cases) and 42 patients with meningiomas (controls) that met acceptance criteria. Patients with meningiomas were chosen as the control group as these tumors are benign, allowing for a close comparison of patients that had similar conditions – with the only difference being malignancy. All patients came from the Peruvian regions of La Libertad, Ancash, and Cajamarca. The demographic characteristics of both groups are summarized in Table 1. Ages were similar, but the gender ratio was reversed between cases and controls. ECOG scores were also distributed differently between cases and controls. Furthermore, both groups had high proportions of diabetes (14%) and high blood pressure (29%).

Table 1. Sociodemographic and clinical parameters of cases (high-grade glioma) and controls (meningioma).

CharacteristicsTumor type
Cases: High-grade glioma (n = 21)Controls: Meningioma (n = 42)
Age, y53.91 (±14.45)56.64 (±12.44)
Male (%)12 (57.1%)17 (40.5%)
Comorbidities
Diabetes6 (28.6%)3 (7.1%)
High Blood Pressure7 (33.3%)11 (26.2%)
ECOG
ECOG 16 (28.6%)36 (85.7%)
ECOG 213 (61.9%)6 (14.3%)
ECOG 32 (9.5%)0 (0.0%)

Table 2 records the proportions of cases and controls with presurgical abnormal blood count and coagulation results. High proportions of abnormal results were found for aPTT, INR, lymphocytes, and neutrophiles.

Table 2. Blood panel results of cases and controls, presenting the number and proportion of abnormal results.

Blood parameter (abnormal)Tumor type
Cases: High-grade glioma (n = 21)Controls: Meningioma (n = 42)
PT3 (14.3%)0 (0.0%)
aPTT16 (76.2%)32 (76.2%)
INR9 (42.9%)9 (21.4%)
PC4 (19.0%)0 (0.0%)
Leukocytes5 (23.8%)3 (7.1%)
Neutrophiles13 (61.9%)10 (23.8%)
Lymphocytes17 (81.0%)15 (35.7%)
Eosinophiles1 (4.8%)4 (9.5%)
Basophiles0 (0.0%)1 (2.4%)
Erythrocytes5 (23.8%)11 (26.2%)
Hemoglobin7 (33.3%)16 (38.1%)
Hematocrit7 (33.3%)14 (33.3%)
Band neutrophiles0 (0.0%)0 (0.0%)
Monocytes0 (0.0%)0 (0.0%)

Multivariate analysis showed that PT (aOR = 1.45; 95% CI = 1.13 – 2.28; p = 0.01), PC (aOR = 1.43; 95% CI = 1.06 – 2.25; p = 0.01) and ECOG 2 or 3 (aOR = 14.78; 95% CI = 3.71 – 58.86; p = 0.01) were associated with said high-grade glioma (Table 3). Other components of the blood profile did not show significant differences between groups.

Table 3. Bivariate and multivariate analysis of variables associated with the presence of high-grade glioma.

FactorBivariate AnalysisMultivariate Analysis
ORcCI 95%pORaCI 95%p
LowHighLowHigh
Age (≥ 60 y vs. < 60 y)0.910.322.610.860.820.272.470.94
Sex1.960.685.670.211.650.584.650.49
Diabetes5.201.1523.500.026.470.8549.200.21
High blood pressure1.410.454.400.550.540.122.570.69
ECOG (2 or 3 vs. 1)15.004.1654.050.0114.783.7158.860.01
PT3.332.274.910.011.451.132.280.01
aPTT1.000.293.421.000.890.243.230.87
INR2.750.888.560.081.290.354.710.97
PC3.472.325.180.011.431.062.250.01
Leukocytes4.060.8719.050.064.640.6732.280.31
Neutrophiles5.201.6816.120.011.040.224.940.74
Lymphocytes7.652.1726.940.013.730.7319.030.23
Eosinophiles0.480.054.540.510.890.0612.550.60
Erythrocytes0.880.262.980.840.810.193.450.94
Hemoglobin0.810.272.440.710.730.312.750.83
Hematocrit1.000.333.041.000.920.212.860.72

