Primary anemia

Primary anemias result from production of red blood cells that have a structural defect, leading to increased red cell destruction such as in sickle cell anemia, beta-thalassemia, and others (Box 34-1). Primary anemias are no longer strictly childhood illnesses. The ability to replace defective red blood cells with transfusion or partial exchange transfusion has revolutionized the care of these children, extending life expectancy well into the sixth decade or beyond. As these diseases have been converted into chronic illnesses, patients suffering from these diseases are rarely included in the dialogue of palliative care.

Frequent transfusions have brought new challenges to the care of children and young adults affected by primary anemias. During the 1980s and 1990s, blood-borne infection with Hepatitis B and C, and HIV infected many people who received transfusions due to primary anemia. Although the risk of transfusion-associated infection is now decreased to approximately 1 in 2 million transfusions,^1,2 relieving symptoms of primary anemia continues to carry a significant cost in the form of iron overload. The deposits of iron in tissues, especially the liver and heart, ultimately compromises end-organ function leading to heart failure and death. Development and clinical use of first intravenous and more recently oral iron chelators are once again revolutionizing delivery of care to patients with primary anemia. Nonetheless, significant challenges and opportunities for improving palliative care to this often overlooked population remain. David Nathan has written a poignant description of one patient’s journey navigating the waves of innovation in care for patients with thalassemia. He discusses the burdens of subcutaneous desferoxamine infusion and how much his patient hated it, to the extent of refusing to take the desferoxamine. That decision resulted in repeated episodes of heart failure. Dr. Nathan talks about the development of the oral chelator, desferisirox and the positive impact on quality of life for his patient to be free of the iron-chelator infusion pump.³

Secondary anemia

The most common cause of secondary anemia is exposure to marrow-suppressive chemotherapy and radiation therapy in the course of treatment for childhood cancer. Overall survival for childhood cancer has improved significantly during the past 30 years and is 80%.⁴ Cure rates of some childhood cancers, such as low-risk acute lymphoblastic leukemia (ALL), Hodgkin Lymphoma, and low stage Wilms tumor are 95 percent or better.⁴ However, many chemotherapeutic agents used in the treatment of childhood cancers have bone marrow suppression or transient bone marrow aplasia as a side effect. Children receiving intensive chemotherapy are frequently at risk for development of anemia, bleeding, and infection. For many modern chemotherapy regimens, transfusions of packed red blood cells (pRBC) and apheresed platelets are an integral and anticipated component of supportive care.

Progressive or recurrent malignancy may be accompanied by even greater bone marrow insufficiency as a result of cumulative toxicity to the bone marrow. Extreme cases may result in therapy-associated bone marrow aplasia. Cancer progression may result in marrow space infiltration by tumor. Both bone marrow aplasia and marrow infiltration can result in increased transfusion frequency.

In contrast, children receiving palliative care for medical conditions other than cancer may have a completely different etiology for anemia. An immobile child with neurologic deficits may also be anemic. Absence of weight-bearing activity weakens bones and leads to fatty replacement of bone marrow. These children may have deficiencies of iron, folic acid, or biotin, which can lead to anemia. In this situation, transfusion is rarely required. Appropriate steps should be taken to detect and to the extent possible, correct the underlying cause of anemia.

symptoms associated with anemia

Fatigue during treatment for malignancy, in part related to anemia, is the most frequently reported symptom for adults with cancer. A survey of major pediatric hematology- oncology centers in Europe documented more than 80 percent of children with cancer as being anemic.⁵ For children, symptoms related to anemia can extend far beyond a complaint of fatigue (Box 34-2). Children manifest different symptoms of anemia in different age groups. Many young school-age and toddler-age children appear very active and apparently feel well with moderate anemia where hemoglobin is in the 8 g/dL range. For infants and toddlers, symptomatic anemia may be expressed by a decreased ability to nurse, take a bottle, or eat. Many a mother has made the simple statement that their infant or toddler “probably needs to be transfused” because the child just isn’t eating as well as usual. Administration of a transfusion can be the difference between a child who is able to eat consistently with his or her personal baseline and one who is not eating well. For other children, anemia may be recognized by longer nap times, change in temperament or limitations in ability to engage in activities or play. All of these are important issues of quality of life for families of children with life- threatening illness, whether they are pursuing curative therapy or during terminal care.

