Hematologic Symptoms

Published on 09/04/2015 by admin

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34 Hematologic Symptoms

Mary Elizabeth Ross, Pedro A. De alarcón

Many patients develop hematologic symptoms requiring medical intervention. As suggested in the poem, the manner in which we go about attending to these symptoms can be as important as relief of the symptoms. From a pathophysiology standpoint, patients fall into two general categories: those who are symptomatic as a result of a primary hematologic disorder, and those with hematologic symptoms secondary to an underlying disease or treatment for the disease, such as cancer. Broad categories of hematologic symptoms include anemia, thrombocytopenia, neutropenia, bleeding disorders, and thrombosis. In this chapter, we address anemia, thrombocytopenia, and bleeding disorders.

Anemia

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.

BOX 34-1 Common Causes of Anemia

Primary

• Sickle cell disease, Hemoglobin SS, SC, Sβthalassemia

• Thalassemia

• Pyruvate kinase deficiency

• Hereditary spherocytosis

• Hereditary elliptocytosis

• Diamond-Blackfan anemia

• Glucose-6-dehydrogenase deficiency

Secondary

Increased loss and/or destruction:

• Acute and/or chronic hemorrhage due to primary disease

• Hemolysis

• Acquired antibodies from transfused products

• Autoimmune antibodies

• Hepatorenal failure

• Hemophagocytosis

• Drug induced

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:

• How quickly the anemia has developed,

• Whether a person is beginning therapy or has experienced multiple cycles of chemotherapy,

• Anticipated time to recovery of adequate marrow function to resolve the anemia,

• Which chemotherapeutic agents have been administered,

• Psychosocial context such as whether the child is well enough to attend school or participate in social functions important to them.

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.

Guidelines for Transfusion

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).

Specifications of the Product

Leukoreduced ABO and D blood group appropriate and cross-matched pRBC are used in primary as well as secondary anemia to decrease alloimmunization and febrile transfusion reactions. Contaminating white blood cells, especially lymphocytes, are responsible for the majority of allergic transfusion reactions. Leukocyte reduction can be achieved either during processing soon after collection of the product or before administration to a patient. The American Association of Blood Bank Standards requires leukoreduced units to have less than 5 million leukocytes per unit.¹⁰ Packed RBC for immunocompromised individuals should be leukoreduced. In some geographic regions, blood banks provide exclusively leukoreduced red cells or platelets.

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.

Transfusion Side Effects

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.

Alternatives to Transfusion

Erythropoietin is produced by the kidney in response to anemia. Hematopoietic stem cells differentiate along the erythroid lineage in response to erythropoietin. Erythropoietin was first licensed in 1989 for treatment of anemia associated with chronic renal failure. There are two erythropoietin formulations, epoetin alpha is marketed by Amgen as Epogen and by Ortho Biotech as Procrit. Epoetin alpha is administered 2 to 3 times a week. The second formulation, Darbepoetin, is longer acting and is marketed by Amgen as Aranesp. These agents are frequently used in adults receiving chemotherapy. In fact they have become the first and second ranked expenditures for individual drugs by Medicare Part B. However, recent studies have led to FDA warnings about increased thromboembolic events and increased risk for cardiovascular events.²⁰ Poorer survival in some studies where epoetin was used has again raised questions about whether epoetin may be a growth factor for some types of cancer. The American Society of Hematology/American Society of Clinical Oncology clinical practice update cautions against the use of epoetins in patients with malignancy who are not receiving either chemotherapy or radiation therapy.²¹

There are fewer randomized studies using erythropoietin in pediatric cancer patients. Epoetin alpha has been shown to be well tolerated by pediatric oncology patients and results in increased hemoglobin levels.^22,²³ However, results differed with respect to affecting the number of transfusions administered or quality of life parameters. In one study of patients with solid tumors receiving platinum-based chemotherapy regimens, epoetin alpha decreased transfusion requirements.²² Another study reported 224 patients receiving chemotherapy for nonmyeloid malignancy who were randomized to receive either epoetin alpha or placebo. The group receiving epoetin alpha had greater improvement in hemoglobin and a higher percentage of the patients were independent of transfusions at 4 weeks. Pediatric Quality of Life Inventory Generic Core Scales (PedsQL-GCS) did not differ between treatment groups.²³ However, further analysis demonstrated correlation between PedsQL-GCS and improved hemoglobin.²⁴ Use of epoetin alpha in combination with granulocyte colony stimulating factor (G-CSF) for children with high-risk neuroblastoma resulted in an increased number of transfusions compared with patients in the control group receiving G-CSF without epoetin alpha.²⁵ After reviewing these studies and others, the French National Cancer Institute’s evidenced-based practice guideline does not recommend systematic administration of erythropoietin for prevention of chemotherapy associated anemia in children with cancer.²⁶

Although FDA warnings and mixed results in pediatric oncology studies raise concerns, erythropoietin may be useful for patients who object to blood transfusions on ethical or religious grounds, as do many of the Jehovah’s Witness faith.⁵ Indeed, patients of the Jehovah’s Witness faith have taught us that much more severe anemia can be tolerated than was initially supposed.²⁷^–³¹ Additionally, they have helped drive the interest in development of blood conservation programs and blood alternatives. Blood alternatives such as human and bovine hemoglobin based oxygen carriers (HBOC), which are acellular cross-linked hemoglobin molecules, have been described as bridging the gap between life-threatening anemia and recovery of normal red cell mass after trauma.³² These products are in clinical trials in Africa and other countries. As yet, none are available for clinical use in the United States, but may have a future role in palliation of anemia.