Discussion

We observe that PT was shortened in the cases compared to the controls. This result is consistent with two published studies using 58 cases and 22 meningioma controls8 and 172 cases and 47 healthy controls.10 The PT test evaluates the extrinsic coagulation pathway, which is initiated at the site of injury in response to the release of TF, which is often overexpressed in tumor cells. These results suggest that high-grade glioma is more likely to overexpress TF than other related cancers.8 Another parameter calculated from PT that evaluates the extrinsic coagulation pathway is INR. The difference in INR between cases and controls came close to (p=0.08), but did not reach statistical significance. This difference is likely a result of the use of different cutoff values for normal values, as INR is a ratio with PT in the numerator and a control PT in the denominator. Because PT was significantly shortened, INR also decreased, and another study comparing patients with healthy controls also found a statistically significant difference in these parameters,11 it would be reasonable to affirm that glioma patients have a more altered extrinsic clotting pathway compared to other patients with benign brain tumors and even more so when considering healthy controls.

Another parameter that was significantly associated with high-grade glioma was PC – no members of the control group had abnormal PC, while 4 patients in the case group had abnormal PC (Tables 2 and 3). Furthermore, cases of thrombocytosis and thrombocytopenia were observed in the case group. This result differs from previous investigations8,10 in which no statistically significant differences were found in PC between cases and controls were found (p>0.05). Small study size as well as differences in the timing of blood sample collection may explain the differences in these results with other studies.

The aPTT test is mainly used to evaluate the intrinsic coagulation pathway. In this study, no statistical significance was found between aPTT and the presence of glioma, with proportions of altered aPTT equal between cases and controls (Tables 2 and 3). This result differs from the findings of a study in which aPTT was shown to be significantly reduced in glioma cases, suggesting a hypercoagulable state.8

Blood count can be used to assess general condition, detect disease-related complications, and, in some cases, predict survival in patients with high-grade glioma. In this study, alterations were observed in leukocytes, erythrocytes, hemoglobin, and hematocrit; however, no significant association with high-grade glioma was found in the multivariate analysis (Table 3). Navone et al. observed a significant increase in leukocyte count in glioblastoma patients compared to meningioma patients (p < 0.001), while hemoglobin did not show significant differences between the two study groups.8 On the other hand, Kim et al. assessed the clinical importance of lymphopenia in patients with glioblastoma and reported that 42.0% (92 patients) showed decreased levels of lymphocytes, concluding that lymphopenia is a frequent event during progression and disease treatment.12 In turn, Serban et al., when studying the preoperative immunoinflammatory status of patients with glioblastoma, found elevated leukocyte counts, suggesting that this could predict reduced overall survival.13

Finally, multivariate analysis also identified that a preoperative ECOG score of 2 or 3 was significantly associated with high-grade glioma. However, no studies have been found to determine whether the ECOG value is related to glioma, so more research would be needed to determine the relationship between the two. However, in cancer patients, an ECOG 3-4 is associated with a higher risk of in-hospital mortality.14,15

This study presented certain limitations, such as limited sample size and scope since patients were not subjected to additional tests. Furthermore, it was not determined when the parameters of the coagulation profile were altered, so the study could not determine when a blood analysis would produce meaningful results.

Conclusions

Taken together, it appears that high-grade glioma patients have hypercoagulability to a greater degree than patients with benign brain tumors and are more likely to be diagnosed when the disease interferes more strongly with their self-care and work activities. This suggests a more careful treatment of coagulation among these patients.

