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MEDICATION-INDUCED
BLOOD DYSCRASIAS
Etiology And Disease Types
Jassin M. Jouria, MD
Dr. Jassin M. Jouria is a medical doctor, professor
of academic medicine, and medical author. He
graduated from Ross University School of
Medicine and has completed his clinical clerkship
training in various teaching hospitals throughout
New York, including King’s County Hospital
Center and Brookdale Medical Center, among others. Dr. Jouria has passed all
USMLE medical board exams, and has served as a test prep tutor and instructor for
Kaplan. He has developed several medical courses and curricula for a variety of
educational institutions. Dr. Jouria has also served on multiple levels in the academic
field including faculty member and Department Chair. Dr. Jouria continues to serves
as a Subject Matter Expert for several continuing education organizations covering
multiple basic medical sciences. He has also developed several continuing medical
education courses covering various topics in clinical medicine. Recently, Dr. Jouria
has been contracted by the University of Miami/Jackson Memorial Hospital’s
Department of Surgery to develop an e-module training series for trauma patient
management. Dr. Jouria is currently authoring an academic textbook on Human
Anatomy & Physiology.
Abstract
Although drug-induced hematologic disorders are less common than other
types of adverse reactions, they are associated with significant morbidity
and mortality. Some agents, such as hemolytics, cause predictable
hematologic disease, but others induce idiosyncratic reactions not directly
related to the drug’s pharmacology. The most important part of managing
hematologic disorders is the prompt recognition that a problem exists. The
main mechanisms to manage hematologic disorders include vigilance to
observe signs and symptoms indicating a blood disorder and patient
education of the warning symptoms to alert them of the need to report a
condition to their primary care provider or an emergency health team.
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Continuing Nursing Education Course Director & Planners
William A. Cook, PhD, Director, Douglas Lawrence, MA, Webmaster,
Susan DePasquale, MSN, FPMHNP-BC, Lead Nurse Planner
Policy Statement
This activity has been planned and implemented in accordance with the
policies of NurseCe4Less.com and the continuing nursing education
requirements of the American Nurses Credentialing Center's Commission on
Accreditation for registered nurses. It is the policy of NurseCe4Less.com to
ensure objectivity, transparency, and best practice in clinical education for
all continuing nursing education (CNE) activities.
Continuing Education Credit Designation
This educational activity is credited for 4 hours. Nurses may only claim credit
commensurate with the credit awarded for completion of this course activity.
Pharmacology content is 0.5 hours (30 minutes).
Statement of Learning Need
Clinicians need to know how to manage the risk of hematologic disorders
induced by medication. Understanding the risk, recognizing the signs and
symptoms that may indicate a blood disorder, and being skilled in how to
educate the patient are essential knowledge needs of clinicians to ensure
patients, caregivers and health teams are able to recognize the warning
symptoms of hematologic disorders.
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Course Purpose
To provide nurses and health team associates with knowledge about
medication-induced dyscrasias to better recognize, treat, and educate
patients, caregivers and all health team members on acute and long-term
management.
Target Audience
Advanced Practice Registered Nurses and Registered Nurses
(Interdisciplinary Health Team Members, including Vocational Nurses and
Medical Assistants may obtain a Certificate of Completion)
Course Author & Director Disclosures
Jassin M. Jouria, MD, William S. Cook, PhD, Douglas Lawrence, MA
Susan DePasquale, MSN, FPMHNP-BC – all have no disclosures
Acknowledgement of Commercial Support
There is no commercial support for this course.
Activity Review Information
Reviewed by Susan DePasquale, MSN, FPMHNP-BC
Release Date: 5/19/2016
Termination Date: 5/19/2019
Please take time to complete a self-assessment of knowledge, on
page 4, sample questions before reading the article.
Opportunity to complete a self-assessment of knowledge learned will
be provided at the end of the course.
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1. __________ is a lowered threshold to the normal
pharmacological action of a drug.
a.
b.
c.
d.
Dyscrasia
Intolerance
Hypersensitivity
Idiosyncrasy
2. True or False: Idiosyncrasy differs from intolerance in that it is
not an exaggeration of the normal response; it is an abnormal
response per se.
a. True
b. False
3. The development of corneal opacities and retinal damage in
patients treated with chloroquine as an antimalarial or for
arthritis and amebiasis is an example of a drug
a.
b.
c.
d.
side effect.
intolerance.
hypersensitivity.
overdosage.
4. The principal ions necessary for normal cell function include
calcium, sodium, potassium, __________, magnesium, and
hydrogen.
a.
b.
c.
d.
albumin
bilirubin
chloride
heme
5. The main protein constituent of plasma is ________, which is
the most important component in maintaining osmotic
pressure.
a.
b.
c.
d.
intrinsic factor (IF)
bilirubin
heme
albumin
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Introduction
Hematologic disorders have long been a potential risk of modern
pharmacotherapy. Although drug-induced hematologic disorders are less
common than other types of adverse reactions, they are associated with
significant morbidity and mortality. Some agents, such as hemolytics, cause
predictable hematologic disease, but others induce idiosyncratic reactions
not directly related to the drug’s pharmacology. The most important part of
management of a hematologic disorder is the prompt recognition when a
problem exists. This is done by two mechanisms: firstly, vigilance for signs
and symptoms that may indicate a blood disorder; and, secondly, patient
education about the warning symptoms that should alert them to the need
to urgently contact their medical provider or emergency services if a prompt
medical appointment is not possible. This two-part course series discusses
the link between modern pharmacotherapy and hematologic disorders and
the identification and management of this risk.
Medication-Induced Hematologic Disease: An Overview
Some agents cause predictable hematologic diseases, such as antineoplastic
medication, but others induce idiosyncratic reactions not directly related to
the drug’s pharmacology. The most common drug-induced hematologic
disorders include aplastic anemia, agranulocytosis, megaloblastic anemia,
hemolytic anemia, and thrombocytopenia.
The incidence of idiosyncratic drug-induced hematologic disorders varies
depending on the condition and the associated drug. Few epidemiologic
studies have evaluated the actual incidence of these adverse reactions, but
these reactions appear to be rare. Women are generally more susceptible
than men to the hematologic effects of drugs. The incidence varies based on
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geography, which suggests that genetic differences may be important
determinants of susceptibility.
Drug-induced thrombocytopenia is the most common drug-induced
hematologic disorder. Some reports of heparin-induced thrombocytopenia
suggest as many as 5% of patients who receive heparin develop
thrombocytopenia. The Berlin Case-Control Surveillance Study was
conducted from 2000 to 2009 to assess the incidence and risks of druginduced hematologic disorders. This evaluation found that almost 30% of all
cases of blood dyscrasias were possibly attributable to drug therapy.
Although drug-induced hematologic disorders are less common than other
types of adverse reactions, they are associated with significant morbidity
and mortality. An epidemiologic study conducted in the United States
estimated that 4,490 deaths were attributable to blood dyscrasias from all
causes. Aplastic anemia was the leading cause of death followed by
thrombocytopenia, agranulocytosis, and hemolytic anemia. Similar to most
other adverse drug reactions, drug-induced hematologic disorders are more
common in elderly adults than in the young; and, the risk of death also
appears to be greater with increasing age.
Because of the seriousness of drug-induced hematologic disorders, it is
necessary to track the development of these disorders to predict their
occurrence and to estimate their incidence. Reporting during postmarketing
surveillance of a drug is the most common method of establishing the
incidence of adverse drug reactions. The MedWatch program supported by
the Food and Drug Administration (FDA) is one such program. Many facilities
have similar drug-reporting programs to follow adverse drug reaction trends
and to determine whether an association between a drug and an adverse
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drug reaction is causal or coincidental. In the case of drug-induced
hematologic disorders, these programs can enable practitioners to confirm
that an adverse event is indeed the result of drug therapy rather than one of
many other potential causes; general guidelines are readily available.1
Adverse Drug Effect1,2
Blood dyscrasias are a rare, yet extremely serious, adverse effect of drug
treatment. Outside of the more predictable bone marrow depression seen
with cytotoxic and immunosuppressant agents, drugs in more common use
have also been associated with blood disorders. Drug-induced blood
disorders have also been the reason for withdrawal for a number of drugs,
notably remoxipride in 1994. Although anecdotal reports of drug-induced
blood disorders are common in the literature, they often have speculative
mechanisms and questionable causality. The true incidence of drug-induced
dyscrasias is therefore difficult to ascertain, but it is clear that they make a
major contribution to the incidence of blood disorders.
In practice, drug-induced reactions can be difficult to avoid, but knowledge
of the propensity of drugs to initiate such reactions does allow prescribers to
be both vigilant for early signs of blood disorders and inform patients about
signs and symptoms. Early recognition is crucial in mitigating the effects of
these serious and sometimes fatal adverse effects. Dyscrasia, a word of
Greek origin, means unwanted mixture and, as used herein, connotes a
disorder of the blood caused by an undesirable effect of a drug. The
undesirable effects of drugs may be divided into six categories: overdosage,
intolerance, side effects, secondary effects, idiosyncrasy and
hypersensitivity.
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Overdosage with any drug may produce serious ill effects which are usually
predictable from animal experiments and which occur in direct relation to the
total amount of drug administered; it may be absolute, the result of
ignorance or error, or it may be relative. Impairment of excretion or
destruction in the presence of disease of the kidney or liver may render a
normal dose toxic though accumulation of the drug. Examples are the
dangerous effect of a normal dose of morphine in the presence of hepatic
damage, and the potentiation of digitalis action when an increase in the
blood level of potassium co-exists.
Intolerance is a lowered threshold to the normal pharmacological action of a
drug, and until recently was explained in terms of biological variation. Now,
however, a more satisfactory explanation may be available on a biochemical
basis. Side effects are therapeutically undesirable but inevitable effects of
drug action. Examples are numerous, such as the masculinizing effect of
androgen used for carcinoma of the breast, the osteoporosis and edema
following the administration of cortisone to patients with rheumatoid
arthritis, and the acoustic nerve damage due to streptomycin. Examples of
unexpected and unpredictable side effects are the congenital deformities
following the use of thalidomide in pregnancy, and the development of
corneal opacities and retinal damage in patients treated with chloroquine as
an antimalarial or for arthritis and amebiasis.
Secondary effects are the indirect consequences of primary drug action.
They have become common since the introduction of antibiotics and include
the development of avitaminosis due to interference with the normal flora of
the gut, as well as super-infection by other organisms.
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Idiosyncrasy differs from intolerance in that it is not an exaggeration of the
normal response; it is an abnormal response per se. It differs from
hypersensitivity in that it does not depend on previous contact with the
drug; it occurs when the drug is first administered. The clinical anaphylactoid
reaction fits into this category of an inherent qualitatively abnormal response
to a drug; this is exemplified by the sudden collapse and syncope that may
follow the application of cocaine to the conjunctiva for the removal of a
cinder.
Hypersensitivity is an antigen-antibody phenomenon in which the antibodies
produced by previous contact with the foreign substance - chemical or
biological, humoral or bound to fixed tissue - cause a reaction, which may be
immediate or delayed. This mechanism is held by many to be involved in
most of the common drug reactions, although an antigen-antibody reaction
cannot often be demonstrated. Hypersensitivity reactions, it must be
emphasized, occur in only a very small percentage of patients exposed to
drugs. It is possible that idiosyncrasy may predispose certain individuals to
such reactions; it is well known that those with an allergy are more likely to
become candidates for other hypersensitizations than patients without a
history of allergy.
Drug Effects on Bone Marrow2
The bone marrow performs the task of providing the body with a balanced
supply of all circulating blood cells throughout life. Variability in demand for
differing types of blood cells is provided by the self-renewing pluripotential
stem cells, from which the fully mature cell lines such as erythrocytes,
granulocytes, platelets, macrophages and lymphocytes arise. Drugs can
have differing effects on the various cell types, at differing stages in cell
development.
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Failure of stem cells leading to peripheral blood cytopenia is termed
hypoplasia or aplasia. This can take two forms: aplastic anemia, due to
damage sustained by the pluripotential stem cells, or single-cell
pancytopenia, where damage is due to a specific committed cell line. Such
diversity of effects leads to a wide spectrum of potential blood disorders
depending on where and at what point in the production of the cell line the
drug acts upon. The risk for individuals can also vary. The decline in the size
of the hemopoietic bone marrow with age increases susceptibility. Certain
blood disorders can be more linked to the sex of the individual, or to a
genetic propensity to suffer the reaction.