Teenagers are more likely to present with classic symptoms associated with anemia. While fatigue, or need for increased hours of sleep may be a part of their symptoms, they may also experience headaches, fast heart rate, feeling like their heart is pounding, or lightheadedness when rising to sit or stand. For teens, symptoms related to anemia can be apparent when the hemoglobin drops below 9 gm/dL, a level where younger children are often apparently asymptomatic. Other parameters that affect symptoms from anemia include:

As with secondary anemias, symptoms of primary anemia are varied. Fatigue, tiredness, increased requirements for sleep, and decreased tolerance for activity are common. However, children who are chronically anemic have a lower threshold hemoglobin for symptoms. Sequelae of uncorrected severe chronic anemia include cardiomegaly, progressive decrease in exercise endurance, congestive heart failure, growth abnormalities, and pulmonary hypertension. Patients with uncorrected β-thalassemia major suffer bone deformities and massive hepatosplenomegaly from ineffective hematopoiesis. Those with sickle cell disease suffer avascular osteonecrosis, and can suffer debilitating central nervous system ischemia or acute chest syndrome as consequence of vasocclusion from deformed red blood cells.

Diagnostic evaluation

Hemoglobinopathies are frequently identified because of presence of family history or newborn screening. However, some defects of red cell structure, such as hereditary spherocytosis, may cause sufficiently mild anemia to go undetected into adulthood in otherwise healthy parents. Diagnostic evaluation includes a thorough patient and family history, physical exam, examination of the blood smear, hemoglobin electrophoresis, evaluation of nutritional status, and osmotic fragility studies to name the most frequently used tests. A detailed diagnostic algorithm is beyond the scope of this text. Readers are referred to other resources such as Practical Algorithms in Pediatric Hematology and Oncology for more information.⁶

For patients experiencing secondary anemia, the depth to which a diagnostic evaluation is pursued is dependent upon where the child is in their illness trajectory. A child who develops anemia from a chemotherapy regimen that is known to be myelosuppressive may not need any further evaluation. However, it is appropriate to pursue more aggressive diagnostic evaluation of a child with anemia greater than anticipated for the chemotherapeutic regimen used. Conversely, the cause of worsening anemia for a child receiving terminal care may be of minimal relevance. Foregoing further evaluation may be appropriate when the focus of care is on provision of relief from symptoms no matter the cause.

Primary anemia

The most recent recommendations for medical management of sickle cell disease are available from the National Heart, Lung, and Blood Institute of the National Institutes of Health (NIH).⁷ General indications for transfusion of children with sickle cell anemia include hemoglobin less than 5 to 6 g/dL, development of acute chest syndrome, aplastic crisis, preoperative prophylaxis, or to resolve protracted pain crises. Similarly, transfusion goals for patients with β-thalassemia major is to maintain a hemoglobin in the range of 9 to 9.5 g/dL.^8,9

Secondary anemia

Several transfusion guidelines exist.^8,9 While many centers use a guideline of hemoglobin less than 7 to 8 g/dL as a parameter for transfusion, the ultimate indication for transfusion is a symptomatic patient who is unlikely to correct the anemia in a timely manner without medical intervention. Symptoms of anemia include: tachycardia, tiredness, orthostatic hypotension, increased fatigue, and sleeping more hours per day (see Box 34-2).

Primary anemia

Extensive transfusion exposure in this largely immunocompetent population leads to alloimmunization and development of antibodies to minor blood group antigens. The blood bank should be made aware of the primary anemia history, blood transfusion history, and the need for more extensive blood antigen typing, such as E, C, Kell, and Duffy. As children with primary anemias receive increased numbers of transfusions, finding an appropriate donor unit becomes more challenging. Alloimmunization and iron overload are two of the reasons efforts are made to minimize transfusions in children with sickle cell disease. Children and teens with sickle cell disease should receive sickle negative blood so that determinations of hemoglobin S are solely reflective of the patient and can be used to reliably guide management of exchange transfusion. Because patients with primary anemias are in large part immunologically intact, there is less concern about transfusion associated graft-versus-host disease GVHD. Therefore, irradiation of pRBC is not routinely used. However, irradiation of blood products should be considered for primary anemia patients who are candidates for stem cell transplantation in the near future.

