Desk Reference for hematology - part 7 docx

588 LYOPHILIZED COAGULATION FACTOR CONCENTRATES The decision to inactivate is not based upon any specific DNA sequence. The mechanism of X inactivation is unclear but may involve repression by heterochromation (position- effect variegation) or DNA methylation. Clonally derived cell populations show a single X-inactivation pattern, and this is used for many available clonality assays. LYOPHILIZED COAGULATION FACTOR CONCENTRATES See Coagulation factor concentrates. LYSOSOME A membrane-bounded cytoplasmic organelle containing a variety of hydrolytic enzymes that can be released into a phagosome or to the exterior of the cell. Release of lysosomal enzymes in a dead cell leads to autolysis. Early endosomes are located at the periphery of a cell, and late endosomes are located in the perinuclear region, with the lysosomes between. Lysosomes are composed of membrane and vesicles containing hydrolytic enzymes. Primary lysosomes are small and contain no inclusions; secondary lysosomes are larger and contain partially degraded organelles. Secondary lysosomes are phagocytic vesi- cles with which primary lysosomes have fused. They often contain undigested material. Functioning at a low pH (4.8), the enzymes are a series of acid hydrolases, including proteases to degrade proteins and polypeptides, nucleases to degrade RNA and DNA, and phosphatases, among others. Their function is to mediate in the degradation of senescent membrane components and organelles and to digest endocytosed foreign mate- rial within the cell. Following contact with bacteria they form phagosomes. Lysosomal Storage Diseases 339 Although the first description of a lysosomal storage disorder was that of Tay-Sachs disease in 1881, the lysosome was not discovered until 1955, by Christian De Duve. The first demonstration by Hers in 1963 of a link between an enzyme deficiency and a storage disorder (Pompe’s disease) paved the way for a series of seminal discoveries about the intracellular biology of these enzymes and their substrates, culminating in the successful treatment of Gaucher’s disease with beta-glucosidase in the early 1990s. It is now recog- nized that these disorders are not simply a consequence of pure storage, but result from perturbation of complex cell-signaling mechanisms. These, in turn, give rise to secondary structural and biochemical changes that have important implications for therapy. Defective lysosomal acid hydrolysis of endogenous macromolecules leads to accumulation of lipids and mucopolysaccharides (see Lipid-storage disorders; Mucopolysaccharidoses). Over 40 disorders have been described. They are all single-gene, autosomally recessive disor- ders. Excessive accumulation occurs in macrophages, including microglia and in mesen- chymal cells. The disorders are multisystem but particularly affect the liver, spleen, and central nervous system (CNS). This produces disturbances due to space occupation, but there is also macrophage activation and possibly disturbance of cellular mitochondrial function. Where the enzyme defect can be identified, enzyme-replacement therapy is the most likely effective treatment. Allogeneic stem cell transplantation can help, but the outcome is variable. Significant challenges remain, particularly the treatment of CNS disease. It is hoped that recent advances in understanding of lysosomal biology will enable successful therapies to be developed. 