Blood Composition and Signs of Disease3,4
Blood is composed of a liquid called plasma and of cellular elements,
including leukocytes, platelets, and erythrocytes. The normal adult has about
6 liters of this vital fluid, which composes from 7% to 8% of the total body
weight. Plasma makes up about 55% of the blood volume; about 45% of the
volume is composed of erythrocytes, and 1% of the volume is composed of
leukocytes and platelets. Variations in the quantity of these blood elements
are often the first sign of disease occurring in body tissue. Changes in
diseased tissue may be detected by laboratory tests that measure deviations
from normal in blood constituents; hematology is primarily the study of the
formed cellular blood elements.
The principal component of plasma is water, which contains dissolved ions,
proteins, carbohydrates, fats, hormones, vitamins, and enzymes. The
principal ions necessary for normal cell function include calcium, sodium,
potassium, chloride, magnesium, and hydrogen. The main protein
constituent of plasma is albumin, which is the most important component in
maintaining osmotic pressure. Albumin also acts as a carrier molecule,
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transporting compounds such as bilirubin and heme. Other blood proteins
carry vitamins, minerals, and lipids. Immunoglobulins, synthesized by
lymphocytes, and complement are specialized blood proteins involved in
immune defense. The coagulation proteins responsible for hemostasis (arrest
of bleeding) circulate in the blood as inactive enzymes until they are needed
for the coagulation process. An upset in the balance of these dissolved
plasma constituents can indicate a disease in other body tissues.
Blood plasma also acts as a transport medium for cell nutrients and
metabolites; for example, the blood transports hormones manufactured in
one tissue to target tissue in other parts of the body. Albumin transports
bilirubin, the main catabolic residue of hemoglobin, from the spleen to the
liver for excretion. Blood urea nitrogen, a nitrogenous waste product, is
carried to the kidneys for filtration and excretion. Increased concentration of
these normal catabolites can indicate either increased cellular metabolism or
a defect in the organ responsible for their excretion. For example, in liver
disease, the bilirubin level in blood increases because the liver is unable to
function normally and clear the bilirubin. In hemolytic anemia, however, the
bilirubin concentration can rise because of the increased metabolism of
hemoglobin that exceeds the ability of a normal liver to clear bilirubin.
When body cells die, they release their cellular constituents into surrounding
tissue. Eventually, some of these constituents reach the blood. Many
constituents of body cells are specific for the cell’s particular function; thus,
increased concentration of these constituents in the blood, especially
enzymes, can indicate abnormal cell destruction in a specific organ. Blood
cells are produced and develop in the bone marrow. This process is known
as hematopoiesis. Undifferentiated hematopoietic stem cells (precursor cells)
proliferate and differentiate under the influence of proteins that affect their
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function (cytokines). When the cell reaches maturity, it is released into the
peripheral blood.
Each of the three cellular constituents of blood has specific functions.
Erythrocytes contain the vital protein hemoglobin, which is responsible for
transport of oxygen and carbon dioxide between the lungs and body tissues.
The five major types of leukocytes are neutrophils, eosinophils, basophils,
lymphocytes, and monocytes. Each type of leukocyte has a role in defending
the body against foreign pathogens such as bacteria and viruses. Platelets
are necessary for maintaining hemostasis. Blood cells circulate through
blood vessels, which are distributed throughout every body tissue.
Erythrocytes and platelets generally carry out their functions without leaving
the vessels, but leukocytes diapedese (pass through intact vessel walls) to
tissues where they defend against invading foreign pathogens.
Hematopoietic System
The adult hematopoietic system includes tissues and organs involved in the
proliferation, maturation, and destruction of blood cells. These organs and
tissues include the bone marrow, thymus, spleen, and lymph nodes. Bone
marrow is the site of myeloid, erythroid, and megakaryocyte as well as early
stages of lymphoid cell development. Thymus, spleen, and lymph nodes are
primarily sites of later lymphoid cell development. Tissues in which lymphoid
cell development occurs are divided into primary and secondary lymphoid
tissue. The hematopoietic system is reviewed in this section with a summary
of normal organ/gland and cell function and emphasis on how medication
can adversely impact normal blood cell function as well as the treatment
required when hematological disease states arise.5
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Primary lymphoid tissues (bone marrow and thymus) are those in which T
and B cells develop from nonfunctional precursors into cells capable of
responding to foreign antigens (immunocompetent cells). Secondary
lymphoid tissues (spleen and lymph nodes) are those in which
immunocompetent T and B cells further divide and differentiate into effector
cells and memory cells in response to antigens.
Bone Marrow
Blood-forming tissue located between the trabeculae of spongy bone is
known as bone marrow. (Trabecula refers to a projection of bone extending
from cortical bone into the marrow space; it provides support for marrow
cells). This major hematopoietic organ is a cellular, highly vascularized,
loose connective tissue. It is composed of two major compartments: the
vascular and the endosteal. The vascular compartment is composed of the
bone marrow arteries and veins, stromal cells, and hematopoietic cells. The
endosteal compartment is primarily the site of bone remodeling but also
contains hematopoietic stem cell (HSC).
Vasculature Supply of Bone Marrow
The vascular supply of bone marrow is served by two arterial sources, a
nutrient artery and a periosteal artery, that enter the bone through small
holes, the bone foramina. Blood is drained from the marrow via the central
vein. The nutrient artery branches around the central sinus that spans the
marrow cavity.
Arterioles radiate outward from the nutrient artery to the endosteum (the
inner lining of the cortical bone), giving rise to capillaries that merge with
capillaries from periosteal arteries to form sinuses within the marrow. The
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sinuses, lined by single endothelial cells and supported on the abluminal side
(away from the luminal surface) by adventitial reticular cells, ultimately
gather into wider collecting sinuses, which open into the central longitudinal
vein. The central longitudinal vein continues through the length of the
marrow and exits through the foramen where the nutrient artery entered.
Nerve fibers surrounding marrow arteries regulate blood flow into the bone
marrow, which in turn controls hematopoietic progenitor release into the
circulation.
The major arterial supply to the marrow is from periosteal capillaries and
capillary branches of the nutrient artery that have traversed the bony
enclosure of the marrow through the bone foramina. The capillaries join with
the venous sinuses as they re-enter the marrow. The sinuses gather into
wider collecting sinuses that then open into the central longitudinal vein
(central sinus).
Bone Marrow Stroma
The bone marrow stroma (supporting tissue in the vascular compartment)
provides a favorable microenvironment for sustained proliferation of
hematopoietic cells, forming a meshwork that creates a three-dimensional
scaffolding for them. Stromal cellular components also provide cytokines
that regulate hematopoiesis. The stroma is composed of three major cell
types: macrophages, reticular cells (fibroblasts), and adipocytes (fat cells).
Macrophages serve two major functions in the bone marrow: phagocytosis
and secretion of hematopoietic cytokines (proteins secreted by a cell, which
modulate the function of another cell). Macrophages phagocytose the
extruded nuclei of maturing erythrocytes, B cells that have not differentiated
properly, and differentiating cells that die during development. Some
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macrophages serve as the center of the erythroblastic islands, as discussed
in the section below on hematopoietic cells. Macrophages also provide many
colony-stimulating factors (cytokines that stimulate the growth and
development of immature hematopoietic cells) needed for the development
of myeloid lineage cells. Macrophages stain acid phosphatase positive.
Reticular cells are located on the abluminal surface of the vascular sinuses
and send long cytoplasmic processes into the stroma. They are an abundant
source of CXCL12 (SDF-1), which is critical for maintaining an HSC pool in
the marrow. These cells also produce reticular fibers, which contribute to the
three-dimensional supporting network that holds the vascular sinuses and
hematopoietic elements. The fibers can be visualized with light microscopy
and after silver staining. Reticular cells are alkaline phosphatase positive.
Adipocytes are cells whose cytoplasm is largely replaced with a single fat
vacuole. They differentiate from mesenchymal stem cells (MSCs), and their
production is inversely proportional to osteoblast formation. MSCs are
multipotent stromal cells that can differentiate into bone, cartilage, and fat
cells. Adipocytes mechanically control the volume of bone marrow in which
active hematopoiesis takes place. They also provide steroids and other
cytokines that influence hematopoiesis and maintain osseous bone integrity.
The proportion of bone marrow composed of adipocytes changes with age.
For the first 4 years of life, nearly all marrow cavities are composed of
hematopoietic cells, or red marrow. After 4 years of age, adipocytes or
yellow marrow gradually replaces the red marrow in the shafts of long
bones.
By the age of 25 years, hematopoiesis is limited to the marrow of the skull,
ribs, sternum, scapulae, clavicles, vertebrae, pelvis, upper half of the
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sacrum, and proximal ends of the long bones. The distribution of red:yellow
marrow in these bones is about 1:1. The fraction of red marrow in these
areas continues to decrease with aging. Osteoblasts and osteoclasts are
found in the endosteum (internal surface of calcified bone). These cells can
be dislodged during bone marrow biopsy and can be found in the specimen
with hematopoietic cells.
Osteoblasts differentiate from MSCs; and, osteoclasts differentiate from
HSCs. Osteoblasts are involved in the formation of calcified bone and
produce cytokines that can positively or negatively regulate HSC activity.
They are large cells (up to 30 mcM (μm) in diameter) that resemble plasma
cells except that the perinuclear halo (Golgi apparatus) is detached from the
nuclear membrane and, in Wright-stained specimens, appears as a light area
away from the nucleus. In addition, the cytoplasm can be less basophilic,
and the nucleus has a finer chromatin pattern than plasma cells. Osteoblasts
are normally found in groups and are more commonly seen in children and
in metabolic bone diseases. The cells are alkaline phosphatase positive.
Osteoclasts are cells related to macrophages that are involved in resorption
and remodeling of calcified bone. Up to 100 mcM in diameter, they are even
larger than osteoblasts. The cells are multinucleated, form from fusion of
activated monocytes, and have granular cytoplasm that can be either
acidophilic or basophilic. They resemble megakaryocytes except that the
nuclei are usually discrete (whereas the megakaryocyte has a single, large
multilobulated nucleus) and often contain nucleoli.
Hematopoietic Cells
These cells are arranged in distinct niches within the vascular compartment
of the marrow cavity. Erythroblasts constitute 25–30% of the marrow cells
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and are produced near the venous sinuses. They develop in erythroblastic
islands composed of a single macrophage surrounded by erythroblasts in
varying states of maturation. The macrophage cytoplasm extends out to
surround the erythroblasts. During this close association, the macrophages
regulate erythropoiesis by secreting various cytokines.
The least mature cells are closest to the center of the island, and the more
mature cells are at the periphery. The location of leukocyte development
differs depending on the cell type. Granulocytes are produced in nests close
to the trabeculae and arterioles and are relatively distant from the venous
sinuses. These nests are not quite as apparent morphologically as are
erythroblastic islands.
Megakaryocytes are very large, polyploid cells (DNA content more than 2N)
that produce platelets from their cytoplasm. They are located adjacent to the
vascular sinus. Cytoplasmic processes of the megakaryocyte form long
proplatelet processes that pinch off to form platelets. Lymphocytes are
normally produced in lymphoid aggregates located near arterioles. Lymphoid
progenitor cells can leave the bone marrow and travel to the thymus where
they mature into T lymphocytes. Some remain in the bone marrow where
they mature into B lymphocytes. Some B cells return to the bone marrow
after being activated in the spleen or lymph node. Activated B cells
transform into plasma cells, which can reside in the bone marrow and
produce antibody.
Bone marrow stromal location of erythrocyte, granulocyte, platelet, and
lymphocyte differentiation is essential to understand. The bone forms a rigid
compartment for the marrow. Thus, any change in volume of the
hematopoietic tissue, as occurs in many anemias and leukemias, must be
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compensated for by a change in the space-occupying adipocytes. Normal red
marrow can respond to stimuli and increase its activity to several times the
normal rate. As a result, the red marrow becomes hyperplastic and replaces
portions of the fatty marrow.
