Iatrogenic anemia

Article written and reviewed by Dr Luca Moretti

Iatrogenic anemia is one of the most underestimated yet pervasive acquired complications of modern medicine and can be regarded as a genuine “collateral product” of clinical practice in hospitals and advanced care settings. Defined as a reduction in hemoglobin concentration caused by medical interventions or procedures rather than by primary disease, iatrogenic anemia reflects the biological cost borne by patients in exchange for access to increasingly complex, invasive, fragmented and specialized care.

The condition has become increasingly relevant over recent decades because of longer hospital stays, more intensive diagnostic and therapeutic protocols, and the extension of intensive care to increasingly older, frail patients with multiple diseases. Technological advances, ranging from continuous laboratory monitoring and cytotoxic therapies to major surgery and extracorporeal life-support techniques, have multiplied the opportunities for blood loss, drug-induced bone marrow suppression and iatrogenic disruption of the homeostatic mechanisms governing hematopoiesis.

It is therefore not merely a “statistical” complication, but a clinically, organizationally and prognostically relevant problem. Hospital-acquired anemia is associated, even after adjustment in several observational studies, with longer stays, poorer functional status and higher mortality; these associations do not establish that iatrogenic anemia is always an independent cause of outcomes, because illness severity and intensity of care are important confounders. The concept of iatrogenic anemia encompasses a range of clinical conditions produced by the convergence of numerous factors: occult and subclinical blood loss, from diagnostic blood sampling to minor surgical bleeding, the myelosuppressive effects of drugs and radiation, hemolysis caused by artificial devices, treatment-related nutritional disturbances or dietary restrictions, hormonal imbalances induced by systemic therapy, and even secondary bone marrow aplasia. These mechanisms often overlap and potentiate one another, particularly in patients already exposed to chronic proinflammatory conditions or complex polypharmacy.

The clinical significance of iatrogenic anemia is further amplified by its frequent underdiagnosis and underestimation: it may present with subtle symptoms or overlap with manifestations of the underlying disease, and may therefore be incorrectly attributed to the patient's natural clinical course or regarded as “unavoidable” in the context of severe illness. Early recognition of the underlying pathophysiological mechanisms, analysis of risk factors, active prevention and integrated management are now essential pillars of patient blood management and hospital quality-improvement strategies.

Etiology

Iatrogenic anemia results from factors induced by medical or healthcare interventions, but in an individual patient these may add to intrinsic causes or the underlying disease; the clinical picture is therefore often multifactorial. Its etiology is multifaceted and develops through the interaction between the diagnostic and therapeutic strategies used to manage the patient and the patient's baseline characteristics.

The principal etiological categories include:

• Acute and chronic blood loss caused by healthcare procedures: iatrogenic bleeding is the most obvious and frequent cause. Serial blood sampling for laboratory monitoring, especially in intensive care units where the volume may exceed 40 mL per day, surgical drains, hemorrhagic complications during surgery or invasive procedures such as biopsies, catheterization and device insertion, and gastrointestinal bleeding caused by antiplatelet agents, anticoagulants, NSAIDs and thrombolytics constitute the primary source of irrecoverable red blood cell loss.
• Drug-induced or radiation-induced bone marrow suppression: cytotoxic drugs, some immunosuppressants, selected antibiotics and ionizing radiation may reduce bone marrow production, with variable mechanisms and reversibility. For example, chloramphenicol may cause reversible, dose-dependent bone marrow suppression, which is distinct from rare idiosyncratic aplastic anemia that is unpredictable and not dose-dependent. The severity of cytopenias and the risk of marrow failure depend on the specific agent, dose, duration of exposure and individual susceptibility.
• Mechanical or immune-mediated hemolysis caused by healthcare intervention: prosthetic valves, cardiopulmonary bypass pumps and ECMO can expose red blood cells to shear forces; hemolysis in hemodialysis circuits is rare and suggests a malfunction or a thermal, osmotic or chemical problem. Transfusion reactions and some drugs may also cause immune hemolysis.
• Deficiency of essential nutrients secondary to treatment: gastrointestinal resections and bariatric surgery may cause malabsorption; proton pump inhibitors may reduce absorption of iron and vitamin B12, metformin is associated mainly with vitamin B12 deficiency, and some anticonvulsants interfere with folate metabolism.
• Impaired erythropoietin regulation: chronic kidney disease reduces the appropriate erythropoietin response; inflammation, infection and functional iron restriction may also cause marrow hyporesponsiveness. Dialysis and nephrotoxic drugs contribute mainly through blood loss, inflammation or kidney injury, not through a uniform direct effect on erythropoietin secretion.

