Desk Reference for hematology - part 4 pps

ERYTHROCYTE SEDIMENTATION RATE 279 Cellular reaction • Intense CD4 + T-cell response in paracortical areas of lymph follicles (see In- fectious mononucleosis), with production of IL-6, IFN-γ, and TNF contribut- ing to the fever and patient fatigue • Some CD4 + and CD8 + T-cells become memory cells and help in any future response to infection by the virus Immunodeficient Persons Lymphoblastic transformation to Burkitt lymphoma or, more rarely, non-Hodgkin lymphoma 181,182 Epithelial transformation to nasopharyngeal carcinoma Acute fatal infectious mononucleosis, sometimes with splenic rupture Lymphoid interstitial pneumonitis in children with acquired immunodeficiency syndrome (AIDS) Those with X-linked recessive lymphoproliferative immunodeficiency show an increased prevalence to the first two effects. EPSTEIN’S SYNDROME An autosomally dominant syndrome of mild thrombocytopenia with giant platelets, associated with nephritis and sensorineural deafness. Platelet function may be normal. In others, platelet aggregation may be reduced in response to weak agonists (adenosine diphosphate [ADP], iron deficiency, collagen). It is one of a group of giant-platelet syn- dromes, similar to Alport’s syndrome. ERYTHREMIC MYELOSIS See Acute myeloblastic leukemia — erythroleukemia. ERYTHROBLASTEMIA See Normoblastemia. ERYTHROBLASTOPENIA OF CHILDHOOD See Transient erythroblastopenia of childhood. ERYTHROCYTE See Red blood cell. ERYTHROCYTE SEDIMENTATION RATE (ESR) The measurement of the rate of fall of red blood cells through a column of plasma. Increased rates are due to increased levels of large plasma proteins such as fibrinogen 3393_book.fm Page 279 Thursday, October 25, 2007 5:17 PM 280 ERYTHROCYTIC PROTOPORPHYRIN and immunoglobulins, which cause rouleaux formation and clumping of red blood cells. The original method using Westergren open-ended glass pipettes has now limited avail- ability due to biological hazard, but under strictly standardized conditions and with care to avoid spillage of blood, it is reserved as the primary reference method. A secondary reference method, 183 traceable to the primary reference method, uses undiluted venous blood of packed-cell volume 0.35 l/l or lower, anticoagulated with EDTA to give a dilution of <1%. The blood is then well mixed under standardized conditions and drawn into a standardized sedimentation tube, which is held upright by a rigid holding device. The blood sample is suspended under standardized conditions at 20 ± 3°C for 60 min, when the height of the red cell column is read. For routine practice, the venous blood is collected into EDTA and then diluted with trisodium citrate before pipetting. This allows the blood to be drawn up by vacuum in a closed system with reduced biohazard. With all methods, once collected, the blood must be tested within 4 h. Decreased levels occur with erythrocytosis and increased levels with reduced red blood cell concentration, but mathematical corrections for anemia have no value. The ranges in normal health are given in Table 60. The ESR is a nonspecific test for the assessment and monitoring of the acute-phase response, particularly used for monitoring progress and response to therapy. Despite the wide range of alternative methods of assessing the acute-phase response, particularly plasma viscosity, the ESR remains a widely used test, mainly due to its low cost and convenience, it being easily performed at many sites of clinical practice, both laboratory- based and point-of-care testing (near patient testing) sites. A normal result helps to exclude organic disease, whereas a raised ESR indicates the need for further investigation. ERYTHROCYTIC PROTOPORPHYRIN See Heme — synthesis; Hemoglobin. ERYTHROCYTOSIS An increase in the concentration of red blood cells within the circulation associated with a rise in hemoglobin and packed-cell volume (PCV). The normal range of red blood cell counts is 3.8 to 4.8 × 10 12 /l for females and 4.5 to 5.5 × 10 12 /l for males. Erythrocytosis TABLE 60 Erythrocyte Sedimentation Rate Ranges in Health Age (years) 95% Upper Limit Men 17–50 10 51–60 12 61–70 14 >70 ~30 Women 17–50 12 51–60 19 61–70 20 >70 ~35 Source: Data from Lewis, S.M., Miscellaneous tests, in Dacie and Lewis Practical Haematology, 10th ed., Lewis, S.M., Bain, B.J., and Bates, I., Eds., Churchill Livingstone, Edinburgh, 2001, p. 529. With permission. 