Bone marrow hyperplasia (an excessive proliferation of normal cells)
accompanies all conditions with increased or ineffective hematopoiesis. The
degree of hyperplasia is related to the severity and duration of the
pathologic state. Acute blood loss can cause erythropoietic tissue to
temporarily replace fatty tissue; severe chronic anemia can cause
erythropoiesis to be so intense that it not only replaces fatty marrow but
also erodes the bone’s internal surface.
In malignant diseases that invade or originate in the bone marrow, such as
leukemia, proliferating abnormal cells can replace both normal hematopoietic
tissue and fat. In contrast, the hematopoietic tissue can become inactive or
hypoplastic (a condition in which the hematopoietic cells in bone marrow
decrease). Fat cells then increase, providing a cushion for the marrow.
Environmental factors such as chemicals and toxins can suppress
hematopoiesis whereas other types of hypoplasia can be genetically
determined. Myeloproliferative disease, which begins as a hypercellular
disease, frequently terminates in a state of aplasia (absence of
hematopoietic tissue in bone marrow) in which fibrous tissue replaces
hematopoietic tissue.
Blood Cell Egress
Special properties of the maturing hematopoietic cell and of the venous
sinus wall are important in migration of blood cells from the bone marrow to
the circulation. These cells must migrate between reticular cells but through
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endothelial cells to reach the circulation. As cell traffic across the sinus
increases, the reticular cells contract, creating a less continuous layer over
the abluminal sinus wall. When the reticular cell layer contracts, it creates
compartments between the reticular cell layer and the endothelial layer
where mature cells accumulate and can interact with sites on the sinus
endothelial surface.
The new blood cell interacts with the abluminal endothelial membrane by a
receptor-mediated process, forcing the abluminal membrane into contact
with the luminal endothelial membrane. The two membranes fuse, and
under pressure from the passing cell, they separate, creating a pore through
which the hematopoietic cell enters the lumen of the sinus. These pores are
only 2–3 mcM in diameter; thus, blood cells must have the ability to deform
so that they can pass through the sinusoidal lining. Progressive increases in
deformability and motility have been noted as granulocytes mature from the
myeloblast to the segmented granulocyte stage, facilitating the movement of
cells into the sinus lumen.
Many soluble factors are important in regulating the release of blood cells
from bone marrow, including granulocyte-colony stimulating factor (G-CSF),
granulocyte monocyte-colony stimulating factor (GM-CSF), and a large
number of chemokines. Some of these molecules are used clinically to
increase circulating granulocytes or release HSCs into the circulation to
obtain granulocytes for transfusion or stem cells for transplantation.
Extramedullary Hematopoiesis
Hematopoiesis in the bone marrow is called medullary hematopoiesis.
Extramedullary hematopoiesis denotes blood cell production in
hematopoietic tissue other than bone marrow. In certain hematologic
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disorders, when hyperplasia of the marrow cannot meet the physiologic
blood needs of the tissues, extramedullary hematopoiesis can occur in the
hematopoietic organs that were active in the fetus, principally the liver and
spleen. Organomegaly frequently accompanies significant hematopoietic
activity at these sites.
Thymus
The thymus is a lymphopoietic organ located in the upper part of the
anterior mediastinum. It is a bilobular organ demarcated into an outer
cortex and central medulla. The cortex is densely packed with small
lymphocytes (thymocytes), cortical epithelial cells, and a few macrophages.
The medulla is less cellular and contains more mature thymocytes mixed
with medullary epithelial cells, dendritic cells, and macrophages.
The primary purpose of the thymus is to serve as a compartment in which T
lymphocytes mature. Precursor T cells leave the bone marrow and enter the
thymus through arterioles in the cortex. As they travel through the cortex
and the medulla, they interact with epithelial cells and dendritic cells, which
provide signals to ensure that T cells can recognize foreign antigen but not
self-antigen. They also undergo rapid proliferation. Only about 3% of the
cells generated in the thymus successfully exit the medulla as mature T
cells; the rest die by apoptosis and are removed by thymic macrophages.
The thymus is responsible for supplying the T-dependent areas of lymph
nodes, spleen, and other peripheral lymphoid tissue with immunocompetent
T lymphocytes. The thymus is a well-developed organ at birth and continues
to increase in size until puberty. After puberty, however, it begins to atrophy
until old age when it becomes barely recognizable. Increased steroid levels
beginning in puberty and decreased growth factor levels in adults may drive
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this atrophy. The atrophy is characterized by reduced expression of a
transcription factor (FOXN1) required for thymic epithelial cell differentiation.
The atrophied thymus is still capable of producing some new T cells if the
peripheral pool becomes depleted as occurs after the lymphoid irradiation
that accompanies bone marrow transplantation.
Spleen
The spleen is located in the upper-left quadrant of the abdomen beneath the
diaphragm and to the left of the stomach. After several emergency
splenectomies were performed without causing permanent harm to the
patients, it was recognized that the spleen was not essential to life.
However, it does play a role in filtering foreign substances and old
erythrocytes from the circulation, storage of platelets, and immune defense.
Architecture of the Spleen
Enclosed by a capsule of connective tissue, the spleen contains the largest
collection of lymphocytes and macrophages in the body. These cells,
together with a reticular meshwork, are organized into three zones: white
pulp, red pulp, and the marginal zone. The white pulp, a visible grayishwhite zone, is composed of lymphocytes and is located around a central
artery. The area closest to the artery, which contains many T cells as well as
macrophages and dendritic cells, is termed the periarteriolar lymphatic
sheath (PALS). Peripheral to this area are B cells arranged into follicles (a
sphere of B cells within lymphatic tissue).
Activated B cells are found in specialized follicular areas called germinal
centers, which appear as lightly stained areas in the center of a lymphoid
follicle. The germinal centers consist of a mixture of B lymphocytes, follicular
dendritic cells, and phagocytic macrophages. The immune response is
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initiated in the white pulp. In some cases of heightened immunologic
activity, the white pulp can increase to occupy half the volume of the spleen
(it is normally ≤20%). The marginal zone, a reticular meshwork containing
blood vessels, macrophages, and specialized B cells, surrounds white pulp.
This zone lies at the junction of the white pulp and red pulp and is important
in initiating rapid immune responses to blood-borne pathogens and
performing functions similar to that of the red pulp. The red pulp contains
sinuses and cords.
The sinuses are dilated vascular spaces for venous blood. The pulp’s red
color is caused by the presence of large numbers of erythrocytes in the
sinuses. The cords are composed of masses of reticular tissue and
macrophages that lie between the sinuses. The cords of the red pulp provide
zones for platelet storage and destruction of damaged blood cells.
Spleen Blood Flow
The spleen is richly supplied with blood. It receives 5% of the total cardiac
output, a blood volume of 300 mL/minute. Blood enters the spleen through
the splenic artery, which branches into many central arteries. Vessel
branches can terminate in the white pulp, red pulp, or marginal zone. Blood
entering the spleen can follow either the rapid transit pathway (closed
circulation) or the slow transit pathway (open circulation). The rapid transit
pathway is a relatively unobstructed route by which blood enters the sinuses
in red pulp from the arteries and passes directly to the venous collecting
system. In contrast, blood entering the slow transit pathway moves
sluggishly through a circuitous route of macrophage-lined cords before it
gains access to the venous sinuses.
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Plasma in the cords freely enters the sinuses, but erythrocytes meet
resistance at the sinus wall where they must squeeze through the tiny
openings. This skimming of the plasma from blood cells sharply increases
the hematocrit in the cords. Sluggish blood-flow and continued erythrocyte
metabolic activity in the cords result in a splenic environment that is
hypoxic, acidic, and hypoglycemic. Hypoxia and hypoglycemia occur as
erythrocytes utilize available oxygen and glucose, and metabolic byproducts
create the acidic environment.
Spleen Function
Blood that empties into the cords of the red pulp or the marginal zone takes
the slow transit pathway, which is very important to splenic function
including culling, pitting, and storing blood cells. The discriminatory filtering
and destruction of senescent (aged) or damaged red cells by the spleen is
termed culling. Cells entering the spleen through the slow transit pathway
become concentrated in the hypoglycemic, hypoxic cords of the red pulp — a
hazardous environment for aged or damaged erythrocytes. Slow passage
through a macrophage-rich route allows the phagocytic cells to remove
these old or damaged, less deformable erythrocytes before or during their
squeeze through the 3 mcM pores to the venous sinuses. Normal
erythrocytes withstand this adverse environment and eventually re-enter the
circulation.
Pitting refers to the spleen’s ability to pluck out particles from intact
erythrocytes without destroying them. Blood cells coated with antibody are
susceptible to pitting by macrophages. The macrophage removes the
antigen–antibody complex and the attached membrane. The pinched-off cell
membrane can reseal itself, but the cell cannot synthesize lipids and proteins
for new membrane due to its lack of cellular organelles. Therefore, extensive
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pitting causes a reduced surface-area-to-volume ratio, resulting in the
formation of spherocytes (erythrocytes that have no area of central pallor on
stained blood smears). The presence of spherocytes on a blood film is
evidence that the erythrocyte has undergone membrane assault in the
spleen.
The white pulp and marginal zones of the spleen are important lines of
defense in blood-borne infections because of their rich supply of lymphocytes
and phagocytic cells (macrophages) and the slow transit circulation through
these areas. Blood-borne antigens are forced into close contact with
macrophages (functioning as antigen-presenting cells) and lymphocytes
allowing for recognition of the antigen as foreign and leading to
phagocytosis, T- and B-cell activation, and antibody formation.
The spleen’s immunologic function is probably less important in the welldeveloped adult immune system than in the still-developing immune system
of the child. Young children who undergo splenectomy may develop
overwhelming, often fatal, infections with encapsulated organisms such as
Streptococcus pneumonia and Hemophilus influenza. This can also be a rare
complication of splenectomy in adults. The loss of the marginal zone can be
especially important in this regard. The red pulp cords of the spleen act as a
reservoir for platelets, sequestering approximately one-third of the
circulating platelet mass.
Massive enlargement of the spleen (splenomegaly) can result in a pooling of
80–90% of the platelets, producing peripheral blood thrombocytopenia.
Removal of the spleen results in a transient thrombocytosis with a return to
normal platelet concentrations in about 10 days.
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Hypersplenism
In a number of conditions, the spleen can become enlarged and, through
exaggeration of its normal activities of filtering and phagocytosing, cause
anemia, leukopenia, thrombocytopenia, or combinations of cytopenias. A
diagnosis of hypersplenism is made when three conditions are met: (1) the
presence of anemia, leukopenia, or thrombocytopenia in the peripheral
blood, (2) the existence of a cellular or hyperplastic bone marrow
corresponding to the peripheral blood cytopenias, and (3) the occurrence of
splenomegaly. The correction of cytopenias following splenectomy confirms
the diagnosis.
Hypersplenism has been categorized into two types: primary and secondary.
Primary hypersplenism is said to occur when no underlying disease can be
identified. The spleen functions abnormally and causes the cytopenia(s). This
type of hypersplenism is very rare. Secondary hypersplenism occurs in those
cases in which an underlying disorder causes the splenic abnormalities.
Secondary hypersplenism has many and varied causes. Hypersplenism can
occur secondary to compensatory (or workload) hypertrophy of this organ.
Inflammatory and infectious diseases are thought to cause splenomegaly by
an increase in the spleen’s immune defense functions. For example, an
increase in clearing particulate matter can lead to an increase in number of
macrophages, and hyperplasia of lymphoid cells can result from prolonged
infection.
Several blood disorders can cause splenomegaly. In these disorders,
intrinsically abnormal blood cells or cells coated with antibody are removed
from circulation in large numbers (i.e., hereditary spherocytosis, immune
thrombocytopenic purpura). Infiltration of the spleen with additional cells or
metabolic by-products can also cause hypersplenism. Such conditions
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include disorders in which the macrophages accumulate large quantities of
undigestible substances; some of these disorders, such as Gaucher’s
disease, will be discussed later. Neoplasms in which the malignant cells
occupy much of the splenic volume can cause splenomegaly. If the tumor
cells incapacitate the spleen, the peripheral blood will show evidence of
hyposplenism (similar to the findings after splenectomy). Congestive
splenomegaly can occur following liver cirrhosis with portal hypertension or
congestive heart failure when blood that does not flow easily through the
liver is rerouted through the spleen.