Caring for patients of the Jehovah’s Witness faith who refuse transfusion may cause ethical conflicts for medical personnel who feel strongly that transfusion is medically indicated.³³ The moral distress caused by discordance between the values and goals of the medical staff and the values and goals of the patient can be destructive to delivery of patient-centered care as well as to the medical team striving to provide care. It can take considerable emotional and ethical work for the team to honor a patient’s autonomy and freedom to refuse specific treatments without destroying staff-patient or staff-staff relationships. At times it may be necessary to use the experience and expertise of resources such as patient advocates, the hospital ethics committee, and human resources for the staff.

In sickle cell anemia, administration of hydroxyurea switches on production of fetal hemoglobin, decreasing percentage of hemoglobin S. Some patients experience a significant decrease in acute vaso-occlusive and acute chest syndrome episodes, therefore decreasing the need for transfusion.⁷

Blood conservation strategies

While not strictly an alternative to transfusion, attention paid to limiting iatrogenic blood loss can decrease the frequency of transfusion. Whenever blood is drawn from a heparin- locked venous access device, be it Broviac, Hickman, Mediport, or another, that is heparin locked, 3 to 10 mL of blood and heparin mixture are drawn out and discarded to prevent dilution of the blood sample, leading to erroneous laboratory results. Relatively simple maneuvers, such as making sure to draw all desired blood tests at one time rather than at different times throughout the day, may minimize that discard volume. Frequent blood tests such as CBC and chemistries can become more a matter of routine than medical management. Careful consideration of the frequency of laboratory studies needed to manage a patient may also result in significant decreases in blood loss. Obtaining finger-stick or venopuncture blood samples, when the central line is not going to be accessed that day for any other reason decreases blood loss by eliminating the need for a waste volume. Use of smaller-volume microtainer tubes can similarly result in a savings of 2 to 9 mL of blood per blood test. These measures can result in decreased transfusion needs in small children. Indeed, many NICUs have implemented blood-conservation strategies. These measures are less routine for chemotherapy infusion, but are worth consideration when limiting the number of transfusions is an important goal for the individual patient.

Donor directed transfusions

Faced with their child’s need for transfusions, many families inquire about having blood provided by family donors or friends of the family. It is often useful to check the motivation behind the request. For some it is a fear of unknown donors and potential transmission of infection. For others it is a way for extended family to do something useful during a crisis. It is often sufficient to educate them with regard to general issues such as the need for blood types to match, the safety of the blood supply, and the need for complete testing even when the blood donation is directed. Additionally, there are many situations where family members are not the ideal donors or may even increase the chance for complications for the child.

The ideal donation scenario for family members to fully meet the transfusion needs of the child would be where infrequent transfusions were required, and the transfusions can be anticipated days if not weeks ahead. When donated blood is directed to a specific recipient, the blood bank has an increased administrative burden tracking and storing the blood. The Red Cross does have procedures in place to meet this need. A direct donation unit is still required to undergo thorough testing and processing, which takes days. Direct donation for urgent and emergent transfusion is often technically challenging due to the time required for processing.

For patients with primary anemia, family members are often not suitable donors. For example, in sickle cell anemia each parent has at least sickle trait, if not sickle cell disease themselves. This makes the parents and most siblings an inappropriate candidate for directed donation. Similarly, the frequency of transfusions for children with primary anemias can be more often than an individual is allowed to make blood donations. Additionally, the physical demands of frequent blood donation may put additional burden on a family already under stress simply from caring for an ill child.

Families of children diagnosed with cancer also often inquire about direct donation. Here, too, the frequency of required transfusions is generally too often for any one parent or family member to safely donate. For patients with either malignant disorders or with primary hematologic failure disorders who are candidates for hematopoietic stem cell transplantation (HCST), transfusions from family members are strongly discouraged. Siblings and, in some cases, parents are potential HSCT donors. Family-member blood transfusions before HSCT sensitize the patient to minor histocompatibility antigens, which increases the risk of graft failure. Similarly, because of shared histocompatibility antigen, related donor transfusions carry a risk of inducing transfusion associated graft versus host disease even in immunocompetent individuals. Therefore, all transfusions from a donor related to the recipient must be irradiated, adding cost to the transfusion. Finally, due to the emotional incentives for family and friends to donate for a specific patient, there may be a higher risk of transfusion-related infections than from a blood bank unit. A safer product is likely to come from a donor who has donated multiple times and therefore been frequently screened.³⁴

Many friends and family do want to donate blood in an effort to help. Once the reasons why those donations should not be designated for a specific patient, it is prudent to encourage friends and family to donate blood without specifying a recipient. In this way the precious resources can be built up and donors receive a sense of having helped someone in need. In fact, having a blood drive is an often-employed way for a community group to show support for a community member fighting illness.

Palliative Care Considerations in Secondary Anemia

I’m not afraid of dying, I’m afraid of not living.

—KERRI COSTELLO

Despite the incredible improvement in disease-free survival achieved with modern chemotherapy and multi-modality treatment, nearly 20% of all children diagnosed with childhood cancer will die of their malignancy. In fact, among all children with life-limiting illness, cancer remains the leading cause of disease-related death.^35,³⁶ Early in the trajectory of treatment of malignancy, transfusion may be largely a matter of supportive care, allowing administration of more myelosuppressive or more frequent chemotherapy. When cure is not possible, transfusion may be used to maintain the quality of life rather than prolong life. During the days, weeks, or months after the realization that cure can no longer be the endpoint, many short- and long-term goals are reassessed. Transfusion frequency varies considerably during this phase of illness. Transfusions may not be required or may be infrequent for a patient with a solid tumor that is not invading the bone marrow space. Conversely, for a child with a bone marrow failure syndrome or malignancy that involves the marrow space, transfusions may become increasingly frequent. Reassessing the goals with regard to transfusion is an important discussion to have with the patient and family.

