Popular Reports / hematology

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This report is written by MaltSci based on the latest literature and research findings

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What are the mechanisms of anemia?

Abstract

Anemia is a widespread hematological disorder characterized by a deficiency in red blood cells, affecting nearly one-third of the global population and significantly impacting morbidity and mortality rates, particularly in low- and middle-income countries. The pathophysiology of anemia is complex and multifactorial, involving various mechanisms such as nutritional deficiencies, chronic diseases, bone marrow disorders, and hemolytic processes. This review aims to provide a comprehensive overview of these mechanisms, beginning with nutritional deficiencies, which are among the most common causes of anemia. Iron deficiency anemia (IDA) is the most prevalent, resulting from insufficient iron for hemoglobin production, and can be exacerbated by chronic inflammation. Vitamin B12 and folate deficiencies also contribute to megaloblastic anemia, affecting DNA synthesis in red blood cell production. Chronic diseases lead to anemia through mechanisms such as impaired erythropoietin production and iron sequestration due to inflammation, while bone marrow disorders like aplastic anemia disrupt normal hematopoiesis. Hemolytic anemia, categorized into immune and non-immune forms, involves the premature destruction of red blood cells due to intrinsic defects or external factors. Recent advances in diagnostic techniques have improved understanding of anemia's etiology, but challenges remain, particularly in patients with complex comorbidities. This review synthesizes current research findings to enhance understanding of anemia's mechanisms, guiding future research and clinical practice to improve patient outcomes.

Outline

This report will discuss the following questions.

• 1 Introduction
• 2 Mechanisms of Anemia
  • 2.1 Nutritional Deficiencies
  • 2.2 Chronic Diseases
  • 2.3 Bone Marrow Disorders
  • 2.4 Hemolytic Anemia
• 3 Nutritional Deficiencies
  • 3.1 Iron Deficiency Anemia
  • 3.2 Vitamin B12 Deficiency Anemia
  • 3.3 Folate Deficiency Anemia
• 4 Chronic Diseases and Anemia
  • 4.1 Anemia of Chronic Inflammation
  • 4.2 Anemia in Malignancies
• 5 Bone Marrow Disorders
  • 5.1 Aplastic Anemia
  • 5.2 Myelodysplastic Syndromes
• 6 Hemolytic Anemia
  • 6.1 Immune Hemolytic Anemia
  • 6.2 Non-Immune Hemolytic Anemia
• 7 Conclusion

1 Introduction

Anemia is a prevalent hematological disorder characterized by a deficiency in the quantity or quality of red blood cells, resulting in diminished oxygen transport to tissues. It affects approximately one-third of the global population, with significant implications for morbidity and mortality, particularly in low- and middle-income countries [1]. The pathophysiology of anemia is multifactorial, involving various underlying mechanisms such as nutritional deficiencies, chronic diseases, bone marrow disorders, and hemolytic processes. Understanding these mechanisms is essential for developing effective therapeutic strategies and improving patient outcomes.

The significance of studying anemia lies not only in its widespread occurrence but also in its complex etiology, which varies significantly across different populations and settings. Nutritional deficiencies, particularly iron, vitamin B12, and folate deficiencies, are well-documented contributors to anemia. Chronic diseases, including infections and inflammatory conditions, can further complicate the clinical picture, leading to anemia of chronic inflammation [2]. Additionally, genetic factors and environmental influences play critical roles in the development of hemolytic anemia, which can arise from both intrinsic defects in red blood cells and extrinsic factors that lead to their destruction [3].

Recent advances in diagnostic techniques have improved our understanding of anemia's etiology, enabling healthcare providers to differentiate between its various forms and tailor treatment accordingly. However, challenges remain, particularly in identifying the specific mechanisms underlying anemia in patients with complex comorbidities [4]. Moreover, the interplay between genetic predispositions and environmental triggers necessitates a nuanced approach to both research and clinical practice [5].

This review is organized into several sections that will explore the mechanisms of anemia in detail. The second section will discuss the primary mechanisms, including nutritional deficiencies, chronic diseases, bone marrow disorders, and hemolytic anemia. The subsequent sections will delve deeper into each mechanism, beginning with nutritional deficiencies, where we will examine iron deficiency anemia, vitamin B12 deficiency anemia, and folate deficiency anemia. Following this, we will explore the relationship between chronic diseases and anemia, highlighting anemia of chronic inflammation and anemia associated with malignancies. The discussion will then shift to bone marrow disorders, focusing on aplastic anemia and myelodysplastic syndromes. Finally, we will address hemolytic anemia, distinguishing between immune and non-immune forms.

By synthesizing current research findings and clinical insights, this review aims to provide a comprehensive overview of the mechanisms of anemia. Our goal is to enhance understanding of this complex condition and guide future research and clinical practice, ultimately improving outcomes for patients affected by anemia.