Less frequent but clinically relevant causes include:

• Postoperative malabsorption syndromes following gastrectomy, intestinal resection or bariatric surgery, which reduce absorption of iron and water-soluble vitamins and predispose to mixed iron-deficiency and megaloblastic anemia.
• Adverse effects of innovative therapies, including monoclonal antibodies, cellular immunotherapies and targeted drugs, which may induce acute or chronic bone marrow suppression, secondary aplastic syndromes or autoimmune erythroblastopenic crises.
• Documented specific drug effects, including marrow toxicity from antithyroid drugs or other selected agents, bleeding caused by antithrombotic therapy, and nutritional or endocrine abnormalities secondary to treatment; corticosteroids, antiandrogens and estrogens do not share a common direct marrow-suppressive effect causing anemia.

In clinical practice, iatrogenic anemia is a multifactorial condition in which the contribution of individual causes varies according to the setting, including intensive care, major surgery, oncology and nephrology, the interventions performed and the patient's clinical profile. The longer the hospital stay and the greater the number of treatments administered, the higher the likelihood that these mechanisms will combine and produce severe, refractory anemia that is difficult to correct through conventional transfusion or supplementation strategies alone.

Risk factors and prevention

The risk factors for iatrogenic anemia are numerous and reflect both the patient's intrinsic characteristics and the specific features of the diagnostic and therapeutic pathway. Unlike direct causes, risk factors are conditions that increase the probability of anemia developing during healthcare without themselves constituting the primary cause of the hemoglobin deficit.

The principal risk factors identified in the literature include:

• Advanced age and geriatric frailty: older adults have reduced erythropoietic reserve, a higher prevalence of comorbidities such as kidney failure, malnutrition and chronic inflammation, and a less effective compensatory response even to modest blood loss. Overall frailty and polypharmacy place them at particularly high risk of iatrogenic anemia, especially during prolonged hospitalization.
• Preexisting chronic diseases: patients with chronic kidney disease, liver disease, chronic inflammatory disease, endocrine disorders and malignancy already have impaired synthesis, maturation or survival of red blood cells before the acute event, reducing their safety margin with respect to iatrogenic blood loss.
• Prolonged hospitalization and repeated admissions: the longer the period of hospitalization, the greater the number of laboratory blood samples, invasive procedures, potentially hematotoxic treatments and opportunities for occult blood loss. Patients with chronic or complex conditions are particularly exposed.
• Intensity and invasiveness of treatment: intensive care, major surgery, drains, catheters, multiple vascular access devices and extracorporeal technologies such as ECMO, cardiopulmonary bypass, dialysis and plasmapheresis increase the risk of blood loss and mechanical red blood cell damage.
• Polypharmacy and long-term use of high-risk drugs: combinations of myelosuppressive drugs, antiplatelet agents, anticoagulants, chemotherapeutic agents, immunosuppressants and acid-suppressing drugs increase the probability of additive or synergistic effects that reduce red blood cell production or induce occult bleeding.
• Malnutrition and nutritional deficiencies: deficiencies of iron, vitamin B12, folate and protein are common among hospitalized patients, particularly those with chronic disease, reduced food intake, malabsorption or prolonged dietary restrictions.

Additional contextual factors include the absence of structured patient blood management protocols, nonindividualized serial laboratory monitoring and inadequate consideration of hematological risk within multidisciplinary care pathways.