In this part of the illness trajectory as in others, we need to tailor the approach to the needs and priorities of the patient and his or her family. A child who is no longer pursuing curative therapy may have days, weeks, or months of feeling relatively well. They may be able to engage in legacy making, in accomplishing short-term goals that are important to themselves and their families. For example, it may be important to a teenage patient to walk across the stage at high school graduation. If there are symptoms from anemia, continuing regular transfusions may help them achieve short-term goals and decrease symptoms from anemia, allowing them to enjoy these important activities. Supporting children who are symptomatic from anemia with transfusions supports their own definitions of quality of life.

Open and frank discussion about goals should include discussion of what changes should be expected in even such basic components of care as frequency of laboratory studies. Frequent monitoring of laboratory studies may be a recognizable portion of the routine of care that is comfortable and expected by families. Even when decreased laboratory monitoring is meant to limit results that wouldn’t be acted on or to conserve blood, a sudden decrease in laboratory frequency without open dialog is easily misinterpreted by patients and families as abandonment of the child by the medical system. For other patients, particularly ones without central access devices, a decrease in laboratory frequency may be a very welcome change in management. Both venipuncture and finger sticks can be distressing events for children, even if measures such as topical anesthetic cream or freezing solution are used.

Some healthcare providers may believe that transfusions should end when curative therapy ends. By this point in therapy, transfusions can be a familiar and accepted part of medical care. Both patients and families quickly become adept at recognizing signs and symptoms of anemia. They will likely have well-developed expectations about what level of hemoglobin requires transfusion. Transfusion may be as basic a component of therapy for them as acetaminophen is for an otherwise healthy child who has fever. To be told to stop transfusions would be undesirable. It may even be perceived as abandonment by the healthcare team. These decisions, like so many others during illness, need to be arrived at together, with the family perceiving and receiving support for their decisions from the healthcare team.

Continuing transfusion support may complicate other decisions as a family prepares for end-of-life care such as enrollment in hospice care. Although attitudes and practices are changing, some hospice programs still do not support such services as transfusion, parenteral nutrition, or continuing chemotherapy.³⁷ In recent years, the attitude toward providing transfusions for patients enrolled in hospice has begun to shift. In some hospice organizations, transfusion is now allowable if the motivation for administration of the transfusion is solely for relief of symptoms.

Clinical Vignette

Jay was an 11-year-old boy, the only child of a single mother. He developed secondary acute myeloid leukemia while receiving therapy for T cell acute lymphoblastic leukemia. He and his mother had been intensely private throughout their battle against cancer. Although there were some extended family members, mother and son were the main social support for each other. In fact, during uncomplicated admissions for scheduled chemotherapy of uncomplicated fever and neutropenia, she continued to work. He spent the day in the hospital alone, without complaint. When it became clear that the leukemia was not responding adequately to chemotherapy, they chose to enroll in hospice and forgo further chemotherapy. He had a number of weeks where his main complaint was limited to low back pain. While at home he was able to pursue activities that he enjoyed. Intermittently, he was seen in the clinic. Jay and his mother both believed that his quality of life was reasonable and decided to pursue transfusions because he would get tired and cranky when his hemoglobin dropped below 7 or 8. Initially, we transfused him in the pediatric hematology-oncology clinic. After a few additional clinic visits, his mother requested a decrease in the time spent in the clinic. Couldn’t home health draw labs? Was there any way to have transfusions done at home? In the area where he lived, we were able to accomplish transfusion at home through home health and hospice. In a later clinic visit, she indicated that eliminating the hours in clinic for labs to be drawn, waiting for results, and infusing blood was very important to them. They wanted to be at home. Being in their own surroundings for those additional hours was very important to both of them.

Several programs have demonstrated successful administration of transfusions at home.^38,³⁹ However, in many areas, providing transfusion with blood or platelets at home remains technically challenging, if not impossible. In some regions, even if a child is enrolled in hospice with Do Not Resuscitate (DNR) or Allow Natural Death (AND) directives in place, there are no agencies willing to provide transfusions in the patient’s home. This means families must go to an outpatient infusion center or be admitted to the hospital for transfusion. When admission is required to provide a transfusion, some third-party payers require discharge from hospice during the time the child is admitted to the hospital. Upon discharge from the hospital, nursing resources are then questionably used to repeat paperwork for readmission to hospice. For families in more rural areas, many hours may be spent traveling to and from the site for transfusion, receiving a transfusion, and repeating paperwork to resume hospice care. Further efforts are needed for development and dissemination of procedures and protocols for delivery of transfusions at home. Administrative support will be necessary for a personnel intensive investment for home transfusion programs. Payer mechanisms will also have to see the benefit and provide reimbursement commensurate with skill level.

On the other side of the equation are families for whom a transfusion is a physical, emotional, or social burden. For such families, decreasing or even ending transfusion therapy may be very desirable. It may also be reasonable to consider erythropoietin use in the clinical scenario of a child or young adult who is no longer pursuing a curative goal, but continues to have a relatively high level of function for what is anticipated to be a limited time. Goals such as decreased transfusion frequency, decreased travel time to obtain transfusions, and decreased time in the hospital to receive transfusions may be of considerable importance to the patient and family. Clearly, in light of recent FDA warnings, the decision to use an erythropoietin must include disclosure of the concerns for potentiating tumor growth. Given concerns for thromboembolic events and potential tumor growth, erythropoietin should be discontinued once a beneficial effect on hemoglobin levels can no longer be demonstrated.

