Endoscopic intervention in hematologic malignancy patients with severe thrombocytopenia: Methodological concerns, clinical implications, and future research directions

Abstract

Gastrointestinal bleeding (GIB) presents a significant challenge for patients with hematologic malignancies, especially those with severe thrombocytopenia. Although endoscopic intervention is frequently used in managing GIB, its safety and effectiveness in this high-risk group remain unclear. A recent study by Alhumayyd et al provided insight into this issue. However, it has notable limitations, including its retrospective nature, small sample size, and failure to adjust for important confounding factors such as disease severity, hemodynamic status, and platelet function. The study’s findings indicated that urgent endoscopy may help decrease the incidence of recurrent bleeding; however, it did not show a clear benefit in terms of mortality. Future research ought to prioritize prospective, multicenter studies that employ standardized protocols and incorporate risk stratification models to better understand the impact of endoscopic treatment for GIB in these patients. Additionally, integrating platelet function assays could improve clinical decision-making. Addressing these research gaps is essential for improving patient outcomes and developing effective guidelines for managing GIB in individuals with thrombocytopenia.

Key Words: Gastrointestinal bleeding; Thrombocytopenia; Hematologic malignancies; Endoscopic intervention; Clinical outcomes; Hemostatic management

Core Tip: Endoscopic intervention for gastrointestinal bleeding in patients with severe thrombocytopenia is debated due to the lack of standardized platelet thresholds and procedural risks. A recent study by Alhumayyd et al highlighted these challenges but was limited by small sample sizes, retrospective design, and inadequate adjustment for confounders. Key factors like hemodynamic stability, hematologic malignancy severity, and platelet function assessments were insufficiently addressed. Variations in endoscopic timing and hemostasis techniques further complicate results. Prospective, multicenter studies incorporating platelet function assays and standardized protocols are essential to improve gastrointestinal bleeding management in thrombocytopenic patients.

TO THE EDITOR

Patients with hematologic malignancies often present with complex hematological challenges, including anemia and thrombocytopenia, which significantly increase the risk of bleeding during endoscopic interventions. Gastrointestinal bleeding (GIB) is a significant cause of morbidity and mortality in patients with hematologic malignancies, particularly those with severe thrombocytopenia[1]. Thrombocytopenia, commonly worsened by the underlying malignancy or the effects of cytotoxic therapies, significantly increases the risk of spontaneous and severe bleeding[2]. Endoscopy is critical in managing GIB; however, its use in patients with thrombocytopenia remains controversial[3]. This is mainly due to the increased risk of procedural complications and the absence of established guidelines regarding optimal platelet count thresholds for safe endoscopic interventions. The decision to proceed with endoscopy in these patients must carefully consider the platelet count, coagulation status, and overall hemodynamic stability.

Despite the high prevalence of GIB in this population, there is a paucity of robust data on the safety and efficacy of endoscopic interventions in severely thrombocytopenic patients. Current practices are predominantly guided by expert opinions, with a commonly suggested platelet threshold of greater than 50 × 10⁹/L for considering endoscopic intervention[4]. However, this guideline is not universally applicable as a threshold for endoscopic procedures, particularly in patients with underlying platelet dysfunction or those receiving anticoagulant or antiplatelet therapies. Therefore, a comprehensive assessment of hematological parameters, including platelet function assays, is essential to minimize procedural risks and optimize outcomes. In addition, the clinical implications of endoscopy for these high-risk patients, particularly concerning mortality rates, recurrent bleeding, and the need for blood transfusions, remain poorly understood.

The recent study by Alhumayyd et al[5] attempts to address this knowledge gap by examining the outcomes of endoscopic intervention compared to conservative management in patients with hematologic malignancies and severe thrombocytopenia (platelet count ≤ 50 × 10⁹/L). While the study findings provide valuable insights, it is important to consider some study limitations. Additionally, we would like to propose recommendations for future research to improve understanding and patient care.

