Critical Care Medicine
Anemia; Low hemoglobin, low hematocrit, low red cell count
- 1. Description of the problem
2. Emergency Management
- 3. Diagnosis
- 4. Specific Treatment
- 5. Disease monitoring, follow-up and disposition
Special considerations for nursing and allied health professionals.
What's the evidence?
Low hemoglobin, low hematocrit, low red cell count
Aplastic anemia; myelodysplasia; paroxysmal nocturnal hemoglobinuria; myeloproliferative disorders (essential thrombocythemia, myelofibrosis, chronic myelogenous anemia); pure red cell aplasia; chronic renal failure; endocrine-related anemias; drug-induced marrow failure (chemotherapy, other); megaloblastic anemias; nutritional anemias (including iron deficiency); thalassemia; hemoglobinopathies, traumatic blood loss; non-immune congenital hemolytic processes (hereditary spherocytosis, hereditary elliptocytosis, hereditary pyropoikilocytosis); congenital enzymopathies [glucose-6-phosphate dehydrogenase (G6PD) deficiency, fructose-6-phosphate (F6P) deficiency]; non-immune acquired hemolytic disorders [heart-valve hemolysis, march hemoglobinuria, thrombotic thrombocytopenic purpura (TTP), hemolytic-uremic syndrome (HUS), vasculitis, other microangiopathic conditions]; immune-mediated hemolysis (autoimmune hemolytic anemia (AIHA), cryopathic immune hemolytic anemia, drug-induced, delayed hemolytic transfusion reactions, ABO-Rh mismatch); sideroblastic anemia; anemia of chronic disease; myelophthisic anemias; hypersplenism; hemophagocytic lymphohistiocytosis (HLH); infectious marrow failure syndromes (parvovirus, microbacterium avium intracellulare [MAI])
1. Description of the problem
What every clinician needs to know
The physiological effect of anemia is a function of: (1) the interval over which the anemia develops, and (2) the overall hemoglobin level. In general, anemias that evolve over a long interval will have a less pronounced clinical impact than anemias that develop acutely.
The relative importance of anemia--of any cause--is determined by (1) the extent to which tissue oxygen delivery is compromised, and (2) whether the anemia is deteriorating, stable, or improving. Inadequate tissue oxygen delivery may be indicated by physical signs (tachycardia, tachypnea) or symptoms (chest pain, deteriorating cognitive function).
Anemias can be categorized into three main pathophysiologies: (1) erythrocyte loss (hemorrhage, third-space bleeds), (2) accelerated erythrocyte destruction (hemolytic anemias), and (3) decreased production (reticulocytopenia). Some anemias may result from more than one pathophysiology (e.g., gastrointestinal losses and nutritional reticulocytopenia in alcoholics).
Knowledge of the relevant pathophysiology can guide diagnostic and treatment strategies. For example, hemorrhagic blood loss requires attention to the integrity of anatomic and coagulation systems and is generally responsive to red cell transfusion.
In contrast, anemias resulting from accelerated red cell destruction suggest congenital, immune-mediated, or toxic pathophysiologies that, as a group, will exhibit a less predictable response to red cell transfusion and may require additional disease-specific therapies. Reticulocytopenic anemias can result from nutritional, toxic, infectious, malignant, and/or other conditions and may respond to red cell transfusions, but will commonly require additional, disease-specific therapy.
Anemias can also be categorized using other discriminants. One common method distinguishes anemias according to cell size (mean corpuscular volume, MCV) and/or amount of intracellular hemoglobin (mean corpuscular hemoglobin, MCH). Common conditions resulting in a hypochromic microcytic anemia (low MCV and MCH) include thalassemia and iron deficiency; and, less commonly, anemias associated with chronic inflammatory conditions, genetic determinants for Hb C, congenital defects in copper metabolism, some forms of sideroblastic anemia, and other conditions.
Elevations in MCV are typically observed in B12- or folate-deficient states, and can be observed in hypothyroid states or in liver disease. High MCV values are also commonly observed in anemias accompanying myelodysplastic disorders. MCV values can be elevated in the setting of brisk reticulocytosis (reticulocytes are larger than mature erythrocytes) or as an artifact resulting from red cell agglutination.
