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Although the clinical syndromes are the same, the genetic basis of the Rh deficiency syndrome is heterogeneous, and at least two groups Acquired Stomatocytosis Stomatocytes have been noted in diverse acquired conditions, including neoplasms, cardiovascular and hepatobiliary disease, alcoholism, and therapy with drugs, some of which are known to be stomatocytogenic in vitro xerostomia medications side effects order 250 mg divalproex overnight delivery. In some of these conditions, the percentage of stomatocytes on the peripheral blood smear can approach 100%. However, the clinical significance of this observation is unclear because stomatocytes are absent in most patients with the conditions listed. The most consistent association is that of stomatocytosis and heavy alcohol consumption. As mentioned earlier in this chapter, parvovirus B19 selectively infects erythroblasts through interaction with globoside, which encodes the P blood group antigen and temporarily shuts down erythropoiesis. Although this infection is tolerated well by healthy subjects, it can lead to severe, at times life-threatening, aplastic crises in patients with anemias because of premature erythrocyte destruction. As one might predict, parvovirus cannot invade erythroblasts of the rare P-negative individuals. Most infections cause hemolytic anemias triggered by several distinct, and at times overlapping, mechanisms. Plasmodium, Babesia, and Bartonella species directly attack the membrane and lyse the red 612 Part V Red Blood Cells cells. Some bacteria, such as Clostridium perfringens, elaborate hemolytic toxins or phospholipases that damage the membrane. Other infectious agents trigger occasional production of autoantibodies against red cell membrane components, which in turn leads to autoimmune hemolytic anemia. Finally, many sepsis syndromes are associated with anemia because of disseminated intravascular coagulation. Band 3 and Southeast Asian Ovalocytosis Malaria and the Erythrocyte Membrane the red cell membrane defects described earlier in this chapter cause mild to severe hemolytic anemias. At the same time, many red cell membrane alterations have developed as a defense against microorganisms and parasites invading and lysing red cells. Because malaria coexisted with humans over the course of human evolution, it comes as no surprise that multiple erythroid genotypes were selected that confer some level of resistance to infection or mitigate disease severity. The ensuing heritable phenotypes include, among others, resistance to red cell adhesion and/or invasion, slower intraerythrocytic growth, decreased or increased adhesion of infected red cells to vascular endothelium, and increased phagocytosis of parasitized red cells. Malaria and other infections causing hemolytic anemias are described in more detail in Chapter 160, which also discuss hemoglobinopathies and red cell enzyme variants that reduce invasion and/ or retard parasite growth. Consequently we focus here on the heritable erythrocyte membrane alterations that developed as a defense against malaria. Conflicting explanations of the basis of the protective phenotype of Southeast Asian ovalocytosis (described earlier) from malaria have been described. Because this receptor is not expressed in the brain, this raises a possibility that ovalocytosis protects from cerebral malaria by diminishing the number of parasitized red cells available for adhesion to the cerebral vasculature via alternative receptors. It has been hypothesized that this is why the Duffy-negative phenotype is common in large areas of Africa. Elucidation of this mutation explained a longstanding conundrum of transfusion medicine: why individuals with the Duffy-negative phenotype never develop antibodies against the Duffy antigen. Together these data suggest that genetic and age-related differences in complement protein expression contribute to the variability observed in individuals with severe malaria. Although these erythrocyte membrane polymorphisms offer fascinating insight into natural defenses against one of the most serious diseases affecting humans, the mechanism of resistance to malaria has not been fully elucidated for any of them. Malaria has clearly had a profound impact on the genetic makeup of populations living in endemic areas and provided us with multiple clues about the host-parasite relationship. Better understanding of these natural defenses might eventually be converted into effective therapeutic interventions. Barcellini W, Bianchi P, Fermo E, et al: Hereditary red cell membrane defects: Diagnostic and clinical aspects. Barneaud-Rocca D, Pellissier B, Borgese F, et al: Band 3 missense mutations and stomatocytosis: Insight into the molecular mechanism responsible for monovalent cation leak. Bennett V, Healy J: Organizing the fluid membrane bilayer: Diseases linked to spectrin and ankyrin. Glycophorins All major erythrocyte glycophorins, A, B, and C/D, are involved in attachment of P. As noted earlier, the Gerbich-negative phenotype is associated with mild, asymptomatic ovalocytosis. Casale M, Perrotta S: Splenectomy for hereditary spherocytosis: Complete, partial or not at all Guizouarn H, Borgese F, Gabillat N, et al: South-east Asian ovalocytosis and the cryohydrocytosis form of hereditary stomatocytosis show virtually indistinguishable cation permeability defects.

