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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…

Thrombocytopoiesis

Platelets, once regarded simply as ”blood dust,” are now recognized to play essential roles in hemostasis. Not only do they form a hemostatic plug and initiate thrombus formation in the event of vascular injury, but they also repair minute vascular damage that occurs on a daily basis. Platelets also participate in wound healing and angiogenesis via the delivery of key growth factors to sites of vascular…

Granulocytopoiesis and Monocytopoiesis

Granulocytopoiesis Granulocytes (neutrophils, eosinophils, and basophils) are short-lived cells that are critical to both antimicrobial and inflammatory responses. The bone marrow (BM) produces granulocytes, particularly neutrophils, at a prodigious rate to supply the baseline need for circulating cells that survive in the peripheral blood for only 3 to 24 hours. It also has the capacity to sharply increase granulocyte production in response to a wide range…

Biology Of Erythropoiesis, Erythroid Differentiation, And Maturation

The production of erythroid cells is a dynamic and exquisitely regulated process. The mature red cell is the final phase of a complex but orderly series of genetic events that is initiated when a multipotent stem cell commits to the erythroid program. Expression of the erythroid program occurs several divisions later in a greatly amplified population of erythroid cells, which have a characteristic form and structure,…

Treatment of Hematologic Malignancies With Genetically Modified T Cells

Conventional modalities for treating cancer remain unsatisfactory. Despite the introduction of small molecules that target specific molecular lesions or pathways within the cancer cells, cure rates for many common tumors remain low, while adverse events are still distressingly high. Cancer immunotherapy represents a promising extension of highly targeted cAncer therapy with potentially favorable toxicity and pharmacoeconomic profiles. Until recently, most attention has been on the development…

Unmodified Ex Vivo Expanded T Cells

T lymphocytes have the natural ability to destroy viral-infected or tumor target cells by a range of mechanisms that are initiated upon recognition of target peptides presented by histocompatibility antigens. Coupled with their ability to traffic through multiple tissues and self-renew, these properties make T lymphocytes an appealing cell-type for adoptive immunotherapy of cancer. Allogeneic hematopoietic stem cell transplantation (HSCT) is enduring “proof-of-principle” for adoptive immunotherapy…

T-Cell Immunity

Thymus-derived lymphocytes (T cells) play an essential role in the immune response to pathogens and against host cells that have undergone malignant transformation. T cells are critical regulators of the immune system that act through production of soluble mediators and direct interactions between ligands on the T-cell surface and receptors on other immune cells. This chapter reviews T-cell activation after engagement with specific antigens and describes…