Page 2560 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 158 Hematologic Aspects of Parasitic Diseases 2283

immune status, and pregnancy, as well as by the species, genotype, cleared from the circulation. However, in the majority of cases, the
and perhaps the geographic origin of the parasite. In endemic areas, cause of sudden hemolysis cannot be accounted for, and it seems
many infections present as an uncomplicated febrile illness. In more likely that unidentified hemolytic mechanism(s) may operate.
severe forms of the disease, children may present with prostration or
inability to take oral fluids, or in younger children an inability to
suckle. Alternatively, these children may exhibit a number of syn- The Hematologic Features of Malarial Infection
dromes of severe disease, including anemia, coma, respiratory distress,
and hypoglycemia and may also have a high rate of bacteremia. 69,77 The anemia of falciparum malaria is typically normocytic and nor-
In most age groups, anemia is frequently accompanied by more mochromic, with a notable absence of reticulocytes, although
than one syndrome of severe disease, and the already substantial case microcytosis and hypochromia may be present because of the very
fatality rate of 15% to 20% for severe malaria in African children high frequency of α- and β-thalassemia traits and/or iron deficiency
rises significantly when multiple syndromes of severe disease are in many endemic areas. 47,71
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present. The age distribution of anemia and other syndromes of The anemia of malaria may be accompanied by changes in the
severe disease is a consistent but puzzling feature of the epidemiology white cell and platelet counts and in clotting parameters, but these
of clinical malaria. Children born in endemic areas are protected from changes are not in themselves diagnostic, nor do they guide manage-
severe malaria in the first 6 months of life by the passive transfer of ment. Malaria is accompanied by a modest leukocytosis, although
maternal immunoglobulins and by fetal hemoglobin. Beyond infancy, leukopenia may also occur. Occasionally, leukemoid reactions have
the most common form of presentation of severe disease changes been observed. Leukocytosis has been associated with severe
from anemia in children aged 1 to 3 years old, in areas of high disease. 84,85 A high neutrophil count may also suggest intercurrent
transmission, to cerebral malaria in older children, in areas of lower bacterial infection. Monocytosis and increased numbers of circulating
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transmission. As transmission intensity declines further, severe lymphocytes are also seen in acute infection, although the significance
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malaria is most frequently found in older age groups. of these changes is not established. However, malarial pigment is
often seen in neutrophils and in monocytes and has been associated
with severe disease and unfavorable outcome. 87,88
The Clinical Features of Malarial Anemia Thrombocytopenia is almost invariable in malaria and so may be
helpful as a sensitive but nonspecific marker of active infection.
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The blood stage of falciparum malaria may cause life-threatening However, severe thrombocytopenia (platelet count <50 × 10 /L) is
anemia; a hemoglobin level of less than 5 g/dL is considered to rare. Increased removal of platelets may follow absorption of immune
represent severe disease. Children with anemia may present with complexes or platelet activation, but there is no evidence for platelet-
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malaise, fatigue, and dyspnea or respiratory distress, which usually specific alloantibodies. By analogy with erythropoiesis, there may
represents metabolic acidosis, but in an ill child acute respiratory be a defect in thrombopoiesis, but this has not been established.
infection must be carefully excluded. 77,79 Thrombocytopenia has not generally been associated with disease
Acidosis is due largely to excessive lactic acid and other anions. severity, although a study from Papua New Guinea has shown that
Salicylate toxicity and dehydration may also play a role. However, the severe thrombocytopenia identifies both children and adults at
majority of children presenting with respiratory distress are severely increased risk of death from falciparum or vivax malaria, particularly
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anemic, have a metabolic acidosis secondary to reduced oxygen- in those with concurrent severe anemia. Indeed, platelets have been
carrying capacity, and respond to rapid transfusion of fresh blood (for shown to contribute to disease pathology in both animal and human
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review, see English et al ). A minority of those with respiratory malaria. Moreover, in human infections, platelets may form clumps
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distress do not respond to appropriate resuscitation. They probably with infected erythrocytes. One explanation of inconsistent rela-
represent a heterogeneous clinical group and may have renal failure, tionships reported between the severity of malaria and the thrombo-
systemic bacterial infection, or a more profound syndrome of systemic cytopenia may be that findings of low levels of platelets might not
disturbance caused by malarial parasites. only be a marker of parasite burden but also be protective from
However, a large randomized trial of a bolus of fluids in the severe disease and/or be associated with anti-inflammatory cytokine
treatment of African children with shock and life-threatening infec- responses. 93
tions showed somewhat surprisingly that fluid boluses significantly Disordered coagulation and clinical evidence of bleeding are not
increased 48-hour mortality in these critically ill children with infrequent in nonimmune adults contracting malaria and presenting
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impaired perfusion. Fluid resuscitation must be carefully supervised, with severe disease. Patients may present with bleeding at injection
and it may be relevant that after transfusion in children with acute sites, gums, or epistaxis. Abnormal results of laboratory tests for
malarial anemia, BNP levels do fall, suggesting at the very least that hemostasis, suggesting activation of the coagulation cascade, occur in
cardiac function must be carefully monitored during fluid and blood acute infection. However, histologic evidence of intravascular fibrin
therapy for acute malaria. 82 deposition is notably absent in adults dying as a result of severe
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malaria. Factor XIII, normally responsible for cross-linking fibrin,
is inactivated during malarial infection, and these data may explain
Hemolytic Syndromes, Including Blackwater Fever low levels of fibrin deposition in the face of increased procoagulant
activity. 95
The sudden appearance of hemoglobin in the urine, indicating severe During acute disease the levels of a disintegrin and metallopro-
intravascular hemolysis leading to hemoglobinemia and hemoglobin- teinase with thrombospondin motif 13 (ADAMTS13) protease are
uria or blackwater fever, received particular attention in early studies moderately reduced, and the concentration of high-molecular-weight
of anemia in expatriates living in endemic areas. There was an associa- von Willebrand multimers is increased. Such multimers may play a
tion between blackwater fever and the irregular use of quinine for role in the adherence of infected RBCs and platelets to endothelium,
chemoprophylaxis. This drug can act as a hapten and stimulate but the role of this adhesive pathway in the etiology of severe and
production of a drug-dependent, complement-fixing antibody. cerebral malaria has not been established. 96
Recent studies of sudden intravascular hemolysis have shown that it The bone marrow is typically hypercellular. The most striking
is rare in Africa but more common in Southeast Asia and Papua New findings are of grossly abnormal development of erythroid precur-
Guinea, where some cases are associated with G6PD deficiency and sors or dyserythropoiesis. The developing erythroid cells typically
treatment with a variety of drugs, including quinine, mefloquine, and demonstrate cytoplasmic and nuclear bridging and irregular nuclear
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artesunate. Treatment with artesunate may be associated with outline. 39,40 These changes are probably central to the pathophysiology
sudden severe hemolysis, but it is also recognized that artesunate can of malarial anemia and are discussed in detail later. The proportion
cause transient and mild reduction in hemoglobin levels after the of abnormal erythroid precursors and the degree of dyserythropoiesis
acute episode of malaria as previously infected ring-stage parasites are are markedly greater in chronic compared with acute infection,