They play an important role in resistance to intracellular microorganisms and tumors through nonimmunologic mechanisms and in the recognition and clearance of apoptotic cells medicine 93 2264 buy divalproex 250mg overnight delivery. Each of these major dendritic and histiocytic cells has corresponding tumors, as summarized in Table 61. In multifocal unisystem disease (formerly many cases of Hand-Schuller-Christian disease), there is involvement of several sites within one organ system, almost always bone. In the least common multifocal multisystem disease (formerly many cases of Letterer-Siwe disease), multiple organs are involved, usually including the bones, skin, liver and spleen, and lymph nodes, often in a lymphoma-like distribution. Langerhans cell histiocytosis represents a monoclonal proliferation, as revealed by molecular studies of the X-linked androgen receptor gene. Neoplastic Langerhans cells may aberrantly express chemokines of immature dendritic cells, and abnormal reactions between Langerhans cells and macrophages may contribute to production of a cytokine "storm. Langerhans cells are dendritic cells with characteristic grooved, folded, or indented nuclei, inconspicuous nucleoli, a relative bland chromatin pattern, and thin nuclear membranes12. The degree of nuclear atypia or the mitotic rate in general does not correlate with outcome, with the exception that cases with frankly sarcomatous features probably represent rare cases of Langerhans cell sarcoma (see the section "Langerhans Cell Sarcoma"). More mature lesions have greater numbers of histiocytes, which may be nonstimulated, epithelioid, or multinucleated and simulating osteoclasts. Late lesions tend to have variable numbers of foamy macrophages and plasma cells and are often associated with a significant degree of fibrosis. Ultrastructurally, neoplastic Langerhans cells have Birbeck granules, numerous lysosomes, small vesicles, and multivesicular bodies, and irregular cell membranes with an absence of cell junctions. Birbeck granules are specific to Langerhans cells and are usually "tennis racket"-shaped intracytoplasmic membranous bodies, with an osmiophilic core and a double outer sheath. The langerin antibody is an endocytic receptor associated with the formation of Birbeck granules and thus is highly specific and sensitive and has in large part supplanted the need for electron microscopy studies. By enzyme histochemistry, normal and neoplastic Langerhans cells are positive for adenosine triphosphatase, a-d-mannosidase, a-naphthyl acetate esterase, a-naphthyl butyrate esterase, and acid phosphatase. The differential diagnosis includes reactive proliferations of Langerhans cells, including dermatopathic lymphadenitis, socalled pulmonary Langerhans cell histiocytosis, and Langerhans cell histiocytosis-like proliferations associated with malignancy lymphoma. In dermatopathic lymphadenitis, the reactive Langerhans cells occur in the paracortex, in contrast to the sinusoidal or patchy pattern of lymph node involvement by Langerhans cell histiocytosis, and the proliferating Langerhans cells are accompanied by melanin-containing histiocytes and numerous interdigitating dendritic cells. So-called pulmonary Langerhans cell histiocytosis and Langerhans cell histiocytosislike proliferations associated with malignant lymphoma are morphologically indistinguishable from Langerhans cell histiocytosis. Histologically, a proliferation of cytologically malignant histiocyte-like cells is seen. The presence of occasional nuclear features characteristic of Langerhans cells may suggest the diagnosis. The mitotic rate is high, and the characteristic cellular milieu of Langerhans cell histiocytosis is not usually seen. The identification of Birbeck granules on ultrastructural examination is also helpful in confirming the diagnosis. The Ki-67 index is usually much higher than that seen in typical Langerhans cell histiocytosis. Normal follicular dendritic cells are the antigen-processing cells of the germinal center. Follicular dendritic cell sarcoma is a very rare neoplasm, occurring in a wide age range and even gender distribution. Treatment usually consists of complete surgical excision, with or without adjuvant radiotherapy and/or chemotherapy. The tumor usually behaves in an indolent fashion, although local recurrence may occur in about one half of cases, and metastasis may occur in one fourth of cases. The spindled cells may form fascicles and whorls, and there is characteristically an admixture of small mature lymphocytes, both amid the spindled cells or architecturally segregated into a second component, which may include secondary lymphoid follicles. The individual cells usually have bland spindled nuclei, although significant atypia may be seen in a minority of cases. The chromatin may vary from vesicular to granular and generally have small nucleoli. Ultrastructural studies show complex interdigitating cell processes with scattered mature desmosomes, typical of normal follicular dendritic cells, and an absence of Birbeck granules. The differential diagnosis includes other dendritic tumors as well as other sarcomas, carcinoma, and malignant melanoma. Interdigitating dendritic cell tumor is a very rare neoplasm usually occurring in adults, equally in men and women.