3393_book.fm Page 280 Thursday, October 25, 2007 5:17 PM ERYTHROCYTOSIS 281 may be absolute (true) if there is an increase in red cell mass, or relative (pseudo) if there is a fall in plasma cell volume resulting in an apparent erythrocytosis (see Blood volume). Absolute Erythrocytosis This can be primary (polycythemia rubra vera) or secondary, involving appropriate or inappropriate increase in erythropoietin levels (see Table 61). Secondary Erythrocytosis Appropriate Increase in Erythropoietin Levels Hypoxic lung disease. Arterial hypoxia due to many different lung pathologies, e.g., chronic obstructive airways disease, pulmonary fibrosis, hypoventilation syn- dromes, etc., results in erythrocytosis. If the PCV rises above 0.55 l/l, the increase in blood viscosity may reduce cerebral blood flow. Phlebotomy (venesection) down to a PCV of 0.50 to 0.52 l/l is desirable if the patient is symptomatic. TABLE 61 Causes of Erythrocytosis Absolute (True) Primary Idiopathic erythrocytosis Polycythemia rubra vera Secondary Appropriately increased erythropoietin levels Hypoxic lung disease Congenital cyanotic heart disease High altitude High-O 2 -affinity Hb Carbon monoxide intoxication Sleep apnea Right-to-left cardiac or vascular anomalies Tobacco abuse Hepatopulmonary syndrome Congenital methemoglobinemia Inappropriate increased erythropoietin levels Renal disease: cysts, renal transplantation, renal artery stenosis, focal sclerosing glomerulonephritis, and Bartter’s syndrome Tumors: hepatocellular carcinoma, hypernephroma, cerebellar hemangioma, meningioma, uterine leiomyoma, pheochromocytoma, and other adrenal tumors Familial: erythropoietin receptor mutations, VHL mutations (Chuvash polycythemia), and 2,3-BPG mutation Drugs: androgens, recombinant erythropoietin Relative (Pseudo) Androgens Tobacco abuse Hypertension Burns Diuretics Dehydration from any cause Alcohol abuse Diuretic therapy 3393_book.fm Page 281 Thursday, October 25, 2007 5:17 PM 282 ERYTHROCYTOSIS Congenital cyanotic heart disease. A marked left-to-right shunt causes arterial hypoxemia and high PCV values (0.7 to 0.8 l/l). Patients usually have clubbing and cyanosis, with occasional thrombocytopenia. Phlebotomy to a level of a PCV less than 0.65 l/ l may alleviate symptoms due to hyperviscosity and improve blood flow. Altitude erythrocytosis. This occurs upon ascending to heights at which inspired oxygen tension falls, causing excessive antidiuretic hormone and adrenal steroid secretion. This results in a reduced plasma volume and relative erythrocytosis. The low- inspired-oxygen tension stimulates respiration, but the tachypnea causes a left shift in the oxygen-dissociation curve due to hypocapnia and alkalosis. However, hypoxia stimulates 2,3-diphosphoglycerate (2,3-DPG) production, giving a com- pensatory right shift in the oxygen-dissociation curve, allowing increased release of oxygen to tissues. Hypoxia also stimulates erythropoietin secretion and secondary erythrocytosis. Overall, there is a slight right shift in the oxygen-dissociation curve. Red cell counts up to 8 × 10 12 /l with hematocrits over 0.60 l/l are not unusual. If the ascent is rapid, arterial hypoxia leads to acute mountain sickness. Anorexia, vomiting, headache, and irritability occur within 6 to 72 h. Rarely, convulsions, coma, and even death can occur. At heights greater than 15,000 ft above sea level, a defective physiological response may occur (chronic mountain sickness or Monge’s disease), whereby excessive erythrocytosis occurs secondary to alveolar