Normal values for MCV can result from coincident microcytic and macrocytic conditions; this state can be deduced from a particularly large RDW, as well as from microscopic examination of the peripheral smear. Elevations in MCV values are generally paralleled by increases in MCH values. Isolated increases in mean corpuscular hemoglobin concentration (MCHC) value (with normal MCV values) are commonly observed in hereditary spherocytosis. The diagnostic utility of the MCV is reduced or even eliminated in patients who have received one or more transfusions.
Anemias can also be categorized by whether they are (a) congenital (e.g., sickle-cell disease, thalassemias, enzymopathies), or (b) acquired (e.g., AIHA, myelophthisic, hemorrhage, or anemia of chronic disease). The patient's medical records provide an invaluable resource for differentiating congenital from acquired etiologies.
In all conditions, the risks associated with anemia are separate from the risks associated with the underlying medical condition (e.g., anemia accompanying an acute leukemia).
Signs and symptoms
Signs: hypotension, tachycardia, tachypnea, pallor, ecchymoses, hemorrhage.
Symptoms: fatigue, weakness, shortness of breath, chest pain, low exercise tolerance, lightheadedness, cognitive impairment.
Key management points
1. Determine whether the anemia is contributing to tissue hypoxia and/or tissue damage. If so, the patient may benefit from transfusion with packed red blood cells. The risks of standard red cell transfusions may be elevated under some conditions, including hyperhemolysis (an unusual complication of sickle-cell disease), iron-overload conditions, post-transfusion purpura, cardiopulmonary failure or other volume-overload states, religious objection, unavailability of ABO- and crossmatch-compatible product.
A few circumstances may require special preparation of donor red cells by the blood bank: massive ongoing hemorrhage (limited crossmatch), profound autoimmune hemolytic anemia ('least incompatible units'), post-transfusion purpura (washed or filtered units), pre-transplant transfusion (irradiated and leukodepleted red blood cells), patients with sickle cell anemia (C-negative, E-negative, and Kell-negative red blood cells).
Questions and/or concerns about these and other special circumstances should be directed to blood bank personnel when the patient sample is first submitted to the blood bank for typing and crossmatch analysis.
2. Identify chief cause of anemia (blood loss, red cell destruction, marrow failure), its origin (acute vs. chronic), and its tempo (ongoing vs. convalescent). Review medical history to assess possible chronic and/or congenital causes of anemia. Perform physical exam to investigate obvious sites of bleeding, as well as occult (gastrointestinal, third-spacing) hemorrhage. Send samples for diagnostic work-up (see below). Note that serial measures of Hb/Hct will aid in determining both the degree of the anemia, as well as its evolution.
3. Hematological subspecialists will typically request some or all of the following at initial consult: CBC with platelets and leukocyte counts, coagulation studies (prothrombin time, PT and activated partial thromboplastin time, aPTT), peripheral blood smear, reticulocyte count, and markers of hemolysis [lactate dehydrogenase, LDH, haptoglobin, bilirubin (direct and indirect)]; and, less commonly, iron studies (iron, transferrin, ferritin), nutritional studies (folate, vitamin B12), and tests for red-blood cell antibodies (Coombs' direct and indirect).
2. Emergency Management
For all anemias: Assess the physiological impact of the anemia; Hb values >10 g/dL are generally well tolerated. Identify the pathophysiology (hemorrhage, destruction, marrow failure). The benefits of transfusion for patients with erythrocyte loss (hemorrhage) or destruction (hemolysis) will be temporary unless the underlying defect is corrected.
Hemorrhage: Send patient samples to blood bank for typing and crossmatch analyses. Identify the site(s) of hemorrhage. Assess causative factors: loss of vascular integrity (trauma, surgery, vascular rupture), coagulopathy (quantitative or qualitative platelet disorder, abnormal PT or aPTT). Determine tempo of anemia with serial CBCs and measures of physiological compensation (reticulocytosis).
Conditions of severe hemorrhage may require massive or continuous transfusion, which can be exacerbated by corresponding decreases in levels of platelets and/or coagulation factors resulting from blood loss and/or utilization in thrombotic processes. Platelets and coagulation factors should be replaced to levels that permit normal hemostasis.
