George R. Buchanan
Diseases of the blood involving infants, children, and adolescents are commonly encountered by primary care physicians. Many hematologic problems are straightforward and, therefore, easy to diagnose and manage without involvement of a subspecialty consultant. Yet others are rare, serious, or even life threatening, representing complex diagnostic and management challenges. In such cases, engagement of a pediatric hematology-oncology subspecialist is recommended. The American Board of Pediatrics has certified more than 2000 practitioners in this subspecialty.
For good reason, hematology and oncology have been combined as a single subspecialty discipline for several decades.1,2 One of the first recognizable conditions treated by children’s blood specialists was acute leukemia. As the principles of combination chemotherapy became clear during the 1960s, the drugs used to treat leukemia were also found to be effective in treating solid malignant tumors. Accordingly, it was (and still is) the hematology specialist who becomes skilled in these agents’ use in the care of leukemia and other cancer patients. Hematology-oncology thus became a combined specialty by the 1970s and has remained so from the standpoint of board certification. Nevertheless, the increasing complexity of the field during the past few decades has resulted in some practitioners focusing primarily in one clinical area (oncology) or the other (hematology), especially those working in large metropolitan areas where patient numbers justify this subsubspecialization. Hematologyoncology specialists tend to be concentrated in academic medical centers where they conduct clinical or laboratory research as well as teach and provide patient care. For years, the standard of care in childhood cancer has included these patients’ enrollment, if possible, in peer-reviewed multicenter research studies. More recent advances have also fostered clinical trial participation becoming accepted practice in children with nonmalignant hematologic conditions such as sickle cell disease and hemophilia.
CLASSIFICATION OF HEMATOLOGIC DISORDERS
Most hematologic disorders encountered by pediatricians are mild, transient, and/or secondary to another acute or chronic illness. They are usually identified because of abnormalities in the blood count rather than by signs or symptoms specific to the hematologic condition. Nevertheless, some hematologic conditions are chronic, severe, and often familial in nature. Expertise in hematologic disorders during childhood thus requires a keen interest in and knowledge of genetics.
Many diseases during childhood involve a specific organ, such as the heart, lungs, kidneys, or brain. Strictly speaking, the blood is not an organ but a liquid tissue that circulates throughout the body; thus, an abnormality can have diverse clinical consequences affecting many organs. The primary organ of the blood is the bone marrow cavity, where post-natally the majority of blood cells are produced. Other hematologic organs include the spleen and lymph nodes, which contain diverse antibody-producing cells and lymphocytes. The spleen is also a rich source of macrophages that remove senescent blood cells, bacteria, and other soluble and particulate matter from the bloodstream.
CLINICAL PRESENTATION OF HEMATOLOGIC DISORDERS
Children with blood diseases may present with signs and/or symptoms thereof, but more commonly exhibit manifestations that are nonspecific or secondary to an underlying problem such as infection or trauma, or they are discovered incidentally. Frequently, it is a laboratory test result—usually an abnormality in the blood count—that raises the suspicion of a hematologic disorder. When primary physicians and parents learn that a hematologic condition may exist, leukemia often emerges as a possibility. The anxiety resulting from this concern understandably prompts urgent requests for hematology consultation. A positive family history of a blood condition is another common reason for considering the child to be at risk of a potentially serious disorder. For example, a family history of hemophilia warrants evaluation of newborn male infants for this possibility, as does a positive history of hereditary spherocytosis in a first-degree relative.
Although there are advantages to having children with seemingly minor hematologic problems evaluated by a blood specialist, these visits may initially instill further anxiety in the parent (eg, by them sharing an office waiting room with children who are bald and/or acutely or chronically ill from cancer or its treatment). Confirmation that the child suspected of cancer instead has just a minor hematologic disorder, or nothing wrong at all with their blood, usually results in a great sigh of relief on everyone’s part and is a source of great satisfaction for the hematology specialist who conveys the findings.