3393_book.fm Page 588 Thursday, October 25, 2007 5:17 PM LYSOSOME 589 TABLE 103 Immunophenotypes of Lymphoproliferative Disorders Hodgkin Disease Lymphocyte predominance CD45 + , B-cell-associated antigens + , Cdw75a + , EMA +/− , CD115 − , CD30 −/+ , T-cells surrounding L and H cells: CD57 + Nodular sclerosis CD15 +/− , CD30 + , CD45 − Mixed cellularity B- and T-cell-associated antigens − Lymphocyte depletion EMA − Non-Hodgkin Lymphoma B-Cell Neoplasms I. Precursor B-lymphoblastic leukemia/lymphoma Tdt + , CD19 + , CD79a + , CD22 + , CD20 +/− , CD10 +/− , HLA-DR + , SIg − , cMu −/+ , CD34 +/− , may coexpress CD13 or CD33 −/+ II. Peripheral B-cell neoplasms 1. Chronic lymphocytic leukemia/small lymphocytic lymphoma faint SIgM + , SIgD +/− , CIg −/+ , B-cell-associated antigen + , CD5 + , CD23 + , CD43 + , CD11c −/+ (faint), CD10 − 2. Lymphoplasmacytic lymphoma/ Waldenström macroglobulinemia SIgM + , CIgM + (some cells), B-cell-associated antigens + , CD5 − , CD10 − , CD43 +/− , CD25 + , or CD11c + (faint) 3. Mantle-cell lymphoma SIgM + usually IgD + l > k, B-cell-associated antigens + , CD5 + , CD110 −/+ , CD23 − , CD43 + , CD11c − 4. Follicular lymphoma SIg + (IgM +/− IgD > IgG > IgA), B-cell-associated antigen + , CD10 +/− , CD5 − , CD23 −/+ , CD43 − , CD11c − 5. Extranodal marginal-zone B-cell lymphoma (MALT lymphoma) SIg + (IgM > IgG or IgA), CIg + (40%), B-cell-associated antigen + , CD5 − , CD10 − , CD23 − , CD43 −/+ , CD11c +/− 6. Splenic marginal-zone lymphoma Similar to marginal-zone B-cell lymphoma, above 7. Hairy cell leukemia SIg + (M +/− IgD, IgG, or IgA), B-cell-associated antigens + , CD5 − , CD10 − , CD23 − , CD11c + (strong), CD25 + (strong), FMC7 + , CD103 + (MLA: HML-1, B-ly7, Ber-ACT8, LF61) 8. Plasmacytoma SIg − , CIg + (IgG, IgA, rare IgD or IgE; or light chain only); most B-cell-associated antigens − , CD79a +/− , CD45 −/+ , HLA-DR −/+ , CD38 + , EMA −/+ , CD43 +/− , CD56 +/− 9. Diffuse large B-cell lymphoma SIg +/− , CIg −/+ , B-cell-associated antigens + (CD19 + , CD20 + , etc.), CD45 +/− , CD5 −/+ , CD10 −/+ 10. Mediastinal (thymic) large B-cell lymphoma Ig − , B-cell-associated antigens + , CD45 + , CD15 − 11. Burkitt lymphoma/leukemia SIgM + , B-cell-associated antigens + , CD10 + , CD5 + , CD23 − 12. Lymphomatoid granulomatosis CD20 + , CD79a variable + , variable CD30 + , LMP1 + , CD15 T-Cell and NK-Cell Neoplasms I. Precursor T-lymphoblastic CD7 + , CD3 + , Tdt + , CD1a +/− , CD4, 8 ++ or CD4, 8 −− , Ig − , occasional cases express natural killer (NK) antigens (CD16, 57) II. Peripheral T-cell and NK-cell neoplasms 1. T-cell chronic lymphatic CD7 + , T-cell-associated antigens + , CD4 + (65%), CD4 + CD8 + (21%), CD4 − CD8 + (rare), CD25 − 2. T-cell large granular lymphocytic leukemia T-cell: cD2 + , CD3 + , CD5 − , CD7 − , TCRab + , CD4 − , CD8 + , CD16 + , CD56 − , CD57 +/− , CD25 − NK-cell: CD2 + , CD3 − , TCRab − , CD4 − , CD8 +/− , CD16 + , CD56 +/− , CD57 +/− 3. Mycosis fungoides/Sézary syndrome T-cell-associated antigens + , CD7 + (33%), CD4 + , CD25 − , S-100 + CD1a + interdigitating Langerhans cells present 4. Peripheral T-cell lymphoma, unspecified T-cell-associated antigens variable, CD4 > CD8, may be CD4 − , CD8 − 5. Angioimmunoblastic T-cell T-cell-associated antigens + , usually CD4 + 6. Angiocentric lymphoma pan T antigens expressed (CD2 + , CD5 +/− , CD7 +/− ), often CD3 − , may be CD4 + or CD8 + , and often CD56 + 3393_book.fm Page 589 Thursday, October 25, 2007 5:17 PM 590 LYSOSOME 7. Enteropathy-type T-cell lymphoma CD3 + , CD7 + , CD8 +/− , CD4 − , CD103 + (MLA: HML-1, LFG 1, Bly7, Bev-ACTB) 8. Primary cutaneous CD30-positive T-cell lymphoproliferative disorders a: Primary cutaneous anaplastic large- cell lymphoma (C-ALCL) CD4 + , CD30 + (>75%), variable CD2 − , CD5 − , and CD3 − b: Lymphomatoid papulosis CD4 + , CD8 − , CD30 + in type A lesions and CD30 − in type B lesions, variable loss of CD2 − , CD5 − c: Borderline lesions 9. Anaplastic large cell CD30 + , CD45 +/− , CD25 +/− , EMA +/− , CD15 −/+ , CD3 −/+ , T-cell- associated antigens variable, CD45RO −/+ , CD68 − Note: +, >90% cases; +/−, >50% cases; –, <10% cases; −/+, <50% cases. B-cell-associated antigens = CD19, CD20, CD22, CD79a; T-cell-associated antigens = CD2, CD3, CD5. Source: Data derived from Harris, N.L. et al., Blood, 84, 