Blood transfusion in gastric cancer surgery: Necessary support or risk

Abstract

We discuss the study by Chen et al published in World Journal of Gastroenterology that examined the relationship between perioperative blood transfusion and outcomes after radical gastrectomy. Transfusion is often unavoidable in gastric cancer (GC) surgery due to preoperative anemia and substantial blood loss during the procedure. However, its role may extend beyond merely restoring hemoglobin levels and stabilizing the patient. Allogeneic blood transfusion influences immune and inflammatory responses, affecting postoperative recovery and long-term oncologic outcomes. Although perioperative blood transfusion has been associated with higher complication rates and worse overall and disease-free survival, it remains uncertain whether this reflects a direct causal effect. These considerations highlight the importance of balanced transfusion practices and the implementation of patient blood management strategies to optimize short-term safety and long-term prognosis in GC surgery.

Key Words: Blood transfusion; Transfusion-related immunomodulation; Patient blood management; Gastric cancer

Core Tip: Anemia is common among patients with gastric cancer. Early identification and optimization of anemia in the preoperative period are essential to improve surgical safety and long-term outcomes. When transfusion is considered for anemia correction, clinicians should carefully balance the immediate hemodynamic benefits against its adverse effects on inflammation, immune modulation, and survival. The implementation of patient blood management strategies throughout the preoperative and intraoperative phases offers an evidence-based approach to minimize transfusion requirements and enhance both perioperative and oncologic outcomes.

This editorial refers to “Influence of blood transfusion on postoperative inflammation, stress markers, and prognosis in patients with gastric cancer” by Chen et al, 2025; https://doi.org/10.3748/wjg.v31.i39.110751.

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INTRODUCTION

In a study published in World Journal of Gastroenterology, Chen et al[1] examined the relationship between perioperative blood transfusion and outcomes after radical gastrectomy for gastric cancer (GC). Their study draws attention to an important, yet often uncomfortable, question: Although transfusion can be life-saving during major oncologic surgery, does it affect long-term prognosis?

GC remains a leading cause of cancer-related deaths worldwide[2]. Despite advances in systemic therapies, radical gastrectomy with lymphadenectomy remains the only curative option[3]. However, this complex procedure is often associated with substantial blood loss, and many patients have preoperative anemia. Thus, perioperative transfusion is common and sometimes unavoidable in this population. In addition, postoperative recurrence is common and remains devastating even after complete resection[4]. This reality has shifted attention beyond surgical technique and systemic therapies toward modifiable perioperative factors that may influence long-term outcomes. Of these, allogeneic blood transfusion has become a concern.

Blood transfusion is often essential for maintaining hemodynamic stability and adequate oxygen delivery. It remains a common, life-saving treatment for cancer patients experiencing anemia or blood loss[5]. However, questions remain about its potential association with postoperative complications and survival. Blood transfusion has an adverse impact on overall, disease-free, and disease-specific survival in patients with GC[6-9]. Increasing pressure on global blood supplies and growing awareness of transfusion-related risks have strengthened calls for more restrictive transfusion strategies and the wider implementation of patient blood management programs[6,10-13].

ANEMIA, SURGICAL BLOOD LOSS, AND TRANSFUSION IN GC

Patients with GC are predisposed to preoperative anemia and perioperative blood loss[14]. The combination of preexisting anemia and significant surgical bleeding leads to high rates of blood transfusion during surgery in this population. In clinical practice, transfusions are often administered to maintain circulatory stability and ensure adequate oxygen delivery during major resections. Thus, transfusions are not uncommon during GC surgery and are sometimes expected as part of the patient’s perioperative care.

GC often causes chronic anemia through several mechanisms, including occult gastrointestinal bleeding from the tumor, impaired iron metabolism, nutritional deficiencies resulting from early satiety and malabsorption, and systemic inflammation associated with malignancy[15]. Nearly half of these patients undergo surgery with preexisting anemia[16].