2 Mechanisms of Anemia

2.1 Nutritional Deficiencies

Anemia can arise from various mechanisms, particularly nutritional deficiencies, which are significant contributors to its prevalence, especially in low- and middle-income countries. Understanding these mechanisms is crucial for addressing the public health challenges posed by anemia.

Iron deficiency (ID) is the most common nutritional cause of anemia. It occurs when the iron available in the blood is insufficient to meet the demands for red blood cell production and the body's tissue needs. ID anemia develops when this lack of iron leads to an inability to maintain hemoglobin concentrations above the threshold that defines anemia. It is important to note that there are two forms of ID: absolute ID, characterized by absent or reduced body iron stores that do not meet individual needs but may respond to supplementation, and functional ID, where adequate iron stores are present but cannot meet the body's needs due to the effects of infection or inflammation. The latter form is particularly prevalent in low- and middle-income countries and does not respond to iron supplementation, indicating a complex interaction between iron metabolism and inflammatory processes [6].

Nutritional deficiencies other than iron also play a role in the development of anemia. For instance, vitamin A deficiency has been implicated in anemia through mechanisms such as the enhancement of erythrocyte progenitor cell growth and differentiation, as well as the mobilization of iron stores from tissues. Epidemiological data suggest a high prevalence of anemia in populations affected by vitamin A deficiency, although the precise public health impact remains unclear [7].

Additionally, folic acid and vitamin B12 deficiencies are important factors in the pathogenesis of anemia. These vitamins are crucial for DNA synthesis in red blood cell production. Their deficiency can lead to megaloblastic anemia, characterized by the production of large, abnormal red blood cells that cannot function properly [8].

In the context of chronic diseases, anemia can also result from the body’s response to inflammation. Anemia of chronic diseases is a condition where inflammation leads to decreased hemoglobin levels, hematocrit, and erythrocyte counts. This form of anemia is often associated with underlying conditions such as autoimmune diseases, cancer, and chronic infections, which trigger cellular immunity mechanisms and the production of pro-inflammatory cytokines [8].

The complex interplay of these nutritional deficiencies and their interactions with inflammation and chronic disease underscores the need for a multifaceted approach to diagnosing and treating anemia. Understanding the specific causes of anemia in different populations is vital for developing effective interventions and public health strategies to mitigate its prevalence [1][9].

2.2 Chronic Diseases

Anemia associated with chronic diseases, also referred to as anemia of chronic disease (ACD) or anemia of inflammation, is characterized by several complex mechanisms primarily driven by the underlying chronic condition. This form of anemia is the second most prevalent type after iron deficiency anemia and is frequently observed in patients with chronic inflammatory states, autoimmune diseases, malignancies, and renal failure.

The primary mechanisms contributing to ACD include:

1. Impaired Erythropoietin Production: In patients with chronic diseases, the production of erythropoietin (EPO), a hormone essential for red blood cell production, is often inadequate. This is particularly evident in chronic kidney disease (CKD), where EPO levels may not rise appropriately in response to falling hemoglobin levels, resulting in insufficient stimulation of erythropoiesis in the bone marrow (Nangaku and Eckardt, 2006) [10].

2. Iron Sequestration: ACD is characterized by hypoferremia, which is a reduction in serum iron levels due to the sequestration of iron within macrophages and other reticuloendothelial cells. This process is primarily regulated by hepcidin, an iron-regulatory hormone that is upregulated in response to inflammation, particularly by cytokines such as interleukin-6 (IL-6) (Ganz and Nemeth, 2009) [11]. The excessive production of hepcidin leads to decreased iron availability for erythropoiesis, thus contributing to anemia.

3. Decreased Erythroid Response: The erythroid progenitor cells in the bone marrow exhibit a diminished response to EPO due to the inflammatory milieu created by chronic diseases. Inflammatory cytokines can inhibit erythroid colony formation and reduce the proliferative capacity of erythroid progenitor cells, compounding the anemia (Weiss, 2015) [2].

4. Shortened Red Blood Cell Lifespan: Chronic inflammation may also lead to a reduced survival of red blood cells, further exacerbating anemia. This can be a result of increased hemolysis or other factors that impair red blood cell longevity (Roy et al., 2003) [12].

5. Cytokine Effects: Various inflammatory cytokines, including tumor necrosis factor-alpha (TNF-α) and IL-1, have been implicated in the pathogenesis of ACD. These cytokines can inhibit erythropoiesis directly or indirectly by affecting iron metabolism and EPO activity (Bertero and Caligaris-Cappio, 1997) [13].