Destruction: Send patient samples to blood bank for typing and crossmatch analyses. Assess causative factors: (a) hereditary (hemoglobinopathies, thalassemias, spherocytosis, G6PD deficiency, other enzymopathies), (b) mechanical (microangiopathies, including heart-valve hemolysis, TTP, and march hemoglobinuria), (c) nonimmune (malaria, chemical agents), and (d) immune (auto- and alloimmune processes, drug-related). Determine tempo of anemia with serial CBCs and measures of physiological compensation (reticulocytosis). Red-cell transfusions may be helpful in stabilizing the patient.
Reticulocytopenia: Send patient samples to blood bank for typing and crossmatch analyses. Assess causative factors: hereditary, progenitor cell defects (pure red cell aplasia, renal/endocrine disorder), nutritional (iron, folate, vitamin B12), chronic disease, infection (parvovirus), marrow infiltration (tumor, infection, fibrosis), pharmaceuticals and other drugs. Assess tempo of anemia. Red-cell transfusions may be helpful in stabilizing the patient.
In the setting of ongoing blood loss, blood transfusion, and/or volume repletion, laboratory values for hemoglobin and hematocrit may not accurately reflect the deficit in total body red cell mass. Repeat CBCs should be obtained at appropriate intervals until the patient's Hct and Hb values are stabilized at a level that is compatible with physiological demands.
For all anemias: Because many therapies--especially erythrocyte transfusions--can interfere with the diagnostic workup, it is generally recommended that, if possible, relevant studies of whole blood, plasma, and serum are obtained prior to initiating therapy.
Minimal initial evaluation for clinically significant anemias includes CBC with red cell indices, and enumeration of both platelets and leukocyte; coagulation studies (PT and aPTT); peripheral blood smear examination; and reticulocyte count. As a practical matter, iron studies (iron, transferrin, ferritin), nutritional studies (folate, vitamin B12), and markers of hemolysis [LDH, haptoglobin, bilirubin (direct and indirect)] are commonly obtained at the same time.
Hemorrhagic: Critical blood count (CBC) with indices (MCV, MCH, MCHC). Platelet count. Tests of hemostasis (PT, aPTT). Reticulocyte count. Examine peripheral smear. History/chart review (chronicity of disorder), including a drug history for antiplatelet or anticoagulation agents. Fecal occult blood and imaging studies (retroperitoneum, thighs, sites of recent surgery/trauma) if the site of bleeding is not obvious. Less commonly: platelet function studies, von Willebrand evaluation, iron studies.
Destructive: Critical blood count (CBC) with indices (MCV, MCH, MCHC). Platelet count. Tests of hemostasis (PT, aPTT). Reticulocyte count. Examine peripheral smear. Coombs direct/indirect studies. Tests for markers of hemolysis [LDH, haptoglobin, bilirubin (indirect and direct)]. Autoimmune serologies (ANA, ESR). Fibrinogen, D-Dimer (or fibrin split products). Red cell enzymes (G6PD). History/chart review (chronicity of disorder), including a drug history for recently prescribed agents associated with non-immune hemolysis. Less commonly: thick smear prep (parasites), Hb electrophoresis (some hemoglobinopathies and thalassemias), flow cytometry (CD55 for PNH), cardiac valve and/or renal artery imaging.
Reticulocytopenic: Critical blood count (CBC) with indices (MCV, MCH, MCHC). Reticulocyte count. Examine peripheral smear. Nutritional studies [iron (serum iron, transferrin, ferritin), folate, vitamin B12]. Blood tests for renal and liver function. Platelet count; tests of hemostasis (PT, aPTT). History/chart review (chronicity of disorder), including a history for agents with predictable (chemotherapy) or sporadic marrow-suppressive effects; history of alcohol, radiation, and/or industrial exposures. Less commonly: erythropoietin levels, bacterial cultures, parvoviral serologies, bone marrow biopsy, tests for autoimmune disease, cancer, and occult infection.
The morphology of a patient's erythrocytes can frequently provide insights into the etiology of an anemia; these determinations require microscopic examination of a stained peripheral smear by hematologists and/or trained laboratory staff.
Reticulocyte levels can provide clues to the temporal evolution of the anemia, as well as the adequacy of the marrow response. Uncomplicated, sub-acute and chronic anemias will display a variable elevation in the reticulocyte count; the absence of a reticulocytosis in this setting should prompt a search for a coincident reticulocytopenic condition. Acute anemias (e.g., traumatic hemorrhage) will also display a compensatory reticulocytosis, although this response may take several days to manifest.
