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Clinical Presentation and Management of Hemolytic Anemias

Clinical Presentation and Management of Hemolytic Anemias

ABSTRACT: The hallmark of hemolysis is shortened red blood cell survival in the peripheral blood. Hemolysis results in anemia only when bone marrow cannot keep up with the rate of red cell destruction. Even though anemia is very commonly observed in most cancer patients, hemolytic anemias are rather rare. Acute or chronic hemolysis, when present can impact on quality of life adversely, especially when bone marrow has limited compensation capacity. The underlying etiologies and pathophysiologies of the varying types of hemolytic anemias differ vastly, and there are numerous disorders causing red blood cell destruction that result in a similar clinical presentation. Careful review of the peripheral blood smear can provide invaluable information in diagnosing the underlying disorder. The majority of the nonhemolytic anemias have a chronic and stable course. In hemolytic disorders, however, the severity of the hemolysis can also create life-threatening emergencies. Management of hemolytic anemias depend on the diagnosis. Thus clinicians often face added pressure to determine the causative disorder rapidly so that timely interventions can be planned. Thus, even though they are not very common, hemolytic anemias remain a big challenge in the practice of hematology and oncology. [ONCOLOGY 16(Suppl 10):163-170, 2002]

In hemolytic disorders,
the normal life span of erythrocytes in
the peripheral blood of 120 days is substantially shortened because of red cell
destruction. As a compensatory mechanism, there is increased red blood cell (RBC)
production by the bone marrow. Under normal conditions, the bone marrow can
increase its capacity for RBC generation severalfold in response to anemia.[1]
Shortening of RBC life span does not lead to anemia until a relative bone marrow
failure follows with an inability of the marrow to keep up with the loss.
Proportional increases in both destruction and generation of RBCs can result in
compensated hemolysis without significant anemia. Some of the earliest
observations of hemolysis have been the visualization of red-pink urine in
patients with such rare conditions as paroxysmal cold hemoglobinuria, march
hemoglobinuria, or paroxysmal nocturnal hemoglobinuria (PNH).

Classification and Pathogenesis

Hemolytic anemias can be categorized as acute or chronic,
inherited or acquired, by the site of hemolysis (intravascular or extravascular),
or by the location of the abnormality responsible for the hemolysis (intrinsic
or extrinsic to the red cell). The distinction between inherited and acquired is
probably the most useful clinically. Most intrinsic defects are inherited, and
most extrinsic ones are acquired. Exceptions to this rule are few and include
paroxysmal nocturnal hemoglobinuria (acquired intrinsic RBC defect), and G6PD
deficiency (inherited intrinsic defect that depends on an extrinsic factor such
as drugs to become evident).

Inherited intrinsic RBC disorders can be due to impairments
in membrane structure, glycolytic pathway, glutathione metabolism, hemoglobin
structure, or other rare enzyme defects. The acquired hemolytic anemias can be
divided into antibody induced, physical injury related, or due to infection,
physical agents, chemical agents, hypophosphatemia and liver disease.

The site of hemolysis may be intravascular, in which case the
erythrocyte is destroyed in the circulation, or extravascular, in which case the
red cell destruction occurs within macrophages in the spleen, liver, or bone
marrow (see Table 1). Intravascular hemolysis is typically severe and results
from mechanical damage to the red cell due to prosthetic valves, the presence of
fibrin within the vasculature (microangiopathic hemolytic anemia), or thermal
injury to the erythrocytes from serious burns; infections or toxins, such as Clostridium
perfringens
bacteremia, severe falciparum malaria, or certain snake venoms;
or complement-mediated damage to red cells, as with paroxysmal nocturnal
hemoglobinuria, ABO-incompatible blood transfusions, and cold agglutinins.