6. Uremic Toxins in Chronic Kidney Disease: In the context of CKD, the accumulation of uremic toxins due to impaired kidney function can further inhibit EPO synthesis and disrupt erythropoiesis, compounding the anemia experienced by these patients (Hamza et al., 2020) [14].

In summary, the mechanisms of anemia in chronic diseases are multifaceted and involve a combination of impaired EPO production, iron sequestration due to increased hepcidin levels, decreased responsiveness of erythroid progenitor cells, shortened red blood cell lifespan, and the effects of inflammatory cytokines. Understanding these mechanisms is crucial for developing targeted therapies that can effectively address the anemia associated with chronic diseases.

2.3 Bone Marrow Disorders

Aplastic anemia (AA) is a rare disorder characterized by the suppression of bone marrow function, leading to progressive pancytopenia. The pathogenesis of AA is multifaceted and involves several mechanisms that disrupt normal hematopoiesis.

The fundamental mechanism underlying AA is the injury to hematopoietic stem cells (HSCs). This injury can arise from various factors, including exposure to cytotoxic agents, autoimmune responses, and genetic predispositions. For instance, studies indicate that aplastic anemia can result from abnormalities in hematopoietic stem cells, which may lead to ineffective hematopoiesis and subsequent bone marrow failure [15][16]. Additionally, the interaction between HSCs and their microenvironment, which includes accessory cells such as lymphocytes and macrophages, is critical. Abnormalities in this interaction can further exacerbate the hematopoietic failure [16].

In terms of immune involvement, CD8+ T cells have been identified as playing a significant role in the pathogenesis of AA. Research shows that in patients with AA, CD8+ T cells exhibit lower expression of parathyroid hormone (PTH) receptors, which is associated with reduced expression of key Wnt factors that are crucial for mesenchymal stem cell (MSC) differentiation. This insensitivity to PTH may lead to imbalances in MSC adipogenesis and osteogenesis, thereby contributing to the disease's pathology [17].

Another important aspect of AA is the potential for genotoxic stress to induce mitochondrial dysfunction and replicative senescence in HSCs. For example, studies have demonstrated that chemotherapeutic agents can lead to chromatin damage and apoptosis in marrow cells, contributing to the hematopoietic catastrophe seen in aplastic anemia [18]. Furthermore, metabolic alterations, such as oxidative stress and mitochondrial impairment, have been observed in the context of bone marrow failure, indicating that these metabolic derangements may also play a role in the pathogenesis of AA [19].

In summary, the mechanisms of anemia, particularly in the context of aplastic anemia, involve a complex interplay of hematopoietic stem cell injury, immune dysregulation, and metabolic dysfunction, all of which contribute to the disruption of normal hematopoiesis and result in the clinical manifestations of the disease.

2.4 Hemolytic Anemia

Hemolytic anemia is characterized by the premature destruction of red blood cells (RBCs), leading to a variety of clinical manifestations and laboratory findings. The mechanisms underlying hemolytic anemia can be broadly categorized into intrinsic and extrinsic factors.

Intrinsic mechanisms involve defects within the red blood cells themselves. These can include hereditary conditions such as hemoglobinopathies, membranopathies, and enzymopathies. Hemoglobinopathies, such as sickle cell anemia and thalassemia, lead to structural abnormalities in hemoglobin, which can result in chronic hemolysis. Membranopathies, like hereditary spherocytosis, are caused by defects in the RBC membrane, resulting in increased fragility and susceptibility to destruction. Enzymopathies, such as glucose-6-phosphate dehydrogenase deficiency, affect the metabolic pathways of RBCs, leading to hemolysis under oxidative stress conditions [20].

Extrinsic mechanisms involve external factors that lead to the destruction of otherwise normal red blood cells. This includes immune-mediated hemolysis, where antibodies target RBCs for destruction. Immune-mediated hemolytic anemia can arise from various causes, including autoimmune disorders, malignancies, certain medications, and transfusion reactions [21]. Other extrinsic factors include mechanical trauma, such as that seen in microangiopathic hemolytic anemia, where RBCs are damaged as they pass through narrowed blood vessels or in the presence of microthrombi [20]. Additionally, infections, such as malaria and babesiosis, can invade RBCs and lead to their destruction [20].

The pathophysiological mechanisms of hemolytic anemia can manifest in several ways. Patients may present with symptoms such as acute anemia, jaundice, hematuria, dyspnea, fatigue, tachycardia, and potentially hypotension. Laboratory findings typically confirm hemolysis through reticulocytosis, increased lactate dehydrogenase, increased unconjugated bilirubin, and decreased haptoglobin levels. The direct antiglobulin test is crucial in differentiating between immune and non-immune causes of hemolysis [22].