1361–1392, 1994. With permission. TABLE 103 (continued) Immunophenotypes of Lymphoproliferative Disorders 3393_book.fm Page 590 Thursday, October 25, 2007 5:17 PM 591 M MACROANGIOPATHIC HEMOLYTIC ANEMIA (Traumatic mechanical hemolytic anemia; cardiac hemolytic anemia; march hemoglobin- uria) Anemias arising as a result of mechanical trauma to red blood cells circulating through the heart or blood vessels, with and without surgical intervention. Following heart valve replacement, severe hemolysis does not arise from hemodynamic turbulence alone, but in a space bound by a foreign surface. Nonendothelialized surfaces are thrombogenic and may cause platelet aggregation, thrombus formation, and distant embolization. Largely to overcome these thrombogenic problems, nonthrombogenic tissue valves have been developed, which has minimized hemolysis. Mildly compensated hemol- ysis is usually present. Even so, the reticulocyte count is slightly elevated, as is the level of serum lactate dehydrogenase . The peripheral blood shows changes of fragmentation hemolytic anemia — helmet cells, triangular cells, and other fragmented forms. Hemo- globinemia may be present and the haptoglobin level reduced. There is often hemosid- erinuria. Iron deficiency may occur. In severe cases, the only treatment may be to replace the valve. In mild cases, treatment with iron and folic acid will usually prevent decom- pensation. Without surgery, macroangiopathic hemolytic anemia is usually associated with: Aortic stenosis Mitral regurgitation Ruptured sinus of Valsalva Ruptured chordae tendinae Coarctation of aorta Aortic aneurysm March hemoglobinuria MACROCYTES Large red blood cells with a diameter >8.5 µm and mean cell volume usually >96 fl. There are two forms: Oval macrocytes characteristic of megaloblastosis , bone marrow hypoplasia , myelo- dysplasia , and other dyserythropoietic states Round macrocytes found in chronic liver disorders , myelodysplasia, myelomatosis , bone marrow hypoplasia, and tobacco smoking Macrocytes are also found when there is increased erythropoiesis , when they are due to the presence of reticulocytes. On Romanowsky stained blood films, reticulocytes are more basophilic than adult red cells ( polychromasia ). Physiological macrocytosis occurs in the neonatal period and with pregnancy. A rare familial type has been described. 3393_book.fm Page 591 Thursday, October 25, 2007 5:17 PM 592 MACROCYTIC ANEMIA MACROCYTIC ANEMIA The association of a reduced level of hemoglobin with macrocytosis, demonstrated either by automated blood cell counting or upon examination of peripheral-blood film. Differ- entiation is a stepwise process (see Figure 84). The initial investigation is a reticulocyte count ; a raised count suggests either acute hemorrhage or some form of hemolytic anemia . A normal or low reticulocyte count requires a bone marrow aspirate/trephine biopsy to establish the presence or absence of megaloblastosis . Assays for cobalamin and folic acid are then indicated. A dyserythropoietic marrow count less than the megaloblastic count is usually due to one of the forms of myelodysplasi a or, less frequently, aplastic anemia . A normoblastic marrow suggests that the macrocytosis may be due to alcohol toxicity , the commonest cause of macrocytosis, or the result of a liver disorder or thyroid disorder , usually hypothyroidism. MACROGLOBULINEMIA See Lymphoplasmacytic lymphoma/Waldenström macroglobulinemia . MACROPHAGE See Histiocyte . MACROPOLYCYTE Giant neutrophils seen in megaloblastosis . MAJOR HISTOCOMPATIBILITY COMPLEX (MHC) See Human leukocyte antigens . FIGURE 83 Flow diagram of investigation of macrocytic anemias. (Adapted from Bates, I. and Bain, B.J. Approach to the diagnosis and classification of blood disorders, in Dacie and Lewis Practical Haematology, 10th ed., Churchill- Livingstone Elsevier, 2006, Philadelphia, Figure 