DIFFERENTIAL DIAGNOSIS OF HEMATOLOGIC DISEASE
Blood diseases in children can be categorized in many ways. Some of these ways include age, race, gender and Tanner stage, signs and symptoms, and circumstance.
BY AGE
Several components of the complete blood count in young patients differ not only from their adult counterparts, but also according to the child’s age. This often makes it difficult for the nonpediatrician to differentiate normal values from pathologic ones. For example, newborn infants have high hemoglobin values that decline during the first 3 months of life, the period of physiologic anemia of infancy. The hemoglobin concentration then rises slightly but remains substantially less (although increasing with age) than in adults. The mean corpuscular volume (MCV) is also lower than in adults, and it, too, rises with age.3 Neutrophil counts are higher during the first 2 days after birth than any other time during life; however, like red blood cells, these counts decline to rather low levels by adult standards until early to mid-childhood. Platelet counts are similar at all ages. However, blood coagulation factor levels in plasma are lower in premature and term neonates than in older patients. This particularly applies to the contact factors (factors XI, XII, prekallikrein, and high-molecular-weight kininogen); the vitamin K-dependent clotting factors (II, VII, IX, X); and certain anticoagulant proteins such as anti-thrombin, protein C, and protein S.
BY RACE
Certain hematologic disorders are seen primarily in individuals who are not of northern European Caucasian extraction. These include the most common hemoglobinopathies (hemoglobins S, C, and E, as well as both alpha and beta thalassemia). Abnormalities involving hemoglobin, as well as glucose-6-phosphate dehydrogenase (G-6-PD), are seen almost exclusively in persons of African, Mediterranean, Middle Eastern, or south and Southeast Asian heritage.4The gene frequencies of G-6-PD mutations and hemoglobin disorders range from 5% to 40% in some of these populations. Therefore, an anemic child with such a genetic background always needs to be evaluated for these conditions. Another blood measurement affected by a person’s race is the white blood cell (WBC) count.5,6 The term ethnic pseudoneutropenia has been used to describe the somewhat lower neutrophil counts encountered in persons of African ancestry compared to Caucasians. The mechanism of this phenomenon is unclear, but knowing about it prevents normal black children from undergoing an evaluation and/or being labeled as neutropenic.
BY GENDER AND TANNER STAGE
During the early to mid-adolescent years, a major determinant of the hemoglobin concentration in boys is their Tanner stage.7 Androgens increase the production of erythropoietin, the hormone produced in the kidneys that stimulates the bone marrow to produce red blood cells. Therefore, in males, the androgen “burst” accompanying puberty stimulates erythropoiesis. For example, the mean hemoglobin concentration for a 13-year-old Tanner stage 1 boy is 12.5 g/dL but would be 14.0 g/dL if the youngster were Tanner stage 5. Thus, a comprehensive physical examination is required in all anemic children. In girls, where androgen production during puberty is limited, there is no relationship of Tanner stage with red blood cell measures.
BY SIGNS AND SYMPTOMS
The specific clinical manifestations of hematologic disorders are diverse (Table 428-1). It should be noted, however, that children may have few disease manifestations, even when their blood count is strikingly abnormal.
BY CIRCUMSTANCE
Some children with blood disorders are identified by routine screening either during the newborn period (eg, for sickle cell disease) or at 1 to 2 years of age (eg, for iron-deficiency anemia). When a blood count is performed for a nonhematologic condition (infection, failure to thrive, monitoring of drug therapy, etc), an unexpected abnormality may be uncovered. In other circumstances, one of the signs or symptoms listed in Table 428-1 prompts a complete blood count and, as needed, other studies (eg, blood coagulation tests, bone marrow examination) to define the nature and severity of the hematologic condition.