In summary, hemolytic anemia can arise from a complex interplay of intrinsic defects within the red blood cells and extrinsic factors that lead to their premature destruction. Understanding these mechanisms is vital for accurate diagnosis and effective management of the condition.

3 Nutritional Deficiencies

3.1 Iron Deficiency Anemia

Iron deficiency anemia (IDA) is a common type of anemia characterized by a deficiency of hemoglobin due to insufficient iron availability for red blood cell production. The mechanisms underlying IDA can be categorized into several key aspects, primarily focusing on the availability of iron and the body's ability to utilize it effectively.

Iron deficiency develops when the iron circulating in the blood cannot meet the demands required for red blood cell production and tissue needs. This deficiency may be classified into two types: absolute iron deficiency and functional iron deficiency. Absolute iron deficiency refers to a condition where there is an absence or reduction of body iron stores that do not meet the individual’s iron requirements but may respond to iron supplementation. In contrast, functional iron deficiency occurs when there are adequate or increased iron stores that cannot meet the iron needs due to the effects of infection or inflammation, and this condition does not respond to iron supplementation. Functional iron deficiency is frequently responsible for anemia in low- and middle-income countries, and both absolute and functional iron deficiencies may coexist [6].

The mechanisms leading to iron deficiency anemia involve several interrelated factors. One of the primary causes is inadequate dietary intake of iron, which can occur due to poor nutrition or malabsorption issues. In addition, chronic blood loss, such as that seen in gastrointestinal cancers, inflammatory bowel disease, or excessive menstrual bleeding, can deplete the body's iron stores, contributing to IDA. Moreover, in individuals with chronic inflammatory conditions, the retention of iron in macrophages can occur, making it unavailable for erythropoiesis, thereby leading to anemia [2].

Inflammation plays a significant role in the pathophysiology of IDA. The inflammatory cytokine interleukin-6 (IL-6) is a prominent inducer of hepcidin, a key iron-regulatory hormone that controls iron homeostasis. An increase in hepcidin levels leads to the endocytosis and degradation of ferroportin, the only known cellular iron exporter, trapping iron in macrophages and enterocytes, thus limiting its availability for hemoglobin synthesis [11]. This mechanism highlights how inflammation can lead to functional iron deficiency, where iron stores are present but are not accessible for erythropoiesis due to regulatory mechanisms influenced by inflammatory states.

Furthermore, in chronic kidney disease (CKD), anemia is prevalent, and iron deficiency is a significant contributor to impaired erythropoiesis. In this context, both absolute and functional iron deficiencies may arise due to factors such as blood losses, impaired iron absorption, and chronic inflammation associated with the disease [23].

In summary, the mechanisms of iron deficiency anemia are multifaceted, involving nutritional deficits, chronic blood loss, and the impact of inflammation on iron metabolism. The interplay between these factors ultimately leads to insufficient hemoglobin production, resulting in anemia. Understanding these mechanisms is crucial for effective diagnosis and treatment strategies for IDA.

3.2 Vitamin B12 Deficiency Anemia

Vitamin B12 deficiency anemia primarily arises from a failure of physiological absorption of vitamin B12, which is crucial for red blood cell production and neurological function. The mechanisms leading to this type of anemia can be attributed to several factors, including dietary inadequacy, absorption issues, and specific medical conditions.

One of the most common causes of vitamin B12 deficiency is pernicious anemia, an autoimmune condition that impairs the gastric phase of vitamin B12 absorption. In pernicious anemia, the body's immune system attacks the gastric mucosa, leading to a lack of intrinsic factor, a protein essential for the absorption of vitamin B12 in the ileum. This results in severe deficiency, which is often accompanied by megaloblastic anemia, characterized by the production of large, immature red blood cells due to impaired DNA synthesis (Green 2017).

In addition to pernicious anemia, vitamin B12 deficiency can occur due to dietary inadequacies, particularly in populations with limited access to animal products, as vitamin B12 is primarily found in meat, dairy, and eggs. Mild deficiencies may not lead to megaloblastic anemia but can still have significant neurocognitive consequences, underscoring the importance of adequate dietary intake and absorption of vitamin B12 (Green 2017).

Moreover, certain conditions such as autoimmune gastritis can increase the risk of gastric carcinoids, as observed in a case study involving a Russian seafarer. This patient presented with profound vitamin B12 deficiency, microangiopathic anemia, and a gastric carcinoid tumor, highlighting the complex interplay between nutritional deficiencies and gastrointestinal health (Chaunzwa et al. 2018).

The clinical manifestations of vitamin B12 deficiency anemia can be varied, often presenting with hematological symptoms like anemia, but also neurological symptoms due to the vitamin's critical role in myelin synthesis and neuronal health. Deficiency may lead to conditions such as myelopathy and neuropsychiatric disorders, including depression, as vitamin B12 plays a role in neurotransmitter synthesis and regulation (Hathout & El-Saden 2011; Rao et al. 2008).