23.2. With permission.) Raised MCV/macrocytic blood film Acute hemorrhage Hemolytic anemia Alcohol Liver disorders Hypothyroidism Myelodysplasia Folic acid defic. Cobalamin defic. Reticulocytes Reticulocytes or N Normoblastic BM Dyserythro BM Megaloblastic BM Folate B 12 3393_book.fm Page 592 Thursday, October 25, 2007 5:17 PM MALARIA 593 MALARIA The pathogenesis, clinical and laboratory features, and management of infection by species of the genus Plasmodium , which is composed of P. falciparum , P. malariae , P. ovale , and P. vivax . On a global basis, this is the commonest infection of humans, 340 accounting for 300 to 500 million cases per annum, with a mortality of up to 2 million per annum. Transmis- sion is by a bite from the female Anopheles mosquito, which resides in tropical climates of Central and South America, Asia, Africa, and Oceania. Many patients with malaria enter Europe and the U.S. as travelers from the tropics, but transmission onward in these countries is rare. Transmission of the erythrocyte cycle can be a transfusion-transmitted infection as a result of shared needles or syringes in drug abusers, by needle-stick injury in health-care workers, by organ transplantation, or by accidental laboratory inoculation. The species of infecting plasmodium varies from one region of the world to another, but in endemic areas, mixed infections can occur. Pathogenesis The life cycle of the plasmodia is a sexual cycle between human and mosquito, with an asexual cycle within humans (see Figure 84). Sporozoites enter the human circulation from mosquito saliva. They are rapidly cleared by liver histiocytes (macrophages), from where they enter the hepatic parenchymal cells — the hepatic phase of infection. Here they transform to schizonts, which subdivide rapidly during schizogony. A single sporozoite can divide to produce 2,000 to 40,000 merozoites in 1 to 2 weeks. These are released into the circulation when the schizont bursts and invades red blood cells . With infection by P. falciparum and P. malariae , the hepatic phase now ends, but with P. ovale and P. vivax , some schizonts can remain in the liver cells for years, from which later red blood cell invasion can occur. Entry into the red blood cells occurs by receptor-mediated endocyto- sis . For this, P. vivax is associated with Duffy blood group determinants (Fya, Fyb) so that Duffy-negative persons are naturally resistant to invasion by this parasite. P. falciparum FIGURE 84 Life cycle of malaria plasmodium. 3393_book.fm Page 593 Thursday, October 25, 2007 5:17 PM 594 MALARIA receptor is associated with red blood cell membrane proteins Band 3 and glycophorin A. Malarial parasite invasion has the following effects on the red cell membrane: Reorganization of the phospholipid distribution New permeability pathways introduced New surface antigens Increased areas of attachment to endothelium associated with protrusions seen on electron microscopy; this specifically occurs with P. falciparum invasion and leads to cerebral microvascular infarctions — cerebral malaria Intracellular merozoites transform to trophozoites — ring forms. These devour hemo- globin with the production of oxidized heme — hematin or “malarial pigment.” For this reaction, P. falciparum can remove iron from ferritin , but the presence in the cell of hemo- globin F , hemoglobin S , or deficiency of the enzyme glucose-6-phosphate dehydrogenase confers resistance. This leads to a natural selection for survival in tropical areas of these genetic disorders. The trophozoites enlarge, taking an amoeboid shape that differs from one plasmodium to another, and by which a microscopic diagnosis can be made. The trophozoites undergo schizogony to form a new generation of merozoites — the asexual reproduction cycle. The red blood cell is eventually lysed, with the merozoites entering the circulation to