Hematologic Complications of HIV Infection

Hematologic Complications of HIV Infection

ABSTRACT: Hematologic complications of HIV disease are commonly encountered by physicians and other health-care workers caring for patients infected with this virus. Ineffective hematopoiesis, infiltrative diseases of the bone marrow, nutritional deficiencies, peripheral destruction of blood cells secondary to splenomegaly or immune dysregulation, and drug effects all contribute to the variety of hematologic abnormalities seen in these patients. This review explores the causes of isolated or trilineage cytopenias and coagulopathies; the utility of bone marrow biopsy examination; and the role of colony-stimulating factors as therapeutic agents in patients with HIV disease. [ONCOLOGY 10(5):671-680, 1996]


Hematologic complications of HIV infection are common and challenge
physicians treating patients at all stages of HIV disease [1,2].
Ineffective hematopoiesis from direct suppression by HIV infection
or excessive cytokine secretion [3-5], infiltrative bone marrow
disease of infectious or neoplastic origin, nutritional deficiencies,
and drug effects all impact on hematopoiesis.

Peripheral Cytopenias

The presence of isolated or trilineage cytopenias is frequently
noted in patients infected with HIV. Anemia, granulocytopenia,
and thrombocytopenia occur in 17%, 8%, and 13%, respectively,
of asymptomatic HIV-infected individuals [6], and these percentages
increase with advancing HIV disease.


Anemia is the most common hematologic abnormality noted in patients
with HIV infection [7] (see Table 1). It may develop in patients
with persistent lymphadenopathy who are otherwise asymptomatic
but is more prevalent in patients with overt AIDS, occurring in
66% to 85% of those with advanced disease [5,6].

The anemia appears to be due to ineffective erythropoiesis, possibly
as a direct consequence of HIV infection of erythroid precursors
or, more likely, as a result of the inappropriate release of tumor
necrosis factor (TNF), an inhibitor of erythroid maturation in
vitro [7-9]. The anemia is typically classified as an anemia of
chronic disease, characterized by a low reticulocyte count, elevated
ferritin level, but adequate iron stores noted on bone marrow
biopsy. Review of the peripheral blood smear generally reveals
normocytic, normochromic red blood cells (RBCs).

Common Causes--Infiltrative disease of the bone marrow
caused by Mycobacterium avium complex commonly causes isolated
anemia in patients with advanced HIV disease [10]. The most profound
anemias, with hematocrit concentrations in the 15% to 20% range,
occur in patients with mycobacterial disease. Other infiltrative
processes of the bone marrow, such as fungal infections and lymphoma,
may also cause profound anemia but are usually associated with
decrements in the other cell lines. Anemia associated with constitutional
symptoms, such as fever, night sweats, and weight loss, should
be evaluated with a bone marrow biopsy to rule out an infiltrative
bone marrow condition.

Persistent infection with B19 parvovirus has been associated with
intractable anemia in immunosuppressed patients [11,12]. Classically
associated with transient aplastic crises in patients with underlying
hemolytic diseases or erythroblastosis fetalis, parvovirus selectively
infects actively replicating erythroid precursors, resulting in
RBC lysis and erythroid hypoplasia. Clearance of this infection
is mediated by an intact humoral response; thus, immunocompromised
patients may fail to clear the infection [13,14] or maintain an
adequate IgG antibody response [15].

Diagnosis of B19 parvovirus infection is made by serologic studies
or bone marrow examination. The presence of giant, abnormal pronormoblasts
is typical of parvovirus infection, (Figure 1) and in situ hybridization,
using sequence-specific DNA probes for B19 parvovirus, confirms
the diagnosis.

Therapy for this disorder includes a course of intravenous or
intramuscular immunoglobulin, packed RBC transfusions (if indicated),
and folate therapy.

Less common causes of anemia include antibody-mediated
hemolysis and nutritional deficiencies. The presence of RBC autoantibodies
is common in patients at all stages of HIV infection. However,
these autoantibodies rarely are associated with clinically significant
hemolysis [16,17].

Nutritional deficiencies described in patients with HIV infection
include disorders of iron metabolism or iron deficiency and occult
vitamin B12 deficiency. Folate deficiency does not appear to be
more prevalent in this patient population. Iron deficiency with
a microcytic, hypochromic anemia may result from chronic blood
loss secondary to Kaposi's sarcoma or lymphomatous involvement
of the gastrointestinal tract. Thrombocytopenia may lead to chronic
blood loss, resulting in iron deficiency.

Vitamin B12 deficiency secondary to gastrointestinal malabsorption
has been described increasingly in patients with AIDS. Low serum
vitamin B12 levels associated with altered cobalamin transport
proteins or abnormal absorption of vitamin B12 secondary to chronic
diarrhea have been observed [5,18-20]. Occult vitamin B12 deficiency
may worsen the anemia associated with zidovudine(Retrovir) [21].
Therefore, it is prudent to monitor vitamin B12 levels periodically
in patients with chronic gastrointestinal dysfunction, especially
those receiving zidovudine therapy.


Infection with HIV affects the lymphocyte, neutrophil, and macrophage-monocyte
cell lines. Despite the hypergammaglobulinemia noted in patients
with HIV disease, they exhibit both defective cellular immunity
and dysregulated humoral immunity. The hallmark of HIV infection
is the progressive depletion of CD4+ lymphocytes [22]. This decrement
presumably occurs through direct viral invasion of these cells.
Early in HIV infection, one may see an initial increase in the
CD8+ population before a decline in the number of CD4+ cells is

Infection of macrophages and monocytes and the triggering of an
autoimmune response are two other mechanisms by which lymphocyte
depletion may occur [8]. Normally, activated T-lymphocytes and
monocytes produce cytokines or growth factors necessary for stem-cell
growth and differentiation. Decreased production of these cytokines
may result from HIV invasion of these cells.

