Which of the following statements regarding anemia in hospitalized patients is MOST correct?
Correct Answer: A
Reasons for anemia in hospitalized patients are myriad and can include exacerbation of an underlying disease, blood loss from procedures, hemodilution from fluid administration, and impaired erythropoiesis. Phlebotomy for diagnostic purposes is also major cause of anemia. One study showed that 74% of patients developed anemia during their hospitalization.
Evaluation of the RBC indices can help determine the cause of anemia. The mean corpuscular volume (MCV) is the average volume of the patient’s RBC and can be low, normal, or elevated. Microcytic RBCs are formed because of decreased production of hemoglobin, which can be due to abnormal globin (thalassemias) or heme (sideroblastic anemias) production or lack of iron (iron-deficiency, anemia of inflammation). Iron studies can help elucidate the cause of microcytic anemias. Iron-deficiency anemia is characterized by low serum iron, a high transferrin, and low ferritin levels. Anemia of inflammation is associated with low iron levels due to reduced iron absorption from the gastrointestinal tract as well as decreased release of iron from body stores. The serum transferrin is usually normal to low and serum ferritin is usually normal to high. Serum iron and ferritin levels are usually normal to high in sideroblastic anemias and thalassemias.
An elevated MCV (macrocytic) is usually due to red cell membrane defects or DNA synthesis defects. Defects in DNA synthesis is associated with folate or vitamin B12 (cobalamine) deficiency, abnormal RBC maturation (eg myelodysplastic syndrome), or certain chemotherapeutic medications. Liver disease or hypothyroidism can cause red cell membrane defects.
However, the RBCs are normal sized (normocytic) in many cases. In these cases, it may be helpful to determine the mechanism underlying the anemia. Mechanisms leading to anemia include decreased RBC production, increased RBC destruction, and blood loss. These mechanisms are not mutually exclusive and can be operating at the same time in a patient.
The reticulocyte count can help distinguish between decreased RBC production and increased RBC destruction. However, because the reticulocyte count is often reported as a percentage of all RBCs, it can be falsely elevated in anemia. Furthermore, younger reticulocytes with a longer lifespan are released into the circulation in the setting of anemia. The reticulocyte production index is a calculated index that corrects for both hematocrit and reticulocyte lifespan.
A 57-year-old man has been in the ICU for 10 days with acute respiratory distress syndrome (ARDS) and sepsis due to pneumonia. His hemoglobin level is 7.5 g/dL.
Which of the following statements is MOST correct regarding management of his anemia associated with critical illness?
Correct Answer: D
Anemia is common in ICU patients. Ninety-seven percent of critically ill patients are anemic by day 8. Anemia results from RBC loss from injury, phlebotomy, procedures, etc., and decreased RBC production. Hepcidin plays a central role in iron homeostasis. Its synthesis is upregulated by inflammatory cytokines, resulting in decreased iron absorption and decreased release of iron from body stores creating an iron-deficiency–like state. Decreased renal function and proinflammatory cytokines decrease EPO production.
In a prospective, multicenter, randomized, double-blind, placebocontrolled trial involving 1460 patients, the use of recombinant human EPO (epoetin alfa) to treat anemia in critically ill patients was not associated with decreased red transfusions using a target hemoglobin concentration between 7 and 9 g/dL. In this study, patients who received EPO had a higher rate of thrombotic events if they did not receive prophylactic or therapeutic doses of heparin. Overall mortality was the same between the group that received EPO and the group that received placebo.
The use of iron supplementation is controversial in critically ill patients because it can promote bacterial growth and infection. Hepcidin’s upregulation by inflammatory cytokines may be protective. One multicenter, randomized, placebo-controlled trial of intravenous iron supplementation in critically ill trauma patients showed no difference between groups in hemoglobin concentration, packed red blood cell transfusion requirement, risk of infection, length of stay, or mortality at 14 days. A meta-analysis of five randomized controlled trials involving 665 patients showed iron supplementation did not reduce RBC transfusion. However, the strength of this conclusion is limited by moderate heterogeneity between the studies.
In a study comparing a transfusion threshold of 9 versus 7 g/dL in patients with septic shock, there was no difference in 90-day mortality, rates of ischemic events, or use of life support between the two groups. Patients assigned to the lower transfusion group received fewer transfusions. The Surviving Sepsis guidelines recommend not transfusing RBCs in adults with sepsis until the hemoglobin falls below 7.0 g/dL.
Phlebotomy can result in a daily loss of 40 to 70 mL of blood in a critically ill patient exceeding the basal RBC formation rate of 15 to 20 mL/d under normal conditions. Strategies to minimize blood loss such as use of small volume phlebotomy tubes, point-of-care testing, reinfusion of discard sample from indwelling lines, and reducing the number of laboratory studies obtained can decrease this source of blood loss.
Which of the following statements regarding red blood cell transfusion in critically ill patients is MOST correct?