This vulnerability is further compounded by the physiological demands of radical gastrectomy, which is an abdominal procedure often associated with significant blood loss during surgery[17]. While blood loss of 300-400 mL is common in less complex cases, blood loss of 1000 mL or more is not uncommon in more complex or hemorrhagic surgeries[18]. In addition to blood loss, the surgical stress response alters oxygen metabolism and increases the need for oxygen. During oncologic procedures, maintaining adequate tissue oxygenation and hemodynamic stability becomes a central anesthetic and surgical priority. From a physiological perspective, correcting significant anemia may be justified for certain patients.

However, although perioperative blood transfusion addresses immediate hemodynamic and oxygen delivery concerns, its frequent use has sparked discussions about its potential impact on long-term oncologic outcomes[19]. Importantly, in this setting, transfusion may function less as an independent causal factor and more as a marker of an advanced disease stage, greater surgical complexity, or increased blood loss during surgery. In other words, it is unclear whether transfusions contribute to a poorer prognosis or if they are administered preferentially to patients whose outcomes are already determined by the severity of their underlying condition.

This distinction is clinically relevant. Although transfusion thresholds are guided by international recommendations and patient blood management strategies, real-time intraoperative decisions are often made under conditions of physiological instability and limited certainty[20,21]. In such circumstances, the decision to transfuse is often made under considerable clinical pressure. Understandably, immediate physiological stability takes priority. This tendency is often a pragmatic response to acute risk rather than indifference to long-term outcomes. Thus, each transfusion decision requires careful individualization. This involves balancing the short-term physiological necessity against the complexity of interpreting its potential relationship with long-term outcomes.

TRANSFUSION-RELATED ADVERSE EFFECTS AND OUTCOMES

For decades, the primary concern surrounding allogeneic blood transfusion was the risk of transmitting infections, such as human immunodeficiency virus and other blood-borne diseases. Other potential consequences received comparatively little attention. Therefore, it was considered a safe and necessary component of perioperative management[22]. This traditional view has been substantially revised in light of mounting evidence suggesting an association between perioperative transfusion and adverse postoperative outcomes in oncologic surgery[23]. This association extends beyond the typical complications of transfusion, such as anaphylactoid reactions, infection, and acute hemolytic events. The literature describes links between transfusion and unfavorable oncologic outcomes, including higher rates of tumor recurrence, reduced disease-free and overall survival rates, increased postoperative infectious complications, and higher mortality rates[9,23-25]. However, most of the data are derived from retrospective or observational analyses. Therefore, residual confounding factors, indication bias, and reverse causality cannot be ruled out.

Growing evidence in oncology suggests that allogeneic blood is biologically active. Blood transfusion has been linked to changes in immune function and the activation of inflammatory responses. It also facilitates the transfer of biologically active substances that accumulate during storage. These changes influence immune surveillance and affect tumor behavior[26].

Importantly, intraoperative blood loss may exert comparable biological effects. Excessive bleeding can lead to antitumor immunosuppression by depleting plasma constituents that regulate the immune system. Clinical observations suggest that hematogenous recurrence, which has been linked to impaired immune competence, occurs more often in patients who experience substantial blood loss during surgery. Furthermore, significant bleeding increases patients’ risk of postoperative complications by creating a proinflammatory environment involving local and systemic tissue injury. Such inflammatory responses worsen immunosuppression and negatively impact long-term oncologic outcomes[22].

Despite these mechanistic insights, the available prospective evidence for GC is insufficient to determine whether the observed biological changes and differences in survival stem from transfusion or from the severity of blood loss and surgical stress[26]. Differentiating these overlapping mechanisms is methodologically challenging. From a clinical perspective, however, what matters is their potential impact on postoperative survival and cancer-related outcomes. Chen et al[1], in their retrospective analysis, highlighted this unresolved complexity and emphasized the need for well-designed prospective studies that can distinguish association from causation.

TRANSFUSION-RELATED IMMUNOMODULATION

Transfusion-related immunomodulation (TRIM) is a complex, multifactorial biological response to the administration of allogeneic blood products. This response results in a transient, yet clinically relevant, state of proinflammation and immunosuppression in the recipient[27]. Although this immune alteration can be beneficial in situations like organ transplantation, it raises serious concerns in oncology and postoperative recovery. It has been linked to an increased risk of infection and tumor recurrence[9,23-25]. TRIM is a proposed mechanistic framework, not definitive proof. While the concept provides a theoretical explanation for the observed associations between transfusion and adverse oncologic outcomes, it does not establish that transfusion directly worsens prognosis.