further invade red blood cells. Some intracellular merozoites become sexual gametocytes, which are dormant and do not lyse the host cell. If these cells are ingested by a female Anopheles mosquito, sexual fertilization of male and female gametocytes occurs in the mosquito stomach wall. An oocyst develops within the egg cavity, with eggs eventually passing to the mosquito salivary gland. From here, the human cycle continues. Malarial infection stimulates T-lymphocyte s and histiocytes (macrophages). Release of opsonizing antibodies allows killing of parasites by cytotoxic T-lymphocytes and natural killer (NK) cells. This may be the mechanism for natural protection against malaria, with the parasitized cells being removed by the cells of the reticuloendothelial system . Adhesion of infected red blood cells to vascular endothelium may be a factor in the cause of normocytic anemia . With massive cell lysis, intravascular hemolysis due to disseminated intravascular coagulation can occur, particularly with P. falciparum , result- ing in hemoglobinemia and hemoglobinuria (blackwater fever). Hypovolemia and renal failure result, with a mortality of 20 to 30%. This is a particular complication in those taking quinine. Adhesion of P. falciparum -infected erythrocytes to cerebral vessels gives rise to the syndrome of cerebral malaria. Extravascular hemolysis from erythrophagocytosis associated with splenic pooling of red blood cells and phagocytosis follows prolonged or recurrent infection, which can end with the syndrome of hyperreactive malarial splenomegaly . Clinical Features Incubation period from the mosquito bite to symptoms: 10 to 14 days for P. falciparum and P. vivax ; 18 days to 6 weeks for P. malariae (see Table 104). Not all infected individuals develop symptoms, probably due to their level of reactive nitrogen intermediates (RNI) and their major histocompatibility complex (MHC) genes. Non-falciparum malaria is usually benign. The presenting illness is fever with headache. This has a periodicity depending upon the infecting plasmodium — tertian (every 3 days), quartan (every 4 days). Concomitant infection, particularly by HIV, has a deleterious and progressive effect on the malarial disease. 3393_book.fm Page 594 Thursday, October 25, 2007 5:17 PM MALARIA 595 Benign Malaria Patients develop cyclic fever with weakness, malaise, headache, and myalgias, followed by pallor with hepatosplenomegaly. The illness usually resolves without treatment but with recurrent febrile illness. Malignant Malaria Fever tends to be continual rather than cyclical, followed by convulsions and an impaired level of consciousness. Respiratory distress and circulatory collapse may occur. Severe pallor from hemolytic anemia with jaundice and hemoglobinuria is a common complica- tion (blackwater fever). Renal failure may follow. Splenic rupture can complicate severe splenomegaly. There is a high mortality rate. Laboratory Features 341,342 Normochromic normocytic anemia or anemia of chronic disorders Identification of invading plasmodium by: • Peripheral-blood film stained by either Giemsa or Field’s technique. Thin blood films or thick blood smears can be used, the thicker smears increasing the efficiency but in practice reducing the reliability. Buffy coat films may be preferred. Fluorescent microscopy using Kawamoto acridine orange or benz- thiocarboxypurine is an alternative method of staining, but this requires special training and expensive equipment and reagents. Irrespective of technique, the smear should, whenever possible, be obtained at the height of the fever. The principal differentiating features are: P. falciparum : numerous small ring forms with double chromatin dots P. malariae : single ring forms with single chromatin dot P. ovale : ovoid ring forms; Schuffner’s dots; large gametocytes P . vivax : single ring forms with single or double