++
Hemolytic anemia in children can also result from disease processes
or mechanical forces that arise external to the erythrocyte. These
extrinsic RBC defects are typically acquired disorders, although
some have a genetic component. Extrinsic RBC defects vary widely
and can be most easily classified into immune-mediated and non–immune-mediated
etiologies.
+++
Immune-Mediated Hemolytic
Anemia
++
Both IgG and IgM antibodies can bind to the RBC surface and lead
to hemolysis. IgG-sensitized RBCs are usually eliminated in the
extravascular compartment (spleen and liver) by interactions with
specific FcR or complement receptors on phagocytes within the reticuloendothelial
system (RES). In contrast, IgM-sensitized RBCs often undergo hemolysis
in the intravascular compartment via complement, although extravascular
clearance also occurs in the liver.11
++
The related condition, alloimmune hemolytic anemia, occurs when
antibodies develop in response to “foreign” erythrocytes.
This occurs in hemolytic disease of the newborn (see Chapter 53),
where maternal antibodies cross the placenta and destroy fetal erythrocytes,
and in chronically transfused children who develop alloantibodies
against transfused cells. In both conditions, immune-mediated hemolysis
occurs as long as self–nonself interactions continue.
+++
Clinical Features
and Diagnosis
++
Autoimmune hemolytic anemia (AIHA) is, by definition, a condition
in which antibodies arise with specificity against surface antigens
present on the child’s own erythrocytes. The most common form
is warm-reactive AIHA, characterized by IgG autoantibodies that
bind optimally at warm (37�C) temperatures. Most cases are idiopathic,
although some arise in association with immunodeficiency, lymphoproliferative
diseases, or a broad autoimmune process such as systemic lupus erythematosus.
Warm-reactive AIHA occurs in all ages and can be clinically severe;
infants and teenagers have increased morbidity and occasionally
mortality. The IgG antibodies bind circulating common antigens on
the erythrocytes (eg, Rh proteins), and these opsonized (antibody-sensitized) cells
are then cleared in the extravascular compartment, especially the
spleen. Macrophages within the reticuloendothelial system (RES)
often remove a portion of the IgG-coated RBC membrane, and the remaining
cells reform into spherocytes that can return briefly to the circulation
before removal by splenic filtration (Fig. 433-4A). Complement
is not fixed to a substantial degree; hence, intravascular hemolysis
is not common. The sine qua non of AIHA is a positive direct antiglobulin
test (DAT), formerly known as the direct Coombs test. In warm-reactive
AIHA, the DAT is positive for IgG and, occasionally, a small amount
of C3.
++
++
A second form of childhood AIHA is paroxysmal cold hemoglobinuria (PCH),
which is usually self-limited and typically follows a virallike illness.
The autoantibodies are IgG, but bind best at cold (4�C) temperatures
and fix complement avidly; hence, the clinical presentation includes
intravascular hemolysis with dramatic hemoglobinuria and severe
anemia. The DAT is positive for C3 but usually not for IgG. A third
form of childhood AIHA is cold agglutinin disease (CAD),
featuring IgM autoantibodies that bind circulating erythrocytes
and fix complement well; the DAT is positive for C3, and both intravascular
and extravascular hemolysis occurs. In children, CAD is usually
self-limiting and develops in association with an infection such
as Epstein-Barr virus (EBV) or mycoplasma; cold-induced agglutination
of the erythrocytes can occasionally be observed on the peripheral
blood smear (Fig. 433-4B).
++
The treatment of AIHA in children depends on the type and the
etiology. Warm-reactive AIHA responds well to corticosteroids and
to splenectomy in severe or refractory cases. IVIG is not beneficial,
although rituximab (anti-CD20 monoclonal antibody) that destroys
circulating B-lymphocytes shows promise for this disorder.12 In
cold-reactive disorders such as PCH or CAD, corticosteroids are of
limited benefit, but treatment of the underlying infection can help. In
all forms of AIHA, supportive care is usually sufficient; however, transfusions
are occasionally needed for severe anemia. Although cross-matching
of blood will not identify compatible units, blood should be administered when
anemia is severe and life threatening because even incompatible
erythrocytes will survive as well as endogenous cells.13
+++
Paroxysmal Nocturnal Hemoglobinuria
++
This is a rare acquired clonal stem cell disorder characterized
by chronic intravascular hemolysis. Paroxysmal nocturnal hemoglobinuria
(PNH) most often develops in adults, although children and adolescents
can be affected.14 Although not exclusively a disorder
of erythrocytes, PNH features an increased sensitivity to complement-mediated
intravascular hemolysis, which then leads to symptomatic hemoglobinuria.