RESIDUAL LEUKOCYTES AND MEDIATORS

Historically, residual leukocytes in transfused blood components were considered the main mediators of TRIM. Allogeneic white blood cells, particularly antigen-presenting monocytes and dendritic cells, introduce foreign human leukocyte antigens into the recipient’s circulation and may induce either alloimmunization or immune tolerance[28]. These cells undergo apoptosis and release a variety of bioactive mediators, including interleukins (ILs) and transforming growth factor-β, during storage and soluble Fas ligand. During transfusion, soluble Fas ligand binds to Fas receptors on activated T lymphocytes and natural killer cells. This triggers apoptosis and weakens cell-mediated immunity[29].

Although universal leukoreduction before storage has mitigated many complications related to leukocytes, it does not eliminate TRIM completely. Even in leukoreduced units, cytokines and other soluble mediators accumulate during storage, suggesting that additional leukocyte-independent mechanisms contribute to immunomodulation[30].

THE RED BLOOD CELL STORAGE LESION

The storage lesion concept describes the biochemical and structural changes that erythrocytes undergo while being preserved under refrigeration. As storage time increases, cell membranes gradually lose integrity, making hemolysis more likely. This results in the release of free hemoglobin, heme, and non-transferrin-bound iron into the bloodstream[31]. These products may reduce the availability of nitric oxide, which can lead to vasoconstriction, oxidative stress, and endothelial dysfunction. At the same time, free heme and iron can alter the functions of macrophages and monocytes, which can dampen antimicrobial defenses and modify inflammatory responses[32]. These mechanisms provide a plausible biological framework, but it is uncertain whether storage-related changes in transfused erythrocytes meaningfully influence oncologic outcomes.

EXTRACELLULAR VESICLES AND MICROPARTICLES

Recently, extracellular vesicles, including exosomes, microvesicles, and apoptotic bodies, have been recognized as important mediators of TRIM. These vesicles are released from stored red blood cells, platelets, and residual leukocytes, and they progressively accumulate in the supernatant over time. Instead of representing inert cellular debris, they contain proteins, lipids, and nucleic acids that interact directly with the recipient’s immune system. Their biological effects vary depending on their cellular origin. Some extracellular vesicles promote neutrophil activation and amplify inflammatory responses. Others express Fas ligand, inducing lymphocyte apoptosis and contributing to immunosuppression[33,34]. In addition, hemoglobin within extracellular vesicles may scavenge nitric oxide more efficiently than free hemoglobin in circulation, which can bypass haptoglobin-mediated clearance and increase oxidative and vascular stress[33].

THE POSTOPERATIVE INFLAMMATORY AND STRESS RESPONSE

Major surgery triggers a well-known inflammatory and neuroendocrine response. Tissue injury leads to the release of cytokines, the activation of leukocytes, and an increase in stress hormones, such as cortisol and catecholamines[35]. Adding blood transfusion to the mix during or immediately after surgery can amplify inflammatory pathways beyond what surgery alone could do.

The inflammatory enviroment of stored blood is further enriched by cytokines [IL-6, IL-10, tumor necrosis factor-alpha (TNF-α)], eicosanoids (prostaglandins, thromboxanes, leukotrienes), and lyso-phosphatidylcholines, which can alter T cell and natural killer cell function, promote dendritic cell maturation, and enhance pro-tumor signaling. These molecules drive regulatory T cell differentiation and suppress Th1 responses, thereby shifting the immune balance toward tolerance[30,36].

In addition to the direct infusion of mediators, transfusions can amplify the recipient’s inflammatory response. Postoperative IL-6 levels were significantly higher in patients who received transfusions, suggesting that transfusions enhance the body’s production of inflammatory cytokines. Similarly, IL-1 and TNF-α were upregulated approximately 24 hours after receiving blood transfusion[37]. It remains uncertain whether these findings reflect a direct biological contribution of transfusion or differences in baseline clinical severity.