hypoventilation. Chronic hypoxia and carbon dioxide retention causes lethargy, headache, somnolence, and coma. Patients are cyanosed, with finger clubbing and peripheral edema. This condition is more likely to occur in older (>40 years of age) patients. Both forms of mountain sickness rapidly improve with descent to sea level. High oxygen affinity to hemoglobin disorders. Abnormalities in both α- and β-globin chains cause impaired oxygen release. The tissue hypoxia stimulates compensa- tory erythrocytosis. Over 80 different abnormalities have been described with an autosomally dominant inheritance, e.g., Hb Malmo, Hb Chesapeake, Hb Heath- row. The oxygen-dissociation curve is left-shifted. Most patients are asymptomatic, although a few have suffered from thromboses. Phlebotomy therapy is usually not necessary. Methemoglobinemia. This condition can be inherited or acquired. Methemoglobin has high affinity for oxygen, and the dissociation curve is left-shifted. Acquired causes are due to drugs, e.g., sulfonamides, phenacetin, primaquine. Vascular anomalies. Large atrioventricular malformations may result in arterial hypoxia and erythrocytosis. Tobacco excess. Heavy smokers have increased levels of carbon monoxide, with a resultant left shift in the oxygen-dissociation curve. Smoking can also lead to a reduction in plasma volume. Pickwickian syndrome of gross obesity and somnolence causes central and peripheral hypoventilation but more common is sleep apnea syndrome due to upper airway obstruction. Inappropriate Increase in Erythropoietin Levels Renal tract disorders, where erythrocytosis secondary to increased erythropoietin production has been described in a wide range of renal diseases, including tumors, parenchymal disease, and renal-artery stenosis. The mechanism is usually renal ischemia, and treatment of the underlying disease usually reverses the erythrocytosis. 3393_book.fm Page 282 Thursday, October 25, 2007 5:17 PM ERYTHROMELALGIA 283 Tumors, particularly those associated with the von Hippel Lindau syndrome, may secrete erythropoietin, and upon removal, resolution of erythrocytosis occurs. Often, however, the serum erythropoietin level is not increased outside the normal range. Familial erythrocytosis. Mutations of the von Hippel Landau protein (VHL) have now been recognized as a common inherited cause of erythrocytosis. Initially identified in the Chuvash people of Russia, this form of erythrocytosis has been found worldwide. Relative Erythrocytosis Many different terms have been used to describe relative erythrocytosis, including Gais- bock’s syndrome, stress, and apparent and pseudo-erythrocytosis, in which there is a raised packed-cell volume (PCV) but a normal red cell mass (RCM). Relative erythrocytosis is due to a reduced plasma volume, which can be caused by many differing conditions (see Table 61). The risk of venous thromboembolic disease is less than that seen in absolute erythrocytosis, but the risk is not trivial. Where possible, the cause of the relative erythrocytosis should be corrected. If unsuccessful, phlebotomy should be instituted to maintain a PCV below 0.45 l/l, since phlebotomy expands the plasma volume. Differential Diagnosis 184 To differentiate absolute from relative erythrocytosis, simultaneous measurement of the red cell volume (using 99m Tc-labeled red cells) and plasma volume (using 125 I-labeled albumin) is necessary. The normal range of red cell volume is 25 to 35 ml/kg for males and 20 to 30 ml/kg for females, whereas the normal range for plasma volume is 40 to 50 ml/kg for both sexes. The differentiation of cause can be determined by a diagnostic algorithm using: Measurement of the red cell volume Measurement of oxygen saturation Measurement of serum erythropoietin ERYTHROKINETICS The movement of red blood cells through the body from the bone marrow to the peripheral organs. The size of the red blood cell mass defines anemias and erythrocytosis, while the kinetics of red blood cell