Palliative Care Considerations for Primary Anemia

Children with primary anemias are not typically included in the discussion of palliative care. Now that children with hemoglobinopathies can expect to reach adulthood and have the potential to live into their fifth decade and beyond, we are met with new challenges for providing high-quality palliative care for this population. The principles of palliative care offer new opportunities to address the evolving needs of these patients.^40,⁴¹

The hemoglobinopathies are characterized by largely unpredictable episodic acute pain from vaso-occlusion. Adequately addressing these painful episodes remains a challenge to the medical system. Many physicians are uncomfortable managing both acute and chronic episodes of pain.⁴¹ The problem is compounded by an often adversarial patient-physician relationship.⁴¹ Parents of children with sickle cell disease are more frequently dissatisfied with their child’s care in the hospital.⁴² The care of this population is complicated by decreased access to care, resulting in increased emergency room use, and therefore inconsistent care.^41,⁴³ New models of care such as the “Day Hospital” design used by the Bronx Sickle Cell Center are needed to provide rapid and consistent access to pain medications.⁴¹ Additionally, when children with sickle cell disease are not followed by a hematologist, they miss out on the benefit of preventative care.⁴⁴

Children with cancer often carry physical reminders of their disease on their bodies, including hair loss, pallor, anorexia, limb deformities, surgical scars, and deformities from tumors or the therapy to rid them of the tumor. Children with primary anemias, especially sickle cell disease, often suffer without outwardly obvious reminders. Pain, the major debilitating symptom for children with sickle cell disease, cannot be seen at all. It is an internal experience. Even a major symptom of anemia, pallor, can be difficult or impossible for classmates, teacher, nurses, and doctors with lighter skin pigmentation to appreciate.

Contrast as well the social experience of the child with cancer who is in school. Often the school and even the broader community rallies around this child, celebrating each day he or she is in school, working hard to arrange alternate education plans for the days, weeks, or months when therapy or illness prevents school attendance. The child with sickle cell disease doesn’t receive that community and school support. Missed school days are difficult to make up. Where patients with cancer may miss school in large blocks of time, patients with primary hematologic disease miss smaller blocks of time but multiple times throughout the year and throughout their school career. There are relatively few studies examining the impact of sequelae of sickle cell disease on school and school performance. Several small studies suggest that adolescents with sickle cell disease miss an average of 12% to 21% of school days.^45,⁴⁶ In a recent study, 35% of the children followed missed a month of school from one school year.⁴⁶ Children with sickle cell disease miss more days of school than their siblings.⁴⁷ Falling behind in schoolwork missed because of pain, hospitalization, and clinic follow-up may develop into a pattern of school avoidance for some. Many missed days can leave the child who has primary anemias socially alienated and educationally delayed. There are only limited studies evaluating healthcare quality of life in children with sickle cell disease. However, in two studies using the health related quality of life questionnaire (HRQOL) parent report form, parents identified their children as being more limited in physical, psychological, and social well-being and having more limitations on schoolwork and interaction with peers than healthy children.^48,⁴⁹

There are simple practical challenges for children with sickle cell anemia in school. Maintaining adequate hydration is a very basic component of self care. Water fountains, if they exist, are located in hallways, but children spend most of their time in classrooms. They are not allowed free access to the water fountains except at appointed times of the day. It often takes a letter from the physician for a child to be allowed to carry a water bottle to class. Even with the letter, the effort is not always successful. Access to water is only half of the equation. If a child is drinking more water than the average classmate, he or she will need to use bathroom facilities more often as well. For a busy teacher with a classroom full of children to teach and discipline, structured bathroom times are a necessity. Increased water consumption will lead to the need for bathroom facilities outside the normally structured time. It only takes a few conflicts or embarrassing interactions for the child to learn to avoid drinking the extra water to avoid the need to use the bathroom. Ultimately these experiences thwart basic lessons in self care and are counterproductive to the child learning that they can have some control and ownership over this disease. Lessons learned in childhood, including not drinking sufficient water, are difficult to undo in adulthood.

Truly challenging are the issues of ready access to pain medications, at times including opioids, while children are at school. Schools have legitimate concerns about children having and controlling their own medications. In our society, it is not a stretch to understand that a child with opioids in his or her own possession may be in physical danger. Similarly, where medications are kept and who at school has access to them are very real and often challenging issues. Yet, prompt access to oral pain medications and simple interventions such as rest and oral hydration are key components of care to prevent mild pain from progressing to more extensive vaso-occlusive crises or acute chest syndrome.

We need more school programs to educate the educators and classmates about why children with sickle cell disease miss school. We need to develop innovative and novel ways to keep children engaged in education and to help them keep up with studies despite hospitalizations. One such program might be a mentoring program pairing young teens struggling with the challenges of a chronic disease and its unwanted and uninvited effects on their lives with an adopted medical role model, a medical version of Big Brothers Big Sisters or a medical grandparent. The role model could be someone who also struggles with chronic disease of any sort but continues to be productive in the community and job force despite the medical challenges. There are scholarship programs for survivors of childhood cancer and young adults with hemophilia. More scholarship programs designated for children with primary anemias could help them access and complete higher levels of education and thereby obtain jobs with healthcare benefits.

Cancer affects 14 to 16 in 100,000 children. Sickle cell disease affects 500 in 100,000 African American children, and African American children are 18% of the population. Hemophilia affects 1 child in every 5000 male births, which translates to 10 in 100,000 children. There are 141 federally funded hemophilia treatment centers for children and adults; the listing is available at www.cdc.gov/ncbddd/hbd/htc_list.htm. Funding for these centers is specifically focused on provision of medical care. Comprehensive hemophilia treatment centers were first established in 1973. There were 10 funded Comprehensive Sickle Cell Centers for treatment of children and adults with sickle cell disease. Only a portion of affected children received care in centers specialized in providing treatment for those affected by sickle cell anemia. Recently, these programs have been eliminated and are now converted to funded Basic Translation Research Programs for sickle cell centers primarily engaged in clinical research. After reorganization, funding for provision of care to patients with sickle cell disease is through HRSA and the CDC on a limited and competitive basis. Children not treated by specialists are often missing the opportunity for the preventive care so essential for preventing life-altering complications from end organ damage, such as stroke.⁴⁴ The most effective management occurs in the context of a consistent albeit unique interdisciplinary approach. Within the medical field we need to continue to build and strengthen medical homes for not only children but also adults with chronic anemias.