Splenectomy
Splenectomy can relieve the effects of hypersplenism; however, this
procedure is not always advisable, especially when the spleen is performing
a constructive role such as producing antibody or filtering protozoa or
bacteria. Splenectomy appears to be most beneficial in patients with
hereditary or acquired conditions in which erythrocytes or platelets are
undergoing increased destruction, such as hemolytic disorders or immune
thrombocytopenia. The blood cells are still abnormal after splenectomy, but
the major site of their destruction is removed. Consequently, the cells have
a more normal life span.
Splenectomy results in characteristic erythrocyte abnormalities that
experienced clinical laboratory professionals can note easily on blood
smears. After splenectomy, the erythrocytes often contain inclusions (i.e.,
Howell Jolly bodies, Pappenheimer bodies), and abnormal shapes can be
seen. The lifespan of healthy erythrocytes is not increased after
splenectomy. Other organs, primarily the liver, assume the culling function.
Blood flow through the liver also is slowed by passage through sinusoids,
which are lined with specialized macrophages called Kupffer cells. These
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macrophages can perform functions similar to those of phagocytes in the
splenic cords and marginal zone.
Even when a spleen is present, the liver, because of its larger blood flow, is
responsible for removing most of the particulate matter of the blood. The
liver, however, is not as effective as the spleen in filtering abnormal
erythrocytes, probably because of the relatively rapid flow of blood past
hepatic macrophages.
Acquired hyposplenism is a complication of sickle cell anemia. The spleen’s
acidic, hypoxic, hypoglycemic environment leads to sickling of the
erythrocytes in the spleen. This leads to blockage of the blood vessels and
infarcts of the surrounding tissue. The tissue damage is progressive and
leads to functional splenectomy (also referred to as autosplenectomy).
Common Blood Disorders
This section covers the common medication induced blood disorders that can
impact an individual’s state of health. Blood disorders can involve disease of
a number of body vessels, glands and organs, such the red or white blood
cells and components of the blood, bone marrow, spleen and the lymph
system. General guidance for health professionals to recognize signs and
symptoms of an acute or chronic blood condition is offered here for
appropriate diagnosis and treatment, and to help establish a framework for
prevention and promotion of blood safety and health (discussed in more
depth during the second part of this study series focused on Medication
Induced Blood Discrasias: Diagnosis, Treatment And Prevention).
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Aplastic Anemia
The term aplastic anemia is used to describe the condition of pancytopenia
that is associated with a hypocellular bone marrow. The mature blood cells
that are produced in aplastic anemia (AA) usually appear normal. Aplasia of
the bone marrow is only one of several possible causes of peripheral blood
pancytopenia, but pancytopenia due to causes other than AA can result in
morphologically abnormal blood or bone marrow cells. Whereas AA is usually
characterized by pancytopenia, granulocyte, platelet, and erythrocyte, levels
may not be depressed uniformly.6
Aplastic anemia is a bone marrow failure disorder (or group of disorders)
characterized by cellular depletion and fatty replacement of the bone
marrow. The concomitant decreases in hematopoietic progenitors lead to
diminished production of erythrocytes, leukocytes, and platelets and
development of peripheral blood cytopenias or pancytopenia. The loss of
functional bone marrow may occur following a variety of bone marrow
insults that include drugs, chemicals, irradiation, infections, and immune
dysfunction. Though the inciting mechanisms vary, all lead to the loss of
bone marrow precursor cells or damage of the bone marrow
microenvironment required to sustain bone marrow cell growth and
differentiation. Thus, the hematopoietic progenitor cells that give rise to the
various peripheral blood elements lose their ability to self renew and produce
progeny. This leads to a loss of bone marrow cellular mass and bone marrow
failure.
Clinical criteria that have been used to define aplastic anemia include (1)
marrow of less than 25% normal cellularity and (2) at least two blood
cytopenias defined as neutrophil count less than 500 per microliter or
platelets less than 20,000 per microliter or anemia with corrected
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reticulocyte count of less than 1%.6 With disease progression,
concentrations of cells in all three cell lineages eventually become further
depleted. This reflects an impaired proliferative capacity of the marrow stem
cells, which lose their ability for normal cellular renewal.7
Aplastic anemia can be classified as either acquired or inherited. Historically,
much attention has focused on an association between acquired AA and
environmental exposures. Drugs, chemicals, radiation, infectious agents, and
other factors have been linked to the development of acquired AA, which can
be temporary or persistent. In most cases, no environmental link can be
identified, and the cause is said to be idiopathic. The immune
pathophysiologic model (discussed in the previous section) provides a
unifying basis for understanding the disorder regardless of the presence or
absence of environmental factors. Although acquired AA is more common in
adults, it is also an infrequent cause of aplasia in children.
Drugs Associated with Aplastic Anemia
A wide variety of drugs have been associated with development of aplastic
anemia. These are often the result of a nonpredictable or idiosyncratic
reaction to a drug. As discussed previously, this may be a result of direct
toxicity or development of an abnormal immune reaction whereby antibodies
against a drug cross-react with bone marrow cells. The antibiotic
chloramphenicol and the anti-inflammatory drug phenylbutazone are
probably the best-documented examples of drugs causing aplastic anemia.
The toxicity associated with these drugs is usually not related to the total
dosage of the drug received, and drug-induced antibodies have been
identified in only a few patients. Thus, the association between the drug and
development of aplastic anemia is dependent on epidemiologic data and a
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temporal relationship to drug ingestion and development of bone marrow
failure.
The mechanism of drug-induced bone marrow failure suppression is usually
unknown, and it is impossible to identify which patients will react adversely
to a drug. Luckily, such idiosyncratic reactions to drugs are relatively rare. It
is estimated that 1 person in 20,000 to 30,000 may have an idiosyncratic
reaction to chloramphenicol, which is about 10 times the incidence of
developing aplastic anemia for the general population not taking
chloramphenicol.
Agents Regularly Producing Aplastic Anemia
Agents that regularly produce bone marrow hypoplasia with sufficient doses
are discussed in this section and include:6,8,9

Ionizing radiation

Benzene and benzene derivatives

Chemotherapeutic agents (i.e., busulfan, vincristine)

Drugs that produce bone marrow hypoplasia in an idiosyncratic
manner
Type of Drug
Antimicrobials
Anticonvulsants
Analgesics
Hypoglycemic
Relatively Frequent
Rare
Chloramphenicol Penicillin,
Streptomycin
tetracycline
Amphotericin B Sulfonamides
Methylphenylethylhydantoin
Methylphenylhydantoin
Trimethadione
Diphenylhydantoin Primidone
Phenylbutazone
Aspirin Tapazole
Tolbutamide Chlorpropamide
agents
Insecticides
Chlorophenothane Parathion
Miscellaneous
Colchicine Acetazolamide Hair dyes
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Chloramphenicol has been shown to cause two types of bone marrow
effects. The most common reaction is a reversible bone marrow suppression
that occurs while the patient is receiving the drug and is associated with
vacuolization of bone marrow precursor cells and increased serum iron
levels, reflecting ineffective erythropoiesis. The second reaction seen is
development of an irreversible aplastic anemia that occurs weeks to months
after drug exposure. This more severe reaction is not predictable on the
basis of the dose, duration, or route of administration of the drug. Because
of the strong association with development of aplastic anemia,
chloramphenicol use has decreased. Currently the drug is administered only
for specific indications when no other reasonable alternative exists.
A wide variety of other drugs have been implicated as direct suppressors of
hematopoiesis and are occasionally associated with development of bone
marrow aplasia. The incidence and predictability of bone marrow suppression
vary with the type of drug. For example, chemotherapeutic agents are well
known to regularly cause bone marrow hypoplasia in a dose-related manner.
Other drugs (antibiotics, anticonvulsants, analgesics) are much less
predictable. Knowledge of potential bone marrow side effects must be kept
in mind when using these drugs and appropriate monitoring of peripheral
blood indices performed. Often, drug-induced bone marrow hypoplasia is
fully reversible on removal of the drug. A small minority of patients may
develop irreversible damage.
Recent research has shown that exposure to drugs or chemical agents is not
as commonly associated with aplastic anemia, although historically these
associations were given prominent attention. A study conducted in Thailand,
where the incidence of AA is 2–3 times higher than in the United States,
indicated that an elevated risk of developing AA was associated with
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exposure to only a small number of substances, including sulfonamides,
thiazide diuretics, and mebendazole.
In the Thai study, an increased risk was not found for chloramphenicol, a
drug frequently implicated in case reports of AA. Other drugs that have been
implicated include gold, anticonvulsants, nonsteroidal analgesics,
antiprotozoals, and antithyroid medications. Most individuals taking such
medications, however, do not develop AA. One possible explanation is that
persons with diminished P-glycoprotein, an efflux pump that is the product
of the multi-drug resistance gene MDR-1, may have excessive accumulation
of drugs that can increase susceptibility to HSC damage. In cases associated
with drug exposure, the pathophysiology is thought to involve an abnormal
immune response to the HSC. The following table provides a thorough
overview of the most common drugs associated with aplastic anemia.
Chloramphenicol
Chloramphenicol was one of the first drugs associated with aplastic
anemia. A relatively common dose-dependent reversible bone
marrow depression can appear in the second week of treatment,
characterized by an inhibition of erythroid cells and anemia; this
reaction is usually reversible by drug withdrawal. A more serious
idiosyncratic aplastic anemia can evolve after more sustained
usage.
Although less common, with wide variations in genetic
susceptibility, this is a potentially fatal reaction. For this reason,
chloramphenicol is now reserved for life threatening conditions and
then only with regular monitoring. The evidence that ocular
chloramphenicol is associated with aplastic anemia is extremely
limited, and it remains the agent of choice for superficial eye
infections.
NSAIDs
NSAIDs have also been associated with aplastic anemia and
agranulocytosis. Phenylbutazone, a pyrazole derivative, was
withdrawn because of aplastic anemia, which was fatal in 50 % of
cases. Indomethacin, piroxicam, diclofenac and sulindac are also
associated with aplastic anemia. Other NSAIDs have been linked,
but on a more anecdotal basis.
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Diseasemodifying
antirheumatic
drugs (DMARDs)
Aplastic anemia has also been associated with DMARDs, such as
gold, sulfasalazine, penicillamine and leflunomide. Some have
recommendations for routine blood monitoring – falling platelet
and neutrophil counts can indicate oncoming aplastic anemia. The
Medicines and Healthcare products Regulatory Agency (MHRA) has
received a number of reports of blood disorders associated with
methotrexate, including aplastic anemia. It should be noted that
error can contribute to blood disorders caused by methotrexate
due to prescribing and dispensing errors, in particular the use of a
daily instead of a weekly dose.
The National Patient Safety Agency (NPSA) has produced guidance
to address this issue, and patient education is an important
method of avoiding these potentially fatal errors.
Antiepileptic
drugs
The use of antiepileptic drugs also appears to be linked to an
increased risk of aplastic anemia. In a retrospective case-control
study, the risk of aplastic anemia had an odds ratio of 9.5 (95% CI
3.0-39.7) compared with no use. Use of multiple antiepileptic
agents was more strongly associated with aplastic anemia, with
carbamazepine and valproic acid particularly strongly associated.
Clinical Findings in AA
The onset of symptoms in AA is usually insidious and related to the
cytopenias. Common initial signs are bleeding accompanied by petechial and
mucosal hemorrhages and infection. Pallor, fatigue, and cardiopulmonary
complications can be present as the anemia progresses.
Hepatosplenomegaly and lymphadenopathy are absent. Splenomegaly has
occasionally been noted in later stages of the disease, but if found in the
early stages, the diagnosis of aplastic anemia should be questioned.
Laboratory Findings6,9-11
Laboratory studies of peripheral blood and bone marrow are essential if a
diagnosis of aplastic anemia is suspected.
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Peripheral Blood:
Pancytopenia is typical. Although the degree of severity can vary, the
diagnosis of AA should be questioned unless the leukocyte count,
erythrocyte count, and platelet count are all below the reference intervals.