As a measure of compensatory marrow erythropoiesis, reticulocyte levels must be corrected for the degree of anemia. This is done by multiplying the observed reticulocyte count by the ratio of the patient's hematocrit to a normal hematocrit. The resulting number is known as the reticulocyte index (RI). Low RI values indicate an erythropoietic response that is inappropriate to the level of anemia, a situation that can occur in the context of a reticulocytopenic state, or in the setting of acute blood loss/destruction where the erythropoietic response is not yet fully compensatory.
Microcytic hypochromic erythrocytes (low MCV, low MCH): characteristic of thalassemias and iron-deficient states.
Sickled cells (drepanocytes): correspond to sickle-cell disease; infrequently observed in sickle-cell trait.
Spur cells (acanthocytes): observed in alcoholic liver disease, abetalipoproteinemia, and other less common conditions.
Burr cells (echinocytes): can indicate uremia or pyruvate kinase-deficient states. Burr cells are commonly observed as an artifact of peripheral smear preparation.
Elliptocytes (ovalocytes): common in iron deficiency, thalassemia, and hereditary elliptocytosis.
Target cells (codocytes): seen in thalassemias, hemoglobinopathies (hetero- or homozygosity for Hbs S, C, E), iron deficiency, and obstructive liver disease.
Teardrop cells: characteristic of myelofibrosis and many myelophthisic disorders (marrow space-occupying conditions).
Spherocytes: common in hereditary spherocytosis, but can also be seen in immune-mediated anemias.
Fragmented cells (schistocytes): observed in a number of disorders, including TTP, HUS, diffuse carcinomatosis, malignant hypertension, eclampsia, allograft rejection, cardiac valvular disease, glomerulonephritis, march hemoglobinuria, and in some cases of diffuse intravascular coagulation (DIC).
Red cell inclusion bodies: Howell-Jolly bodies (spherical basophilic bodies comprising nuclear remnants) occur in hyposplenic states including post-splenectomy and sickle-cell disease, and less commonly in hemolytic anemias and megaloblastic anemias. Basophilic stippling (persistent RNA) is associated with lead intoxication, thalassemia, and conditions characterized by defective heme synthesis.
Nucleated RBCs: almost always indicate a severe underlying pathology, including severe anemia, myelodysplasia, TTP, critical illness, and post-resuscitation.
Confirming the diagnosis
Low (and high) values for hemoglobin or hematocrit should be confirmed by repeat analysis.
There are specific situations in which spurious values for Hb or Hct can be observed, including:
(1) Dilution with intravenous fluid when sample has been drawn through an indwelling line. If possible, samples should be re-drawn by direct venipuncture. A similar artifact can arise when samples are drawn from a site that is proximal to an intravenous access site.
(2) Lipemia and icterus, which can interfere with hemoglobin determination. In this case the clinical laboratory should report a "spun hematocrit" or "packed-cell volume".
(3) Cold agglutinin antibodies can produce erythrocyte clumping, resulting in erroneous values for RBC number (falsely decreased) and MCV (falsely elevated). In many cases agglutination can be reversed by warming the blood sample prior to analysis. Cold agglutinins do not affect accuracy of spun hematocrit measurements.
Abnormal proteins (myeloma, cryofibrinogens) can interfere with RBC analyses; spun hematocrit measurements are reliable under these conditions.
4. Specific Treatment
Red blood cell transfusions should be considered for clinically significant anemias, particularly if there is evidence for cardiovascular compromise, or signs of tissue hypoxia and/or damage. For hemorrhagic etiologies, anatomic/structural vascular defects should be identified and repaired, and disorders of the coagulation pathway corrected (including platelet number, platelet function, and levels and functions of individual coagulation factors).
Transfusion goals should include (a) maintaining organ oxygenation, and (b) accommodating anticipated loss of functional circulating red blood cells through hemorrhage and/or hemolysis. Consider complicating factors [fluid overload, cardiopulmonary compromise, religious objection, immune dysregulatory state (hyperhemolysis, post-transfusion purpura)]. Transfusion goals may differ depending upon the degree and chronicity of the anemia, and the extent to which it compromises organ function. A target Hb>10 may improve hemostasis in some settings.
