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442 Part IV Disorders of Hematopoietic Cell Development

Perhaps the best studied virally induced thrombocytopenia is that of amegakaryocytic thrombocytopenia. Folate deficiency is frequently
associated with HIV infection. Mild to moderate reduction in platelet associated with ethanol abuse, and the etiology of the thrombocyto-
counts is quite common in patients with this disease. In a large study penia in patients who abuse ethanol is often complex.
of HIV-positive patients with hemophilia, the cumulative frequency Patients with iron deficiency typically exhibit thrombocytosis, but
of thrombocytopenia 6 years after seroconversion was 16% for chil- rare patients may become thrombocytopenic. The extremely rapid
dren and 18% for adults. At 10 years, the frequency increased to 27% increase in platelet counts after initiation of iron therapy suggested
in children and 43% in adults. In another study, the frequency of an essential role for iron in a late stage of thrombopoiesis. Curiously,
thrombocytopenia was 16% among 103 homosexual men and 37% thrombocytopenia has been caused by iron therapy in a patient with
among 182 IV drug users with a new diagnosis of HIV infection. severe iron deficiency.
Thrombocytopenia was also reported to be relatively common in
HIV-negative homosexual men (3%) and IV drug users (9%). It was
speculated that this might be caused by the high rates of hepatitis in MARROW INFILTRATION
these patient groups. Except for patients who acquire HIV in the
background of hemophilia, bleeding secondary to thrombocytopenia It is not rare for marrow infiltrative diseases of any type to cause
is unusual, because the counts are rarely less than 50,000/µL. The ineffective hematopoiesis. Blood cell production disorders are com-
principal cause of thrombocytopenia appears to vary with the stage monly observed when the marrow is involved with metastatic cancer,
of disease. lymphoma, or leukemia. Table 32.3 categorizes the infiltrative pro-
Examination of a bone marrow aspirate and biopsy specimens may cesses associated with thrombocytopenia. Physical replacement of
be required to assess whether infiltration by granulomatous infection marrow is the cause of the thrombocytopenia in many cases; it is also
or a malignancy is contributing to, or causing, the thrombocytopenia possible that inhibitory factors produced by the infiltrating cells are
in an HIV patient. Assuming no other obvious cause of the throm- toxic to the cells of the megakaryocytic lineage or interfere with
bocytopenia, and the presence of typical megakaryocytic morphologic normal regulatory mechanisms. The diagnosis of infiltrative disease
abnormalities, antiretroviral therapy is the principal treatment. For is made by marrow examination, although diagnostic clues are usually
patients with severe and/or symptomatic thrombocytopenia, immune provided by history, physical examination, and a leukoerythroblastic
thrombocytopenia purpura (ITP) regimens, including splenectomy, blood smear. The marrow shows decreased megakaryocytes, which
may well be effective. may be larger than normal because of a compensatory physiologic
response to the thrombocytopenia.
CHEMOTHERAPY AND IRRADIATION
ETHANOL-RELATED DISORDERS
Chemotherapy and irradiation reliably damage bone marrow in a
dose-dependent fashion. Megakaryocytes and their progenitors seem Ethanol abuse is very commonly associated with thrombocytopenia,
to be particularly sensitive to the effects of these agents. As a result, which may result from several different mechanisms. These include,
thrombocytopenia is one of the most frequent adverse effects of total most commonly, increased splenic pooling as a result of portal
body irradiation and chemotherapy. Allogeneic or autologous marrow hypertension and ineffective production related to folate deficiency
transplantation is often complicated by prolonged thrombocytopenia, (which may lead to severe thrombocytopenia). Ethanol itself can be
which may persist long after restoration of neutrophil and RBC directly toxic to the marrow. In vitro studies have shown that alcohol
counts. Various strategies to ameliorate this problem have been tried, concentrations achievable in vivo inhibit megakaryocyte maturation
including the use of peripheral blood “stem cells,” which may lead but do not inhibit CFU-Mk. Megakaryocyte numbers usually are
to a faster rate of platelet recovery when compared with marrow normal, but markedly decreased megakaryocytes have been observed.
transplantation. More recently, attempts have been made to expand Rarely, marrow panhypoplasia has been observed in association with
megakaryocyte progenitor cells, with cMpl agonists including Nplate alcohol ingestion. Anemia and macrocytosis accompanied by mega-
and Promacta. loblastic changes and ringed sideroblasts in the erythroid marrow are
Alkylating agents in general produce more prolonged thrombocy- typically observed in the marrows of patients who abuse ethanol.
topenia than antimetabolites. It has been claimed that some alkylating
agents spare megakaryocytes (e.g., cyclophosphamide), but this is a
relative phenomenon. Agents such as busulfan, the nitrosoureas, or OTHER DRUG-RELATED DISORDERS
platinum may cause cumulative damage of the more primitive pro-
genitor cells. Other chemotherapeutic agents, such as the vinca A variety of drugs and toxins have been implicated in the etiology of
alkaloids, may not decrease the platelet count significantly. isolated platelet production defects. Estrogen, for example, has been
Various potential mechanisms for the relative sparing of platelet reported to decrease platelet counts through an unknown mechanism.
production by certain chemotherapeutic regimens have been investi- Thrombocytopenia arising from thiazide diuretics has been reported
gated. For patients who suffer from severe or prolonged thrombocy- frequently. Although the cause of the thrombocytopenia in most cases
topenia, reducing the intensity of the chemotherapy is the most is probably increased clearance, decreased marrow megakaryocyte
appropriate approach to management. It had been anticipated that numbers have been noted. Interferon and IL-2 may induce throm-
the use of recombinant thrombopoietin or Promacta might signifi- bocytopenia. The most likely explanation is inhibition of CFU-Mk.
cantly ameliorate this problem. Anagrelide is a very useful drug for lowering platelet counts in
At the present time, in addition to cMpl-agonists Nplate and patients with myeloproliferative neoplasms and appears to work
Promacta supportive therapy with platelet transfusions and drugs by reducing megakaryocyte size and ploidy and by disrupting
such as ε-aminocaproic acid for patients who have become refractory maturation
to platelet transfusions remain the mainstays of therapy.

Paroxysmal Nocturnal Hemoglobinuria
NUTRITIONAL DEFICIENCIES
PNH is a clonal disorder resulting from mutations in the X-linked
Thrombocytopenia of various degrees can be observed in patients with gene PIGA that encodes for an enzyme required in the initial step of
either folate or vitamin B 12 deficiency. The mechanism of thrombocy- biosynthesis of glycosylphosphatidylinositol anchors (PNH is dis-
topenia is ineffective platelet production. Megakaryocyte numbers are cussed in Chapter 31). Approximately 25% of patients with PNH
normal or increased in the marrow, and platelet survival is normal or have significant marrow aplasia. Thrombocytopenia at diagnosis is a
slightly shortened. Vitamin B 12 deficiency was reported to cause a case poor prognostic indicator. Because platelet survival is usually normal