Intravascular hemolysis liberates hemoglobin into the
bloodstream, where it binds to haptoglobin. The haptoglobin/hemoglobin complex
is then removed by the liver. A reduced serum haptoglobin level is one of many
findings in intravascular hemolysis, but it also occurs in extravascular
hemolysis. When the amount of free hemoglobin in the circulation exceeds the
binding capacity of haptoglobin, it makes the plasma pink and is filtered
through the kidneys. The urine may become red, and proves positive for blood
upon dipstick testing in the absence of erythrocytes on urine microscopy. The
renal tubular cells, which reabsorb some of the hemoglobin and convert it to
hemosiderin, are shed into the urine. Iron stains of urinary sediment
demonstrate the hemosiderin within these renal tubular cells and confirm ongoing
or recent intravascular hemolysis, even when hemoglobin has become undetectable
in the plasma or urine.

Most hemolytic disorders are extravascular. The causes of
extravascular hemolysis include infections, drugs, or immunologic processes;
red cell membrane defects, such as hereditary spherocytosis; erythrocyte
metabolic defects, such as deficiencies in pyruvate kinase or G6PD; and
hemoglobin structural defects, such as sickle cell anemia or hemoglobin C.

Another classification of hemolytic anemias distinguishes
between disorders intrinsic to the red cell, generally hereditary, and those
extrinsic to the red cell, generally acquired. The intrinsic disorders include
abnormal hemoglobins, such as HbS or HbC; enzyme defects, such as deficiencies
in G6PD; and membrane abnormalities, such as hereditary spherocytosis or
elliptocytosis. The extrinsic abnormalities are immunologic—alloantibodies,
such as those associated with ABO incompatibility; autoantibodies, as in warm (IgG)
or cold (IgM) antibody hemolytic anemias; drug-induced antibodies; mechanical
factors, such as trauma from prosthetic valves or fibrin deposition in small
vessels, as in microangiopathic hemolytic anemias; infections and toxins, such
as falciparum malaria or certain snake venoms; and severe hypophosphatemia. See
Table 2
for the causes of hemolysis broken down by the site of abnormality.

Clinical Aspects

Chronic Congenital
Hemolytic Anemias

Even though there are numerous congenital hemolytic
disorders, their clinical features are very similar. Chronic congenital
hemolytic anemias are usually characterized by anemia, jaundice, periodic
crises, splenomegaly, and black pigment gallstones.[2] Other than during a
crisis, symptoms are usually mild to moderate because of compensation by several
organ systems, including the bone marrow. Chronic symptoms may become severe at
times of crisis. Aplastic crisis can be induced by infection with human
parvovirus type B19 (fifth disease).[3] The presence of the parvovirus-specific
IgM antibody in serum is a marker of recent infection. A single infection
results in lifelong immunity (IgG). The virus infects and inhibits proliferation
of erythroid progenitors, only in the bone marrow (very low reticulocyte count).

The clinical picture can also worsen with increased RBC
destruction (splenic crisis) or folate deficiency (megaloblastic crisis). Leg
ulcers can be seen with chronic hemolytic disorders, especially with hereditary
spherocytosis and sickle cell anemia. When hemolysis is severe during growth and
development, as in thalassemia major, marked expansion of the bone marrow may
lead to skeletal changes such as tower-shaped skull, thickening of the frontal
and parietal bones, dental abnormalities, and other bony distortions.[4]

Acquired Hemolytic Anemias

If hemolytic anemia develops acutely, as in hemolytic
transfusion reaction or G6PD deficiency, the symptoms may suggest an acute
febrile illness with skeletal pains, headache, malaise, fever, and chills.[5]
Symptoms of shock, renal failure, jaundice, and anemia may be evident in severe
cases. Usually, however, the symptoms are more gradual and mimic a congenital
hemolytic disease. In other patients, symptoms may be more related to the
underlying disease, such as lupus, lymphoma, and mycoplasma infection.

Laboratory Observations

Laboratory abnormalities seen with hemolysis can be traced to
increased RBC destruction, increased erythropoiesis by the bone marrow, and
disease-specific findings.

