Chapter 23: Hemolytic Anemia Resulting from Infectious Agents

• Hemolysis represents a prominent part of the overall clinical picture in many infections. Table 23–1 lists the microorganisms associated with the induction of hemolytic anemia.

• Hemolysis may be caused by:

  — Direct invasion by infecting organisms (malaria).

  — Elaboration of hemolytic toxins (Clostridium perfringens).

  — Development of autoantibodies against red blood cell antigens (Mycoplasma pneumoniae).

Etiology and Pathogenesis

• The world's most common cause of hemolytic anemia.

• Transmitted by bite of an infected female Anopheles mosquito.

• Parasites grow intracellularly and parasitized cells are destroyed in the spleen.

• Uninvaded cells are also destroyed (estimated at 10 × the number of infected cells).

• Erythropoietin low for degree of anemia secondary to release of inhibitory cytokines, especially in Plasmodium falciparum infection.

• Certain heterozygous mutations that interfere with invasion of red blood cells by parasites have developed in endemic areas (G-6-PD deficiency, thalassemia, other hemoglobinopathies, and hereditary elliptocytosis).

Clinical Features

• Febrile paroxysms are characteristically cyclic: Plasmodium vivax every 48 hours, Plasmodium malariae every 72 hours, and P. falciparum daily.

• Rigors, headache, abdominal pain, nausea and vomiting, and extreme fatigue accompany the fever.

• Splenomegaly typically is present in chronic infection.

• Falciparum malaria is occasionally associated with very severe hemolysis and dark, almost black urine (blackwater fever).

• Cerebral malaria may result in delirium, other neurologic manifestations.

• Organ dysfunction (respiratory insufficiency and renal failure) may be present.

Laboratory Features

• Signs of hemolytic anemia.

• Thrombocytopenia nearly always present.

• Diagnosis depends on demonstration of the parasites on the blood film (Fig. 23–1) or the appropriate DNA sequences in the blood.

• If greater than 5 percent of red cells parasitized or if two ring forms in a red cell, P. falciparum infection usually present.

Treatment and Prognosis

• The blood form of malaria should be treated as soon as possible. Artemisinins are effective against P. falciparum, but numerous studies are in progress to determine efficacy of individual drugs and drug combinations.

• Tissue stages of vivax malaria have been treated with primaquine. Primaquine, as well as certain sulfones, may produce severe hemolysis in patients with G-6-PD deficiency.

• Transfusions may be necessary in treatment of severe blackwater fever, and if renal failure occurs, dialysis may be required.

• In patients with severe malaria, cerebral malaria, or high levels of parasitemia, erythrocytapheresis or erythrocyte exchange may be beneficial.

• With early treatment, prognosis is excellent. When therapy is delayed or the strain is resistant, malaria (particularly falciparum) may be fatal.

• Bartonella bacilliformis is transmitted by the sand fly.

• The organism adheres to the exterior surface of red blood cells, which are rapidly removed from the circulation by the spleen and liver.

Clinical Features

• Disease develops in two stages:

  — Acute hemolytic anemia (Oroya fever).

  — Chronic granulomatous disorder (verruca peruviana).

• Most patients manifest no other clinical symptoms during the Oroya fever phase, but some may develop severe hemolytic anemia accompanied by anorexia, thirst, sweating, and generalized lymphadenopathy. Severe thrombocytopenia may occur.

• Verruca peruviana is a nonhematologic disorder characterized by bleeding warty reddish-purple nodules over the face and extremities.

Laboratory Features

• Severe anemia develops rapidly.

• Large numbers of nucleated red cells appear in the blood and the reticulocyte count is elevated.

• Diagnosis is established by demonstrating the organisms on the surface of red cells on a Giemsa-stained smear (red-violet rods 1 to 3 μm in length).

Treatment and Prognosis

• Mortality in untreated patients is very high. Those who survive experience sudden clinical improvement with increase in red cell count and change of the organisms from an elongated to a coccoid form.

• The acute phase usually responds to treatment with ciprofloxacin, chloramphenicol, and β-lactam antibiotics or combinations of the aforementioned, especially in children.

• Intraerythrocytic protozoa transmitted by ticks infect many species of wild and domestic animals (rodents and cattle).

• Humans are rarely infected, usually via ticks, but transmission by transfusion has been reported.

• Most common in the U.S. northeastern coastal region, but also encountered in the midwest.

• Gradual onset with malaise, anorexia, fatigue, followed by fever, sweats, myalgias, and arthralgias.

• May be more severe in splenectomized patients.

• Parasites seen in the red blood cells on Giemsa-stained blood films (Fig. 23–1).

• Treatment with clindamycin and quinine.

• Whole-blood exchange has been used with marked improvement.

• Most common in patients with septic abortion and occasionally seen following acute cholecystitis.

• In C. perfringens septicemia, the toxin (a lecithinase) reacts with red blood cell lipids, leading to severe, often fatal hemolysis with striking hemoglobinemia and hemoglobinuria; serum may be a brilliant red and the urine a dark-brown mahogany color.

• Acute renal and hepatic failure usually develops.

• The blood film shows microspherocytosis, leukocytosis with a left shift, and thrombocytopenia and occasionally intracellular gram-positive rods. (Fig. 23–1).

• The hematocrit may approach zero, but the blood (plasma) hemoglobin may be about 60 to 100 g/L at the time of acute massive intravascular hemolysis.

• Treatment is with intravenous fluid support, high-dose penicillin or a similar antibiotic (e.g., ampicillin) and surgical debridement.

• Mortality is greater than 50 percent, even with appropriate therapy.

• Viral agents may be associated with autoimmune hemolysis (see Chap. 24). The mechanisms include absorption of immune complexes, crossreacting antibodies, and loss of tolerance.

• Evidence for CMV infection is found in a high percentage of children with lymphadenopathy and hemolytic anemia.

• High cold agglutinin titer may develop with M. pneumoniae infection and occasionally results in hemolytic anemia or compensated hemolysis (see Chap. 25).

• Microangiopathic hemolytic anemia (see Chap. 21) may be triggered by a variety of infections, including Shigella, Campylobacter, and Aspergillus.

• Thrombotic microangiopathy with fragmentation hemolytic anemia (hemolytic uremic syndrome), especially in children, can be caused by enterotoxigenic gram-negative microorganisms, notably Escherichia coli serotype O157:H7 (see Chap. 21).