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Neutrophilic Leukocytosis, Neutropenia, Monocytosis, and Monocytopenia

Abnormalities of leukocyte number are commonly encountered in medical practice. The clinical significance of leukocytosis or leukopenia varies from none at all to being an early clue to a life-threatening process, whether that is a primary hematologic or secondary reactive process. Potential causes of leukocytosis or leukopenia are myriad. This chapter considers disorders faced by adult practitioners in hospital and outpatient clinics where the predominant hematologic…

Extrinsic Nonimmune Hemolytic Anemias

By definition, extrinsic causes of hemolysis are abnormalities in the environment in which the red blood cells (RBCs), usually normal themselves, circulate. These abnormalities can be acute or chronic in nature. They can arise from congenital lesions but usually result from acquired insults. Inherited anomalies of glucose-6-phosphate dehydrogenase (G6PD) deficiency, which reduces the RBCs’ ability to deal with oxidative stressors, can leave RBCs more vulnerable to…

Autoimmune Hemolytic Anemia

Autoimmune hemolytic anemia (AIHA) is a rare autoimmune disease caused by autoimmune-mediated destruction of red blood cells (RBCs) by autoantibodies with various properties and target specificities. Exact laboratory diagnosis may sometimes be difficult; therefore, experienced diagnostic reference centers play an important role. The disease can be primary (idiopathic) or caused by an underlying condition (secondary), including systemic autoimmune diseases, infections, primary immunodeficiencies, drugs, or neoplasms (mostly…

Red Blood Cell Membrane Disorders

Characterization of the structure and function of red blood cell (RBC) membrane proteins and their genes ( Fig. 46.1 ) has led to considerable advances in our understanding of the molecular pathology of membrane-associated disorders, including the definition and characterization of mutations of membrane proteins as a well-defined cause of hereditary hemolytic disease. Likewise, knowledge of the molecular mechanisms underlying changes in RBC deformability, structural integrity,…

Red Blood Cell Enzymopathies

Red blood cells (RBCs) are highly specialized cells with the sole function of delivering oxygen to the tissues. During oxygen delivery, a highly destructive reactive oxygen species (ROS)—such as superoxide—is generated from a small fraction of the oxygen released from hemoglobin. ROS oxidizes hydroxylated sulfur groups (SH), leading to profound alterations in protein structures. This is most marked by the transformation of the hemoglobin present in…

Hemoglobin Variants Associated With Hemolytic Anemia, Altered Oxygen Affinity, and Methemoglobinemias

Hemoglobinopathies are inherited diseases caused primarily by mutations affecting the globin genes. Nearly 1000 mutations are known to alter the structure, expression, or developmental regulation of individual globin genes and the hemoglobins that they encode. Of these, only a few produce clinical disease. Many are highly instructive for students of gene structure, function, and regulation, but further consideration of most is not warranted in a clinically…

Clinical Aspects of Sickle Cell Disease

Hemoglobinopathies are the most common genetic diseases in humans. In sickle cell disease (SCD), a single nucleotide substitution (GTG for GAG, rs334 ) in the sixth codon of the β-globin gene produces an abnormal sickle hemoglobin (HbS). Due to a change in the convention for numbering amino acid residues in the human β-hemoglobin chain, the HbS mutation becomes E7V rather than E6V and the current numbering…

Pathobiology of Sickle Cell Disease

Since it was recognized as the “first molecular disease,” sickle cell anemia (HbSS) caused by homozygosity for the mutant sickle beta-globin gene has provided the classic paradigm for single-gene disorders. Predominant clinical features include hemolytic anemia, episodic painful vasoocclusive events, an inflammatory vasculopathy, chronic organ deterioration, and a foreshortened life span. The genesis of clinical HbSS is complicated, and an understanding of its pathophysiology integrates concepts…

Thalassemia Syndromes

The thalassemia syndromes are a heterogeneous group of inherited anemias which result from defects in the synthesis of one or more of the globin chain subunits of the hemoglobin (Hb) tetramer. The basic defect, decreased or absent production of a globin subunit, results in an imbalance between globins produced as a result of expression of genes from the alpha-globin gene cluster on chromosome 16, and those…

Megaloblastic Anemias

The term megaloblastic anemia is used to describe a group of disorders characterized by a distinct morphologic pattern in hematopoietic cells. A common feature is a defect in deoxyribonucleic acid (DNA) synthesis, with lesser alterations in ribonucleic acid (RNA) and protein synthesis, leading to a state of unbalanced cell growth and impaired cell division. Most megaloblastic cells are not resting but vainly engaged in attempting to…