As with anemia, neutropenia is a frequent complication of HIV
infection, but it is generally caused by the use of antiretroviral
drugs or drugs used to treat opportunistic infections (see "Hematologic Consequences of HIV Therapy"below).
Neutropenia is noted in 8% of asymptomatic individuals [6] and
increases in frequency with advancing disease and therapeutic

The most common cause of neutropenia not due to drug therapy appears
to be ineffective granulopoiesis [23]. Antineutrophil antibodies
have been implicated in certain circumstances [4,5,24,25], but
their prevalence and clinical significance are not well understood.
Defects in qualitative functions, such as defective polymorphonuclear
leukocyte chemotaxis, deficient degranulating responses, inhibition
of leukocyte migration, and ineffective killing have all been
reported [26,27], but their clinical importance remains elusive.
Similarly, HIV-infected monocytes exhibit marked reductions in
chemotaxis and phagocytosis in in vitro studies [22].


The most common platelet abnormality found in HIV-infected patients
is thrombocytopenia, perhaps due to platelet-associated immunoglobulin
[28]. Other causes of HIV-related thrombocytopenia include circulating
immune complexes that precipitate on the platelet surface [28],
cross-reactive antibodies to platelet surface glycoproteins [29],
and direct retroviral infection of megakaryocytes [30-32].

Most patients with HIV-related immune thrombocytopenia have only
minor submucosal bleeding, characterized by petechiae, ecchymoses,
and occasional epistaxis. Rare patients have gastrointestinal
blood loss. Unlike non-HIV-related immune thrombocytopenia, mild
splenomegaly may occur, especially in patients with generalized
lymphadenopathy. Laboratory findings reveal isolated thrombocytopenia,
generally without concomitant anemia or leukopenia. Examination
of the peripheral blood smear and bone marrow biopsy are nonspecific,
except for decreased circulating platelet forms and increased
numbers of megakaryocytes seen in the bone marrow.

Drug-induced thrombocytopenia should be ruled out in these patients,
as in non-HIV-infected patients presenting with isolated thrombocytopenia.
Medications that have thrombocytopenia as a side effect should
be discontinued.

Immediate Restoration of Platelet Count--For autoimmune-mediated
thrombocytopenia, steroid and immunoglobulin therapy can be initiated
for patients needing immediate restoration of the platelet count.
This may include patients who are experiencing bleeding, those
who will be undergoing a splenectomy procedure, or those in whom
the platelet count is dangerously low and the treating physician
wishes to raise the count immediately. The response of patients
with HIV-related immune thrombocytopenia to steroid therapy is
variable, and the risk of further immune suppression is real.
Often, the platelet count falls as the steroid dose is tapered.

Splenectomy has been a successful therapeutic intervention for
patients who fail to respond to steroid therapy and generally
is not associated with greater morbidity or mortality than in
patients with non-HIV-associated immune thrombocytopenia [33,34].

As mentioned, intravenous gammaglobulin (400 mg/kg/d for 4 to
5 days) may be used to raise the platelet count rapidly, although
its effects are transient, lasting 2 to 3 weeks [35]. The probable
mechanism of its effect is blockade of the reticuloendothelial
system. The high cost and transient nature of immunoglobulin therapy
limit its use to situations in which acute bleeding is occurring
or as a preoperative intervention for patients undergoing splenectomy
when rapid elevation of the platelet count is necessary.

Although platelet transfusions generally are not indicated in
patients with thrombocytopenia of immune origin, treatment with
intravenous gammaglobulin before transfusion in emergency situations
may improve platelet elevation.

Nonimmediate Restoration of Platelet Count--For patients
who do not require an immediate increase in platelet count, the
institution of antiretroviral therapy, if the patient is not yet
on such therapy, may be warranted. Normalization and partial responses
of platelet counts have been noted with the institution of zidovudine
therapy [36,37].

Interferon-alfa (Intron A, Roferon-A) also has been shown to be
efficacious in treating patients with HIV-associated immune thrombocytopenia
in several small studies, although it may be more beneficial in
patients with less advanced HIV disease [38-40]. Partial responses
appear to be more common than complete normalization of platelet
counts, and the drug is relatively well-tolerated at doses of
3 million units given subcutaneously three times a week.

Intravenous or intramuscular administration of anti-D immunoglobulin
has been shown to benefit some Rh-positive patients who, preferably,
have not had a splenectomy [41-43]. The presumed mechanism is
Fc-receptor blockade by antibody-coated RBCs substituting for
the antibody-coated platelets. Clinically significant hemolysis
does not appear to complicate this approach [43].

The nonandrogenizing testosterone danazol (Danocrine), initially
thought to effectively reverse HIV-related thrombocytopenia, has
not proved to be efficacious in large-scale clinical trials. Less
widely accepted interventions include vincristine and plasmapheresis.

Observation--In the spectrum of HIV-infected individuals,
patients with isolated thrombocytopenia associated with HIV infection
are generally the most healthy. Clinical bleeding is minimal in
these patients, responses to therapeutic interventions are variable,
and spontaneous remissions do occur. Thus, a viable alternative
is to simply observe the patient closely and institute no therapies
directed at correcting the thrombocytopenia until necessary.


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