Table 428-1. Nonspecific Clinical Manifestations Suggesting a Hematologic Disorder
The differential diagnosis and management strategy usually depends greatly on whether the child is “sick” in the hospital or emergency department or “well” and being seen in the office or clinic. When immediate medical attention is required for the ill child, the diagnosis is often readily apparent to the physician. The most common reason for hospitalization of children with an underlying hematologic disease in the United States is a complication of sickle cell disease. The cause is most frequently a pain crisis, acute chest syndrome, or acute worsening of the anemia resulting from splenic sequestration or transient red cell aplasia due to parvovirus infection. Sudden hematologic emergencies may also occur in children with immune thrombocytopenic purpura (eg, profuse mucous membrane hemorrhage resulting in anemia or intracranial bleeding). Severe and even life-threatening anemia may result from acute hemolysis or bone marrow failure due to diverse causes. Many sick children with hematologic complications have a primary underlying disease that triggers disseminated intravascular coagulation or severe liver injury. These children—like babies with congenital heart defects requiring complex surgery and patients receiving solid organ transplants—may develop either large vessel thrombosis or hemorrhage. Drug-induced alterations in hemostasis and in the WBC are also commonplace in such children.
Hematologic problems, however, are most commonly encountered in the outpatient setting and involve children who are not acutely ill. These office or clinic visits often lead to an abnormal laboratory test result in an otherwise healthy child or are prompted by signs or symptoms (Table 428-1) suggesting a hematologic disease. These include bleeding (as discussed further later in the chapter), pallor, jaundice, frequent infections, or a poor response to iron therapy in a child diagnosed (correctly or not) with iron deficiency, the most prevalent hematologic problem encountered by primary physicians.
RESERVE AND RESILIENCE OF CHILDREN WITH HEMATOLOGIC DISORDERS
The bone marrow rapidly produces and releases literally millions of blood cells into the circulation when the need arises. For example, during acute infection, leukocyte counts can rise within hours by 10-fold or more, and acute anemia is often followed by marked increase in circulating nucleated red blood cells and reticulocytes. Various hematopoietic growth factors are also responsible for mobilizing increased numbers of blood cells, although this process may take several days. However, the bone marrow is “resilient,” as usually are children with hematologic diseases and cancer. It is quite amazing how quickly children with life-threatening anemias, bleeding disorders, or advanced cancer can bounce back from their disease or its therapy and resume normal play and school activities.
GENERAL PRINCIPLES OF TREATMENT
Fortunately, treatment—effective and sometimes curative—is available for most children with hematologic conditions. Several examples are illustrative. Iron-deficiency anemia, a preventible condition that remains extremely common, usually responds promptly to medicinal iron therapy after identification and elimination of its cause.8 Immune thrombocytopenic purpura (ITP) is of unknown cause, but usually resolves promptly and forever with little or no drug treatment. Neutropenia is also generally transient and self-limited, lasting a week or two when secondary to a viral infection or occasionally as long as 12 to 18 months when it is antibody mediated during infancy. Treatment is also often highly effective, even in chronic and inherited hematologic disorders. Bleeding in hemophilia can now be prevented altogether by means of regular prophylactic factor VIII or IX infusions. Children with sickle cell disease receive penicillin, which wards off serious pneumococcal infection, and many have benefited from hydroxyurea, a chronic blood transfusion program, or curative hematopoietic stem cell transplantation. Unfortunately, these effective treatments are extremely costly and generally unavailable in developing countries. Anemia due to malaria, iron deficiency, and hemoglobinopathies remain tragic and untreatable diseases in many parts of the world.
A general therapeutic principle in pediatric hematology is to treat the child rather than the abnormal blood count. Not only may drug treatments for conditions such as ITP be costly, but they may also result in adverse effects that are often more troublesome to the child and family than the bleeding disorder itself. Ensuring a correct diagnosis is critical when embarking on treatment. For example, children with thalassemia minor often receive medicinal iron inappropriately for months or even years. The therapeutic strategy for every suspected hematologic disorder should include an appreciation of its natural history, its burdens on the patient and family, and the often diverse nature of available management options.