Hemoglobin is usually <70 g/L. Erythrocytes appear normocytic and
normochromic, or they can be slightly macrocytic. The presence of nucleated
erythrocytes and teardrops is not typical of AA but suggests marrow
replacement (myelophthisic anemia).
Myelodysplastic syndrome, rather than AA, is suggested by the presence of
dysplastic neutrophils and other abnormal cells. The relative reticulocyte
count (%) can be misleading due to the severe anemia. Therefore, the
reticulocyte count should always be determined in absolute concentration
and/or be corrected for anemia before interpretation. The absolute
reticulocyte count is usually <25×109/L. The corrected reticulocyte count is
<1%. Most often, thrombocytopenia is present at the time of diagnosis.
Neutropenia precedes leukopenia; initially, lymphocyte and monocyte counts
are normal. Because of the neutropenia, the differential count reflects a
relative lymphocytosis.
When the leukocyte count is below 1.5×109/L, an absolute lymphocytopenia
is also present. The band to segmented neutrophil ratio is increased, and
occasionally more immature forms are found. Neutrophil granules are
frequently larger than normal and stain a dark red; these granules should be
distinguished from toxic granules, which are bluish black. Flow cytometry of
the peripheral blood can be ordered to detect CD59+ cells when PNH is
suspected.
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Other abnormal findings are not specific for aplastic anemia but are
frequently found associated with the disease. Hemoglobin F can be
increased, especially in children. Erythropoietin is often increased,
particularly when compared with the erythropoietin levels in patients with
similar degrees of anemia. Serum iron is increased with >50% saturation of
transferrin, reflecting erythroid hypoplasia. The clearance rate of
iron (Fe59) from the plasma is decreased because of the decrease in iron
utilization by a hypoactive marrow. Patients who are younger than age 50
should be screened for FA using tests for chromosomal breakage. Results of
these tests will be normal in other forms of inherited AA and in
acquired/idiopathic forms of AA.
Bone Marrow:
Examination of the bone marrow is necessary to differentiate aplastic
anemia from other diseases accompanied by pancytopenia. In AA, the bone
marrow is hypocellular with >70% fat. Thus, it is often difficult to obtain an
adequate sample. Bone marrow infiltration with granulomas or cancer cells
can lead to fibrosis, also resulting in a hypocellular dry tap on aspiration.
Both aspiration and biopsy are needed for a correct diagnosis. It is
recommended that several different sites be aspirated because focal
sampling of the marrow can be misleading. Some areas of acellular stroma
and fat can be infiltrated with clusters of lymphocytes, plasma cells, and
reticulum cells. Areas of residual hematopoietic tissue termed hot spots can
be found primarily early in the disease but can occasionally be found in
severe refractory cases. Iron staining reveals many iron granules in
macrophages, but granules are rarely seen in normoblasts. Flow cytometry
should be performed; the percentage of CD34+ cells in the bone marrow in
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AA is typically <0.3%. Bone marrow karyotyping is useful for differentiating
hypocellular forms of myelodysplastic syndromes from aplastic anemia.
Prognosis and Therapy6,11
Recent advances in treatment have tempered the previously grim prognosis
of patients diagnosed with aplastic anemia. HSCT and immunosuppressive
therapy (IST) have greatly improved survival. Presently, the 5-year survival
rate is 79%.
Choice of definitive therapy for severe acquired AA depends on the age of
the patient and availability of a matched donor. HSCT is recommended for
patients up to age 45 who have a matched sibling donor, although some
recommendations extend the age limit to age 55. HSCT is also
recommended for patients up to age 21 with a fully compatible HLA-matched
unrelated donor. IST is recommended for patients without a matched related
donor, the situation faced by the majority of patients with aplastic anemia.
Before beginning HSCT or IST, putative causative drugs should be withdrawn
or the patient removed from a hazardous environment. The immediate
treatment is often supportive with the administration of erythrocytes,
platelets, and antibiotics. Granulocyte transfusions can be given to severely
neutropenic patients with life-threatening sepsis. To avoid alloimmunization,
transfusion should be minimized if HSCT is anticipated. Irradiated and/or
leukocyte-reduced blood products can be ordered. Hematopoietic growth
factors such as G-CSF generally do not have a beneficial effect on patients
with AA and may increase the risk of MDS.
HSCT using cells collected from bone marrow has become a relatively
common procedure and is curative in many patients with aplastic anemia.
Bone marrow is preferred over peripheral blood stem cells due to the
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increased risk of graft-vs-host disease with the latter. Antithymocyte
globulin (ATG) and cyclosporine are typically used as preconditioning
regimens to suppress the immune response of the recipient. Preconditioning
is nonmyeloablative.
The current 5-year survival rate is 77% for HLA-matched sibling donors.
Survival rates are highest for children and for patients who have been
minimally transfused. Treatment complications and post-transplant mortality
remain high, especially in older patients; therefore, the probability for longterm cure must be weighed against the inherent risks of complications,
including graft-vs-host disease and early and late toxicities of the
conditioning regimen. Although engraftment of HSCs is successful in many
cases, some transplants, even when performed between identical twins, do
not correct the AA. These unsuccessful transplants suggest that the donor
HSC growth is suppressed by the same immune mechanism that induced the
original aplasia. An additional constraint to HSCT is that matched sibling
donors are available for only 20–30% of patients with aplastic anemia.
Combined, intensive immunosuppressive therapy (IST) using ATG in
combination with cyclosporine has become standard treatment for those
patients with acquired severe aplastic anemia who lack a suitable bone
marrow donor. IST is effective in restoring hematopoiesis in 60–90% of
patients who are over 45 or who lack an HLA-matched sibling donor. More
favorable outcomes are observed in children. Relapse requiring additional
IST occurs in 30–40% of patients. About 15% of patients treated with IST
develop clonal disorders such as paroxysmal nocturnal hemoglobinuria
(PNH), leukemia, and myelodysplastic syndromes.
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Neutropenia/Agranulocytosis12-21
Neutropenia is defined as an absolute decrease in the number of circulating
neutrophils and is suspected when patients present with absolute neutrophil
counts of less than 1.5 × 109/L. The absolute neutrophil count (ANC) can be
obtained by multiplying the total WBC count by the percentage of
neutrophils (and bands) seen in the differential cell count.
A low neutrophil count is not the sole indicator of disease and should be
correlated with patient history as well as clinical and laboratory findings. The
normal level of circulating neutrophils varies with age and race, and refers to
mature polymorphonuclear and band forms only. Recurrent bacterial
infections are the hallmark of persistent neutropenia, with the clinical
severity being reflected by the absolute neutrophil count as well as the
frequency and duration of neutropenic episodes.
Neutropenia can range from mild, with absolute counts from 1.0 to 1.5 ×
109/L, to moderate, with counts from 0.5 to 1.0 × 109/L, to severe, with
counts less than 0.5 × 109/L. Life-threatening infections are not generally
observed until blood counts fall below 0.2 × 109/L. Most of the neutrophils
are contained in the bone marrow, either as mitotically active (one third) or
postmitotic mature cells (two thirds). Granulocytopenia is defined as a
reduced number of blood granulocytes, namely neutrophils, eosinophils, and
basophils. However, the term granulocytopenia is often used synonymously
with neutropenia and, in that sense, is again confined to the neutrophil
lineage alone.
Neutropenia is defined in terms of the absolute neutrophil count. The ANC is
calculated by multiplying the total white blood cell (WBC) count by the
percentage of neutrophils (segmented neutrophils or granulocytes) plus the
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band forms of neutrophils in the complete blood count (CBC) differential. It
should be noted that many modern automated instruments actually calculate
and provide the ANC number in their reports. These instruments do not
separately analyze bands from segmented neutrophils, and so the combined
number is termed the absolute neutrophil count (ANC), representing both
bands and more mature segmented neutrophils. If a band number is
reported separately, usually by smear review, then one can divide the ANC
into bands and segmented neutrophils by subtracting the absolute band
number from the total ANC. The lower limit of the reference value for ANC in
adults varies in different laboratories from 1.5-1.8 109/L or 1500-1800/µL
(mm3). For practical purposes, a value lower than 1500 cells/µL is generally
used to define neutropenia. Age, race, genetic background, environment,
and other factors can influence the neutrophil count. For example, black
people may have a lower but normal ANC value of 1000 cells/µL, with a
normal total WBC count.
Neutropenia is classified as mild, moderate, or severe, based on the ANC.
Mild neutropenia is present when the ANC is 1000-1500 cells/µL, moderate
neutropenia is present with an ANC of 500-1000/µL, and severe neutropenia
refers to an ANC lower than 500 cells/µL. The risk of bacterial infection is
related to both the severity and duration of the neutropenia.
The term agranulocytosis is used to describe a more severe subset of
neutropenia. Agranulocytosis refers to a virtual absence of neutrophils in
peripheral blood. It is usually applied to cases in which the ANC is lower than
100/μL. The reduced number of neutrophils makes patients extremely
vulnerable to infection. Cardinal symptoms include fever, sepsis, and other
manifestations of infection.
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Acquired agranulocytosis is a rare blood disorder that affects males and
females in equal numbers. People who are taking certain medications such
as cancer (chemotherapeutic) drugs, alkylating agents, anti-thyroid drugs,
dibenzepin compounds, or other drugs can be at risk for this disorder.
Causes other than drugs can include chemicals, infective agents, ionizing
radiation, immune mechanisms, primary bone marrow failure syndromes,
and heritable genetic aberrations. Some cases, such as those from benign
familial neutropenia, are characterized by only mild neutropenia and are of
no obvious significance for health. This article is limited to discussing
neutropenia (ANC <1500/µL) and agranulocytosis (ANC <100/µL). It does
not address the transient neutropenia associated with cancer chemotherapy,
nor does it consider agranulocytosis occurring as part of primary marrowfailure syndromes (i.e., aplastic anemia, pancytopenia, acute leukemia,
myelodysplastic syndromes).
Acquired agranulocytosis, as previously mentioned, is a rare, drug-induced
blood disorder, and it is characterized by a severe reduction in the number
of white blood cells (granulocytes) in the circulating blood. The name
granulocyte refers to grain-like bodies within the cell. Granulocytes include
basophils, eosinophils, and neutrophils. Although acquired agranulocytosis
may be caused by a variety of drugs, certain drugs are more commonly
administered with standard monitoring precautions for possible drug-induced
agranulocytosis, such as with chemotherapeutic agents as well as specific
antipsychotic medications, for example, clozapine.
The symptoms of acquired agranulocytosis come about as the result of
interference in the production of granulocytes in the bone marrow.
People with this disorder are susceptible to a variety of bacterial infections,
usually caused by otherwise benign bacteria found in the body. Not
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infrequently, painful ulcers also develop in mucous membranes that line the
mouth and/or the gastrointestinal tract.
Signs and Symptoms
The first symptoms of acquired agranulocytosis are usually those associated
with a bacterial infection such as general weakness, chills, fever, and/or
extreme exhaustion. Symptoms that are associated with rapidly falling white
blood cell levels (granulocytopenia) may include the development of infected
ulcers in the mucous membranes that line the mouth, throat, and/or
intestinal tract. Some people with these ulcers may experience difficulty
swallowing due to irritation and pain.
Granulocytopenia causes a concurrent decrease in the number of neutrophils
in the circulating blood (neutropenia). As neutrophil levels decrease the
susceptibility of patients with acquired agranulocytosis to bacterial infections
becomes even greater. Fevers and abnormal enlargement of the spleen
(splenomegaly) are characteristic features of neutropenia. If neutropenia is
not treated, bacterial infections can lead to life-threatening complications
such as bacterial shock or bacterial contamination of the blood (sepsis).
Chronic acquired agranulocytosis generally progresses more slowly than
acquired agranulocytosis. Canker sores in the mouth and chronic
inflammation of the gums (gingivitis) may be recurring symptoms. Other
systemic infections may recur regularly.
Causes
Acquired agranulocytosis is almost invariably caused by exposure to drugs
and/or chemicals. Any chemical or drug that depresses the activity of the
bone marrow may cause agranulocytosis. Some drugs cause this reaction in
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anyone given large enough doses. Other drugs may cause an idiosyncratic
reaction in one person but not in another. Clinicians do not understand why
some people are susceptible to agranulocytosis and others are not.