With regard to prevention, the key concept is avoidable anemia. Modern hospital strategies aim not only to correct iatrogenic anemia once established, but primarily to prevent it through a coordinated set of clinical and organizational interventions. International guidelines emphasize the importance of:

• Reducing unnecessary blood sampling: optimizing the frequency and volume of blood draws, using microsampling systems, avoiding duplicate diagnostic tests and preferring point-of-care testing whenever possible.
• Active monitoring of hematological parameters: identifying a downward hemoglobin trend early, stratifying risk and intervening promptly in vulnerable patients.
• Assessment and correction of nutritional deficiencies: targeted supplementation with iron, vitamin B12, folate and protein in patients with a documented risk of deficiency.
• Optimization of drug management: continually reassessing the need for myelotoxic drugs, antiplatelet agents and anticoagulants, and individualizing dose and duration.
• Prevention of surgical and postprocedural hemorrhagic complications: careful hemostasis, drain monitoring and individualized peri-procedural management of antithrombotic drugs according to the specific agent, procedure, bleeding risk and thrombotic risk; some drugs should be interrupted, while others may be continued.
• Implementation of patient blood management strategies: multidisciplinary involvement and use of evidence-based protocols to reduce transfusion requirements and optimize endogenous red blood cell production.

When applied systematically, these interventions can significantly reduce the incidence and severity of iatrogenic anemia and improve outcomes and quality of life among hospitalized patients.

Pathogenesis and pathophysiology

The pathogenesis of iatrogenic anemia represents the combined effect of multifactorial processes that often coexist and act synergistically, ranging from simple loss of red blood cell mass to impaired bone marrow production, increased red blood cell destruction and disturbances of iron metabolism and homeostasis. The pathophysiology differs clearly from that of primary anemias because it develops against a background of an already precarious balance that is continually stressed by the clinical and therapeutic events characteristic of modern hospitalization.

Most cases of iatrogenic anemia are based on one or more of the following mechanisms:

• Direct loss of red blood cells: serial blood sampling, particularly in intensive care patients, may result during hospitalization in clinically relevant cumulative blood loss, exceeding 200 to 400 mL per week in some studies and sometimes approaching the volume of a whole-blood donation. This is compounded by perioperative blood loss, occult or minor bleeding associated with invasive procedures, drainage and drug-related hemorrhage.
• Suppression or hyporesponsiveness of erythropoiesis: myelotoxic drugs and radiation may directly reduce precursor proliferation; inflammation and infection contribute mainly through cytokines, hepcidin and reduced response to erythropoietin, not through uniform direct marrow toxicity.
• Increased red blood cell destruction (hemolysis): artificial devices, microangiopathies associated with innovative therapies, and adverse reactions to drugs or transfusions may accelerate red blood cell turnover, shorten red blood cell survival and worsen anemia.
• Disturbed iron metabolism: iatrogenic anemia is often accompanied by dysregulation of iron metabolism, with sequestration in tissue stores, reduced recycling, increased hepcidin in response to systemic inflammation and, when blood loss is prolonged, progressive depletion of iron reserves.
• Deficiency of essential cofactors: deficiency of vitamin B12, folate, iron and protein reduces the compensatory capacity of erythropoiesis and may cause mixed anemia, including iron-deficiency and megaloblastic components, sometimes worsened by iatrogenic malabsorption or increased consumption during metabolic stress.

From a pathophysiological perspective, the progressive reduction in hemoglobin concentration decreases oxygen-carrying capacity and activates systemic compensatory mechanisms:

• Increased heart rate and cardiac output to maintain tissue perfusion
• Increased 2,3-diphosphoglycerate in red blood cells, which promotes oxygen release to tissues but reduces hemoglobin affinity for O₂
• Redistribution of blood flow toward vital organs, with a risk of subclinical ischemia in peripheral tissues
• Activation of the renin-angiotensin-aldosterone system, with sodium and water retention and expansion of plasma volume

When these mechanisms are insufficient, or when the hemoglobin deficit progresses rapidly, organ failure, tissue ischemia, deterioration in general condition and increased mortality occur, particularly in patients with limited cardiopulmonary reserve.

In patients receiving intensive care or undergoing major procedures, the pathogenesis of iatrogenic anemia is often complicated by concomitant chronic inflammation, multiorgan dysfunction, nosocomial infections and aggressive polypharmacy. This produces extremely variable clinical patterns, ranging from a slow and progressive, often underestimated reduction in hemoglobin to rapidly worsening acute anemia requiring massive transfusion and advanced hemodynamic support.

In summary, the pathophysiology of iatrogenic anemia is the final result of a complex interaction among red blood cell loss, production and destruction in a setting of clinical frailty and reduced functional reserve. Only an integrated approach that takes all components of the pathogenic process into account can ensure effective and individualized management.