BLEEDING OR THROMBOSIS AS A CLINICAL MANIFESTATION
Probably the most dramatic presentation of a potential of hematologic disease is hemorrhage. The appearance of blood flowing from a skin wound or body orifice is always frightening for parents and children. Unless the bleeding is obviously secondary to trauma and rapidly responsive to local control, the possibility of a hemorrhagic disorder clearly exists. Some simple considerations in the history and physical examination are critically important in determining whether the bleeding is due to a defect in primary hemostasis (platelet number or function or a disorder of the microvasculature) or secondary hemostasis(involving one or more blood coagulation factors). The presence of a positive family history, location, duration, and extent of hemorrhage, and whether an underlying disorder is present, are important determinants, as is the age of the child. Neonates are uniquely vulnerable to both hemorrhage and thrombosis, particularly when they are ill with an underlying condition. Sometimes children with apparent hemorrhagic disorders have no alterations at all in their hemostatic mechanism but have a vascular or connective tissue disorder instead. Examples include Henoch-Schönlein purpura and Ehlers-Danlos syndrome.
Henoch-Schönlein Purpura
Henoch-Schönlein purpura deserves special mention. Although a vasculitis (described more completely in Chapter 203), this disorder frequently presents with hemorrhagic manifestations, thus prompting performance of blood coagulation studies, the results of which are invariably normal. Children with Henoch-Schönlein purpura often have petechiae and purpuric lesions. What is different from similar lesions seen in patients with thrombocytopenia or coagulopathies is that they are generally limited to very specific areas of the body. The rash is seen most prominently on the buttocks and lower extremities but only rarely on the back and chest. The lesions are also often palpable, whereas the petechiae and purpura associated with thrombocytopenia are not. Overt bleeding from the lower gastrointestinal tract—due to vasculitis involving intestinal mucosa rather than an impaired hemostasis—can further mislead the clinician into believing that a child with Henoch-Schönlein purpura has a primary bleeding disorder. The importance of promptly making the correct diagnosis of Henoch-Schönlein purpura lies in the other important disease manifestations (soft tissue and joint involvement, abdominal pain, and, most especially, renal impairment) that are not typical of primary hematologic conditions and which occasionally cause substantial morbidity. Treatment of Henoch-Schönlein purpura is further described in Chapter 203.
Thrombosis was once rare during infancy and childhood; however, it is now frequently encountered as a result of improved medical and surgical care of critically ill children and advanced imaging tests, which can often detect large vessel thrombi, even when clinical signs are inapparent. Another situation is when thrombosis risk is suspected in an asymptomatic child whose first-degree relative has a genetic prothrombotic mutation with or without clinical thrombosis. The need for management strategies for these scenarios was unnecessary just a decade ago but is now commonplace.
POLYCYTHEMIA
Polycythemia or erythrocytosis is a hematologic condition that is covered briefly but incompletely in other chapters; thus, it is summarized here. Polycythemia is characterized by an increased number of circulating red blood cells. The high hematocrit and hemoglobin concentration causes increased blood viscosity and can have a number of sequelae. Polycythemia is most commonly encountered in neonates; its differential diagnosis and management are addressed in Chapter 50. Sometimes apparent polycythemia is spurious, most commonly resulting from dehydration, with the high hemoglobin concentration due to diminished plasma volume rather than a true increase in red blood cell mass.
Polycythemia can either be primary or secondary.9 Primary polycythemia is extremely rare during childhood, although in adults it occurs as polycythemia vera, a myeloproliferative disorder secondary to a JAK2 gene mutation. More commonly, polycythemia during childhood is a secondary phenomenon—an appropriate increase in red blood cell mass secondary to chronic hypoxemia due to residence at high altitude, cyanotic congenital heart disease, or chronic pulmonary disease. In other cases, secondary polycythemia is the result of an erythropoietin-secreting neoplasm, most often Wilms tumor, or an alteration in one of several genes important in the oxygen-sensing apparatus. The best example is a mutation in the von Hippel-Lindau gene as a component of the entire syndrome or occurring as an isolated event seen frequently in the Chuvash area of Russia.