chromatin dot; few Schuffner’s dots; multiple merozoites occur; large gametocytes (see Table 105); in ad- dition, spherocytes are present • Serological methods used for screening those suspected at blood donation , but these are too slow for routine diagnostic use • Immunochromatographic technique is available to identify antibodies against a histidine-rich protein-2 synthesized by P. falciparum when invading red blood cells • Molecular probes using polymerase chain reaction techniques can be used 343 Increase in the reticulocyte count Hemoglobinemia, hyperbilirubinemia, and hemoglobinuria TABLE 104 Febrile Illness Depending upon Type of Plasmodium Species Clinical Disease P. falciparum malignant tertian malaria P. vivax benign tertian malaria P. malariae quartan malaria P. ovale tertian malaria 3393_book.fm Page 595 Thursday, October 25, 2007 5:17 PM 596 MALARIA Reduced red cell life span (see Erythrokinetics) Autoantibodies to red blood cells, both IgM and IgG, giving a positive direct anti- globulin (Coombs) test Bone marrow hypoplasia and dyserythropoiesis; multinucleate erythroblasts, kary- orrhexis, and erythrophagocytosis are seen Leukopenia due to neutropenia, particularly with P. falciparum invasion associated with hypersegmentation; eosinophils are reduced, except following antimalarial therapy; initial lymphopenia may be followed by lymphocytosis, particularly of B-cells Monocytosis with vacuolation, erythrophagocytosis, malarial pigment, and hemo- siderin inclusions Thrombocytopenia in 85% of cases Hematological Disorders Associated with Malaria Burkitt lymphoma: high incidence in malarious areas, which may be due to stimu- lation of centroblast proliferation, defective cell-mediated toxicity, or enhanced Epstein-Barr virus-induced lymphocyte transformation. Sickle cell disorders: reduction of asexual parasitemia by P. falciparum gives advan- tageous protection. This may arise by blocking the entry of parasites into the red cells, by restriction of parasite development due to the presence of hemoglobin S, or by an increase in antibody-mediated opsonization with premature red cell removal. Thalassemia: red blood cells containing high levels of hemoglobin F suppress parasite development, thus offering some protection. This may be the explanation for the greater incidence of survival in those with thalassemia in tropical areas. TABLE 105 Microscopic Differentiation of Malaria Plasmodia P. falciparum P. vivax P. ovale P. malariae Infected red blood cells normocytic; Maurer’s clefts macrocytic; Schuffner’s dots macrocytic; oval and fimbriated; Schuffner’s dots normocytic or microcytic Ring forms 2 or more, delicate peripheral; small chromatin dot 1–2 in cell; large, thick; large chromatin dot single, thick, compact single, small, compact Later trophozoites compact; vacuolated; small chromatin dot amoeboid central vacuole; light blue cytoplasm amoeboid band across cell; deep blue cytoplasm Schizonts 18–24 merozoites filling 2/3 cell 12–24 merozoites, irregular spacing 8–12 merozoites filling cell 6–12 merozoites around central pigment mass Pigment clumped dark mass fine, granular, yellow- brown coarse, light brown distinct dark mass Gametocytes crescentic; diffuse chromatin; single nucleus spherical; compact; single nucleus oval filling 3/4 cell round filling 2/3 cell Source: Adapted from Bain, B.J., and Lewis, S.M., Preparation and staining methods for blood and bone marrow films, in Dacie and Lewis Practical Haematology, 10th ed., Churchill-Livingstone Elsevier, Philadelphia, 2006, Table 4.3. With permission. 