production and their destruction determines pathogenesis. The three main components of red cell kinetics — the size of the red cell mass, the rate of red cell production (erythropoiesis, as quantified by ferrokinetics and the reticulocyte count), and the rate of red blood cell destruction (red blood cell survival) — can be measured. ERYTHROLEUKEMIA (Di Guglielmo’s disease; Erythemic myelosis) See Acute myeloid leukemia — M6. ERYTHROMELALGIA A syndrome of erythremia and burning pain in the hands and feet occurring in a variety of disorders: 185 3393_book.fm Page 283 Thursday, October 25, 2007 5:17 PM 284 ERYTHRON Thrombocytosis with platelet-mediated arteriolar inflammation and thrombosis, which responds to treatment with aspirin Primary disorder from childhood of bilateral distribution upon exposure to warmth or exercise, probably of genetic origin but refractory to drug therapy Secondary to peripheral vascular disease of all forms ERYTHRON The collective term for progenitor and adult red blood cells as a functional organ. The erythron has three cell components: The pool of early erythroid progenitors characterized by their capability to give rise to erythroid colonies in vitro An intermediate compartment comprising proerythroblast-to-marrow reticulocyte Mature red blood cells ERYTHROPHAGOCYTOSIS See also Histiocytosis. Ingestion of red blood cells by histiocytes (macrophages), monocytes, or neutrophils. Physiologically, the red blood cells are removed in the liver and spleen with the mediation of complement. Pathologically, it occurs with: Complement-fixing antibodies in immune hemolytic anemias (particularly paroxys- mal cold hemolytic anemia) Protozoal infection disorders Bacterial infection disorders Viral infection disorders, usually herpetic Chemical toxic disorders Some forms of histiocytosis, e.g., Rosai-Dorfman histiocytosis; familial erythroph- agocytic lymphohistiocytosis is a rare, usually fatal, disorder that is inherited as an autosomally recessive trait To a mild degree, erythrophagocytosis commonly occurs at the margins of tumors, particularly lymphomas, but here it is not of sufficient degree to account for any anemia. It is an uncommon appearance in peripheral-blood films and usually presents as a cytope- nia. It can be diagnosed by bone marrow aspiration or, occasionally, by lymph node biopsy, where histiocytes that have ingested red blood cells (and sometimes associated leukocytes or platelets) can be readily identified. ERYTHROPOIESIS See Hematopoiesis; Hematopoietic regulation; Ineffective erythropoiesis; Normoblasts; Reticulocytes. ERYTHROPOIETIC PROTOPORPHYRIA See also Porphyrias. 3393_book.fm Page 284 Thursday, October 25, 2007 5:17 PM ERYTHROPOIETIN 285 The clinical disorder resulting from an autosomally dominant partial deficiency of ferro- chelatase due to mutations on Ch18q; penetrance is variable. Splicing mutations are most frequent, although a variety of missense and other mutations have been described. Increased levels of free protoporphyrin occur in red blood cells, plasma, and feces. Abnor- malities usually occur first in childhood and are associated with cutaneous photosensitivity, including sensations of burning, itching, edema, erythema, onycholysis, thickening of the skin, and scarring. Some patients develop anemia or progressive liver injury. Children with mild disease can be managed by avoiding exposure to direct sunlight and by using topical sunscreen products. Oral beta-carotene (120 to 180 mg/day) may reduce photosensitivity in 1 to 3 months. Cholestyramine reduces photosensitivity by decreasing hepatic protoporphyrin content. If severe hemolysis is present, splenectomy may be help- ful. The benefit of liver transplantation was temporary in children with hepatic failure. ERYTHROPOIETIN (EPO) A glycosylated α-globulin with a molecular mass of 38 kDa. The gene responsible for EPO is located on chromosome 7. The site of production is the kidney (several renal cell types may be involved) in response to hypoxia. 