What accounts for the difference between the approach to treatment for hemophilia and treatment for sickle cell disease? In part, the existence of the National Hemophilia Foundation (NHF) established 1948. NHF is a very strong advocate for patients with hemophilia, and lobbies for healthcare legislation that improves care for those who suffer from hemophilia. Goals of NHF are: to increase lifetime insurance caps, increase funding for hemophilia treatment centers, and eliminate any travel ban for people with HIV (www.hemophilia.org/nhfweb). NHF is an organization of consumers, that is people with hemophilia, with an advisory board of providers. There are numerous sickle cell foundations that are more recently formed, smaller, and generally local or regional organizations. These foundations primarily focus on community education and testing for sickle cell trait and disease. As yet, they do not have as extensive private-sector funding or federal lobbying influence. Such efforts on behalf of patients with sickle cell disease would result in more resources focused on addressing the palliative care needs of these patients.

Public education, treatment and palliative efforts in sickle cell disease could benefit from a well-known celebrity or sports figure that championed the cause of children and adults affected with sickle cell disease. Recently, Michael J. Fox has raised public awareness, participated in raising money for research and lobbying the federal government to increase the investment in Parkinson disease research. Similarly, Lance Armstrong’s “LiveStrong” foundation and the Susan G. Komen Foundation raise public awareness and billions of dollars in cancer research support. Examples of more long-term celebrity champions include Jerry Lewis, whose 2009 telethon raised $60.5 million dollars for the Muscular Dystrophy Association, which supports research, provision of care and services, and education (www.mda.org).

Thrombocytopenia and Functional Platelet Disorders

Platelet failure may be due to abnormal numbers or abnormal function (Box 34-3). Both of these may be primary, due to an intrinsic platelet disorder or secondary to underlying disease, such as malignancy. As with secondary anemia, poor bone marrow reserve and hematopoietic toxicities from chemotherapeutic agents can lead to thrombocytopenia. Frequent platelet transfusion can lead to development of alloimmunization against platelet antigens, which in turn can worsen thrombocytopenia due to increased platelet destruction.

Primary thrombocytopenia

Severe primary thrombocytopenia occurs principally in four disorders. Three are primary failures of platelet production while the fourth is primarily an increased destruction process. Aplastic anemia is an autoimmune disorder leading to failure of production of all three hematopoietic cell lines. Infection and hemorrhage are the leading causes of death for patients with aplastic anemia. Platelet transfusions are essential for survival and to provide a reasonable quality of life in patients who await definitive therapy with HSCT or immunosuppressive therapy. Equally important is the transfusion support of patients for whom disease-directed therapy does not succeed. In the initial phase awaiting therapy, maintaining a platelet count greater than 20,000/uL can improve quality of life. However, a major risk is platelet sensitization, and transfusions must be used with care. In fact, graft rejection is seen more frequently in patients who have received many blood products prior to HSCT. In patients for whom primary therapy was not successful, platelet transfusions for symptomatic hemorrhage is better than the prophylactic use because it decreases the use and cost and is just as effective. It is prudent to have a specific plan in place for accessing transfusions when needed, because prolonged bleeding such as nose or gum bleeding can be very disturbing to patients even when it is not life-threatening.

Amegakaryocytic thrombocytopenia is a rare inherited failure of platelet production due to mutations in c-mpl, the thrombopoietin receptor, in about 50% of cases.⁵⁰ The disorder has a tendency for malignant transformation. Platelet transfusions are essential in the support of these patients as they await definitive therapy with HSCT.

Thrombocytopenia and absent radii (TAR) syndrome is an inherited autosomal recessive disorder with characteristic radial abnormalities not involving the thumbs and thrombocytopenia. The disorder presents at birth and, in most cases, the platelet count improves so that most patients achieve a platelet count sufficient to suppress hemorrhage by 1 year of age. Therefore platelet transfusion support to maintain platelet count greater than 20,000/uL is both life saving and greatly improves quality of life of these children. The requirement for transfusion usually decreases during the first year of life.

Primary Platelet Dysfunction

Primary platelet dysfunction in general causes mild bleeding problems. Only two disorders, Glanzmann thrombasthenia and Bernard-Soulier Syndrome, could be classified as life threatening.⁵¹ Both are genetic defects affecting the critical platelet receptors for fibrin and von Willebrand factor, respectively. Infants with severe Glanzmann thrombasthenia present early in life including the neonatal period. Severe hemorrhages are responsive to platelet transfusion, but sensitization to platelet antigens makes the long term use of platelet transfusion therapy difficult. Judicious use of platelet transfusion allows these children to have a reasonably normal life. Because of the risk of platelet sensitization, definitive therapy with hematopoietic stem cell transplantation is indicated for children with the severe form of Glanzmann thrombasthenia. Bernard-Soulier syndrome is less severe and patients have a reasonable quality of life when supported with the judicious use of platelet support.⁵²

Hemorrhage secondary to platelet dysfunction is best exemplified by renal disease. As renal function decreases and blood urea nitrogen levels increases to above 50 mg/dL, platelet dysfunction becomes clinically significant.⁵³ Menorrhagia and nosebleeds are the most common clinical manifestation and the most disturbing to the quality of day to day living. Several strategies can improve these patients’ quality of life. The hematocrit has an inverse relation to the bleeding time in renal disease. Thus, improving hemoglobin levels with erythropoietin not only improves quality of life from disease fatigue but also decreases the risk of hemorrhage. Clinical hemorrhage can also be treated by increasing the levels of von Willebrand factor with desmopressin acetate (DDAVP) therapy or by transfusions of cryoprecipitate. Finally, anti-fibrinolytic therapy with ∊-amino caproic acid or tranexemic acid can decrease both nasal hemorrhage as well as menorrhagia.