Heme Biosynthesis and Its Disorders: Porphyrias and Sideroblastic Anemias

The porphyrias and the sideroblastic anemias are metabolic disorders that involve defects in heme biosynthesis. Most forms of porphyria are inherited in a Mendelian autosomal dominant pattern, but some types are recessive, and others are acquired through exposure to porphyrinogenic drugs and chemicals. A linked group of diseases, the porphyrinurias, are not porphyrias but have in common alterations of heme biosynthesis following exposure to various toxins.…

Anemia of Chronic Inflammation

Anemia of chronic inflammation (ACI) is also termed anemia of chronic disease and considered the second most frequent anemia in the world, after iron deficiency anemia (IDA). ACI is also the most common anemia in hospitalized patients, found in conditions associated with an activated immune response, including chronic infections, autoimmune and inflammatory illnesses, and malignancy. The underlying cause of anemia in these diseases is multifactorial, including…

Disorders of Iron Homeostasis: Iron Deficiency and Overload

Iron is an essential nutrient for every cell of the body. Both decreased and increased total body iron, as well its inappropriate tissue distribution may be clinically important. In iron deficiency, limitation of the synthesis of physiologically active iron-containing compounds can have harmful consequences. In iron overload when iron exceeds the body’s capacity for safe transport and storage, iron toxicity may produce widespread cell (and organ)…

Iron Homeostasis and Its Disorders

Iron is an essential trace element required for energy production, oxygen transport and utilization, and cellular proliferation. Iron is a catalyst, acting as an electron donor and an electron acceptor by readily interconverting between ferric (Fe 3+ ) and ferrous (Fe 2+ ) forms. Iron functions mainly in association with proteins, either within prosthetic groups (heme, iron-sulfur clusters) or bound directly by amino acid side chains.…

Approach to Anemia in the Adult and Child

Anemia is the clinical state of red cell mass inappropriately low for the individual’s physiologic state. Anemias are among the most commonly encountered laboratory findings and clinical disorders in hematology. They encompass a broad range of clinical disorders and diseases with a spectrum of subtle to severe clinical impact on health. The approach to anemias can be direct if the cause is a common, singular or…

Pathobiology of the Human Erythrocyte and Its Hemoglobins

Anemia, polycythemia, and functional derangements of the human erythrocyte together represent a common group of human disorders with a significant impact on public health. Sickle cell disease, hemoglobin E (HbE)–associated disorders, and the thalassemias are humankind’s most common single-gene diseases, but the relevance of red blood cell (RBC) disorders to general medicine extends even beyond their individual clinical severities or the number of patients affected. A…

Acquired Disorders of Red Cell, White Cell, and Platelet Production

Acquired pure red cell aplasia (PRCA) is characterized by the presence of an acquired severe normochromic, most frequently normocytic anemia associated with a complete disappearance of reticulocytes and erythroid precursors in the marrow and normal production of myeloid cells and platelets. Consequently, it is presumed that the defect lies within erythroid precursors and not within stem cells as seen in aplastic anemia. Initially described as progressive…

Paroxysmal Nocturnal Hemoglobinuria

Introduction and History Paroxysmal nocturnal hemoglobinuria (PNH) is an opportunity to expound upon three major topics: hemolytic anemia, autoimmune-mediated bone marrow failure, and thrombosis. For the physician explaining a new diagnosis to the patient, PNH is now a cause for cautious optimism, as we have seen a tremendous improvement in the outcome over the past decades. Indeed, we can now alleviate symptoms and prevent complications in…

Aplastic Anemia

Aplastic anemia (AA), the paradigm of the bone marrow (BM) failure syndromes, is most simply defined as peripheral blood pancytopenia and a hypocellular BM ( Fig. 31.1 ). AA occurring as a primary hematologic disorder is historically denoted idiopathic, but it is now understood as immune-mediated. Constitutional marrow failure syndromes share a similar pathology of an apparently “empty” marrow (see Chapter 30 ) and can be…

Inherited Bone Marrow Failure Syndromes

Introduction Inherited bone marrow (BM) failure is defined herein as decreased production of one or more of the major hematopoietic lineages; i.e., red blood cells (RBCs), neutrophils, and platelets, due to germline mutations that were derived from the parents or occurred de novo ( Table 30.1 ). Although outdated, the term “constitutional” has been used interchangeably with “inherited” and similarly implies that a genetic abnormality causes…