Timely diagnosis of vitamin B12 deficiency is crucial, as untreated deficiency can lead to irreversible neurological damage. Diagnosis typically involves a combination of clinical evaluation and laboratory tests, as no single test is fully reliable for determining vitamin B12 status (Green 2017).

In summary, the mechanisms of vitamin B12 deficiency anemia are multifaceted, involving both intrinsic factors like autoimmune conditions and extrinsic factors such as dietary intake, necessitating a comprehensive approach to diagnosis and management.

3.3 Folate Deficiency Anemia

Folate deficiency anemia, a common type of megaloblastic anemia, is primarily characterized by impaired DNA synthesis due to inadequate folate levels, which is essential for the synthesis of nucleotides. This deficiency can lead to the disruption of normal proliferation in rapidly dividing cells, particularly those in the bone marrow, resulting in the production of large, immature red blood cells known as megaloblasts. The connection between folate deficiency and anemia is well-established, with folate playing a critical role in the biosynthesis of purines and pyrimidines, which are vital for DNA replication and cell division (Green and Miller 1999).

Folate is a crucial cofactor in one-carbon metabolism, a metabolic pathway that supports the biosynthesis of nucleotides, several amino acids, and redox regulators. A deficiency in folate can arise from various factors, including inadequate dietary intake, genetic defects in folate absorption and metabolism, or exposure to certain antimetabolite drugs. These factors can lead to genomic instability and apoptosis, contributing to the pathogenesis of anemia associated with folate deficiency (Mellor et al. 2025).

Recent studies have shown that folate depletion specifically affects erythroid cells, leading to early blockade of purine synthesis and accumulation of intermediates like 5'-phosphoribosyl-5-aminoimidazole-4-carboxamide (AICAR). This accumulation subsequently promotes heme metabolism, hemoglobin synthesis, and erythroid differentiation, indicating a direct link between folate levels and erythropoiesis (Maynard et al. 2024). The differentiation process induced by folate depletion is mediated by protein kinase C, rather than the mechanistic target of rapamycin complex 1 (mTORC1) or AMP-activated protein kinase (AMPK), highlighting a unique pathway through which folate influences erythroid progenitor cells (Maynard et al. 2024).

Moreover, folate deficiency has been associated with other non-hematological manifestations, including an increased risk of occlusive vascular disease and disturbances in mood and cognitive function. These associations suggest that the impact of folate deficiency extends beyond hematological disorders, implicating it in broader health concerns such as neurodegenerative diseases and psychiatric conditions (Abou-Saleh and Coppen 1986; Kao et al. 2014).

In summary, the mechanisms underlying folate deficiency anemia are multifaceted, involving impaired DNA synthesis and cellular proliferation due to insufficient folate levels. This deficiency leads to megaloblastic anemia characterized by the production of abnormally large red blood cells, as well as a range of other health implications that highlight the importance of adequate folate nutrition in maintaining overall health.

4 Chronic Diseases and Anemia

4.1 Anemia of Chronic Inflammation

Anemia of chronic inflammation (AI), also referred to as anemia of chronic disease (ACD), is a common complication associated with various chronic inflammatory conditions, including autoimmune diseases, infections, and malignancies. The pathophysiology of AI is multifaceted and primarily involves the dysregulation of iron metabolism and impaired erythropoiesis.

One of the key mechanisms underlying AI is the sequestration of iron due to the overproduction of the iron-regulatory hormone hepcidin, which is stimulated by inflammatory cytokines such as interleukin-6 (IL-6). Hepcidin leads to the endocytosis and degradation of ferroportin, the main iron exporter in cells, resulting in trapped iron within macrophages and enterocytes. This sequestration limits the availability of iron for hemoglobin synthesis, thereby causing iron-restricted erythropoiesis [11].

Moreover, chronic inflammation is associated with impaired biological activity of erythropoietin (EPO), the hormone responsible for stimulating red blood cell production. Inflammatory cytokines can inhibit erythropoietin production or its action on erythroid progenitor cells, further contributing to anemia [2]. This impaired response to EPO is compounded by the reduced proliferative capacity of erythroid progenitor cells, leading to decreased red blood cell production [2].

The diagnosis of AI is complicated by the need to differentiate it from other types of anemia, particularly iron deficiency anemia. Clinically, AI is characterized by mild to moderate anemia, low serum iron, low total iron-binding capacity, and increased ferritin levels [8]. Additionally, the severity of anemia often correlates with the underlying inflammatory condition [8].

In patients with chronic diseases, anemia can be exacerbated by factors such as chronic blood loss, which may occur in conditions like gastrointestinal cancers or inflammatory bowel disease. This results in true iron deficiency, necessitating a different therapeutic approach [2].