Clinical manifestations

The clinical presentation of iatrogenic anemia is highly variable and depends on several factors, including the rate of onset, magnitude of the reduction in hemoglobin, preexisting functional status, comorbidities and the body's compensatory reserve. Because there is no universally applicable typical presentation, diagnostic suspicion almost always arises from the clinical context: a hospitalized patient undergoing repeated procedures, polypharmacy or a prolonged hospital stay who develops a progressive reduction in hemoglobin without another identifiable cause.

In many cases, iatrogenic anemia develops slowly and insidiously, masked by symptoms of the underlying disease or interpreted as part of the natural evolution of the clinical condition. Skin and mucosal pallor, progressive fatigue, reduced exercise tolerance and progressive tachycardia often become apparent only when hemoglobin falls below critical thresholds, particularly in patients with limited compensatory capacity, including older adults, patients with heart disease, chronic respiratory disease, cancer or kidney disease.

The most common symptoms and signs of iatrogenic anemia include:

• Skin and mucosal pallor; cool skin, reduced venous filling and delayed capillary refill instead suggest concomitant hypovolemia or hypoperfusion
• Marked fatigue, with easy fatigability, reduced walking ability and a need for assistance even with basic activities
• Resting tachycardia, palpitations and increased respiratory rate (tachypnea), even in the absence of preexisting cardiopulmonary disease
• Exertional dyspnea, which may rapidly progress to dyspnea at rest in severe cases
• Lightheadedness, vertigo and presyncope, particularly in patients prone to orthostatic hypotension, those with hypovolemia or patients receiving diuretics
• Reduced tolerance of acute metabolic stress, including fever, infection and surgery, with early development of signs of organ failure

In severe cases, especially when hemoglobin declines rapidly, signs of multiorgan failure may develop, including angina pectoris, acute heart failure, altered consciousness, oliguria and refractory hypotension.

The medical history has a central role: documentation of frequent blood sampling, recent surgical or invasive procedures, treatment with myelotoxic drugs or anticoagulants or antiplatelet agents, and the presence of chronic disease are strongly suggestive clues. Assessment of transfusion history, trends in hematological parameters during hospitalization and nutritional status helps distinguish iatrogenic anemia from primary anemia or acute forms unrelated to medical intervention.

On physical examination, in addition to pallor and tachycardia, anemic cardiac murmurs, typically systolic and accentuated by increased blood flow, orthostatic hypotension, signs of hypovolemia or hypoperfusion when present and, in advanced cases, signs of organ failure such as dependent edema, pulmonary crackles and neurological abnormalities may be detected. In patients with cardiovascular or respiratory comorbidities, even small reductions in hemoglobin concentration may precipitate clinical instability.

The severity of the clinical presentation depends not only on the absolute hemoglobin value, but primarily on the rate at which the deficit develops and the body's capacity to activate compensatory mechanisms. In young people without comorbidities, anemia may remain asymptomatic for a long time even when hemoglobin is moderately reduced; in older, frail or critically ill patients, symptoms may appear well before thresholds generally regarded as indications for transfusion in the general population are reached.

In hospitalized patients, anemia, neurocognitive abnormalities, functional decline, falls, length of stay and morbidity may be associated. These relationships do not establish iatrogenic anemia as an independent cause because underlying disease, frailty, medication and intensity of care are major confounders.

Investigations and diagnosis

The diagnosis of iatrogenic anemia is based on an integrated assessment combining clinical suspicion, including the risk context, symptoms and laboratory trends, with a sequential pathway of hematological and instrumental investigations. Correct identification requires rigorous distinction from other forms of anemia, characterization of the underlying causes and quantification of functional impairment, so that the most appropriate therapeutic strategies can be implemented promptly.

The first step is recognition of iatrogenic risk: anemia that begins or worsens during hospitalization, in the absence of evident spontaneous bleeding or known hematological disease, in a patient undergoing frequent blood sampling, surgery, myelosuppressive treatment, extracorporeal support or polypharmacy should always raise suspicion of an iatrogenic form.