Secondary anemia

Neonates and CMV negative immunocompromised recipients are at risk for blood-borne transmission of cytomegalovirus (CMV). While leukoreduction decreases the risk of transmission of CMV, pRBC from CMV-negative donors are recommended for these most vulnerable patients.

Even with leukoreduction, small T lymphocytes, which have a diameter similar to erythrocytes, can pass through the filter and ultimately into the recipient. These lymphocytes have the potential in immunocompromised individuals to cause GVHD.¹¹ To prevent transfusion-associated GVHD, pRBC are irradiated at 25 to 50 Gy.¹⁰ In large urban areas, hospital blood banks have their own blood product irradiators. Smaller urban areas may rely on a single unit centrally located at the local Red Cross Center. More rural areas may have to special order irradiated units from distant Red Cross Centers, creating a delay in availabity of the product of hours to days.

To raise the hemoglobin 1 gm/dL requires 3 to 5 mL/kg pRBC. For a child with hemoglobin in the range of 7 to 9 g/dL, a reasonable transfusion is 10 to 15 mL/kg. This volume of pRBC should be administered over 2 to 4 hours. Repeat transfusions may be required to adequately improve hemoglobin levels for children with poor red cell production or ongoing red cell destruction. For more profound anemia, or for a patient with chronic anemia, transfusion of smaller aliquots of 5 mL/kg pRBC each transfused over 4 hours may help prevent development of congestive heart failure.

Acute

The most common complications of transfusions include fluid overload, allergic reaction including hives and bronchospasm, febrile reactions, and hemolysis. Patients who are particularly sensitive to fluid loading may require diuresis during or after transfusion to maintain a good fluid homeostasis. Administration of furosemide 0.5 to 1.0 mg/kg immediately following a transfusion is frequently effective.

Minor allergic reactions vary from appearance of few to abundant hives. Minor allergic reactions usually respond quickly to 0.5 to 1 mg/kg diphenhydramine administered intravenously or orally. Alternatively, hydroxyzine 0.5 to 1 mg/kg intravenously or 2 mg/kg orally can be used. Allergic reactions leading to shortness of breath and bronchospasm are more common with transfusion of platelet products, due to the greater volume of donor plasma, which contains antibodies. Anaphylaxis may require administration of hydrocortisone 1 to 5 mg/kg/day intravenously or, in severe cases, epinephrine according to resuscitation protocols. Patients with a history of allergic reaction may do better with prophylactic diphenhydramine or hydroxyzine before transfusion.⁷ Washing pRBC may lessen the amount of plasma in the product, decreasing allergic and hemolytic reactions, at the cost of also decreasing the number of RBC in the unit. The most severe form of allergic reaction is transfusion-related acute lung injury (TRALI), which occurs during or immediately after transfusion and is characterized by difficulty breathing and pulmonary infiltrates on chest x-ray. Patients experiencing TRALI may require intubation and ventilator support.

Profoundly neutropenic patients who develop febrile reactions during a transfusion are generally committed to a minimum of 24 to 48 hours of intravenous antibiotic therapy, until it is clear the fever is not due to bacterial contamination of the product or other bacterial infection in the patient. Culturing the transfusion product bag is ideal. In practice though, febrile reactions often occur after completion of the transfusion, at which point the product bag has been discarded. Many clinicians have reasoned that administration of prophylactic acetaminophen should decrease the febrile inflammatory response to the blood product. If we could decrease the incidence of febrile transfusion reaction, we may be able to spare immunocompromised patients from hospital admission and empiric antibiotics. However, several studies have failed to demonstrate benefit.^12,13 Therefore, routinely administering acetominophen before transfusion is not recommended unless the child has a personal history of transfusion reaction.

Hemolytic transfusion reactions can also start with fever accompanied by abdominal or flank pain. Patients may experience a general sense of feeling unwell or agitation. Tea-colored or cola-colored urine is a supportive finding of intravascular hemolysis. The product infusion should be stopped and returned to the blood bank with new patient samples so evaluation for a hemolytic reaction can be pursued. Routine blood counts demonstrate a decreased hemoglobin. Other supporting laboratory studies include increased haptoglobin levels. Urinalysis may demonstrate urine hemoglobin in the absence of red blood cells. When these symptoms occur in a patient with sickle cell disease, it can be challenging to sort out the presence of a hemolytic transfusion reaction from underlying pathophysiology of hemolysis due to vaso-occlusive crisis. The hallmark of a transfusion reaction is that the patient becomes Coombs positive. Additionally, patients with sickle cell disease can experience delayed transfusion reactions with a fall in hemoglobin below their personal baseline days to weeks after a transfusion. Adding to the challenge of managing these patients is that both acute and chronic transfusion reactions can precipitate an acute vaso-occlusive pain crisis or acute chest syndrome.⁷