METHODOLOGICAL CONSTRAINTS

When evaluating the results of a single-center study, it is important to recognize its inherent limitations. The retrospective design and focus on a single center restrict the ability to generalize the findings to a broader population[6]. Retrospective studies often face challenges such as selection bias, and the dependence on electronic health records can result in incomplete or inconsistent data collection. Furthermore, a single-center approach may not adequately represent the diversity of clinical practices and patient demographics in various healthcare settings. As a result, such studies’ conclusions may not apply to broader populations or different clinical scenarios. It is recommended that studies utilize a prospective, multicenter design to improve the external validity of future research. Such studies would improve the external validity of findings and provide more robust evidence to guide clinical practice. Additionally, implementing standardized data collection protocols will help reduce bias and ensure a thorough and accurate data capture.

The study involved 76 patients, constituting a relatively small sample size, especially when conducting subgroup analyses. This modest sample size may have limited the statistical power required to identify significant differences in key outcomes such as mortality rates, transfusion requirements, and instances of recurrent bleeding. Therefore, larger studies with sufficient power are essential to validate the findings and investigate potential differences among subgroups[7]. Additionally, power calculations should be performed in advance to determine the required sample size for detecting clinically meaningful differences and to improve the statistical robustness of the results[8].

Endoscopic procedures can be classified into three categories based on the potential risk of hemorrhagic complications: Low, moderate, and high risk. Low-risk procedures, such as diagnostic endoscopy, can generally be performed safely in patients with thrombocytopenia, as they pose a minimal risk of significant bleeding. In contrast, high-risk procedures such as therapeutic interventions involving tissue resection or hemostatic measures necessitate carefully evaluating the patient’s platelet count and function. Platelet transfusions are frequently employed to reduce the risk of bleeding in these higher-risk scenarios; however, the optimal timing and dosage for these transfusions are still not well-defined. Future research is needed to investigate the efficacy of prophylactic platelet transfusions in various procedural settings and the advantages of newer hemostatic agents that could help decrease the dependency on transfusions.

When assessing preprocedural prophylaxis in patients with thrombocytopenia, a nuanced approach is important, as relying solely on platelet count may not adequately reflect the bleeding risk. Guidelines have proposed a platelet count threshold of ≥ 50000/μL for endoscopic procedures[5]; however, recent recommendations indicate that many procedures can be conducted safely, even at lower platelet counts[5]. Current evidence highlights that specific interventions may be feasible with diminished platelet counts, provided other hemostatic factors, such as platelet function and coagulation status, are meticulously evaluated. This approach necessitates thoroughly considering the patient’s overall clinical condition, including the severity of thrombocytopenia, the potential for platelet dysfunction, and the specific endoscopic procedure being performed. The absence of standardized protocols for preprocedural prophylaxis is a significant challenge, emphasizing the importance of individualized risk assessments and collaborative decision-making among healthcare professionals.

To improve patient safety, platelet function assessments, primarily through techniques like thromboelastography, offer a more thorough evaluation of hemostatic competence in individuals with hematologic malignancies. These patients often show alterations in platelet functionality due to either the disease itself or the effects of cytotoxic treatments, which are not accurately captured by platelet count alone. Thromboelastography provides real-time information about platelet performance and clot stability, which is crucial in making informed decisions regarding the timing and safety of endoscopic interventions. Moreover, it is vital to consider how hematological malignancies affect other facets of hemostasis, including coagulation and fibrinolysis, as these factors can further modify the bleeding risk and procedure outcomes. Future research should focus on establishing evidence-based thresholds encompassing these variables, potentially integrating platelet function assessments and additional hemostatic parameters to improve decision-making processes.