The diagnostic workup includes:

• Complete blood count with red blood cell indices: this documents the reduction in hemoglobin and hematocrit and assesses MCV, MCH, MCHC and RDW. These parameters help identify microcytic, normocytic or macrocytic patterns and distinguish iatrogenic anemia from primary deficiency, hemolytic or dyserythropoietic forms.
• Peripheral blood smear: useful for detecting indirect signs of hemolysis, including schistocytes, spherocytes and fragmented red blood cells, characteristic morphological abnormalities such as microcytosis, macrocytosis and anisopoikilocytosis, or immature cells that may suggest iatrogenic or secondary bone marrow impairment.
• Measurement of hemolysis markers: LDH, indirect bilirubin, haptoglobin and reticulocyte count help exclude acute hemolysis associated with devices or transfusion reactions.
• Complete iron profile: serum iron, ferritin and transferrin saturation help distinguish pure iatrogenic anemia from forms associated with iron deficiency, which is often secondary to prolonged occult blood loss or postoperative or drug-induced malabsorption.
• Measurement of vitamin B12, folate, renal function and endocrine function: indicated when nutritional deficiencies, acute-on-chronic kidney disease or treatment-induced endocrine disorders are suspected.
• Liver function tests and inflammatory markers: useful for documenting an inflammatory context and interpreting iron indices; normal ESR or CRP values alone do not exclude a chronic or low-grade inflammatory component.

When occult blood loss is suspected, including minimal gastrointestinal bleeding, microhemorrhage from drains or hematuria, the following may be indicated:

• Investigation of a gastrointestinal source: in patients with iron-deficiency anemia or clinical suspicion of occult bleeding, assessment should be guided by age, sex, symptoms and risk; fecal occult blood testing or FIT should not be used alone to exclude or confirm a gastrointestinal cause of anemia
• Monitoring of perioperative blood balance, calculation of losses through collection and analysis of drainage output, and assessment of changes in hemoglobin before and after the procedure
• Ultrasound, CT or endoscopy when internal blood collections or clinically occult bleeding are suspected

Early identification of causes and predisposing factors is essential for targeted intervention. Review of the medication history to identify myelotoxic drugs, anticoagulants and antiplatelet agents, assessment of the frequency and volume of blood sampling, analysis of invasive procedures and documentation of hematological trends during hospitalization are often more effective than laboratory tests in identifying the iatrogenic nature of the condition.

The differential diagnosis must always include other causes of acute or chronic anemia, including spontaneous hemorrhage, primary hematological disease, autoimmune hemolysis, isolated nutritional deficiency anemia and acute or chronic infection. Only an integrated and context-specific assessment can establish a diagnosis of “pure” iatrogenic anemia, avoiding delays in correcting aggravating factors and individualizing patient management.

In summary, diagnosis of iatrogenic anemia is a sequential, reasoned process that begins with recognition of the risk context and suggestive symptoms, proceeds through a detailed laboratory and diagnostic evaluation, and concludes with identification of modifiable causes and risk factors so that prompt and effective treatment can be initiated.

Treatment and prognosis

The management of iatrogenic anemia requires a systematic and multidisciplinary approach aimed not only at correcting the hemoglobin deficit, but also, and above all, at removing or mitigating causal factors, preventing recurrence and optimizing the overall quality of care. Unlike many primary anemias, iatrogenic anemia is often potentially preventable and reversible, provided that intervention is timely and integrated.

The first therapeutic objective is always to identify and correct the underlying causes:

• Reduce the frequency and volume of blood sampling through microsampling, rationalization of test requests and minimization of duplicate investigations.
• Modify or discontinue, whenever possible, nonessential myelotoxic drugs, anticoagulants or antiplatelet agents; assess the need for bridging therapy and individualize doses according to each patient's bleeding and ischemic risk.
• Correct nutritional deficiencies, including iron, vitamin B12, folate and protein, through targeted supplementation, particularly in patients with malnutrition, kidney disease, cancer, parenteral nutrition or malabsorption.
• Prevent perioperative and postprocedural blood loss through careful hemostasis, individualized management of drugs affecting hemostasis according to bleeding and thrombotic risk and the type of procedure, drain monitoring and active surveillance of blood balance.

In clinically compensated mild to moderate anemia, removal of causal factors and iron/nutritional supplementation may be sufficient to promote hemoglobin recovery, which generally occurs over weeks and depends on cause, marrow function and persistence of blood loss. Serial blood-count and clinical monitoring identifies patients requiring more intensive intervention.

