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Hemophilia and von Willebrand Disease

The clinical and laboratory features of the three most common hereditary bleeding disorders—hemophilia A (factor VIII deficiency), hemophilia B (factor IX deficiency), and von Willebrand disease (VWD)—are discussed in this chapter. Hemophilia A and hemophilia B are both caused by a functional deficiency of a plasma protein inherited in an X-linked manner. Because these two proteins, factor VIII and factor IX, are part of the tenase…

Inherited Platelet Disorders

Platelets are small (1 to 4 µm in diameter) and were once thought to be fragments of other mature blood cells, dismissed as “blood dust.” They are now known to be highly specialized and organized structures released (by a still partly understood process called thrombopoiesis ) from megakaryocytes. Platelets are a critical component for the first phase of hemostasis (formation of the platelet plug), which can halt…

Approach to the Child with a Suspected Bleeding Disorder

Introduction Before initiating the laboratory workup of any patient with a suspected defect of hemostasis, the hematologist must first verify that the patient has a clinical history, signs, and symptoms compatible with a bleeding disorder. This is not an easy task because mild bleeding and bruising are common in the general population. Furthermore, bleeding, particularly in the outpatient setting, is difficult to quantify because patient reports…

Molecular Basis of Fibrinolysis

Fibrinolysis is the process by which the insoluble protein fibrin is converted to a defined set of soluble degradation products. It occurs in both intravascular and extravascular locations and is essential to human health and survival. Modern molecular biologic techniques have identified the major fibrinolytic genes, the mechanisms regulating their expression, and the consequences of their deficiency or overexpression in genetically engineered mice. In many cases…

Blood Coagulation

Overview of Coagulation Generation of the enzyme thrombin from its precursor prothrombin is the central event in the blood coagulation process, essential for hemostasis and the culprit in thrombosis. Blood loss through lack of hemorrhage control has captured the attention of individuals from many walks of life throughout history. At the end of the nineteenth century, the role of thrombin in the clotting of fibrinogen was…

Platelets and the Vessel Wall

In an 1881 communication to the Turin Royal Academy of Medicine, the Italian physician Giulio Bizzozero disclosed the presence in circulating human blood of discrete elements that he termed “ piastrine ” (“ Blutplättchen ” in a 1882 publication in a German journal and “ petites plaques ” in a communication in French). Previously speculated to be merely nonphysiologic “granular aggregates,” blood platelets have since become…

Lysosomal Storage Diseases

This chapter provides an overview of the lysosomal storage diseases (LSDs) with particular reference to their specific hematologically related manifestations or treatments. Comprehensive reviews, such as Chapters in the Metabolic and Molecular Bases of Inherited Diseases, 9 th ed., are available for molecular genetics, biochemistry, enzymology, and phenotypes, and these sources should be consulted for details. The Lysosomal System The lysosome is an intracellular organelle originally…

Primary Immunodeficiency Diseases

Immune compromise arises either as a heritable genetic defect (primary immune deficiency diseases, PIDDs) or as a consequence of another pathologic process such as infection, malignancy, malnourishment, or iatrogenic immunosuppression (secondary immune deficiencies). Immune dysfunction in patients with PIDDs is most often manifested as recurrent and chronic infections; however, malignancy and autoimmunity are common and may be prominent in some disorders. In many cases, symptoms and…

Immune Response

The immune system is a complex network of cells that serve to discriminate “self” from “nonself”—that is, to recognize one cell as one's own and another cell as foreign or infected. This capacity helps protect the organism from infection by foreign pathogens (bacteria, viruses, and parasites) and from malignant degeneration. In addition, the cells involved in the immune response mediate rejection of foreign allografts. Although immune…

Phagocyte System and Disorders of Granulopoiesis and Granulocyte Function

Definition and Classification of Phagocytes Phagocytic leukocytes are bone marrow-derived cells that have the capacity to engulf and digest particulate matter. Phagocytes are essential for the host response to infection and injury and are equipped with specialized machinery enabling them to seek out, ingest, and kill microorganisms. Other functions include the synthesis and secretion of cytokines, pyrogens, and other inflammatory mediators, as well as the digestion…