Recent advances in understanding the molecular mechanisms of AI have led to the exploration of novel therapeutic strategies. These include the use of agents that target the inflammation-driven retention of iron and promote iron availability for erythropoiesis, as well as therapies aimed at stimulating endogenous erythropoietin production [2][24].

In summary, the mechanisms of anemia of chronic inflammation are primarily driven by the interplay of iron sequestration due to elevated hepcidin levels, impaired erythropoietin function, and the effects of chronic inflammatory cytokines on erythropoiesis. Understanding these mechanisms is crucial for developing effective diagnostic and therapeutic strategies for managing anemia in patients with chronic inflammatory diseases.

4.2 Anemia in Malignancies

Anemia is a prevalent condition among patients with malignancies, with over two-thirds of individuals suffering from malignant hematological disorders experiencing this issue. The mechanisms underlying anemia in these patients are multifaceted and can be attributed to several key factors:

1. Ineffective Erythropoiesis: A primary cause of anemia in malignancies is ineffective erythropoiesis, which can arise from several mechanisms:

   • Marrow Infiltration: Malignant cells can infiltrate the bone marrow, disrupting normal hematopoiesis and leading to decreased red blood cell (RBC) production.
   • Cytokine-Related Suppression: Tumors often secrete cytokines that suppress erythropoiesis, contributing to lower RBC production.
   • Erythropoietin Suppression: Patients with malignancies may exhibit low levels of erythropoietin, a hormone essential for RBC production, further exacerbating anemia.
   • Nutritional Deficiencies: Deficiencies in vitamins, such as B12 and folate, can also play a role in ineffective erythropoiesis.

2. Accelerated Clearance of RBCs: The presence of malignant diseases can lead to accelerated clearance of RBCs through:

   • Antibody-Mediated Hemolysis: Some malignancies are associated with autoimmune hemolytic anemia, where antibodies target and destroy RBCs.
   • Thrombotic Microangiopathy: This condition can lead to microvascular damage and increased destruction of RBCs.

3. Chronic Nature of Anemia: The anemia associated with malignancies is often chronic, resulting in symptoms that are typically well tolerated and may be non-specific. This chronicity may lead to a gradual adaptation in patients, masking the severity of the condition.

4. Impact of Treatment: Chemotherapy and radiation therapy, while essential for treating malignancies, can also suppress bone marrow function, leading to further anemia. The marrow suppressive effects of these therapies contribute to the overall hematologic dysfunction observed in cancer patients.

In summary, the etiology of anemia in malignancies is complex, involving ineffective erythropoiesis due to marrow infiltration and cytokine suppression, as well as accelerated clearance mechanisms such as hemolysis and thrombotic events. This multifactorial nature necessitates a comprehensive understanding for effective management, including the consideration of alternative treatments such as intravenous iron and erythropoietin-stimulating agents (ESAs) when appropriate[25][26][27].

5 Bone Marrow Disorders

5.1 Aplastic Anemia

Aplastic anemia (AA) is a complex disorder characterized by bone marrow failure leading to pancytopenia, which is the reduction of red blood cells, white blood cells, and platelets. The mechanisms underlying aplastic anemia are multifaceted and involve both intrinsic and extrinsic factors affecting hematopoietic stem cells (HSCs) and their microenvironment.

One primary mechanism involves a deficiency or defect in hematopoietic stem cells. This may manifest as either a primary stem cell deficiency or a secondary defect due to abnormal regulation between cell death and differentiation processes. Studies indicate that alterations in the hematopoietic microenvironment play a crucial role in the pathogenesis of AA. Specifically, the bone marrow microenvironment may become deficient and apoptotic, contributing significantly to the impaired hematopoiesis observed in patients with AA [28].

Another critical aspect of aplastic anemia is the immune-mediated destruction of HSCs. Activated cytotoxic T cells and type 1 cytokines have been implicated in the pathophysiology of the disease. The immune response can lead to increased apoptosis of progenitor cells, exacerbating the condition [29]. Additionally, the presence of inflammatory cytokines has been shown to alter the balance of T lymphocytes, further promoting the progression of the disease [30].

Furthermore, genomic instability and mitochondrial dysfunction have been identified as significant contributors to the pathogenesis of AA. The use of chemotherapeutic agents, such as busulfan and cyclophosphamide, can induce genomic insults that lead to mitochondrial membrane potential disruption, replicative senescence, and ultimately, the apoptosis of marrow cells [18]. This cellular catastrophe is often accompanied by an accumulation of DNA damage and the activation of apoptotic pathways, leading to severe hematopoietic disruption [31].