Polycythemia during childhood is generally treated by focusing on the primary disorder. Some patients develop lethargy, headaches, and an increased predisposition to thrombosis as a result of hyperviscosity. Its management consists of phlebotomy to reduce the hemoglobin concentration and blood viscosity.
STATISTICAL AND TECHNICAL ANEMIA AND OTHER VAGARIES OF THE COMPLETE BLOOD COUNT
The most frequent reason for suspecting a hematologic disorder in a child is the unexpected finding of an apparent abnormality on the complete blood count (CBC). The CBC is probably the most commonly performed laboratory test ordered by pediatricians on their patients, irrespective of age. Indeed, the CBC can provide a great deal of information regarding a child’s diagnosis, disease status, or response to treatment. However, the CBC—like many other laboratory tests—is subject to a variety of limitations and pitfalls that must be understood. This particularly applies to evaluating a child for anemia or abnormalities of the WBC count.10 First, as stated previously, blood count values do vary with age. Second, it is surprising to many that the normal ranges of blood count values in children of different ages have not been well established and are subject to significant variation as a result of minor and transient viral infections and other illnesses. Moreover, the range of normal CBC values, for such measurements as the hemoglobin concentration, mean corpuscular volume (MCV), total WBC count, and absolute neutro-phil count, are defined as the mean and 2 standard deviations above and below the mean.3,10 By definition, 2.5% of totally normal children have “low” or “high” values, respectively. They are thus designated as being “abnormal” or “out of range” on the printed report from the laboratory. These values are bolded, highlighted, or shaded on the report to get the pediatrician’s attention. To some physicians and many parents, who hope and expect the child to be normal, such out-of-range values engender concern and even alarm. Appreciating that 2.5% of totally normal healthy children will have such “statistical anemia” is extremely important. Another example is an activated partial thromboplastin time (aPTT) that is 1 or 2 seconds above the upper limit of normal in the absence of a personal or family history of bleeding. Such an “abnormality” is also likely to be a statistical outlier.
There are also a number of technical considerations that the physician must keep in mind when interpreting laboratory results of children suspected of having hematologic disease. Many point-of-care office instruments employed to measure blood counts lack precision; thus, suspected abnormal results should always be confirmed in a Clinical Laboratory Improvement Amendment (CLIA)-certified laboratory for validation. For economic reasons, local diagnostic laboratories often ship laboratory specimens to distant reference facilities for the analysis. One cannot always be assured that the specimen was properly drawn, stored, and shipped prior to arrival at the reference laboratory hundreds of miles away. This is of particular importance in interpreting blood coagulation studies such as the ristocetin cofactor measurement used to diagnose von Willebrand disease. Many children have been misdiagnosed as a result of reliance on abnormal test results that are erroneous and often inconsistent with the clinical picture.
In summary, the history and physical examination continue to provide far greater diagnostic evidence than laboratory test results when children are suspected of having a hematologic disorder.10,11 Insights regarding specific mechanisms of the diseases and the strategies used by practitioners for diagnosing and effectively treating them are presented in this section.
CAREERS IN PEDIATRIC HEMATOLOGY-ONCOLOGY
There are too few pediatric hematology-oncology specialists in the United States, other developed countries, and, in particular, the developing world.12 Despite great advances in the diagnosis and treatment of blood disorders and cancer, the overall incidence of these conditions is stable or increasing, and the prevalence is therefore rising. This creates substantial demand for physicians with expertise in the diagnosis and management of these conditions. Hematology has always been a research-based specialty, so numerous opportunities for clinical, translational, and laboratory investigation exist in the field. It is gratifying that several professional societies have been instrumental in describing and supporting career opportunities for young people interested in a hematology-oncology career.13