Diagnostic evaluation

Diagnostic evaluation for primary thrombocytopenia includes past medical history, family history, physical exam, complete blood counts, evaluation of the blood smear, and may include a bone marrow aspirate as well as genetic testing. Specifics of the differential diagnostic evaluation of primary thrombocytopenia is beyond the scope of this chapter, and for further diagnostic algorithms the reader is referred to other sources.⁶

In secondary thrombocytopenias, patients experiencing disproportionate thrombocytopenia while receiving chemotherapy in a curative pursuit should certainly be evaluated for other causes of thrombocytopenia. It may be informative to review a blood smear from before the administration of any blood products and chemotherapy to evaluate platelet morphology.

Guidelines for transfusion

A general transfusion guideline has been to transfuse for platelets less than 20,000/uL. This guideline was initially derived from a study correlating the frequency of spontaneous bleeding and platelet count. It was done in the era of administration of aspirin for fever. Because aspirin interferes with platelet function, some institutions have dropped transfusion guidelines to less than 10,000/uL.

Active bleeding, especially intracranial hemorrhage, should be considered an indication for transfusion in any patient with thrombocytopenia regardless of the platelet count. Patients who are expected to receive a HSCT for aplastic anemia or Glanzmann thrombasthenia may benefit from a conservative transfusion approach, limiting transfusions to symptomatic bleeding rather than prophylaxis based on any platelet count.

Specification of the Product

Apheresed platelet units provide a greater number of platelets than the platelet fraction separated from a single unit of whole blood. Apheresed platelets are obtained using a continuous circuit that allows repetitively removing a volume of blood, separating out the platelets, and returning the red cells and plasma to the donor. An apheresis unit contains approximately 10¹⁰ platelets. Transfuse 10 mL/kg of body weight. Platelets can be transfused over 30 to 60 minutes or at a rate of 10 mL/kg/hr.

When administering platelets to immunocompromised patients, platelets should be leukoreduced and irradiated to minimize risks of transfusion reactions and transfusion-related GVHD, respectively. CMV naive or severely immunocompromised patients can be transfused with platelets from CMV-negative donors to limit transmission risks. If alloimmunization develops, platelets from ABO, Rh, and HLA-matched donors can be used to improve platelet response by decreasing immune-mediated destruction.

Transfusion Side Effects

Platelet transfusions are associated with a higher incidence of allergic transfusion reactions because there is a greater amount of donor plasma and donor immunoglobulin in a platelet product than with packed red blood cells. For treatment of allergic reactions, see Transfusion Side Effects in the Anemia section.

With the development of skin cleansing protocols and closed circuit systems for processing of donated products, bacterial contamination is low. Platelet apheresis units are stored at room temperature, which makes growth of any contaminating bacterial agent more likely than in a pRBC unit. As with pRBC, profoundly neutropenic patients who develop fever during or soon after platelet transfusions should be hospitalized and treated with intravenous antibiotics until it can be proved that no bacteremia exists.

Interdisciplinary Considerations

As with pRBC, every medical facility has its own policy regarding infusion of blood components. The reader is referred to their institutional transfusion policy and Essentials of Pediatric Oncology Nursing.¹⁹ Nurses educate patients with severe thrombocytopenia to consider not flossing teeth and using soft toothbrushes to minimize gum bleeding. When a nosebleed happens, the patient is advised to sit up and lean forward so blood loss can be more accurately monitored. Also, this decreases the amount of swallowed blood. Rectal bleeding can occur with the passage of hard stool, so stool softeners are encouraged to decrease bleeding with constipation. Encourage patients to avoid use of rectal thermometers in thrombocytopenic and neutropenic infants. Counsel teens to avoid high-impact sports, and activities associated with high G-forces or high impact such as rollercoasters, mountain biking, and paintball.

Alternatives to transfusion

DDAVP

An alternative to platelet transfusions in mild platelet disorders is the use of desmopressin acetate (DDAVP). DDAVP can be dosed intravenously or subcutaneously at a dose of 0.03 mg/kg. DDAVP can also be administered intranasally, one puff for children and two puffs for adults. It is important that the correct nasal preparation, Stimate, be used for bleeding because it has a much higher concentration than the preparation available for the treatment of diabetes insipidus or enuresis. DDAVP should not be used for children younger than 1 year of age. It can cause severe hyponatremia and seizures because infants cannot easily control their liquid intake. Older children should be instructed to limit their liquid intake and drink only if very thirsty after being treated with DDAVP.

Antifibrinolytics

Antifibinolytics can also be a useful product to stop mild bleeding or to prevent bleeding in patients with hemorrhagic disorders resulting from platelet failure or plasma coagulation failure. Tranexemic acid is no longer available in the United States. Epsilon amino caproic acid comes in tablets, liquid, and intravenous preparations. A loading dose of 200 mg/kg of body weight followed by 100 mg/kg every 4 to 6 hours is the recommendation commonly found in text. However, experience suggests that a loading dose is not necessary and a dose of 25 to 50 mg/kg every 6 hours is effective with less gastrointestinal adverse effects such as nausea, vomiting and abdominal pain, and headaches and dizziness that are frequently seen with higher doses, especially in older children and teenagers.

Bleeding in terminal care

Bleeding, particularly visible bleeding, is a very distressing event for families particularly for those involved in terminal care. A United Kingdom Hospice delivered platelet transfusions at home for children with cancer in terminal care, who had known thrombocytopenia and bleeding lasting more than 1 hour.³⁹ There is greater potential for transfusion-related reactions with platelets than with pRBC because of the greater plasma volume associated with a unit of apheresed platelets. However, the authors were encouraged by a low frequency of transfusion reactions, most of which were mild hives or mild lip swelling. Of all their pediatric oncology patients that died at home, less than 20% received platelet transfusions. The transfusion was effective in stopping the bleeding most times.