UNADDRESSED CONFOUNDERS

The study has certain limitations that may impact the interpretation of its outcomes. Notably, it did not account for various potential confounders that could affect results, including the severity of the underlying hematologic malignancy, concomitant comorbidities, hemodynamic stability, and the use of anticoagulant or antiplatelet medications[9]. Although the study stratified patients by platelet count, it overlooked the assessment of platelet function, an essential factor in determining bleeding risk. Furthermore, the role of platelet transfusions in determining procedure outcomes was not adequately explored. Additionally, the classification of endoscopy as “urgent” (within 24 hours) vs “non-urgent” (beyond 24 hours) did not take into account the timing of the initial bleeding onset or the clinical severity of the situation[10]. The decision-making process for endoscopic procedures appeared to be influenced more by physician preference than established criteria, introducing the potential for bias in treatment allocation. Lastly, variations in clinical decision-making were not considered, including the thresholds for transfusion and stabilization efforts prior to endoscopy, which could influence patient outcomes[11]. Future research should prioritize using multivariable regression analyses or propensity score-matching to adjust for potential confounders that may impact study outcomes. To draw more accurate conclusions, it is essential to explicitly evaluate the effects of platelet transfusions and other hemostatic interventions.

Additionally, integrating thromboelastography or platelet function assays could enhance patient stratification, allowing for more tailored treatment approaches. In addition, these methods would offer a more comprehensive assessment of hemostatic competence, enabling better risk stratification and tailored treatment approaches. Future studies should incorporate these tools to provide more accurate insights into the safety and efficacy of endoscopic interventions in thrombocytopenic patients. On the other hand, validated scoring systems, such as the Rockall or Glasgow-Blatchford scores, would improve risk stratification in clinical settings[12]. Furthermore, developing standardized protocols for determining the necessity of endoscopic interventions is crucial for minimizing subjective biases. Lastly, future analyses should include a comprehensive assessment of pre-endoscopic interventions to ensure a thorough evaluation of patient outcomes.

CHALLENGES IN DATA INTERPRETATION: ADDRESSING BIAS AND STATISTICAL LIMITATIONS

This study’s statistical analysis was restricted to descriptive statistics and univariate comparisons. Since multivariate analysis was not performed, this limitation hinders the evaluation of the independent effect of endoscopy on patient outcomes. Additionally, the research did not investigate potential interactions between critical variables, including the timing of endoscopy and platelet counts. The study did not address several potential sources of bias, such as selection bias, information bias, and confounding by indication. For instance, patients experiencing more severe bleeding or hemodynamic instability may have been more likely to receive endoscopy, which could have influenced the study’s findings.

Furthermore, the authors did not consider the risk of type II error, particularly given the small sample size[13]. Advanced statistical techniques, such as multivariate regression or propensity score matching, would improve the analysis[14]. These methods could help control for confounding variables and better assess the independent impact of endoscopy[14]. Including interaction terms could further clarify potential effect modifiers. Lastly, sensitivity analyses would be required to evaluate the robustness of the findings, considering these potential biases. It is important for the study to explicitly acknowledge its limitations concerning bias and the possibility of type II error. Additionally, the small sample size increases the risk of type II error, highlighting the need for larger, adequately powered studies to validate these findings.

The study indicated that while there was no significant mortality benefit associated with endoscopy, the lack of statistical significance does not necessarily mean that the findings lack clinical importance. It suggests that urgent endoscopy may help reduce the rate of recurrent bleeding within 30 days; however, this observation does not account for differences in bleeding severity or the types of interventions used. Larger studies using rigorous statistical methodologies are important to verify these findings. Future research should also focus on distinguishing between various sources of bleeding and different treatment options to provide more precise insights into these findings.

CHALLENGES IN ENDOSCOPIC TIMING AND STANDARDIZATION: IMPLICATIONS FOR RECURRENT BLEEDING

The authors examined the effects of urgent endoscopy performed within 24 hours on patients experiencing bleeding. The findings indicated that such timely interventions were associated with a lower rate of recurrent bleeding; however, the timing of endoscopy did not significantly influence mortality or other clinical outcomes. Notably, the study did not investigate how clinical factors, including the severity of bleeding or patients’ hemodynamic stability, might affect the timing of endoscopy. Additionally, the study lacked detailed information regarding the standardization of endoscopic interventions, particularly in using various hemostatic techniques, such as thermal coagulation and mechanical clipping[15,16]. The variability in these interventions may have impacted the study’s outcomes.