3393_book.fm Page 596 Thursday, October 25, 2007 5:17 PM MALIGNANCY 597 Glucose-6-phosphate dehydrogenase deficiency: the malarial parasite adapts well to G6PD-deficient cells, so that these disorders coexist. Melanesian ovalocytosis: persons with this disorder are less commonly infected. Hereditary infantile pyropoikilocytosis: affected red blood cells resist invasion by malarial parasites. Management Treatment of Infection 344–349 Benign Malaria Oral chloroquine — initial dose 600 mg (of base), then single dose 300 mg * after 6 to 8 h, followed by single daily doses of 300 mg* for 2 days. In areas with chloroquine-resistant strains of plasmodia, amodiaquine can be used, but adverse reactions may result. For P. vivax and P. ovale infection, to remove liver parasites, primaquine 15 mg daily* for 14 to 21 days should follow, but this is contraindicated for pregnant women. To avoid hemolytic anemia, the dosage should be reduced for those with G6PD deficiency to 30 mg weekly for 8 weeks. Malignant Malaria 348 (P. falciparum chloroquine-resistant strains) Oral quinine 600 mg* (of quinine salt) every 8 h for 7 days, followed by Fansider ® , three tablets as a single dose. If Fansider-resistant, doxi- cyclin (20 mg daily) should be given every 6 h for 7 days. Mefloquine or malarone can replace quinine/Fansider, and should be used for children, where oral quinone and chloroquine or pyrimethamine with sulfadoxine are contraindicated, but resistance has been reported. Other new drug combinations include atovaquine and proguanil, artemisinin derivatives, and mefloquine. 349 An artemisinin compound (artemether) has been used as a rectal suppository. With high parasitemia or therapeutic failure, hemapheresis should be considered. Prophylaxis 350,351,(15) Pharmacological protection, although not absolute, remains the mainstay of prophylaxis, with choice of drug and dosage* depending upon the area to be visited. For most regions, chloroquine 300 mg weekly* 1 week before entry to all endemic areas, throughout the stay, then for 4 weeks after leaving is the usually recommended regime. An alternative regime is malarone for 1 to 2 days before leaving home and continued until 1 week after leaving the malarial zone. Mefloquine 250 mg weekly can be used to cover those who are entering areas where chloroquine-resistant plasmodia are known to be present, where it is considered that the risk of infection outweighs the possible adverse drug reactions. Proguanil hydrochloride 200 mg daily* should be added to chloroquine for those entering sub-Saharan Africa, South Asia, Southeast Asia, and Oceania. Drug resistance by the plasmodia has led to the development of numerous drug combinations with the addition of doxicyclin and atovaquone. Blockade of folate synthesis by the plasmodia is the basis for two recently introduced combinations, sulfadoxine-pyrimethamine and proguanil- dapsone. Many more drug combinations and vaccines are undergoing clinical trial. MALIGNANCY The hematological changes that occur with malignancy, other than those of primary bone marrow disease. 121,352 A summary of these is shown in Table 106. * Dosage for the average weight adult. Reduced dosage for children should be calculated according to weight and age. 3393_book.fm Page 597 Thursday, October 25, 2007 5:17 PM [...]... proteases, leukotrienes, platelet-activating factor, and prostaglandin D2 (PGD2) These enzymes increase mucous secretion and smooth-muscle contraction Mast cells also produce many cytokines, e.g., IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-10, IL-13, tumor necrosis factor (TNF )- , and vascular endothelial growth factor (VEGF) IL-4 activates T-helper cells, and IL-4 and IL-5 stimulate eosinophil production... (40%), B-cell-associated antigens+, CD5−, CD10−, CD23−, CD43−/+, CD11c+/− Cytogenetic studies show no rearrangement of bcl-1 or bcl-2; trisomy 3 and t(11;18) occur in extranodal cases The postulated origin is a marginal-zone B-cell of a lymphoid follicle with capacity to home to tissue compartments Extranodal Marginal-Zone Lymphoma of Mucosa-Associated Lymphoid Tissue (MALT lymphoma; low-grade B-cell... Antibodies that bind receptors