186 Extrarenal tissues, particularly the liver, have some capacity for EPO synthesis in response to severe hypoxia. During fetal life, the liver is the main site of production. It is now possible to synthesize recombinant EPO. The half-life of EPO, both natural and recombinant, is 5 to 6 h, and it is cleared predominantly by the liver (particularly when desialated) and excreted by the kidney when not utilized within the erythron. EPO receptors are found on CD34 + bone marrow cells and on all morphologically identifiable erythroid precursors to orthochromatic erythroblasts. EPO acts principally as a survival factor, preventing apoptosis of erythroid cells, from late colony forming unit BFU-E (burst-forming unit-erythroid) onwards, with the highest density of receptors per cell at the CFU-E (colony forming unit-erythrocytes)/ proerythroblast stage in those cells most responsive to EPO. It acts on progenitor rather than precursor cells, and its actions can be summarized as: Induction of transformation of erythroid-committed CFU-E to proerythroblasts Action in consort with various growth factors such as burst-promoting activity (BPA) to enhance proliferation of BFU-E Increase in transition from proerythroblasts to basophilic erythroblasts, thus shorten- ing marrow transit time Possible control over the release of reticulocytes from the bone marrow (release of stress reticulocytes) Many positive regulatory cytokines synergize with EPO to promote erythroid differentiation. The most potent of these is stem cell factor (SCF), although IL-3, IL-11, granulocyte/ macrophage colony stimulating factor (GM-CSF), and G-CSF produce similar effects. Indeed, BFU-E units are IL-3 dependent. Recombinant EPO, produced commercially, is used for the treatment of end-stage renal tract disorders, antiretroviral-associated anemia in acquired immunodeficiency syndrome (AIDS), aplastic anemia both primary and secondary, and bone marrow hypoplasia, especially when due to cytotoxic agent therapy. EPO also has pleiotropic properties that can provide protection against acute ischemic injuries in several organs and tissues. The main adverse drug reaction is a dose-dependent increase in blood pressure. A rise in platelet count may occur, but thrombocytosis is rare. Another rare reaction is the development of pure red blood cell aplasia. 3393_book.fm Page 285 Thursday, October 25, 2007 5:17 PM 286 ESOPHAGEAL DISORDERS ESOPHAGEAL DISORDERS The effects of esophageal disease on the hematopoietic system. These are all due to hemorrhage, either acute or chronic B from hiatus hernia (associated with esophagitis or ulceration), varices, telangiectases, or carcinoma. ESSENTIAL THROMBOCYTHEMIA (ET; Hemorrhagic thrombocythemia; Primary thrombocythemia) A rare chronic clonal disorder of the stem cell, characterized by megakaryocyte hyperplasia and thrombocytosis. It is one of the myeloproliferative disorders and shares many features, especially with polycythemia rubra vera (PRV). Clinical Features The disorder is uncommon under the age of 50 years, with men and women equally affected. Patients may be asymptomatic at diagnosis or present with hemorrhage or venous thromboembolic disease. Epistaxis and gastrointestinal hemorrhage are the usual bleeding sites, but any part of the body may be affected. Postoperative bleeding is common. Both arterial (skin, central nervous system) and venous (legs, hepatic) thrombosis can occur. Thrombosis is usually microvascular, secondary to platelet plugging. Patients classically present with ischemic lesions of digits, which may progress to gangrene. Cere- bral symptoms such as transient ischemic attacks or amaurosis fugax are common. Sple- nomegaly, usually mild to moderate, is present, with hepatomegaly less common. Splenic atrophy due to splenic vein thrombosis is well described. As with PRV, there is an increased incidence of peptic ulceration. Laboratory Features Thrombocytosis is universal (600 to 3000 × 10 9 /l), with platelet production as much as 15 times above normal. There is platelet anisopoikilocytosis with abnormal granulation, and megakaryocyte cytoplasm may appear in the peripheral blood. Mean platelet volume (MPV) is typically increased, and macrothrombocytes are common. In virtually all patients, there is abnormal platelet aggregation to epinephrine, with loss of both the primary and secondary wave. Fewer patients have abnormal adenosine diphosphate (ADP), arachi- donic acid, and collagen aggregation. In some cases, spontaneous aggregation in vitro is demonstrable. Anemia is usually due to blood loss, but erythrocytosis occurs in 30% of cases. Granulocytosis (12 to 30 × 10 9 /l) with left shift is present in 30 to 70% of patients, with basophilia and eosinophilia also not uncommon. The neutrophil alkaline phosphatase (NAP) score is usually normal or high. Bone marrow examination reveals marked atypical megakaryocyte hyperplasia with clumping. Immature forms are conspicuous and bizarre megakaryocyte morphology is usual. There may also be mild erythroid and myeloid hyperplasia. Marrow reticulin is usually normal, but may be slightly increased. In vitro colony forming unit assays reveal increased BFU-Mk formation, some of which may be spontaneous colonies. A few patients also have increased BFU-E and CFU-GM. Results of cytogenetic analysis of bone marrow cells are usually normal, but various abnormalities have been described. Patients with Philadelphia-chromosome-positive thrombocythemia represent cases of chronic myelog- enous leukemia (CML). Hyperuricemia, pseudohyperkalemia, and increased serum cobalamin levels are often found. 3393_book.fm Page 286 Thursday, October 25, 2007 5:17 PM ETHYLENEDIAMINETETRAACETIC ACID 287 Differential Diagnosis Reactive thrombocytosis occurs in many conditions, but platelet counts rarely exceed 1200 × 10 9 /l, and resolution occurs with successful treatment of the underlying disorder. Dif- ficulties can arise in distinguishing ET from other myeloproliferative disorders, but marrow cytogenetics and the application of the polycythemia rubra vera study group diagnostic criteria 187 aid in distinction from CML and PRV, respectively. Course and Prognosis Essential thrombocythemia is a chronic disorder and, provided that life-threatening thrombosis or hemorrhage does not occur at diagnosis, the survival curve with treatment is the same as normal age-matched controls. However, most patients do ultimately succumb to thromboembolic complications, although transformation to acute myeloid leukemia (5 to 10%) and myelofibrosis (10 to 25%) also occurs. Treatment The risk of thrombosis/hemorrhage increases with increasing platelet count, especially in the elderly. In urgent situations, e.g., digital or cerebrovascular ischemia, plateletpheresis (see Hemapheresis) and aspirin are both useful when used alone or, preferably, in combination. The long-term aim is to achieve a platelet count as near normal as possible without inducing serious adverse side effects. 187a Myelosuppression can be achieved with various cytotoxic agents, e.g., busulfan, melphalan, chlorambucil, α-interferon, and anag- rolide, but the safety, cost, efficacy, and tolerability of hydroxyurea (hydroxycarbamide) make this the agent of choice. Radioactive phosphorus ( 32 P) is useful in elderly patients, but hydroxyurea is also often required for a few weeks until its maximum effect has occurred. ETAMSYLATE A hemostatic agent used orally to reduce capillary bleeding in the absence of thrombocytopenia. Its action is by correction of abnormal platelet adhesion. It is also used for prophylaxis and treatment of periventricular hemorrhage in low-birth-weight infants given by intramuscular or intravenous injection. ETANERCEPT A drug that inhibits the activity of tumor necrosis factor- αα αα . It is used for the treatment of highly active rheumatoid arthritis and ankylosing spondylitis. Adverse drug reactions include bone marrow hypoplasia