The deregulation of signaling pathways, particularly those involving mitotic kinases and phosphatases, also plays a pivotal role in the cellular impairment seen in AA. Alterations in the expression of key regulators, such as Protein kinase-B (PKB) and GSK-3β, have been associated with the proliferative impairment and apoptosis of HSPCs [31].

Overall, aplastic anemia is a heterogeneous disorder with diverse mechanisms at play, including immune-mediated destruction, deficiencies in stem cell populations, and alterations in the bone marrow microenvironment. These factors collectively contribute to the pathophysiological landscape of the disease, complicating diagnosis and treatment strategies.

5.2 Myelodysplastic Syndromes

Anemia in myelodysplastic syndromes (MDS) is primarily attributed to ineffective erythropoiesis, which is characterized by the abnormal proliferation and differentiation of erythroid cells. The underlying mechanisms of anemia in MDS involve several key factors, including increased apoptosis of hematopoietic progenitors, the impact of the bone marrow microenvironment, and genetic abnormalities.

Increased apoptosis of hematopoietic progenitors is a hallmark of MDS, leading to ineffective hematopoiesis. Specifically, erythroid apoptosis is believed to be the main mechanism contributing to the severe anemia observed in low-risk subgroups of MDS, such as refractory anemia (RA) and RA with ringed sideroblasts (RARS). The administration of erythropoietin (Epo) alone or in combination with granulocyte colony-stimulating factor (G-CSF) has shown significant improvement in anemia and reduction in bone marrow apoptosis, particularly in patients with RARS. However, the molecular mechanisms underlying the anti-apoptotic effects of these growth factors remain incompletely understood [32].

Additionally, the age-related inflammatory bone marrow microenvironment has been implicated in the pathogenesis of ineffective erythropoiesis in MDS. Research indicates that damage-associated molecular pattern molecules (DAMPs) increase in aging bone marrow, which in turn upregulates pro-inflammatory cytokines such as TNFα and IL-6 in myeloid-derived suppressor cells (MDSCs). These elevated levels of TNFα and IL-6 inhibit erythroid colony formation and affect terminal erythropoiesis through mechanisms involving reactive oxygen species-induced caspase-3 activation and apoptosis [33].

Furthermore, genetic factors play a significant role in the development of anemia in MDS. For instance, the dual deficiency of mDia1 and miR-146a, which is commonly deleted in del(5q) MDS, has been shown to cause age-related anemia and ineffective erythropoiesis in a mouse model. This genetic alteration underscores the importance of both genetic abnormalities and the aging microenvironment in the pathogenesis of ineffective erythropoiesis [33].

The dysregulation of signaling pathways is also critical in the context of MDS. Ineffective erythropoiesis is linked to various signaling pathways, including those involved in heme synthesis, ferroptosis, senescence, and apoptosis. A study utilizing a transgenic mouse model mimicking MDS revealed that as the disease progresses, signaling pathways dynamically change, indicating that interventions targeting these pathways could be beneficial in managing anemia associated with MDS [34].

In summary, the mechanisms of anemia in myelodysplastic syndromes are multifactorial, involving increased apoptosis of erythroid progenitors, inflammatory changes in the bone marrow microenvironment, genetic abnormalities, and the dysregulation of key signaling pathways. Addressing these mechanisms is crucial for developing effective therapeutic strategies for patients suffering from anemia in the context of MDS.

6 Hemolytic Anemia

6.1 Immune Hemolytic Anemia

Immune hemolytic anemia (IHA) is a type of hemolytic anemia characterized by the destruction of red blood cells (RBCs) due to the immune system's response against them. The mechanisms underlying IHA can be categorized into various aspects, including the production of autoantibodies, the role of immune receptors, and specific clinical manifestations.

Autoimmune hemolytic anemia (AIHA) occurs when autoantibodies target an individual's own RBCs, leading to their enhanced clearance primarily through Fc receptor (FcR)-mediated phagocytosis. The production of IgG autoantibodies against RBC autoantigens is a central focus of research, although relatively little work has been done to elucidate the exact processes involved in their generation. Understanding these immunopathogenic mechanisms is crucial for developing antigen-specific immunotherapies aimed at treating the disease (Semple & Freedman, 2005) [35].

The pathogenesis of IHA involves several immune-mediated mechanisms. For instance, it is noted that hemolytic anemia due to immune function is one of the major causes of acquired hemolytic anemia. Advances in the understanding of the immune system have led to improved treatment options. Specific attention has been given to paroxysmal nocturnal hemoglobinuria (PNH), which is associated with a biochemical defect characterized by the absence of glycosylphosphatidylinositol (GPI)-linked proteins on the cell surface. This defect is linked to hemolysis and thrombosis, emphasizing the importance of complement activation in the pathology of the disease. Innovative therapies, such as humanized monoclonal antibodies targeting complement components, have shown promise in managing these manifestations (Rosse et al., 2004) [21].