In some instances, the action of some drugs or chemicals suggests that the
immune system is involved. In the case of gold, or anti-thyroid drugs, or
quinidine, among others, antibodies are created that appear to break the
granulocytes down. Other drugs that interfere with, or inhibit, granulocyte
colony formation may induce agranulocytosis. Drugs with this characteristic
include valproic acid, carbamazepine, and the beta-lactam antibiotics.
As mentioned, a complicating factor is that several commonly used anticancer drugs are prone to cause agranulocytosis, thus interfering with
treatment. This also may be said for several antipsychotic and mood
stabilizing medications. A variety of drugs can cause acquired
agranulocytosis and neutropenia by destroying special cells in the bone
marrow that later mature and become granulocytes (precursors), such as
phenytoin, pyrimethamine, methotrexate, and cytarabine. In rare cases of
acute acquired agranulocytosis, certain drugs may induce destructive action
of certain white blood cell antibodies (leukocyte isoantibodies), such as
phenylbutazone, gold salts, sulfapyridine, aminopyrine, meralluride, and
dipyrine. The antithyroid drugs carbimazole and propylthiouracil carry a
relatively high risk of hematological dysfunctions including agranulocytosis.
Females and those over 65 years of age may have an increased risk.
Although some have argued for routine blood monitoring, the balance of
opinion is that monitoring is not considered worthwhile due to the rapid
onset of the adverse effect that monitoring would not capture. Recurrence of
agranulocytosis has also been reported when switching from one drug to
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another, such as with carbimazole to propylthiouracil. Approximately half the
fatalities caused by carbimazole and propylthiouracil reportedly resulted
from agranulocytosis and neutropenia. Patients taking anti-thyroid drugs
should be told to notify their medical provider at once if they experience
fever, a sore throat, mouth ulcers, bruising, malaise or nonspecific illness.
Such reports should be treated as medical emergencies.
The atypical antipsychotic medication clozapine is a known cause of
agranulocytosis. It is associated with a 2-3 per cent incidence of neutropenia
and a case fatality rate of between 4 and 16 per cent. For this reason, its
use is restricted to patients enrolled in strict blood-monitoring programs,
although it has been argued that the risk of agranulocytosis after six months
is sufficiently reduced to challenge the continued necessity for such strict
monitoring. Other psychotropic drugs and antidepressants have been
associated with agranulocytosis. Chlorpromazine is associated with a
delayed-onset agranulocytosis, with severe cases occurring in 0.1 per cent of
patients taking standard doses. Antibiotic agents have also been associated
with agranulocytosis including co-trimoxazole, which has a variety of serious
hematological effects.
Diagnosis
The diagnosis of acquired agranulocytosis is made by combining a thorough
history with tests to confirm abnormally low levels of granulocytes in the
circulating blood. Regular periodic blood testing is required for individuals
who take drugs that place them at high risk for acquired agranulocytosis. In
some cases (i.e., people who are taking clozapine), blood tests to monitor
granulocyte levels are done on a weekly basis.
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Treatment
Filgrastim has been designated an orphan drug (developed to treat a rare
medical condition) and approved by the U.S. Food and Drug Administration
(FDA) for the treatment of severe, chronic neutropenia; and it has become a
standard treatment for acquired agranulocytosis. Filgrastim is one of a class
of colony-stimulating factors that does, indeed, stimulate the proliferation
and differentiation of neutrophils. Amgen, Inc., uses recombinant DNA
technology, and manufactures it.
The treatment of acquired agranulocytosis includes the identification and
elimination of drugs or other agents that induce this disorder. Antibiotic
medications may also be prescribed if there is a positive blood culture for the
presence of bacteria or if a significant local infection develops. Treatment in
adults with antibiotics should be limited to about 7-10 days since longer
duration carries with it a greater risk of kidney (renal) complications and
may set the stage for a new infection. When granulocyte levels return to a
near normal range, fever and infections will generally subside.
There is no definitive therapy that can stimulate bone marrow (myeloid)
recovery. Corticosteroids are sometimes used to treat shock induced by
overwhelming bacterial infection. However, these drugs are not
recommended for the treatment of acute agranulocytopenia because they
may mask other bacterial infections.
People with abnormally low levels of immune factors in their blood
(hypogammaglobulinemia) associated with acquired agranulocytosis are
usually treated with infusions of gamma globulin. Mouth and throat ulcers
associated with acquired agranulocytosis can be soothed with gargles of salt
(saline) or hydrogen peroxide solutions. Anesthetic lozenges may also help
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to relieve irritation in the mouth and throat. Mouthwashes that contain the
antifungal drug nystatin can be used to treat oral fungal infection (i.e.,
thrush or candida). A semi-solid or liquid diet may become necessary during
episodes of acute oral and gastrointestinal inflammation.
People with chronic granulocytopenia associated with acquired
agranulocytosis need to be hospitalized during acute episodes of infection.
These affected individuals should be taught to recognize the early symptoms
and signs of acute infection and to seek immediate medical attention when
necessary. The therapy for chronically affected individuals is similar to that
for the acute form of the disease. People with chronic granulocytopenia, who
take low-dose oral antibiotics on a rotating basis, must also be monitored for
the infections caused by drug-resistant bacteria as well as infections with
opportunistic organisms (i.e., fungi, cytomegalovirus).
Investigational Therapies
Acquired agranulocytosis may be helped through the use of new
biotechnology drugs including granulocyte-colony stimulating factor (G-CSF)
and granulocyte macrophage-CSF (GM-CSF). G-CSF and GM-CSF may
stimulate the production and development of immature blood cells that later
become granulocytes, ultimately increasing the number of granulocytes in
the blood. These treatments are currently under investigation, and more
studies are needed to determine the long-term safety and effectiveness of
these factors for the treatment of acquired agranulocytosis.
Megaloblastic Anemia22-28
Megaloblastic anemia is classified as a nuclear maturation defect. Anemia is
attributed primarily to a large degree of ineffective erythropoiesis resulting
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from disrupted DNA synthesis. The anemia was called megaloblastic in an
attempt to describe the giant, abnormal-appearing erythroid precursors
(megaloblasts) in the bone marrow. The generic word megaloblast describes
any maturation stage of the megaloblastic erythroid series (i.e.,
polychromatic megaloblast). Other nucleated cells of the marrow are also
typically abnormal.
About 95% of megaloblastic anemias are caused by deficiencies of vitamin
B12 (cobalamin) or folic acid, which are vitamins necessary as coenzymes
for nucleic acid synthesis. In the majority of cases, cobalamin deficiency is
secondary to a deficiency of intrinsic factor (IF), a protein necessary for
absorption of cobalamin, rather than to a nutritional deficiency of the
vitamin. Folic acid deficiency, on the other hand, is most often due to an
inadequate dietary intake. Inherited disorders affecting DNA synthesis or
vitamin metabolism are rare causes of megaloblastosis.
The onset of megaloblastic anemia is usually insidious; because the anemia
develops slowly, it produces few symptoms until the hemoglobin and
hematocrit are significantly depressed. Patients can present with typical
anemic symptoms of lethargy, weakness, and a yellow or waxy pallor.
Dyspeptic symptoms are common. Glossitis with a beefy red tongue, or
more commonly a smooth pale tongue, is characteristic. Loss of weight and
loss of appetite are common complaints. In pernicious anemia, atrophy of
the gastric parietal cells causes decreased secretion of intrinsic factor and
hydrochloric acid. Bouts of diarrhea can result from epithelial changes in the
gastrointestinal tract.
Neurological disturbances occur only in cobalamin deficiency, not in folic acid
deficiency. They are the most serious and dangerous clinical signs because
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neurological damage can be permanent if the deficiency is not treated
promptly. The patient’s initial complaints occasionally are related to
neurological dysfunction rather than to anemia. Neurological damage has
been reported to occur even before anemia or macrocytosis in some cases,
particularly in elderly people. The bone marrow, however, usually reveals
megaloblastic changes even in the absence of anemia. Tingling, numbness,
and weakness of the extremities reflect peripheral neuropathy. Loss of
vibratory and position (proprioceptive) sensations in the lower extremities
can cause the patient to have an abnormal gait. The patient’s relatives
sometimes note mental disturbances such as loss of memory, depression,
and irritability.
Megaloblastic madness is a term used to describe severe psychotic
manifestations of cobalamin deficiency. A patient with severe anemia
occasionally is asymptomatic, which is probably a reflection of a very slowly
developing anemia. It has been suggested that cobalamin deficiency should
be suspected in all patients who have an unexplained anemia and/or
neurological disturbances or in individuals who are at risk of developing a
deficiency such as elderly people or those with intestinal diseases.
A large number of drugs that act as metabolic inhibitors can cause
megaloblastosis. Some of these drugs are used in chemotherapy for
malignancy. Although aimed at eliminating rapidly proliferating malignant
cells, these drugs are not selective. Any normal proliferating cells, including
hematopoietic cells, are also affected. Megaloblastic anemia has also been
associated with other drugs including oral contraceptives, long-term
anticoagulant drugs, phenobarbital, primidone, and phenytoin. Anemia
occasionally is not present even though serum and erythrocyte folate are
depressed.
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DNA Base Inhibitors
Pyrimidine
Purine
Antimetabolites
Other
Azauridine
Acyclovir
Cytosine arabinoside
Azacytidine
Adenosine
Fluorocytidine
Cyclophosphamide
arabinoside
Fluorouracil
Zidovudine (AZT)
Azathioprine
Hydroxyurea
Gancyclovir
Methotrexate
Mercaptopurine
Thioguanine
Vidarabine
Laboratory Findings
Laboratory tests are critical to a diagnosis of megaloblastic anemia. The
routine CBC with a review of the blood smear gives important diagnostic
clues and helps in selecting reflex tests.
Megaloblastic anemia is typically a macrocytic, normochromic anemia. The
MCV is usually >100 fL and can reach a volume of 140 fL. However, an
increased MCV is not specific for megaloblastic anemia. The MCH is
increased because of the large cell volume, but the MCHC is normal. In
cobalamin deficiency, a macrocytosis can precede the development of
anemia by months to years. On the other hand, the MCV can remain within
the reference interval. Epithelial changes in the gastrointestinal tract can
cause iron absorption to be impaired. If an iron deficiency (which
characteristically produces a microcytic, hypochromic anemia) coexists with
megaloblastic anemia, macrocytosis can be masked, and the MCV can be in
the normal range.
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Common Laboratory Values in Megaloblastic and Nonmegaloblastic Macrocytosis
Laboratory Value
Megaloblastic
Macrocytosis
Nonmegaloblastic Macrocytosis
WBC count
Decreased
Normal
Platelet count
Decreased
Normal
RBC count
Decreased
Decreased
Hemoglobin
Decreased
Decreased
Hematocrit
Decreased
Decreased
MCV
Usually >110 fL
>100 fL
RBC morphology
Ovalocytes, Howell-Jolly
bodies, polychromasia
Polychromasia, target cells, and
stomatocytes (liver disease), schistocytes
(hemolytic anemias)
Hypersegmentation
of neutrophils
Present
Absent
Reticulocyte count
Normal to decreased
Normal, decreased, or increased
Serum cobalamin
Decreased in cobalamin
deficiency
Usually normal
Serum folate
Decreased in folate
deficiency
Normal (except is decreased in
alcoholism)
FIGLU
Increased in folate
deficiency
Normal
MMA
Increased in B12
deficiency
Normal
Homocysteine
Increased
Normal
Serum bilirubin
Increased
Normal to increased
LD
Increased
Normal to increased
MCV = mean corpuscular volume. FIGLU = formiminoglutamic acid.
MMA = methylmalonicacid. LD = lactic dehydrogenase.
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Other conditions that have been shown to coexist with megaloblastic anemia
in the absence of an increased MCV include thalassemia, chronic renal
insufficiency, and chronic inflammation or infection. Sometimes these
coexisting causes of anemia are not recognized until after the megaloblastic
anemia has been treated. It has been suggested that if coexisting iron
deficiency, thalassemia, or chronic disease is suspected, patient medical
history, racial/ethnic background, and previous MCV should be considered.