When RBCs are destroyed at an accelerated rate, bile pigments
and carbon monoxide are excreted more than usual. The unconjugated bilirubin is
elevated, accounting for more than 80% of the total bilirubin, and is not
excreted in the urine. Total bilirubin usually does not exceed 4 to 5 units with
hemolysis.[6] Unlike in liver disease, in patients with hemolysis pruritus is
usually absent. Fecal urobilinogen excretion increases as an indicator of
increased bilirubin metabolism in the liver. When plasma hemoglobin levels
exceed haptoglobin binding capacity, the plasma turns pink and is filtered into
the urine. The urine becomes red and urine iron levels increase. Other than
hemolysis, only in hemochromatosis and nephrotic syndrome can one detect
increased urinary iron levels.[7,8]

In hemolytic anemias the reticulocyte count is elevated; this
is an indicator of accelerated erythropoiesis. Low reticulocyte count is
encountered during aplastic crisis despite hemolysis. The mean corpuscular
volume (MCV) may be normal or increased, depending on how many large, immature
erythrocytes have prematurely left the bone marrow in response to the anemia.
The serum lactate hydrogenase (LDH) level is increased. Of the LDH isozymes,
LDH-2 predominates; in megaloblastic conditions LDH-1 is elevated. LDH values
lack specificity in hemolysis because many other conditions can result in high
levels.

The serum haptoglobin is commonly diminished. Free hemoglobin
in the bloodstream binds to haptoglobin. Haptoglobin/hemoglobin complex is then
removed by the liver. Haptoglobin is an acute-phase reactant and levels increase
in response to inflammation, infection, and malignancy. Haptoglobin levels
decrease in association with not only intravascular hemolysis but also with
extravascular hemolysis (sickle cell anemia, RBC membrane, and enzyme
disorders), and intramedullary hemolysis (megaloblastic anemia).[9] One needs to
be aware of nonhemolytic conditions that can result in low haptoglobin levels
(liver disease, hereditary haptoglobin deficiency after red cell transfusions),
and normalized haptoglobin levels despite hemolysis (acute phase surges) during
work-up of such patients. Glycosylated hemoglobin levels are also reduced in
response to hemolysis, and usually reflect hemolysis over the past 4 to 8
weeks.[10] Glycosylated hemoglobin levels are not reliable in patients with
diabetes mellitus because of high glucose levels and in patients with anemia due
to bleeding because of hemoglobin loss.

Blood smear is the single most valuable test in defining the
underlying disorder causing hemolysis. Spherocytes are the hallmark of
hereditary spherocytosis, sickle cells of sickle cell anemia, target cells of
thalassemia, schistocytes of RBC fragmentation, erythrophagocytosis of red cell
surface damage by complement-fixing antibodies and infections, auto
agglutination of cold agglutinin disease, and elliptocytes of hereditary
elliptocytosis. Morphologic findings of hemolysis can be confirmed on a blood
smear; this may be very helpful in demonstrating polychromatophilia and
nucleated red cells, confirming the early departure of red cells from the bone
marrow. Abnormalities in red cell shape, such as fragments, sickle cells,
spherocytes, or bite cells, provide clues regarding etiology that may be
diagnostic or at least highly suggestive of the cause. Other suggestive findings
include red cell agglutination, indicating IgM-mediated disease; organisms such
as Plasmodium falciparum or Babesia; and erythrophagocytosis, seen
especially with red cell damage from immune mechanisms but also with certain
infections or toxins. The bone marrow usually shows erythroid hyperplasia.

Tests useful in suspected intravascular hemolysis include
evaluation of the plasma and urine for hemoglobin and an iron stain of the urine
sediment to detect hemosiderin. For immune-related hemolytic anemia, the Coombs
test to demonstrate IgG and complement on the red cell or in the serum, and the
cold agglutinin test looking for IgM are indicated. A positive Coombs test
(direct antiglobulin test [DAT]) indicates that RBCs are coated with IgG or
complement, hence an immune etiology for hemolysis. Very rarely a DAT will be
negative in immune hemolytic anemia if the amount of globulin on the RBC surface
is very low.[11]

With suspected hemoglobinopathies, a hemoglobin
electrophoresis is appropriate. An osmotic fragility test may help when
hereditary spherocytosis is suspected.[12] Special stains on blood smear to
identify Heinz body formation (precipitation of hemoglobin to form inclusions)
can help identify patients with G6PD deficiency, unstable hemoglobin disease,
and thalassemia. Other laboratory evaluations depend on the likely abnormality
and may include searching for rare enzyme defects. The following is a brief
review of some of the major categories of hemolytic disorders.

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