Where home transfusion of platelets is not available or not desired by the family, a few simple maneuvers can help minimize the distress of terminal bleeding should it occur. First and most importantly, the caregivers should be warned of the possibility of terminal bleeding and plans discussed. They should be encouraged to remain calm and remain with the child rather than leave to seek help or supplies. Minor gum bleeding may be lessened by application of a dampened tea bag to the child’s gums. Dark colored towels and linens may make the amount of blood lost less distressing for anyone present.

Bleeding Disorder

Primary

Primary plasma coagulation disorders are best represented by hemophilia. A discussion of the care of patients with hemophilia and of subjects suffering from rare factor deficiencies is beyond the scope of this chapter and readers are referred to other sources.⁵⁴^–⁵⁶ However, the principles of therapy of hemophilia as life-saving and improving quality of life are worth discussing.

In the past 70 years, we have moved from a potentially lethal disorder to a chronic illness, with a marked improvement of quality of life and almost achieving life span comparable to the general population. Until 1950, the average life expectancy of patients with hemophilia was about 11 years of age. With the advent of transfusion therapy of plasma in 1950s, cryoprecipitate in 1964 and factor concentrate use in the early 1970s, the expected average life span increased to 68 years. The introduction of effective therapy for hemophilia lead to the understanding that care not only relates to correction of the deficiency of a clotting factor, but also to the attempt of normalization of life. Home care programs as understood by hemophilia providers began in the 1970s. Although more expensive, having factor replacement products at home vastly improved the quality of life of the patients as well as provided prompt care. Still a pediatric disease, hemophilia care became an interdisciplinary collaborative effort. Comprehensive hemophilia treatment centers now bring together social workers, educators, nurses, dentists, physical therapists, orthopedic specialists, and hematologists. In 1989, with the first reported cases of HIV infection in hemophilia, a new challenge for the care team made those providing care for patients with hemophilia concentrate on the quality of life of our patients.

The advent of recombinant factors and viral inactivation strategies for clotting factor concentrates has improved safety during the past 20 years. Once again, prophylaxis with factor replacement became possible and has improved the quality of life of people with hemophilia. This generation of children with hemophilia can expect freedom from infusion-acquired viral infection and good joint health, in addition to a life expectancy nearly equivalent to the general population.⁵⁷ Arthropathy, pain, arthritis, school performance, employment, and psychological adjustment to a chronic illness are cultural aspects of hemophilia care that are becoming the focus of hemophilia centers. The hemophilia growth and development study outlined the school problems of children with hemophilia.⁵⁸ Early intervention and educational consultations are critical in the well being of children with hemophilia. Dutch children with hemophilia are more likely to participate in sports than their peers.⁵⁹ How do we prepare these children and families to cope with sports and the tendency for risk-taking behavior in children with hemophilia? Arthropathy is still a problem with pain. Hemophilia programs have developed techniques to improve pain, and use arthroscopy to improve pain and function and cryo-cuffs to provide pain relief, decrease swelling, and inflammation.

With improved life, people with hemophilia are becoming adults and need to cope with social pressures: employment, social adjustment, sexual function, and problems that come with aging, such as coronary artery disease, diabetes, and Alzheimer’s. These are a few of the challenges that face hemophilia treatment centers, their new focus is the quality of life of the patient they can now cure of what was a lethal disorder 80 years ago.

Secondary

Secondary failure of the plasma coagulation system, manifested by multiple factor deficiencies, is seen in severe liver disease. Initially it may be due to vitamin K deficiency with low levels of factors II, VII, IX, and X, but may progress to include all coagulation factors produced in the liver including I, V, and XI. The hemorrhage due to liver disease may respond to vitamin K early in the course of liver failure. Severe liver failure requires infusion of plasma. The use of activated factor VII is not approved by FDA but can be effective in controlling hemorrhage. Because it is degraded in the liver, the dose may last longer in patients with liver disease. The manufacturer’s recommendation for factor VIIa is a dose of 90 mcg/kg of body weight repeated every 2 hours. However, a single dose may be all that is required in liver failure.

Secondary failure of the plasma coagulation system may also be seen in acute promyelocytic leukemia or acute myelomonocytic leukemia, where the leukemia cells release enzymes leading to consumption of coagulation factors. Infusion of both fresh frozen plasma and cryoprecipitate are often required.

Guidelines for Transfusion

Primary

Primary plasma coagulation disorders are now treated by transfusion of specific factors to replace the deficient factor. A discussion of the particular products and dosing of these factors is beyond the scope of this chapter and the interested reader is referred to several excellent recent reviews.⁵⁴^,^55,⁶⁰ However, there are two principles of the use of these factors that are important when we discuss palliative care in the broader sense. The contamination of these factors with HIV created not only a devastating medical crisis but also left the families of patients with primary plasma coagulation disorders with fear and often distrustful of their care providers. For these patients it is important that their providers are familiar with the products and transparent regarding side effects, particularly transfusion-transmitted infections. The safety of the product becomes very important. The second concept is the purity of the factor. Although often both go together, they are not necessarily the same.

Secondary

Secondary plasma coagulation disorders are often treated with transfusions of fresh frozen plasma because they involve many coagulation factors. Fresh frozen plasma (FFP), 20 mL/kg body weight infused over 2 hours, is frequently enough to provide hemostasis. Alternatively, it can be used as a continuous infusion. Monitor PT, PTT, and fibrinogen. Goals to minimize clinical bleeding, normalize prothrombin time (PT) and activated partial thromboplastin time (PTT), and maintain fibrinogen greater than 50 ng/mL. In clinical scenarios, where there is not only poor synthetic function of clotting factors but also consumption of fibrinogen and clotting factors, cryoprecipitate may be infused. Relative to FFP, cryoprecipitate has a greater content of fibrinogen. A unit of cryoprecipitate per 5 kg of body weight is sufficient to raise the fibrinogen level.