Because of the potential for a variety of transfusion-associated reactions, patients receiving supportive care for primary anemia or those with secondary anemia who are still pursing curative therapy should receive transfusions in a setting that can provide infusion services and respond in a timely manner to any transfusion reactions. This generally means an inpatient setting or outpatient infusion clinic.

Chronic

Other adverse events associated with transfusions include transmission of infectious agents, particularly viruses. Risks of known viral infectious agents such as hepatitis B, hepatitis C, and HIV are approximately 1 in 2 million units.^1,2

Those who are regularly transfused, especially for primary anemia, battle with chronic complications of transfusion. For adults transfused pre-1990, transfusion-acquired viral infection may add additional complexity to their healthcare. Teenagers and young adults with extensive transfusion histories may develop extensive alloimmunization that makes finding an appropriately matched unit challenging. The incidence of alloimmunization in patients with sickle cell disease is 25%, higher than the general population.⁷ The higher incidence of alloimmunization is due in part to the difference in surface expression of red cell antigens between sickle cell patients who are predominantly African American and blood donors, who are predominantly Caucasian.¹⁴ Additionally, alloimmunization makes allergic, acute, and chronic hemolytic transfusion reactions much more frequent in this population than in children receiving transfusions for chemotherapy-induced anemia.

For children and young adults with any primary anemia who receive frequent pRBC transfusions, the major complication is from iron overload. Iron deposition leads to end organ dysfunction, particularly in the heart and liver. Patients receiving regular transfusions should be monitored closely for elevated ferritin levels, our closest noninvasive surrogate measure for assessing iron deposition in tissue. Other noninvasive measures, such as cardiac and liver MRI to measure organ iron loads, are under investigation. Introduction of desferoxamine, an iron chelator, revolutionized care of patients with thalassemia and sickle cell anemia.¹⁵ However, desferoxamine must be administered intravenously or through subcutaneous injections or subcutaneous continuous infusion. These methods are cumbersome and problematic for many patients. Administration of desferoxamine was identified as a source of discomfort and decreased quality of life in several studies.^16–18 Nearly 50% of patients identified iron chelator injections as the most disliked component of therapy. More than 40% identified missed work or school as a quality of life issue whether receiving transfusions or not.¹⁶ In one study, quality of life measures were higher for Malaysian patients with β-thalassemia who were receiving optimal desferoxamine regimens compared with patients receiving suboptimal desferoxamine.¹⁸ Healthcare providers would identify frequent transfusions with a greater medical burden as compared with transfusion independence. One study used the Dartmouth primary care cooperative information chart system (COOP) questionnaire found reported complaints of moderate pain in both transfused and nontransfused patients. Interestingly, 27% of transfused patients reported moderately impaired overall health versus 42% of transfusion independent patients.¹⁷ Additionally, physical fitness and better performance of daily activities were reported by patients receiving regular transfusions. Despite the complication of iron overload, regular transfusions appear to improve the quality of life in at least some populations of patients with primary anemia.

Interdisciplinary team considerations

Each institution has its own policy regarding infusion of blood components, though there are common themes. Some issues relate to safety of administration, including confirmation of appropriate blood type of unit to be transfused, confirmation of identity of recipient, appropriateness of intravenous access and frequent monitoring for signs of transfusion reaction. For details on infusion protocols, the reader is referred to their institutional transfusion policy and Essentials of Pediatric Oncology Nursing.¹⁹ Nurses contribute to team assessment of the patient’s and family’s religious or cultural beliefs, which may affect transfusion administration. Nurses also have an important ongoing role in educating patients and families with regard to symptoms of anemia, what to expect from a transfusion, and signs of transfusion reactions. Some individuals have very strong visceral reactions to the sight of blood, whether their own or someone else’s. In the context of blood transfusion, both nursing and child life specialists have helped address these concerns by finding creative ways to disguise transfusions, such as decorating a pillowcase to cover the pRBC bag.