Hematologic parameters vary considerably. The hemoglobin and erythrocyte
count range from normal to very low. The erythrocyte count is occasionally
<1×1012/L. However, anemia is not always evident. In one study of 100
patients with confirmed cobalamin deficiency, only 29% had a hemoglobin of
<12g/dL. This is significant because neurologic symptoms can be present
even if the MCV and/or hematocrit are normal. Because the abnormality is a
nuclear maturation defect, the megaloblastic anemias affect all three blood
cell lineages: erythrocytes, leukocytes, and platelets. This is unlike most
other anemias that typically involve only erythrocytes.
The leukocyte count can be decreased due to an absolute neutropenia.
Platelets can also be decreased but do not usually fall below 100×109/L .
The relative reticulocyte count (percentage) is usually normal; however,
because of the severe anemia, the corrected reticulocyte count is <2%, the
absolute reticulocyte count is low, and RPI is <2.
The distinguishing features of megaloblastic anemia on the stained blood
smear include the triad of oval macrocytes (macro-ovalocytes), Howell-Jolly
bodies, and hypersegmented neutrophils. Anisocytosis is moderate to
marked with normocytes and a few microcytes in addition to the macrocytes.
Poikilocytosis can be striking and is usually more so when the anemia is
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severe. Polychromatophilia and megaloblastic erythroblasts can be seen,
especially when the anemia is severe, indicating the futile attempt of the
bone marrow to increase peripheral erythrocyte mass. Cabot rings
occasionally can be seen in erythrocytes. Granulocytes and platelets can also
show changes evident of abnormal hematopoiesis.
Hypersegmented neutrophils can be found in megaloblastic anemia even in
the absence of macrocytosis. Finding 5% or more neutrophils with five lobes
or one neutrophil with six or more lobes is considered hypersegmentation.
This finding of hypersegmented neutrophils is considered highly sensitive
and specific for megaloblastic anemia. Therefore, hypersegmented
neutrophils offer an important clue to megaloblastic anemia in the face of a
coexisting disease that tends to keep erythrocyte volume <100 fL. One
study showed that in patients with renal disease, iron deficiency, or chronic
disease with a normal or decreased MCV and 1% hypersegmented
neutrophils, 94% had vitamin B12 or folic acid deficiency. If 5%
hypersegmented neutrophils were counted, the incidence of the
vitamin B12 or folic acid deficiency increased to 98%. Hypersegmented
neutrophils tend to be larger than normal neutrophils. A mild shift to the left
with large hypogranular bands can also be noted. Platelets can be large,
especially when the platelet count is decreased.
If the CBC results suggest megaloblastic anemia, further testing is necessary
to distinguish the cause. Although no major medical organization has
published guidelines for reflex testing, the most common next step is to
measure serum cobalamin and serum or red cell folate. Laboratories use
different methods (chemiluminescence, radioassay) to measure cobalamin,
so there is no “gold standard” to use as a reference interval. Generally
values <150pg/mL are consistent with cobalamin deficiency, whereas levels
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>400pg/mL suggest adequate cobalamin. Borderline levels (150–400
pg/mL) can be associated with cobalamin deficiency.
Measurement of erythrocyte folate is not influenced as much by recent
dietary changes as is serum folate and gives an accurate estimate of the
average folate levels over the preceding several months. On the other hand,
if there is a cobalamin deficiency, folate will leak out of the cells, which will
give a false low red cell folate and false increased serum folate. In addition,
red cell folate is measured by folate-binding protein assays that rely on
chemiluminescence methodology. These methods show considerable analytic
variability. Therefore, the less expensive serum folate measurement is
preferred for initial testing. If serum folate is >4 ng/mL, folate deficiency can
be ruled out.
Early megaloblastic changes can be detected by testing for methylmalonic
acid (MMA) and homocysteine levels in the blood. Tests for these
metabolites are intermediates in folate and cobalamin metabolism and are
elevated early in functional vitamin deficiencies. Tests for these metabolites
are more sensitive than serum cobalamin levels and increase earlier than a
drop in the cobalamin level. By performing tests for both MMA and
homocysteine, it is possible to differentiate cobalamin deficiency from folate
deficiency. Homocysteine is elevated in folate deficiency, whereas MMA is
usually normal. On the other hand, both homocysteine and MMA are
elevated in cobalamin deficiency.
An increase in both MMA and homocysteine is also found in combined
cobalamin and folate deficiencies. In these cases, clinical information is
important to help establish a differential diagnosis. A block in the
metabolism of histidine to glutamic acid occurs in folic acid deficiency and
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causes increased urinary excretion of formiminoglutamic acid (FIGLU), an
intermediate metabolite, after the administration of histidine. These
metabolites return to normal levels when the appropriate vitamin is given to
the patient. It is recommended that clinicians first use the lower cost tests of
serum cobalamin and serum folate to diagnose cobalamin and folate
deficiencies and use the higher cost MMA and homocysteine tests if
cobalamin and folate test results are not definitive.
The large degree of ineffective erythropoiesis results in hemolysis in the
marrow and an increase in plasma iron turnover, serum iron, indirect
bilirubin, and urobilinogen. The characteristic marked increase in fractions 1
and 2 of serum lactic dehydrogenase (LD) is partially caused by the
destruction of megaloblasts rich in LD. The increase is roughly proportional
to the degree of anemia. Haptoglobin, uric acid, and alkaline phosphatase
are decreased.
Bone Marrow
If physical examination, patient history, and peripheral blood findings
suggest megaloblastic anemia, a bone marrow examination can help
establish a definitive diagnosis. In megaloblastic states, the bone marrow is
hypercellular with megaloblastic erythroid precursors and a decreased M:E
ratio. In a long-standing anemia, red marrow can expand into the long
bones. About half the erythroid precursors typically show megaloblastic
changes.
Megaloblasts are large nucleated erythroid precursors that display nuclearcytoplasmic asynchrony with nuclear maturation lagging behind cytoplasmic
maturation. The nucleus of the megaloblast contains loose, open chromatin
that stains poorly; cytoplasmic development continues in a normal fashion.
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At each stage of development, the cells contain more cytoplasm with a more
mature appearance relative to the size and maturity of the nucleus (resulting
in a decreased nuclear:cytoplasmic [N:C] ratio).
The megaloblastic features are more easily noted in later stages of erythroid
development, especially at the polychromatophilic stage in which the
presence of hemoglobin mixed with RNA gives the cytoplasm the gray-blue
color typical of this erythroid precursor. The polychromatophilic megaloblast
nucleus, however, still has an open (lacy) chromatin pattern more typical of
an earlier stage of development.
Leukocytes and platelets also show typical features of a nuclear maturation
defect as well as ineffective leukopoiesis and thrombopoiesis. Giant
metamyelocytes and bands with loose, open chromatin in the nuclei are
diagnostic. The myelocytes can show poor granulation as do more mature
stages. Megakaryocytes can be decreased, normal, or increased. Maturation,
however, is distinctly abnormal; larger than normal forms can be found with
separation of nuclear lobes and nuclear fragments.
Therapy
Therapeutic trials in megaloblastic anemia using physiologic doses of either
vitamin B12 or folic acid produce a reticulocyte response only if the specific
vitamin that is deficient is being administered. For instance, small doses (1
mcg) of vitamin B12 given daily produce a reticulocyte response in
cobalamin deficiency but not in folic acid deficiency. On the other hand, large
therapeutic doses of cobalamin or folic acid can induce a partial response to
the other vitamin deficiency as well as the specific deficiency.
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Generally, it is best to determine which deficiency exists and to treat the
patient with the specific deficient vitamin. Large doses of folic acid will
correct the anemia in cobalamin deficiency but do not correct or halt
demyelination and neurologic disease. This makes diagnosis and specific
therapy in cobalamin deficiency critical. Specific therapy causes a rise in the
reticulocyte count after the fourth day of therapy. Reticulocytosis peaks at
about 5–8 days and returns to normal after 2 weeks.
The degree of reticulocytosis is proportional to the severity of the anemia
with more striking reticulocytosis in patients with severe anemia. The
hemoglobin rises about 2–3 g/dL every 2 weeks until normal levels are
reached. The marrow responds quickly to therapy, as evidenced by
pronormoblasts (normal) appearing within 4–6 hours and nearly complete
recovery of erythroid morphologic abnormalities within 2–4 days.
Granulocyte abnormalities disappear more slowly. Hypersegmented
neutrophils can usually be found for 12–14 days after therapy begins.
Specific therapy can reverse the peripheral neuropathy of cobalamin
deficiency, but spinal cord damage is usually irreversible. Pernicious anemia
must be treated with lifelong monthly parenteral doses of hydroxycobalamin
(OHCbl) because of these patients’ inability to absorb oral cobalamin.
Recently, it was reported that large doses of cobalamin therapy (usually
1000–2000 mcg/day) administered orally could be feasible if the patient is
followed carefully. The oral treatment can be better tolerated and less
expensive. The rationale behind oral therapy using large doses of vitamin is
that a small amount (from 1 to 3%) of the vitamin is absorbed by diffusion
without intrinsic factor.
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Hemolytic Anemia29-41
Drug-associated hemolytic anemia is thought to occur in approximately one
in a million people, with four distinct mechanisms proposed for the majority
of cases: immune complex formation, hapten formation, autoantibody
production and, in those with glucose-6-phosphate dehydrogenase (G6PD)
deficiency, oxidative red cell damage. Immune complexes seem to be the
major cause, with quinine, quinidine, rifampicin, methotrexate,
sulphonylureas and antihistamines among those associated. Penicillin has
been associated with hapten formation – around 3 per cent of patients
receiving high doses will develop a positive antiglobulin test, of which a
small proportion will develop hemolytic anemia. A positive Coombs’ test can
distinguish immune reactions from other causes of hemolytic anemia.
Hemolysis caused by G6PD deficiency is dose dependent and increases with
cumulative doses. Drugs with a definite risk of hemolysis include
nitrofurantoin, primaquine, quinolones and sulphonamides; and, prescribers
are warned of G6PD deficiency and further information on drugs to be
avoided. A hemolytic state exists when the in vivo survival of red cells is
shortened. The presence of anemia in an individual patient is, however,
dependent on the degree of hemolysis and the compensatory response of
the erythroid elements of the bone marrow. Normal bone marrow is able to
increase its output about six- to eightfold, so that anemia is not manifest
until this capacity is exceeded, corresponding to a red cell life span of about
15 to 20 days or less. Anemia may, however, occur with more moderate
shortening of the red cell life span if there is an associated depression of
bone marrow function, which may occur with certain systemic diseases or
exposure to chemicals or drugs.
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A useful classification of the hemolytic anemias entails their subdivision into
those disorders associated with an intrinsic (intracorpuscular) defect of the
red cell and those associated with an extrinsic (extracorpuscular)
abnormality. Red cells from a patient with an intracorpuscular defect have a
shortened survival in both the patient and a normal recipient, whereas
normal donor red cells survive normally in the patient. In contrast, normal
red cells are destroyed more rapidly when transfused into a patient with an
extracorpuscular abnormality. The patient's red cells, when transfused into a
healthy recipient, have normal survival, provided that they have not been
irreversibly damaged. Hemolytic states have also traditionally been regarded
as intravascular or extravascular; that is, sequestration occurs in
reticuloendothelial tissue. However, vigorous extravascular hemolysis may
often be associated with signs of hemoglobin release into the plasma such as
hemoglobinemia and decreased haptoglobin levels. The distinction still is
useful from a clinical standpoint because certain hemolytic states are
associated with predominantly intravascular hemolysis (i.e., paroxysmal
nocturnal hemoglobinuria and infections caused by Clostridium or
Plasmodium falciparum).
Classification of Immune Hemolytic Anemias
Hemolytic anemias may be classified as follows:

Intracorpuscular defects
 Hereditary defects:
Defects in the red cell membrane
Enzyme defects
Hemoglobinopathies
Thalassemia syndromes
 Acquired defects
Paroxysmal nocturnal hemoglobinuria
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
Extracorpuscular defects
 Immune hemolytic anemias
 Infections
 Exposure to chemicals and toxins
 Exposure to physical agents
 Microangiopathic and macroangiopathic hemolytic anemias
 Splenic sequestration (hypersplenism)
 General systemic disorders (in which hemolysis is not the dominant
feature of the anemia)
Determining the underlying process of immune hemolysis is important
because each type requires a specific treatment regimen. Initially, immune
hemolytic anemia can be classified into three broad categories based on the
stimulus for antibody production, which is listed below.