Mentoring

Palliative care has not traditionally been taught in medical school or residency programs. These programs are only now being developed. An important role of physicians caring for patients in palliative care is to mentor young physicians. When considering a patient who is symptomatic from anemia, we teach about transfusion guidelines. We must encourage young physicians to grow a step further, to consider the guidelines as just a guideline. It takes an active dialog with the trainee to encourage him or her to think critically about each individual patient and the patient’s unique circumstances. Is he or she symptomatic despite having a hemoglobin higher than the guideline, and therefore a good candidate for transfusion anyway? Is this patient expected to recover bone marrow function eminently and therefore does not need, or does not want, a transfusion despite meeting guideline criteria for transfusion? The medical art of implementing practice guidelines while tailoring therapy for an individual takes time to teach. With increasing demands on physicians and nurses’ time, it is an easy component to overlook. Both our profession as a whole and our patients as individuals stand to gain from this priceless investment of our time.

Clinical Vignette

A 4-year-old girl who had recently been internationally adopted was brought to the clinic. Limited translations of available records indicated she had received blood transfusions approximately monthly. The average hemoglobin pretransfusion was 3 to 5 gm/dL. On initial presentation, she was pale and jaundiced with frontal bossing and mid-face bony overgrowth characteristic of thalassemia major. She was tachycardic with a palpable thrill and heart rate of 110 and greater with 6-cm hepatomegaly and 8-cm splenomegaly (Fig. 34-1). She was a quiet, polite little girl. Although she cried with IV starts, everyone was impressed with the fact that she was so well behaved and really didn’t offer much resistance. She sat in clinic for hours entertaining herself with coloring and puzzles. She showed little interest in television. She did not walk about to explore the clinic. We assumed that was due to recent changes of environment, unfamiliar people, and even recently new caretakers, her newly adoptive parents. In her new home, she also preferred to sit and play with crayons and small toys. Sometimes she fell asleep on the floor while playing. She refused to walk more than 10 feet before she would sit down and cry. She went to the second floor of the house only when carried. She did not participate in running or playing games with the other children. In fact, there wasn’t much interaction with the other six children in the household. When they were out of the house, she rode in a stroller. Mom had been told prior to the adoption that the girl’s activity level was low. Because she had an international change of surroundings and caretakers, the parents assumed the quiet behavior was due partly to the adjustment to new surroundings and partly to her unique personality. They had a picture of her in the orphanage at age 16 months.

Fig. 34-1 The same child suffering with β-thalessemia at different timepoints. A, In the orphanage at 16 months of age. Note the contrast in color between the same ethnicity adult’s well perfused and pink hand versus the child’s pallor. B, Age 4 years, just as she is arriving in the United States. Her hemoglobin is 4 g/dL. She is somewhat jaundiced. She appears tired. Contrast her pallor especially in fingernail beds and jaundice with the pink caucasian adult’s hand. C, Age 4 years, approximately 2 months after photograph in B. Hemoglobin is 10 g/dL. She is an energetic, smiling child now tan, consistent with her ethnic background, rather than jaundiced. Note less contrast between child’s color and adult’s arm despite different ethnic backgrounds.

Over the ensuing weeks, she came to the clinic at least weekly. She remained polite, quiet and easy to interact with. Her English vocabulary increased. She continued to cry with starting IVs though she fought relatively little and was easily calmed afterward. Despite receiving 20 to 25 mL/kg transfusions, her hemoglobin remained in the 3 to 4 range in 2 weeks. She also had initial worsening of splenomegaly, which extended to 12 cm below the left costal margin and was very firm. Evaluation by cardiology demonstrated cardiomegaly but otherwise adequate function. During this period of time, she continued to walk very little. She arrived at clinic in a stroller because the distance from parking garage to clinic is approximately a quarter mile. When she did walk, she walked with a slow, wide-based gait. Her protuberant abdomen gave her the appearance of a pregnant 4 year old. Mom indicated that she walked inside the house but sometimes stumbled while walking. She did not go up stairs. She did not seem interested in joining the other children with outdoor play.

After several weeks, her hemoglobin before transfusion was 8. Her heart rate was under 100 for the first time since we had begun her care. Her spleen had returned to 8 cm. Her murmur was less prominent and she no longer had a palpable thrill. We proceeded with the transfusion as scheduled. At the end of the transfusion, her heart rate had finally improved to an age-appropriate rate in the 80s. A follow up hemoglobin a few days later was 10 (Fig. 34-1). On the next clinic visit, her mother excitedly described how she was a “totally different” little girl. She had walked much more that week. In fact, she had run for the first time since arriving in the United States. She had engaged in pillow fights with the siblings. She had engaged in a game of her own making called “monster” with the other children. For the next visit to the clinic, she walked through the door. The nurses were struck with how much more physical resistance she put up when they started her IV. Over the next several clinic visits her parents continued to comment on being aware of how much more active she was now that her hemoglobin was higher. They also repeatedly commented on how she now appeared tan consistent with her ethnic heritage rather than pale and yellow. The child also no longer complained of being cold.

This little girl’s experience powerfully illustrates the impact anemia can have on a child’s activity level. Until her chronic anemia was resolved to a level of moderate rather than severe anemia, she did not have the energy to engage in physically active play. Because of her otherwise quiet manner and recent entry into this family unit, even the medical team underestimated how much the anemia contributed to her restricted activity until after she became more active. We attributed some of her tendency to pursue quiet activities to personality and adjustment to a new environment. Indeed, she remains a child who is quiet mannered. She also continues to prefer crayons and small toys to television. Once the anemia was improved from severe anemia to mild anemia, she clearly began to feel better. The jaundice resolved and was replaced by pink lips and ethnically appropriate tan coloration. She became more interactive, of course she is also learning more English words by now, too. She walks around the clinic and explores as would be expected of a 4 year old. Truly the quality of her life and ability to participate in play has drastically improved with correction of the chronic anemia.