Correct Answer: C
The primary goal of red blood cell transfusion is to improve oxygen delivery. However, potential adverse effects include transfusion reactions, infection, transfusion-related acute lung injury (TRALI), transfusionrelated circulatory overload (TRCO), and transfusion-related immunomodulation (TRIM).
Transfusions are associated with immunosuppression (TRIM) and may result in an increased risk of nosocomial infections in hospitalized patients. One small, retrospective study found a dose-related response between the number of transfusions, and the risk for infection showed a dose-response relation such that the risk of infection increased by a factor of 1.5 for each unit transfused. A meta-analysis of 17 randomized trials comparing restrictive versus liberal RBC transfusion strategies involving 7456 patients found an increased risk of serious infections among patients treated with a liberal transfusion strategy with a number needed to treat (NNT) of 48 with a restrictive strategy in order to prevent serious infections.
Leukoreduction not only removes donor leukocytes from packed RBCs but also filters inflammatory mediators (eg, tumor necrosis factor [TNF-α], interleukin-1 [IL-1]) and viruses transmitted via leukocytes (eg, EpsteinBarr virus [EBV], cytomegalovirus [CMV]), and reduces human leukocyte antigen (HLA) alloimmunization. Multiple studies have been performed looking at the effect of transfusion leukoreduced RBCs on infection, organ dysfunction scores, mortality, and risk of ARDS. Many of these studies are limited by size and study design but show no advantage to using leukoreduced RBCs.
The maximum storage period for RBC units is 42 days as mandated by the US Food and Drug Administration. However, the storage of blood for longer periods results in changes in the RBC membrane, which can impede microvascular flow and trigger inflammation, decreased 2,3-DPG concentrations, which can make red cells ineffective as oxygen carriers, and increased concentrations of proinflammatory cytokines. Two recent studies have looked at the effect of age of transfused blood in critically ill patients. The Age of Blood Evaluation (ABLE) trial was a multicenter trial that randomized 2430 critically ill patients (mean APACHE score 21.8 ± 7.6) to receive either fresh red cells (stored a mean of 6.1 ± 4.9 days) or standardissue red cells (stored a mean of 22 ± 8.4 days). There was no difference in 90-day mortality (primary outcome) or duration of respiratory, hemodynamic, or renal support, hospital length of stay, and transfusion reactions (secondary outcomes) between the two groups. The Standard Issue Transfusion versus Fresher Red-Cell Use in Intensive Care (TRANSFUSE) trial randomized 4994 critically ill patients (mean APACHE III score 72.9 ± 29.4, median APACHE III risk of death of 21.5%) to receive either blood that was stored for a mean of 11.8 days or blood that was stored for a mean of 22.4 days. There was no difference between the two groups in the primary outcome of 90-day mortality and secondary outcomes of organ dysfunction, need of mechanical ventilation and renal replacement therapy, blood stream infection, transfusion reactions, and ICU and hospital length of stay.
The Transfusion Requirements in Critical Care (TRICC) trial found no difference in 30-day mortality in 838 euvolemic patients with normal baseline hemoglobin and no active ischemia or bleeding randomized to either a restrictive or liberal transfusion strategy (threshold hemoglobin, 7 vs 10 g/dL). However, there was a higher mortality that was not statistically significant in patients with coronary artery disease receiving a restrictive transfusion strategy. Although not done in critically ill patients, two studies suggest that a transfusion threshold of a hemoglobin of 8 is safe in patients with cardiovascular disease. The Transfusion Requirements after Cardiac Surgery (TRACS) showed that a restrictive transfusion strategy (maintain hematocrit ≥24%) was noninferior to a liberal transfusion strategy (maintain hematocrit ≥30%) in terms of a composite end-point consisting of 30-day all-cause mortality and severe morbidity (cardiogenic shock, ARDS, or acute renal injury requiring dialysis or hemofiltration). A second study randomized 2016 patients with either a history of or risk factors for cardiovascular disease undergoing hip fracture surgery, either a liberal transfusion strategy (if hemoglobin <10 g/dL) or a restrictive transfusion strategy (symptoms of anemia with a hemoglobin <8 g/dL). There was no difference between the groups in the primary outcome of death or functional disability on 60-day follow-up. Furthermore, there was no difference between the groups in the rates of in-hospital acute myocardial infarction, unstable angina, or death.
A 63-year-old man is admitted to the ICU after exploratory laparotomy, superior mesenteric artery (SMA) thrombectomy, and small bowel resection. He received 2 L of crystalloid resuscitation in the operation room, and his estimated blood loss was 150 mL. He did not receive transfusion in the operating room. His:
Which of the following statements regarding his laboratory data is MOST correct?