In more severe or symptomatic cases, particularly when cardiovascular comorbidity, respiratory failure or signs of organ dysfunction are present, red blood cell transfusion may be required. The decision to transfuse is not based on a fixed hemoglobin threshold, but must always be considered in relation to the overall clinical condition, rate of onset of anemia and evidence of tissue hypoxia. International guidelines recommend a restrictive approach: in hemodynamically stable hospitalized adults, transfusion should be considered when hemoglobin is <7 g/dL, integrating symptoms, bleeding, cardiovascular comorbidity and the specific clinical context into the decision. Acute myocardial infarction is an exception: in patients hospitalized with acute myocardial infarction, the 2025 AABB guideline suggests a liberal strategy when hemoglobin is <10 g/dL, with a conditional recommendation and low certainty of evidence.

Transfusions should use leukoreduced blood components according to local standards and, in selected patients, antigen matching beyond ABO/RhD, with careful monitoring of adverse reactions and hemodynamic parameters. In patients at risk of volume overload, heart failure or hemodilution, slow and fractionated administration is preferable, with careful assessment of the balance between benefits and risks.

A crucial aspect of contemporary management of iatrogenic anemia is the implementation of patient blood management (PBM) programs, based on the following principles:

• Optimization of endogenous red blood cell production through correction of deficiencies and erythropoietic stimulation when indicated
• Minimization of iatrogenic and surgical blood loss
• Implementation of individualized transfusion strategies with rigorous clinical and laboratory monitoring

These internationally validated programs reduce transfusion exposure and may improve processes and outcomes in specific settings; effects on length of stay, complications, costs, prognosis and quality of life vary by program and patient population.

In iatrogenic anemia, erythropoiesis-stimulating agents may be considered only for recognized indications, chiefly anemia associated with chronic kidney disease or chemotherapy in selected patients. They are not general treatment for marrow suppression or erythroblastopenia. Their use must balance the specific indication, thrombotic risk and individual response.

The prognosis of iatrogenic anemia is generally favorable when the condition is recognized early, its causes are corrected and progression to severe or complicated forms is prevented. In frail patients, those with multiple comorbidities or when diagnosis is delayed, iatrogenic anemia is associated with longer hospitalization, in-hospital mortality and major complications, including ischemic events and organ failure, while infections depend mainly on the underlying disease, procedures and associated treatments. The quality of follow-up, timely corrective intervention and individualization of PBM strategies are major prognostic determinants.

Complications

The complications of iatrogenic anemia result from the interaction between impaired tissue oxygenation, adverse effects of treatment, particularly transfusion and medication, and worsening of preexisting disease. Although the condition is often reversible, consequences may be severe and sometimes fatal in frail patients or when it is not recognized.

The principal complications include:

• Acute and chronic heart failure: reduced oxygen transport increases cardiac workload and may precipitate ventricular failure, particularly in patients with coronary artery disease, cardiomyopathy or valvular stenosis.
• Myocardial and cerebral ischemia: reduced oxygen reserve may promote angina, myocardial infarction, arrhythmia, transient ischemic attack or stroke, particularly in patients with advanced atherosclerosis.
• Respiratory failure: severe anemia worsens hypoxia in patients with chronic obstructive pulmonary disease (COPD), pulmonary fibrosis or chronic respiratory failure.
• Worsening organ failure, including renal, hepatic and neurological failure, particularly in critically ill patients with multiple comorbidities.
• Infection risk related to the clinical context: nosocomial infection and sepsis depend mainly on the underlying disease, invasive procedures, immunosuppression, neutropenia and length of stay; anemia does not itself cause immunosuppression.
• Transfusion complications: febrile, hemolytic or allergic reactions, volume overload, transmission of infectious agents and red blood cell alloimmunization, which is more common in patients receiving multiple transfusions or those with rare antigens.
• Cognitive and functional impairment: apathy, psychomotor slowing, increased risk of delirium and falls, and loss of residual independence in older adults.
• Association with prolonged hospital stay, loss of independence and in-hospital mortality: observed especially in intensive care, orthopedics, major surgery and geriatrics, with substantial clinical confounding.

Finally, recurrent episodes of iatrogenic anemia, particularly in the absence of preventive strategies, create a vicious cycle of increasing clinical frailty, worsening comorbidities and greater risk of major complications, with adverse effects on both healthcare costs and quality of life for patients and caregivers.

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