Furthermore, immune hemolytic anemia can also present in patients with negative routine serology results. DAT-negative AIHAs constitute about 5% to 10% of all AIHAs. The potential causes for this include low levels of RBC-bound IgG that are undetectable by standard tests, the presence of IgA and IgM autoantibodies, and low-affinity autoantibodies. Additionally, antibody-independent cytotoxic mechanisms involving natural killer (NK) cells may also contribute to hemolysis in these cases. In some instances, antibodies may be detected through specialized serological techniques, indicating a complexity in the immunological landscape of IHA (Garratty, 2005) [36].

In summary, the mechanisms of immune hemolytic anemia involve the production of autoantibodies targeting RBCs, the role of immune receptors in the pathobiology of the condition, and the potential for antibody-independent cytotoxicity. Understanding these mechanisms is vital for the development of targeted therapies and improving clinical outcomes for patients suffering from this form of anemia.

6.2 Non-Immune Hemolytic Anemia

Hemolytic anemia is characterized by the premature destruction of red blood cells (RBCs), leading to a range of clinical manifestations and laboratory findings. It can be categorized into immune and non-immune causes, with non-immune hemolytic anemia (NIHA) being a significant subset that warrants detailed exploration.

NIHA is defined by the presence of positive routine hemolytic tests, alongside a negative anti-human immunoglobulin (Coombs) test. This condition can be further divided into hereditary and acquired forms. Hereditary NIHA includes disorders affecting erythrocytic enzymes, membrane integrity, and hemoglobin stability, which can manifest as both qualitative and quantitative abnormalities. For instance, hereditary conditions such as unstable hemoglobinopathies may result in chronic or episodic hemolysis due to structural defects in hemoglobin molecules. Moreover, disorders affecting erythrocyte metabolism, particularly those involving critical enzymes in the Embden-Meyerhof pathway, can lead to altered erythrocyte function and chronic hemolysis [37].

Acquired forms of NIHA encompass a variety of etiologies, including paroxysmal nocturnal hemolysis (PNH), infections, and drug or metal intoxications that target red blood cells or the endothelial cells of capillaries. Additionally, conditions such as rare acquired forms of thalassemia or erythrocytic membrane disorders can also lead to hemolysis. It is important to note that hemolysis can occur secondary to mechanical factors, such as dysfunctioning artificial cardiac valves, which can cause direct trauma to the RBCs [38].

The mechanisms underlying hemolysis in NIHA are diverse. They include poor deformability of red blood cells, leading to trapping and phagocytosis by macrophages, and antibody-mediated destruction through phagocytosis or direct complement activation. Other mechanisms involve fragmentation of RBCs due to microthrombi or mechanical trauma, oxidative damage, or direct cellular destruction [22].

Clinical presentations of NIHA can include acute anemia, jaundice, hematuria, dyspnea, fatigue, tachycardia, and in severe cases, hypotension. Laboratory findings that confirm hemolysis typically include reticulocytosis, elevated lactate dehydrogenase (LDH), increased unconjugated bilirubin, and decreased haptoglobin levels. A peripheral blood smear is essential to identify abnormal red blood cell morphologies, which can aid in differentiating between various forms of hemolytic anemia [39].

In summary, non-immune hemolytic anemia encompasses a range of hereditary and acquired disorders characterized by distinct pathophysiological mechanisms leading to the destruction of red blood cells. Accurate diagnosis and differentiation from immune-mediated hemolytic anemias are critical for effective management and treatment of affected individuals.

7 Conclusion

This review elucidates the multifaceted mechanisms underlying anemia, a prevalent hematological disorder affecting a significant portion of the global population. Key findings highlight that nutritional deficiencies, particularly iron, vitamin B12, and folate, play crucial roles in the pathogenesis of anemia, especially in low- and middle-income countries. Chronic diseases, such as autoimmune disorders and malignancies, contribute to anemia through mechanisms like impaired erythropoiesis and iron sequestration due to inflammatory processes. Bone marrow disorders, including aplastic anemia and myelodysplastic syndromes, further complicate the landscape of anemia by disrupting normal hematopoiesis. Hemolytic anemia, classified into immune and non-immune types, is characterized by the premature destruction of red blood cells due to various intrinsic and extrinsic factors. Overall, the complexity of anemia's etiology necessitates a comprehensive approach to diagnosis and treatment, emphasizing the need for tailored therapeutic strategies that consider the underlying mechanisms. Future research should focus on unraveling the intricate interplay between genetic, environmental, and pathological factors contributing to anemia, aiming to improve clinical outcomes and public health strategies for affected populations.

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