Future research should investigate the relationship between endoscopy timing and clinical outcomes to improve understanding. Assessing how factors like hemodynamic stability and bleeding severity influence the necessity for urgent endoscopy is important. Furthermore, standardization of endoscopic techniques and comprehensive documentation of the methods employed will be essential to evaluate the effects of different hemostatic approaches on patient outcomes[17].

KEY INSIGHTS AND THEIR ROLE IN CLINICAL MANAGEMENT

The discussion highlighted a notable lack of evidence supporting the benefit of endoscopy in reducing mortality rates. However, it did not thoroughly examine the potential factors that could explain this finding. For instance, the study did not consider whether the underlying hematologic malignancy or the severity of thrombocytopenia might have influenced the outcomes apart from the effects of endoscopic intervention. Furthermore, the role of platelet function assays, such as thromboelastography, in informing endoscopic decision-making is not addressed. An in-depth analysis of the mechanisms contributing to the observed outcomes would provide a more comprehensive understanding. Future research should explore the role of platelet function assays in evaluating the safety and effectiveness of endoscopic procedures for patients with thrombocytopenia.

FUTURE DIRECTIONS

Future research initiatives should prioritize conducting prospective, multicenter studies to validate the current study’s findings. These investigations ought to involve larger and more diverse patient populations to improve the generalizability of the results and increase statistical power. Additionally, the potential of platelet function assays, such as thromboelastography, in influencing endoscopic decision-making warrants further exploration. These assays may offer a more precise evaluation of hemostatic function and assist in identifying patients who are suitable candidates for endoscopic procedures. Moreover, studies implementing standardized protocols for endoscopic interventions, including adopting specific hemostatic techniques, are needed. Establishing such protocols will help determine the most effective and safe methods for managing GIB in patients with thrombocytopenia.

Furthermore, it is essential to investigate the role of platelet transfusions in improving outcomes for thrombocytopenic patients undergoing endoscopic procedures[18]. Research should focus on evaluating the optimal timing and dosage of platelet transfusions to reduce the risk of bleeding. Long-term outcome studies should also be conducted to assess quality of life, recurrent bleeding, and mortality rates in patients with hematologic malignancies experiencing GIB. Understanding these outcomes will provide a more comprehensive view of the effects of endoscopic interventions in this population. Finally, developing risk stratification models is vital for identifying patients most likely to benefit from endoscopic interventions. Such models could integrate clinical, laboratory, and endoscopic findings to report decision-making processes effectively.

Future research should focus on several critical questions to enhance our understanding of endoscopic procedures for patients with low platelet counts. First, it is essential to determine the optimal platelet transfusion thresholds tailored to various endoscopic procedures, distinguishing between diagnostic and therapeutic interventions. Second, the effectiveness of newer hemostatic agents, including fibrin sealants and hemostatic powders, in minimizing bleeding risks for thrombocytopenic patients warrants investigation. Lastly, there is a need to explore how platelet function assays, such as thromboelastography, can be effectively incorporated into clinical decision-making processes to enhance procedural safety. Addressing these issues will lead to a deeper comprehension of the risks and benefits associated with endoscopic procedures in this vulnerable patient population.

CONCLUSION

The study by Alhumayyd et al[5] offered valuable insights into using endoscopy to manage GIB in patients with hematologic malignancies and severe thrombocytopenia. However, the study’s design, sample size, statistical analysis, and failure to account for certain confounding factors present notable limitations. Further research is necessary to understand better how to manage GIB in this high-risk population. Future studies should be prospective and multicenter, utilizing standardized protocols and advanced statistical techniques to provide more comprehensive findings.