and demyelination in the central nervous system. ETHYLENEDIAMINETETRAACETIC ACID (EDTA) A chemical that effectively chelates calcium in blood and is used as such as an anticoagulant for blood cell counting and other procedures involving cells. The lack of solubility of the free acid in aqueous solution makes the sodium and potassium salts preferable for use, the latter being most popular. The dipotassium salt is used in dry form, whereas the tripotassium salt is generally used in liquid form. The recommended range for adequate anticoagulation for both K2 and K3 salts is 3.7 to 5.4 µmol (1.5 to 2.2 mg) 3393_book.fm Page 287 Thursday, October 25, 2007 5:17 PM 288 ETOPOSIDE per ml of blood. 188 EDTA is particularly useful in specimen collection, since it best preserves the cellular components of blood. Three problem parameters are the white blood cell count (method differences), the red blood cell mean cell volume (MCV), and the mean platelet volume (MPV). The International Committee for Standardization in Hematology (ICSH) has recommended the dipotassium salt of EDTA as the anticoagulant of choice for blood cell counting and sizing. 188 ETOPOSIDE (VP16) A synthetic epipodophyllotoxin that is a phase-specific topoisomerase-inhibiting agent active in the G2 phase of the cell cycle. Etoposide is active, and increasingly used, in the treatment of acute myeloid leukemia (AML), especially for the monocytic subtypes. It is also effective for acute lymphoblastic leukemia (ALL), especially in combination with cytosine arabinoside. Adverse drug reactions include gastrointestinal tract upsets, alopecia, fever, and, less commonly, peripheral neuropathy (see Cytotoxic agents). EUGLOBULIN LYSIS TIME (ECLT; ELT) See Fibrinolysis. EVAN’S SYNDROME Auto-immune hemolytic anemia associated with neutropenia and thrombocytopenia. EXCHANGE TRANSFUSION See Fetal/neonatal transfusion; Hemapheresis. EXERCISE The effects of exercise or exertion on hematological values and of hematological disorders on exercise. These are: Leukocytosis, mainly of granulocytes, with strenuous exercise over a short period, probably due to mobilization of the granulocyte pool. Eosinophilic fasciitis, attributed to unusual or excessive physical activity. Increased fibrinolysis, probably due to release of plasminogen activators from the vascular endothelium. In the presence of anemia, the oxygen debt per unit of activity increases, leading to slower recovery of heart rate and respiratory minute volume. Increase in circulating T-lymphocytes as a consequence of catecholamine release. There is a concomitant decrease in their integrin molecules, so that adherence to endothelial cells is reduced. Type I hypersensitivity reactions are also reduced. Prolonged exercise such as in marathon runners results in excess corticosteroid production, which affects the immune system by inhibition of macrophage function and T-cell function, thereby inducing a mild immunodeficiency. March hemoglobinuria occurs following walking or running on hard surfaces for a prolonged period of time. Intense exercise in a warm climate can cause death from disseminated intravascular coagulation. 3393_book.fm Page 288 Thursday, October 25, 2007 5:17 PM [...]... structure that is very similar to that of factor VIII (see Figure 29) It is coded for by a complex 25-exon gene on chromosome 1 (1q2 1-2 5) and encodes a 6.6-kb mRNA Upon activation by thrombin or factor Xa, it is converted into its active two-chain form Thrombin cleaves factor V at Arg709-Ser710, Arg1018-Thr1019, and Arg1 545 -Ser1 546 Following cleavage, the two chains are linked via a divalent metal ion bridge... disulfide bond, that circulates bound to high-molecular-weight kininogen It is coded by a 15-exon, 23-kb gene on chromosome 4 (q3 2-3 5) It has a plasma half-life of approximately 72 h Factor XI is cleaved to active factor XIa by active factor XII, factor XIIa, in the presence of high-molecular-weight kininogen Activation cleavage occurs within