Although the differential diagnosis of an elevated RBC mass is large including volume contraction, chronic hypoxia, and exogenous EPO, PV should be suspected in a patient with unusual thrombosis, thrombocytosis and/or leukocytosis, or splenomegaly. PV is a chronic myeloproliferative neoplasm characterized by an increased RBC mass. It is associated with an increased risk of thrombosis (both arterial and venous), leukemic transformation, and myelofibrosis. Workup for PV should include EPO level and peripheral blood mutation screening for JAK2 V617F. The World Health Organization diagnostic criteria for PV are listed in Table below. Either all three major criteria or the first two major criteria plus the minor criterion is needed for the diagnosis of PV.
The presence of the JAK2 V617F mutation is 97% sensitive and 100% specific for PV. The addition of a low EPO level confirms the diagnosis. Additional mutational analysis for the JAK2 exon 12 mutation should be pursued if the EPO level is low and the JAK2 V617F mutation is not present as 3% of patients with PV are JAK2 V617F-negative.
All patients with PV require phlebotomy to a hematocrit target of <45%. Other treatment depends on risk stratification based on age, history of prior thrombosis, and cardiovascular risk factors. Patients younger than 60 years of age without history of thrombosis can be treated with observation alone or aspirin depending on cardiovascular risk factors. Patients older than 60 years of age or with a history of thrombosis should be treated with aspirin and a cytoreductive agent. Hydroxyurea, interferon alfa, and busulfan are all acceptable initial therapies for PV.
2016 World Health Organization Diagnostic Criteria for Polycythemia Vera:
Which of the following statements regarding hemoglobinopathies is MOST correct?
Hemoglobin is the major protein responsible for oxygen transport and is usually composed of two alpha-globin chains and two beta-globin chains. The synthesis of alpha and beta chains must also be closely matched as free globin units are toxic to red cells. Hemoglobinopathies arise from either (1) a quantitative defect (either reduction or total absence) in the production of one of the globin chains or (2) a structural defect in one of the globin chains. Quantitative disorders of globin chain synthesis result in the thalassemia syndromes. Most mutations that result in structural defects in the one of the globin chains are clinically silent and are discovered as an incidental finding. Those that are clinically relevant can cause the sickle cell disorders, anemia due to hemolysis, changes in oxygen affinity resulting in polycythemia or cyanosis, or methemoglobinemia.
The thalassemia syndromes are inherited disorders that result in either decreased or absence of either the alpha- or beta-globin chains. Under normal circumstances, the synthesis of alpha- and beta-globin chains is highly regulated to prevent excess of one or the other chain. If synthesis of one globin chain is decreased or absent, there is accumulation of the unaffected globin chain that precipitates and leads to hemolysis and decreased red cell survival. The clinical manifestations of the thalassemia syndromes range from asymptomatic carrier status to profound abnormalities including severe anemia, extramedullary hematopoiesis, and skeletal and growth deficits.
The alpha-thalassemias are usually caused by the deletion of one or more alpha-globin genes. Deletion of one or two alpha-globin genes is not associated with severe hematologic abnormalities; a mild hypochromic, microcytic anemia is seen with deletion of two alpha-globin genes. Deletion of three alpha-globin genes (eg, hemoglobin H [HbH] disease) results in a microcytic, hypochromic anemia with hemoglobin levels between 8 and 10 g/dL. The anemia can be exacerbated by acute infections, oxidative stress, and pregnancy and is treated with transfusions as needed. Deletion of all four alpha-globin chains results in hydrops fetalis and is usually fatal during late pregnancy or shortly after birth.
There are two beta-globin genes and beta-thalassemias are usually caused by point mutations in one or both genes. The mutations can result in decreased production or absence of beta-globin. Severity of disease depends on how much beta-globin is made with the most severe disease in homozygotes that make no beta-globin (TM). These patients have severe anemia (Hb range 1-7 g/dL), hemolysis, and ineffective erythropoiesis, resulting in skeletal abnormalities due to expanded marrow cavities and extramedullary hematopoiesis. Iron overload occurs because of increased intestinal iron uptake secondary to ineffective erythropoiesis and from transfusions. Excess iron stores can cause toxicity in the liver, heart, and endocrine organs, with resulting organ dysfunction. Heart failure is the most common cause of death in TM and primarily results from cardiac iron accumulation.
HbS results from an amino acid substitution on the beta-globin chain. Patients with sickle cell disease are homozygous for HbS. Deoxygenation of HbS results in polymerization that distorts the shape of the red cell, which is reversible with reoxygenation of HbS. Sickled RBCs increase blood viscosity and obstruct capillary flow causing vaso-occlusion and pain. Furthermore, repeated cycles of sickling damage the RBC membrane, resulting in premature destruction of RBCs and a chronic hemolytic anemia. The polymerization of deoxygenated HbS is inhibited by HbF. Treatment of sickle cell disease includes pain medications to treat pain associated with vaso-occlusive crises, transfusions, hydroxyurea to increase HbF concentrations, and hematopoietic stem cell transplantation.
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