Additional clinical features of PNH include thrombosis and bone
marrow failure. In some cases, PNH develops in patients with aplastic anemia
who are successfully treated with antithymocyte globulin (ATG) and
cyclosporin. Eculizumab is a novel C5-inhibitor monoclonal antibody
that can reduce intravascular hemolysis in patients with PNH.15 Currently,
the only available cure for PNH is bone marrow transplantation.16
+++
Non-Immune-Mediated
Hemolytic Anemia
++
Occasionally, circulating erythrocytes are damaged by external
forces or toxins that lead to hemolysis. When abnormal amounts of
fibrin or high-molecular-weight von Willebrand factor (vWF) are
present within the blood vessel, RBCs can be trapped and even sheared
on these strands. Erythrocytes appear as schistocytes (torn cells) on
the peripheral blood smear (Fig. 433-4C);
platelets are often trapped, so there is concomitant thrombocytopenia.
This process is known as microangiopathic hemolytic anemia because
it often occurs in the smaller blood vessels.
++
In children, schistocytic anemia occurs most commonly as hemolytic
uremic syndrome (HUS), defined as a triad of microangiopathic
hemolytic anemia, thrombocytopenia, and acute renal failure. HUS
usually affects children younger than 5 years; 90% of cases
occur after the onset of a diarrheal illness, most often from the Shiga
toxin-producing Escherichia coli O157:H7 (see Chapter 472). Children often present with
abdominal pain and bloody diarrhea, sometimes with fever. RBC transfusions
may be necessary to treat severe anemia, but platelet transfusions
are not recommended. Treatment is primarily supportive and focuses
on management of fluids, electrolytes, and hypertension. Antimicrobial
therapy and antithrombotic agents are not helpful. Usually, the
illness is self-limited, although some children will require dialysis
during the acute illness, and a small number will subsequently develop
chronic renal insufficiency.17
++
A related disorder is thrombotic thrombocytopenic purpura (TTP),
which is a pentad that includes microangiopathic hemolytic anemia,
fever, renal dysfunction, thrombocytopenia, and neurologic abnormalities.18 TTP
develops when large vWF multimers are released from endothelial
cells into the circulation, but the naturally occurring plasma vWF-cleaving
protease (ADAMTS13) is not present to cut the large vWF
molecules into smaller pieces. The large multimers cause a localized
microangiopathy in multiple organs, especially the kidney and brain.
TTP can occur in a congenital form with low amounts of vWF-cleaving
protease due to genetic mutations in the ADAMTS13 gene;
these children develop recurrent and relapsing microangiopathic
hemolytic anemia. TTP also can occur as an acquired condition, usually
in teenagers or adults who sometimes have a broad autoimmune disorder
such as systemic lupus erythematosus. These patients develop a specific
autoantibody inhibitor that neutralizes ADAMTS13 in
plasma, rendering it functionally deficient. Treatment includes plasmapheresis,
to remove the inhibitor and provide fresh plasma containing the
vWF-cleaving protease, as well as corticosteroids and other immunomodulatory therapies.
++
Microangiopathic hemolytic anemia can occur in other clinical
settings such as disseminated intravascular coagulation (DIC), pregnancy
(preeclampsia, eclampsia, HELLP syndrome), drug exposure (ie, cocaine,
cyclosporine, tacrolimus), mechanical heart valves, and malignant
hypertension. The brown recluse spider (Loxosceles reclusa)
produces a toxin that can lead to a painful local wound and occasionally
severe hemolysis (Fig. 433-4D).
+++
Complications
of Hemolysis
++
Chronic hemolysis has substantial pathophysiologic consequences. Extravascular
hemolysis leads to splenomegaly, jaundice, and increased risk of
pigmented (bilirubin) gallstones. Intravascular hemolysis releases
hemoglobin into the plasma; chronically, this can lead to renal
damage. Plasma hemoglobin also binds nitric oxide (NO) produced
by endothelial cells and monocytes for local smooth muscle relaxation
and vasodilatation. Depletion of NO leads to relative vasoconstriction and
eventual endothelial vasculopathy, culminating in an overall hypercoagulable
state and occasionally pulmonary hypertension.19 The
long-term consequences of intravascular hemolysis have only more
recently been described, but pulmonary hypertension may ultimately
prove to be a cause of substantial morbidity and even mortality
among persons with chronic hemolytic anemia.
++
There are also long-term consequences to splenectomy. The most widely
recognized complication is an increased risk of overwhelming sepsis,
particularly from encapsulated bacteria. The development of a hypercoagulable
state is less well known, but is increasingly recognized as a postsplenectomy
complication. Most patients will have mild asymptomatic thrombocytosis
after splenectomy. This elevation in platelet count and platelet activation
may lead to thromboembolic complications with significant morbidity
and mortality. A more recent study found that splenectomy greatly
increased the likelihood of developing chronic thromboembolic pulmonary
hypertension.5 Taken together, the available data suggest
that patients who undergo splenectomy for hemolytic anemia during
childhood may have late effects as adults. Additional research is
needed to help clinicians determine the risks and benefits of splenectomy
for individual patients with hemolytic anemia.