each subunit at Arg369-Ile370 in a region bound by a disulfide... binding), epidermal growth factor-like domain, and trypsin-like domain (catalytic site) Twelve N-terminal glutamic acid residues are terminal gamma carboxylated to form the Gla domain Calcium-binding properties of factor IX are crucial to its normal function and biological activity Activation of factor IX occurs via cleavage of two peptide bonds, Arg 145 -Ala 146 and Arg180-Val181 This activation can be... EXTRAMEDULLARY MYELOID TUMOR See Myeloid sarcoma EXTRAMEDULLARY PLASMACYTOMA See Plasmacytoma EXTRANODAL MARGINAL-ZONE B-CELL LYMPHOMA OF MUCOSA-ASSOCIATED LYMPHOID TISSUE (MALT-lymphoma) See Marginal-zone B-cell lymphoma; Non-Hodgkin lymphoma EXTRANODAL T-CELL LYMPHOMA, NASAL TYPE (REAL: angiocentric T-cell lymphoma; Others: malignant midline reticulosis, polymorphic reticulosis; Angiocentric immunolymphoproliferative... and are clustered together within a 50-kb span of DNA on chromosome 4 (4q23–32) The Aα gene is located in the middle of the fibrinogen gene cluster downstream of the χ-chain and upstream of the α-chain and consists of five exons spanning 5 .4 kb of DNA Alternative splicing of a sixth exon leads to the formation of an extended α-chain (aE) The Aα gene encodes a 625-amino acid polypeptide and a signal peptide... non-cross-linked fibrin involves an initial cleavage of several small peptides FIGURE 34 Plasmin digestion of fibrinogen and non-cross-linked fibrin by plasmin 3393_book.fm Page 313 Thursday, October 25, 2007 5:17 PM FIBRINOGEN 313 FIGURE 35 Plasmin digestion of cross-linked fibrin (termed fragments A, B, and C) from the C-terminal portion of the Aα chain, followed rapidly by removal of the N-terminal 42 ... sometimes occurs with a form of T-cell lymphocytosis of the large granular type The neutropenia is probably a consequence of accelerated apoptosis of granulocyte precursors FEMALE REPRODUCTIVE ORGAN DISORDERS See Gynecological disorders FERRITIN A water-soluble complex of ferric hydroxide and the protein apoferritin This is a 44 0-kDa protein consisting of 243 subunits arranged to form a hollow sphere,... Coagulation factors; Hemostasis A 40 6-amino acid plasma glycoprotein and serine protease of molecular weight 50,000 It is a component in the initiation of blood coagulation that forms a complex with tissue factor to generate an enzyme complex that activates factor X and factor IX It is coded for by a 13-kb, nine-exon gene on chromosome 13 It is a vitamin K-dependent protein and has 10 N-terminal glutamic acid... provided that the inhibitor shows low cross reactivity (see Coagulation factor concentrates) Long-term treatment to reduce the inhibitor may be performed using immune-tolerance-induction regimens Such regimens may be low-dose or high-dose factor VIII concentrate regimes High-dose regimes involve infusions twice daily for upwards of 12 months at a dose of 100 IU/kg or greater Such regimes usually give factor... cleavage is 3393_book.fm Page 295 Thursday, October 25, 2007 5:17 PM FACTOR VIII 295 the rate-limiting step, which yields 5 0- and 40 -kDa fragments from the heavy chain, both of which are essential for catalytic activity The Arg 740 cleavage removes any remaining B-domain remnant, to yield a 90-kDa heavy chain At the same time, a small fragment is cleaved that removes VWF from factor VIII Activated factor VIII, . Plasmacytoma. EXTRANODAL MARGINAL-ZONE B-CELL LYMPHOMA OF MUCOSA-ASSOCIAT- ED LYMPHOID TISSUE (MALT-lymphoma) See Marginal-zone B-cell lymphoma; Non-Hodgkin lymphoma. EXTRANODAL T-CELL LYMPHOMA, NASAL TYPE (REAL:. may be performed using immune-tolerance-induction regimens. Such regimens may be low-dose or high-dose factor VIII concentrate regimes. High-dose regimes involve infusions twice daily for upwards. 295 the rate-limiting step, which yields 5 0- and 40 -kDa fragments from the heavy chain, both of which are essential for catalytic activity. The Arg 740 cleavage removes any remaining B-domain remnant,