CrediT author statement

NJQP: Investigation, Writing – Original Draft

APGR: Supervision, Project administration

LJFR: Conceptualization, Writing – Review & Editing

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Version 2
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Quispe-Pastor NJ, Gorritti-Rubio AP and Fernández-Rodríguez LJ. Altered coagulation profile of patients with high-grade glioma: clinical study with control group. [version 1; peer review: 2 approved with reservations]. F1000Research 2024, 13:980 (https://doi.org/10.12688/f1000research.154700.1)
NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article.
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Key to Reviewer Statuses VIEW
ApprovedThe paper is scientifically sound in its current form and only minor, if any, improvements are suggested
Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.
Not approvedFundamental flaws in the paper seriously undermine the findings and conclusions
Version 1
VERSION 1
PUBLISHED 29 Aug 2024
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Reviewer Report 24 Sep 2024
Joab Chapman, Department of Neurology and Neurosurgery, Tel Aviv University, Tel-Aviv, Israel 
Approved with Reservations
VIEWS 9
This is a solid addition to the data associating high grade glioma with systemic coagulation changes.

Major comments
Introduction: Secretion of thrombin and other active coagulation factors by gliomas is well known and excess thrombin may ... Continue reading
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CITE
HOW TO CITE THIS REPORT
Chapman J. Reviewer Report For: Altered coagulation profile of patients with high-grade glioma: clinical study with control group. [version 1; peer review: 2 approved with reservations]. F1000Research 2024, 13:980 (https://doi.org/10.5256/f1000research.169759.r324060)
NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article.
  • Author Response 31 Oct 2024
    Lissett Fernández, Medical School, Universidad Privada Antenor Orrego, Trujillo, 13008, Peru
    31 Oct 2024
    Author Response
    Thank you for this review. I have replied to your comments and explained the changes to the article in a point-by-point manner. The comments are preceded by “>>”


    ... Continue reading
COMMENTS ON THIS REPORT
  • Author Response 31 Oct 2024
    Lissett Fernández, Medical School, Universidad Privada Antenor Orrego, Trujillo, 13008, Peru
    31 Oct 2024
    Author Response
    Thank you for this review. I have replied to your comments and explained the changes to the article in a point-by-point manner. The comments are preceded by “>>”


    ... Continue reading
Views
15
Cite
Reviewer Report 16 Sep 2024
Darko Orešković, Department of Neurosurgery, Clinical Hospital Dubrava, Zagreb, Croatia 
Approved with Reservations
VIEWS 15
This is an important and currently overlooked issue in treating neuro-oncological patients and I applaud the authors for their work writing this brief report. 

Their objective is clear and their methods are sound. Also, the discussion is ... Continue reading
CITE
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HOW TO CITE THIS REPORT
Orešković D. Reviewer Report For: Altered coagulation profile of patients with high-grade glioma: clinical study with control group. [version 1; peer review: 2 approved with reservations]. F1000Research 2024, 13:980 (https://doi.org/10.5256/f1000research.169759.r320124)
NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article.
  • Author Response 31 Oct 2024
    Lissett Fernández, Medical School, Universidad Privada Antenor Orrego, Trujillo, 13008, Peru
    31 Oct 2024
    Author Response
    Thank you for this review. I have replied to your comments and explained the changes to the article in a point-by-point manner. The comments are preceded by “>>”


    ... Continue reading
COMMENTS ON THIS REPORT
  • Author Response 31 Oct 2024
    Lissett Fernández, Medical School, Universidad Privada Antenor Orrego, Trujillo, 13008, Peru
    31 Oct 2024
    Author Response
    Thank you for this review. I have replied to your comments and explained the changes to the article in a point-by-point manner. The comments are preceded by “>>”


    ... Continue reading

Comments on this article Comments (0)

Version 2
VERSION 2 PUBLISHED 29 Aug 2024
Comment
Alongside their report, reviewers assign a status to the article:
Approved - the paper is scientifically sound in its current form and only minor, if any, improvements are suggested
Approved with reservations - A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.
Not approved - fundamental flaws in the paper seriously undermine the findings and conclusions
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