Beyond immune changes, transfusions can affect the neuroendocrine response to surgery. Transfusion can trigger the release of stress hormones due to volume and immune stress. Major surgery triggers a significant neuroendocrine stress response, which is characterized by the activation of the hypothalamic-pituitary-adrenal axis and the sympathetic nervous system. This results in the systemic release of stress hormones that modulate metabolic and immune functions[35,38]. High cortisol levels can lead to immune suppression by impairing T cell and macrophage function[35]. It can interfere with cytokine production and hinder the function of immune cells, including macrophages and neutrophils. The stress response involves an increase in the catecholamines epinephrine and norepinephrine. These hormones are essential for mobilizing energy and maintaining cardiovascular stability during periods of high physiological demand. Similar to cortisol, catecholamines exert immunosuppressive effects and contribute to a shift toward an anti-inflammatory Th2 cytokine profile. This shift can result in depressed cellular immunity during the later postoperative period. These stress hormones can remain elevated for a longer duration postoperatively in adult patients compared with pediatric patients[35].

COMPARISON OF TRANSFUSED AND NON-TRANSFUSED PATIENTS

Transfused patients experience higher rates of postoperative complications and less favorable long-term outcomes[9,23-25]. This clinical trend is reflected in laboratory findings. Compared with non-transfused patients, transfused patients show elevated cytokine levels and inflammatory markers during the early postoperative period, such as greater surges in IL-6 and higher increases in the neutrophil-to-lymphocyte ratio[39,40]. This amplified inflammatory response likely reflects the immunological stimulation of the donor blood and the effects of TRIM. By comparison, patients undergoing similar surgeries who do not receive transfusions tend to demonstrate a less pronounced inflammatory response, with smaller elevations in the neutrophil-to-lymphocyte ratio and lower peaks in inflammatory markers. Transfusion combined with postoperative infection creates a proinflammatory state that is not observed in patients who did not receive transfusion[40].

These findings highlight the importance of minimizing unnecessary transfusions in GC surgery as part of patient blood management. This approach reduces excessive inflammatory activation and may improve recovery.

PATIENT BLOOD MANAGEMENT STRATEGIES IN GASTRIC SURGERY

Patient blood management in gastric surgery is an evidence-based approach that aims to optimize patients’ hematologic status before surgery, minimize intraoperative blood loss, and ensure the judicious use of transfusion. Ideally, patients should be screened for anemia and iron deficiency at least two to four weeks before the procedure. Iron deficiency should be treated with intravenous iron and appropriate supplementation with folate, vitamin B12, or erythropoietin as surgery approaches. This can decrease the need for transfusions during surgery. In addition, a full assessment of bleeding risk and anticoagulant use should be conducted. Management should be individualized according to surgical and anesthetic plans[20].

Intraoperatively, meticulous surgical technique and hemostasis are crucial. Adopting minimally invasive methods, maintaining normothermia, and using goal-directed fluid therapy all help to limit blood loss and maintain coagulation integrity[21]. In high-risk cases, antifibrinolytic therapy, such as tranexamic acid, may be used to reduce bleeding. Intraoperative cell salvage with leukocyte-depletion filters can safely reduce the need for allogeneic transfusions when major blood loss is expected, even during oncologic gastrectomies. A restrictive transfusion strategy is generally recommended, using a hemoglobin threshold of about 7 g/dL in hemodynamically stable adults, combined with a single-unit transfusion and clinical reassessment after each unit. Consistent application of patient blood management principles is ensured by close interdisciplinary communication among surgeons, anesthesiologists, and transfusion specialists[41,42].

CONCLUSION

Although perioperative blood transfusion can save lives in GC surgery when needed to maintain stability, it may also increase inflammation, weaken the immune system, and worsen long-term outcomes. A patient blood management plan that includes correcting anemia before surgery and minimizing blood loss can help improve both recovery and survival. Transfusions should only be used when truly necessary.