Large, purple, superficial ecchymoses may be seen, particularly on the back and thighs medicine xl3 order 500mg divalproex mastercard. Circular ecchymoses often surround even atraumatic venipuncture sites, but external bleeding from such sites is uncommon. Hemorrhagic vesicles or bullae may be seen inside the mouth and on other mucous surfaces. The bullae probably are the result of severe acute thrombocytopenia rather than a specific feature of any particular pathogenetic form. A long history of hemorrhagic symptoms of mild to moderate severity is often described by the patient, but antecedent infections or fever are uncommon. Episodes of bleeding may last days or weeks and may be intermittent or even cyclic. Spontaneous remissions are very uncommon in adults, with an estimated occurrence of <5%. Bleeding manifestations in relation to platelet count in patients with primary immune thrombocytopenia. Bleeding manifestations (or duration) are graded from 0 to 4, as follows: 0, no bleeding; 1, minimal, resulting from trauma; 2, spontaneous, but selflimited; 3, spontaneous, requiring special attention. Pinpoint, nonblanching erythematous capillary bleeding sites are most common in dependent body areas or pressure points. The latter usually responds for a time to conservative measures, such as nasal packing or tamponade, often to recur intermittently. Such lesions also may be found in the mucous membranes of the throat and mouth, sometimes in the absence of cutaneous hemorrhage. Hematuria also is a common symptom, the blood coming from the kidneys, the bladder, or the urethra, although bleeding into the kidney parenchyma is rare. Gastrointestinal bleeding is usually manifested by melena or, less often, by hematemesis. Fortunately, it is rare, affecting 1% to 2% or less of patients with severe thrombocytopenia. Numerous small hemorrhages often are seen in the retina; subconjunctival hemorrhage may also occur. In contrast to the hereditary coagulation disorders, such traumatic bleeding is seldom voluminous or rapid. Anemia, if present, is proportional to the extent of blood loss and is usually normocytic. Occasionally, recent severe hemorrhage may produce reticulocytosis and moderate macrocytosis. Eosinophilia has been noted, particularly in children, but this finding is by no means consistent. Lymphocytosis with abnormal cells resembling those characteristic of infectious mononucleosis also has been reported. The results of tests of blood coagulation, including prothrombin time, partial thromboplastin time, and fibrinogen, are normal in patients with uncomplicated thrombocytopenia. The leukocytes are essentially normal with the exception of occasional eosinophilia. The platelets often are abnormally large (3 to 4 mm in diameter) and reveal more than normal variation in size and shape. It is also essential to eliminate the possibility that the thrombocytopenia is secondary to heparin administration. In the usual case, this presentation may be associated with thromboembolic manifestations, anticardiolipin antibodies, and coagulation inhibitors of the lupus type (see Chapter 54). A number of different types of antiplatelet antibody tests have been developed and reported through the years. These tests measured different types of Ig, including serum antiplatelet antibodies, platelet-associated surface Ig, or total platelet Ig and are now generally regarded as unreliable.

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