controlling growth again cross link and trigger signal transduction, e.g., anti-CD3 for T-cells and anti-IgM for B-cells Certain proteins function as so-called superantigens These are powerful mitogens for helper T-cells; they function by cross-linking the Vb domain of the T-cell antigen receptor with any class II histocompatibility antigens on another cell Superantigens include... transfused, although these are unusual Anti-M, anti-S, and anti-s are sometimes implicated as the cause of a delayed hemolytic transfusion reaction The selection of blood for patients with anti-M, -N, -S, or -s should not be difficult, and compatible blood should be provided in all but life-threatening situations The provision of blood for patients with anti-U will be problematic because of the high... 618 Thursday, October 25, 20 07 5: 17 PM 618 MOLECULAR GENETIC ANALYSIS Antibodies and Their Clinical Significance Some anti-M and most anti-S and anti-s antibodies are immune in origin and are of the IgG class Some anti-M and most anti-N antibodies are naturally occurring and are of the IgM class MNS antibodies are not commonly found Anti-M is the most frequent Anti-S and anti-s are likely to be encountered... Antimetabolites: purine analogs, 6-mercaptopurine, 6-thioguanine, azathioprine, acyclovir, pyrimidine analogs, 5- uorouracil, 5- uorodeoxyuridine, 6-azauridine, zidovudine Cycloserine Dihydrofolate reductase inhibitors: methotrexate, aminopterin, pyrimethamine, trimethoprim, sulfasalazine, proguanil, triamterene Cobalamin-absorption interferents: p-aminosalicylic acid, metformin, phenformin, neomycin, colchicine... 20 07 5: 17 PM 602 MAST CELL provides excellent local control Chemotherapy is efficacious, including doxycycline for ocular adnexal MALT, cefotaxime for cutaneous MALT, and broad-spectrum antibiotics for IPSID Nodal Marginal-Zone Lymphoma The majority occur in patients with Sjögren’s syndrome or with other extranodal MALTtype lymphomas Tumors with morphologic features identical to those described for. .. death MARGINAL-ZONE B-CELL LYMPHOMA See also Gastric disorders; Lymphoproliferative disorders; Non-Hodgkin lymphoma (Lukes-Collins: small lymphocytic lymphoplasmacytoid, diffuse small cleaved cell lymphoma, small lymphocyte B, lymphocytic-plasmacytic, parafollicular B-cell; MALT lymphoma; Rappaport: well-differentiated lymphocytic, poorly differentiated lymphocytic, mixed lymphocytic-histiocytic) A... 20 07 5: 17 PM 610 MELPHALAN deformability It is not associated with clinical symptoms or anemia, but there is a geographical association with reduced incidence of malaria in those affected MELPHALAN See Alkylating agents MEPOLIZUMAB A monoclonal antibody that neutralizes anti-leukin-5 antibody It is under trial for use in treatment of the hypereosinophilic syndrome with eosinophilic dermatitis 6-MERCAPTOPURINE... LARGE B-CELL LYMPHOMA (Large-cell lymphoma of the mediastinum) See also Diffuse large B-cell lymphoma 3393_book.fm Page 605 Thursday, October 25, 20 07 5: 17 PM MEGAKARYOCYTE 605 A subtype of diffuse large B-cell lymphoma that involves localized disease in the mediastinum It characteristically involves females in the third to fifth decades of life The immunophenotype is that of diffuse large B-cell lymphoma . October 25, 20 07 5: 17 PM 590 LYSOSOME 7. Enteropathy-type T-cell lymphoma CD3 + , CD7 + , CD8 +/− , CD4 − , CD103 + (MLA: HML-1, LFG 1, Bly7, Bev-ACTB) 8. Primary cutaneous CD30-positive T-cell lymphoproliferative. mucous secretion and smooth-muscle contraction. Mast cells also pro- duce many cytokines, e.g., IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-10, IL-13, tumor necrosis factor (TNF )- , and vascular endothelial. (strong), FMC7 + , CD103 + (MLA: HML-1, B-ly7, Ber-ACT8, LF61) 8. Plasmacytoma SIg − , CIg + (IgG, IgA, rare IgD or IgE; or light chain only); most B-cell-associated antigens − , CD79a +/− ,