PO: Preferred route of administration. Goal is to provide 150 - 200 mg elemental iron per day. Available as ferrous fumarate (106 mg elemental iron/tablet); ferrous sulfate (65 mg elemental iron/tablet); ferrous gluconate (36 mg elemental iron/tablet).
IV: Concern for anaphylactic reactions; most formulations require a 'test' dose. Available as ferric gluconate (test dose, followed by 125 mg in 100 ml saline infused over 30 - 60 minutes); iron sucrose (test dose, followed by 200 mg over 60 minutes); iron dextran (test dose, followed by treatment dose).
Transfused blood: One unit of transfused blood contains approximately 250 mg of iron.
Folate: 1 mg PO or IV daily; chronic hemolytic states may require higher doses.
Vitamin B12: 1 mg SQ daily for one week, then 1 mg SQ weekly for 4 weeks; can also be administered PO 1-2 mg/day. The etiology of vitamin B12-deficient states should always be determined.
Erythropoietin: Dose may vary; typically 75-150 units/kg SQ weekly.
Rituxan: 375 mg/m2 IV weekly for 4 weeks.
Schedules for other agents vary widely depending upon the specific condition that is being treated and the patient's underlying medical condition; these pharmaceuticals include steroids and other immunosuppressive agents, intravenous immunoglobulins, replacement hormones, and chemotherapeutic agents.
An attempt should be made to determine the nature of the underlying anemia (blood loss, red cell destruction, marrow failure). For refractory cases, consider the possibility that the etiology of the anemia has evolved (e.g., a new nutritional anemia in a patient who recently completed marrow-suppressive chemotherapy), or that the anemia reflects more than one pathology (co-existing gastrointestinal hemorrhage, marrow suppression, and nutritional deficiency in a chronic alcoholic). Identify and treat any underlying disorders. Provide supportive care, including colloid, crystalloid, and/or red cell transfusions as required. Consult a hematological subspecialist to assist with diagnosis and management.
5. Disease monitoring, follow-up and disposition
Several conditions can alter the half-life of both normal and transfused red blood cells. Rapid decreases in post-transfusion Hb/Hct should prompt (a) a search for occult blood loss, (b) consideration of a delayed hemolytic transfusion reaction, (c) evolution of an autoimmune disorder, and (d) consideration of a drug effect. The prognosis of an anemia is largely dictated by the prognosis of the corresponding underlying disorder. The patient should be continually monitored and supportive care provided while disease-specific therapy is administered.
Several features of the CBC may suggest the presence of artifacts in measures of Hb or Hct: (a) a Hb:Hct ratio that does not approximate 1:3; (b) serial values for Hb or Hct that vary widely or do not suggest a clear trend, or that are inconsistent with the patient's clinical course, (c) an increase in Hb in the context of reticulocytopenia, or (d) a decrease in Hb in the setting of reticulocytosis that cannot be explained otherwise.
In all cases, laboratory tests should be repeated using samples that are drawn by direct venipuncture (not through a vascular access line, and not proximal to an intravenous access site). Note that automated values for Hb can be affected by lipemia, icterus, cold agglutinin antibodies, and by some abnormal proteins (myeloma, cryofibrinogens). Spun hematocrit measurements are generally reliable under all of these conditions.
Consult a hematology subspecialist
Anemia reflects blood loss that exceeds replacement by physiological marrow erythropoiesis and/or red cell transfusions. In many cases the location of hemorrhage may be obvious--or easily deduced--from the patient's history and physical exam: trauma, surgical sites, extensive hematoma, melana, hematemesis, menorrhagia, epistaxis, third-space hemorrhage (Cullen's sign, Turner's sign).
In other cases the site of blood loss may be difficult to determine, requiring endoscopic examinations and/or imaging studies of the retroperitoneum, peritoneum, and soft tissue. Hemorrhagic anemia can be complicated by qualitative or quantitative platelet defects, and by congenital, acquired, or therapeutic changes in the quantity or activity of blood coagulation proteins.
Destructive defects can be broadly classified as inherited, mechanical, acquired non-immune, and acquired immune.