Thalassemias

The thalassemias are a heterogeneous group of inherited forms of anemia caused by mutations that affect the synthesis of hemoglobin. Milder forms are among the most common genetic disorders, whereas the severe forms, which are seen less often, lead to significant morbidity and mortality worldwide ( Fig. 21-1 ). Open full size image Figure 21-1 Geographic distribution of thalassemia. Study of the thalassemias traces the history…

Sickle Cell Disease

The first report of sickle cell anemia (SCA) in the medical literature described a dental student from Grenada, Walter Clement Noel. It was by Herrick and Irons in 1910 and introduced the word sickle in the title of the case report. Sydenstricked described the first cases in children, recognized the association with hemolytic anemia, and introduced the term crisis to describe periodic acute episodes of pain.…

Normal and Abnormal Hemoglobins

Studies of hemoglobin (Hb) structure, function, and expression over more than 50 years have produced many paradigms in biology and medicine. The first part of this chapter describes the structural and biochemical properties of Hb, emphasizing those that underlie its physiological roles. The conserved globin protein fold with the heme prosthetic group confers the basic function of reversible oxygen (O 2 ) binding, which is common…

Glucose-6-Phosphate Dehydrogenase Deficiency

Most hemolytic anemias can be categorized, at least at first approximation, as being either inherited or acquired as a result of either intracorpuscular or extracorpuscular causes. Hemolytic anemia associated with deficiency of glucose-6-phosphate dehydrogenase (G6PD) glaringly defies this categorization. Indeed, most persons with inherited G6PD deficiency have no anemia and almost no hemolysis; both develop only as a result of challenge by exogenous agents. Because the…

Pyruvate Kinase Deficiency and Disorders of Glycolysis

The mature erythrocyte, devoid of nucleus, mitochondria, ribosomes, and other organelles, has no capacity for cell replication, protein synthesis, or oxidative phosphorylation. The glycolytic production of adenosine triphosphate (ATP), the sole known energy source of erythrocytes, is sufficient to meet their limited metabolic requirements. The discovery that hemolytic anemia may result from any of several glycolytic enzymopathies has underscored the dependence of erythrocytes on glycolysis. In…

Disorders of the Red Cell Membrane

During erythropoiesis the red cell membrane responds to erythropoietin and imports the billion or so iron atoms each red cell needs to complete hemoglobin synthesis. It sequesters the reductants required to protect hemoglobin and other cell proteins from corrosion by oxygen, and selectively retains other vital components such as organic phosphates, manufactured with precious adenosine triphosphate (ATP) energy, but it lets metabolic detritus escape. It even…

Red Cell Membrane

The erythrocyte membrane is the most thoroughly studied biologic membrane. It is a small structure, less than 0.1% of the cell's thickness and only about 1% of its weight, but its easy accessibility has enabled researchers to characterize both its primary structure and a number of its important functions. It was the original example of the fluid mosaic membrane model, a breakthrough concept proposed by Singer…

Paroxysmal Nocturnal Hemoglobinuria

Medical textbooks usually include paroxysmal nocturnal hemoglobinuria (PNH) among the hemolytic anemias (as is the case herein). Doing so is not wrong because hemolysis is a defining feature of the disease. However, placing too much emphasis on the hemolytic component of the disease risks obscuring the essence of PNH. Two features distinguish PNH from all other hemolytic anemias. First, and most importantly, the abnormality that underlies…

Autoimmune Hemolytic Anemia

Autoimmune hemolytic anemia (AIHA) is an immunologic disorder in which antibodies are produced that target red blood cells (RBCs). AIHAs can be classified into four major types of disease: warm-reacting AIHA, cold agglutinin disease (CAD), paroxysmal cold hemoglobinuria (PCH), and mixed-type AIHA ( Box 13-1 ). Patients with no underlying associated diseases are classified as having primary or idiopathic AIHA. AIHA in patients with associated autoimmune…

Porphyrias

The porphyrias are caused by reduced activity of enzymes that constitute the heme biosynthetic pathway. With the exception of porphyria cutanea tarda (PCT), all are. Porphyrins are planar molecules comprised of four pyrrole rings connected by four methene groups. Porphyrins are also referred to as tetrapyrroles ( Fig. 12-1, A ). Porphyrins are intensely colored compounds (the word porphyria is derived from the Greek porphuros, meaning…