Inherited anemias of this type can result from congenital defects in hemoglobin, metabolic enzymes, and/or red cell membranes. These defects, which result in increased clearance of red cells through a number of different mechanisms, generally result in accelerated destruction of red blood cell progenitors in the marrow (ineffective erythropoiesis) and shortened half-life of mature erythrocytes in the peripheral circulation (hemolysis).
As a group, these disorders are characterized by markers of hemolysis (increased LDH and bilirubin, reduced haptoglobin) with normal Coombs studies, as well as a compensatory elevation in erythropoiesis (can manifest as a reticulocytosis).
Mechanical anemias of this type can be traced to defects in normal vascular flow by therapeutic devices (artificial heart valves, extracorporeal circulation), structural defects (aortic stenosis, renal artery stenosis), or several conditions that result in microvascular occlusion. This last group of disorders includes the microangiopathies, which are characterized by fragmented red cells (schistocytes), including DIC, TTP, HUS, eclampsia, carcinomatosis, allograft rejection, and malignant hypertension.
Non-immune conditions that result in red cell destruction include malaria, chemical agents that are directly toxic to red cells, and thermal injury (burns).
Immune processes that cause red cell destruction typically result from the deposition of antibodies on the red cell membrane. The specific clinical manifestation may depend upon the antibody class: IgG antibodies are directed against red cell membrane proteins, while IgM antibodies typically target membrane polysaccharides. Auto-antibodies may occur spontaneously, or in response to an inciting factor (e.g., infection or drug).
IgG ('warm-reacting') antibodies generally adhere to red cell membranes at or near core body temperature, while IgM ('cold-reacting') antibodies may display a lower thermal amplitude. Blood-bank studies based upon the Coombs principles can generally distinguish autoimmune from non-immune causes of hemolysis.
In healthy individuals, red blood cells survive in the peripheral circulation for approximately 100-120 days. Senescent cells are continuously removed by the reticuloendothelial system and are replaced by maturing red blood cells that are released from the bone marrow into the peripheral circulation (generally at the reticulocyte stage of development). Conditions that reduce marrow erythropoiesis--even in the absence of hemorrhage or pathological destruction--can result in significant anemia.
Nutritional deficiencies (iron, vitamin B12, folate) are common causes of reticulocytopenic (hypoproliferative) anemias, as are a several infections, including parvovirus. Toxic, malignant, and other conditions can produce hypoproliferative anemias, while inflammatory conditions can produce defects in iron trafficking and a corresponding "anemia of chronic disease."
The wide variability in the reported prevalence of anemia results, in part, from the lack of standard universal definitions. As a general rule, anemias can be defined as hemoglobin values <13 g/dL in men, and <12 g/dL in women (World Health Organization). A high prevalence of anemia is observed in elderly inpatients and in nursing-home residents.
Anemia in this elderly population has been associated with increased morbidity and mortality, and is commonly attributed to nutritional deficiencies (iron, vitamin B12, and folate), chronic medical conditions, myelodysplasia, and/or other etiologies, including MDS.
The prognosis for a patient with anemia is generally determined by the underlying disorder, but can also depend upon the speed and accuracy with which the pathophysiology of the anemia is identified; this is particularly true for hemorrhagic and destructive causes of anemia.
Special considerations for nursing and allied health professionals.
What's the evidence?
Description of the Problem:
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Greer, JP, Foerster, J, Lukens, JN, Rodgers, GM, Paraskevas, F, Glader, B. Wintrobe's Clinical Hematology. Lippincott Williams & Wilkins. 2004.
Adamson, JW. "The erythropoietin/hematocrit relationship in normal and polycythemic man: Implications of marrow regulation". Blood. vol. 32. 1968. pp. 597-609.
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Cotes, PM, Tam, RC, Reed, P, Hellebostad, M. "An immunological cross-reactant of erythropoietin in serum which may invalidate EPO radioimmunoassay". Br J Haematol. vol. 73. 1989. pp. 265-8.
Goodnough, LT, Price, TH, Parvin, CA. "Erythropoietin response to anaemia is not altered by surgery or recombinant human erythropoietin therapy". Br J Haematol. vol. 87. 1994. pp. 695-9.
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Disease Monitoring, Follow-up and Disposition:
World Health Organ Tech Rep Ser. vol. 405. 1968. pp. 5.
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