Classification
Causes
Autoimmune
Warm-reactive antibodies (37°C)
Primary or idiopathic
Secondary
Autoimmune disorders (systemic lupus erythematosus,
rheumatoid arthritis, and others)
Chronic lymphocytic leukemia and other immunoproliferative
diseases
Viral infections
Neoplastic disorders
Chronic inflammatory diseases
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Classification
Causes
Cold-reactive antibodies (<30°C)
Primary or idiopathic (cold hemagglutinin disease)
Secondary
Infectious diseases (Mycoplasma pneumonia, Epstein-Barr
virus, other organisms)
Lymphoproliferative disorders
Paroxysmal cold hemoglobinuria
Idiopathic
Secondary
Viral syndromes
Syphilis (tertiary)
Mixed type
DAT negative
Drug induced
Drug dependent
Drug independent
Nonimmunologic protein adsorption (NIPA)
Alloimmune
Hemolytic transfusion reaction
Hemolytic disease of the fetus and newborn
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Autoimmune hemolytic anemia (AIHA) is a complex and incompletely
understood process characterized by an immune reaction against selfantigens and shortened erythrocyte survival. Individuals produce antibodies
against their own erythrocyte antigens (autoantibodies), which are usually
directed against high-incidence antigens (antigens present on the
erythrocytes of most people). The autoantibodies characteristically react not
only with the individual’s own erythrocytes but also with the erythrocytes of
other individuals carrying that antigen. The reactions that occur with
autoantibodies include sensitization (attachment of antibody or complement
to the erythrocytes), agglutination of the erythrocytes, or erythrocyte lysis.
Autoimmune hemolytic anemias are further classified as warm or cold
hemolytic anemia based on clinical symptoms and on the optimal
temperature at which the antibody reacts in vivo and in vitro. Some
antibodies react best at body temperature (37°C); the anemia they produce
is termed warm autoimmune hemolytic anemia (WAIHA). About 70% of the
AIHAs are of the warm type. The majority of warm autoantibodies are of the
IgG class (most frequently IgG1) and cause extravascular hemolysis of the
erythrocyte. A few warm-reacting autoantibodies of either the IgM or IgA
class have been identified.
Cold hemolytic anemias, on the other hand, are usually due to the presence
of an IgM antibody with an optimal thermal reactivity below 30°C. Hemolysis
with cold-reacting antibodies results from IgM binding to and activating
complement. The IgM antibody attaches to erythrocytes in the cold and fixes
complement. After warming, the antibody dissociates from the cell, but the
complement remains, either causing direct cell lysis or initiating
extravascular destruction. Included in the cold hemolytic anemia
classification is a special condition, paroxysmal cold hemoglobinuria (PCH),
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which is characterized by a cold-reacting IgG antibody capable of fixing
complement.
Characteristics of Agglutinins in Hemolytic Anemia
Warm-Reacting
Antibodies
Immunoglobulin
(Ig) class
Cold-Reacting
Antibodies
IgG
IgM
IgM (rare)
IgG (PCH only)
IgA (usually with IgG)
Optimal
reactivity
37°C
<30°C, usually <10°C
Mechanism of
hemolysis
Extravascular
Attachment of
membrane-bound IgG or
C3b to macrophage
receptors
Intravascular:
complement-mediated
lysis
Extravascular:
attachment of
membrane-bound C3b to
macrophage receptors
Specificity
Usually broad specificity
anti-Rh
Usually autoanti-I
Occasionally autoanti-i
PCH: autoanti-P
PCH = paroxysmal cold hemoglobinuria
A third category, mixed-type autoimmune hemolytic anemia, demonstrates
both warm-reacting (IgG) autoantibodies and cold-reacting (IgM)
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autoantibodies. Drugs that attach to the erythrocyte membrane or alter it in
some way can cause drug-induced hemolysis.
Historically, several different mechanisms of hemolysis have been
hypothesized based on whether the drug binds directly to the cell, reacts
with an antibody in the circulation to form an immune complex that binds to
the cell, or alters the erythrocyte antigens to stimulate formation of
autoantibodies. Now, however, these antibodies are broadly classified as
either drug dependent or drug independent based on reactions of patient’s
erythrocytes and the drug in in vitro test systems.
Autoimmune hemolytic anemia occurs as a result of antibody development
to an erythrocyte antigen that the individual lacks. When an individual is
exposed to erythrocytes from another person, there could be antigens on the
transfused cells that are not present on the recipient’s erythrocytes.
Therefore, the recipient’s lymphocytes recognize antigens on the transfused
cells as foreign and stimulate the production of antibodies (alloantibodies).
In contrast to autoantibodies, these alloantibodies react only with the
antigens on the transfused cells or cells from individuals who possess the
antigen. The alloantibodies do not react with the individual’s own
erythrocytes. Examples of alloimmune hemolytic anemia are:

Hemolytic disease of the fetus and newborn (FDFN) in which the
mother makes antibodies against antigens on the fetal erythrocytes.

Transfusion reactions in which the recipient makes antibodies to
antigens on the transfused (donor) cells.
The presence of alloantibodies can be detected in vitro by performing an
antibody screen in which the patient’s serum reacts with commercial
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erythrocytes containing most of the clinically significant antigens. An
autocontrol consisting of the patient’s serum and erythrocytes can also be
set up. When only alloantibodies are present, the autocontrol shows no
hemolysis or agglutination whereas the mixture of the patient’s serum and
the commercial cells produce agglutination and (in rare cases) hemolysis.
Erythrocytes
Erythrocyte life span can be significantly shortened if the cell is intrinsically
defective (intracorpuscular defect). Hemolytic anemia has been associated
with defective erythrocyte membranes, structurally abnormal hemoglobins
(hemoglobinopathies), defective globin synthesis (thalassemias), and
deficiencies of erythrocyte enzymes. Almost all of these defects are
hereditary.
An erythrocyte membrane that is normal in both structure and function is
essential to the survival of the cell. Composed of proteins and lipids, the
membrane is responsible for maintaining stability and the normal discoid
shape of the cell, preserving cell deformability, and retaining selective
permeability. Erythrocytes that have normal hemoglobin structure, enzymes,
and membranes can be prematurely destroyed by factors extrinsic to the
cell. This destruction can be immune-mediated via antibodies and/or
complement. However nonimmune factors also can cause either
extravascular or intravascular hemolysis, depending on the type and extent
of injury to the erythrocyte. This section discusses nonimmune causes that
lead to premature erythrocyte destruction.
Erythrocytes can undergo traumatic physical injury in the peripheral
circulation, resulting in the presence of schistocytes in the peripheral blood.
Contact with fibrin strands or platelet aggregates in the microcirculation or
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with foreign surfaces such as artificial heart valves commonly induce such
damage. There are other causes of injury, including Shiga toxin from
organisms such as Esherichia coli 0157:H7. Infectious agents such
as Plasmodium sp. and Babesia sp. can cause injury to the erythrocytes
during their intracellular life cycle. Some drugs and chemicals can cause
membrane oxidant injury, leading to intravascular hemolysis or removal of
the damaged cell by the spleen.
Various chemicals and drugs have been identified as possible causes of
erythrocyte hemolysis; many of these are dose dependent. In addition to
erythrocyte hemolysis, chemicals and drugs can also produce
methemoglobinemia and cyanosis, or in some instances bone marrow
aplasia.
Hemoglobinemia and hemoglobinuria can occur as a result of osmotic lysis of
erythrocytes when water enters the vascular system or when inappropriate
solutions are used during a blood transfusion. Some drugs known to cause
hemolysis in G6PD-deficient persons can also cause hemolysis in normal
persons if the dose is sufficiently high. The hemolysis mechanism is similar
to that in G6PD deficiency with hemoglobin denaturation and Heinz body
formation because of strong oxidants.
Anemia associated with lead poisoning is usually classified with sideroblastic
anemias because the pathophysiologic and hematologic findings are similar.
Lead inhibits heme synthesis, causing an accumulation of iron within
mitochondria. However, lead also damages the erythrocyte membrane,
which is manifested by an increase in osmotic fragility and mechanical
fragility.
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Acquired nonimmune hemolytic anemias represent a diverse group of
conditions that lead to the shortened survival of red cells by various
mechanisms. Often a number of mechanisms are operative at the same
time; for example, malaria leads to mechanical destruction of red cells and,
in addition, immunologic factors play a role in shortened red cell survival.
Classifications may be made along either causative or mechanistic lines.
Sites and Factors that Affect Hemolysis
Regardless of whether it is caused by alloantibodies or autoantibodies,
hemolysis can be intravascular or extravascular, depending on the class of
antibody involved and whether the complement cascade has been
completely activated. Most immune-mediated hemolysis is extravascular.
Erythrocytes sensitized (coated) with antibody (IgG) or complement
components (i.e., C3b) attach to macrophages in the spleen or liver via
macrophage receptors for the Fc portion of IgG or the C3b component of
complement. These cells are then phagocytized. Intravascular hemolysis
occurs if the complement cascade is activated through C9 (the membrane
attack complex), resulting in lysis of the cell. The rate at which hemolysis
occurs in hemolytic anemia is related to several factors.
Approach to Diagnosis of a Hemolytic State
The approach to diagnosis of a hemolytic state initially involves establishing
the fact that the rate of red cell destruction is increased and then focuses on
determining the cause of hemolysis. Establishing the presence of hemolysis
diagnostic tests used to establish the presence of hemolysis rely on the fact
that hemolysis is characterized by both increased cell destruction and
increased production.
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Tests Reflecting Increased Red Cell Destruction
The most frequently used tests in this category are the serum unconjugated
(indirect) bilirubin and serum haptoglobin determinations. The serum
unconjugated bilirubin level seldom exceeds 3 to 4 mg/dL in uncomplicated
hemolytic states and reflects the catabolism of heme derived from red cells
phagocytosed by the reticuloendothelial system. The test is, however,
relatively insensitive, as is the measurement of fecal stercobilinogen and
urine urobilinogen that represents further stages in the degradation of
unconjugated bilirubin by the liver. Because the unconjugated bilirubin is
bound to albumin it cannot pass the glomerular filter, and the jaundice is
said to be acholuric.
On the other hand, a decreased serum haptoglobin level is a very sensitive
test of both intravascular and extravascular hemolysis, and reflects the rapid
clearance by the reticuloendothelial system of a complex formed between
liberated hemoglobin and circulatory haptoglobin. Drawbacks to the use of
serum haptoglobin levels are that low levels may occur in hepatocellular
disease, reflecting decreased synthesis by the liver, and that some
individuals, particularly in black populations, may have a genetically
determined deficiency of haptoglobin. Increased synthesis of haptoglobin in
acute inflammatory states or malignancy may also mask depletion of serum
haptoglobin caused by hemolysis.
Other tests that reflect increased red cell destruction, particularly if it is
primarily intravascular, are those that test for the presence of
hemoglobinemia, hemoglobinuria, and hemosiderinuria. The assessment of
hemoglobinemia requires stringent precautions in the prevention of
hemolysis during blood collection. Once the hemoglobin-binding capacity of
serum haptoglobin is exceeded, hemoglobin passes through the glomerulus
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as alpha–beta (αβ) chain dimers and reassociates to α2β2 tetramers in the
tubule, where the hemoglobin is reabsorbed and degraded. The liberated
iron is conserved as ferritin and hemosiderin. When the tubular reabsorptive
capacity for hemoglobin is exceeded, hemoglobinuria ensues and is
detectable by either spectroscopic examination or commercially available
dipsticks that detect heme. Staining of the urine sediment for iron (i.e., with
Prussian blue) will detect the hemosiderin- and ferritin-containing renal
tubular cells that are sloughed several days after a hemolytic episode.
Some of the free plasma hemoglobin may be oxidized to methemoglobin
with subsequent dissociation of ferriheme, which combines with albumin to
form methemalbumin. Methemalbumin can be detected spectroscopically by
the Schumm's test. This test is relatively insensitive and is seldom positive
in mild hemolytic states. In routine practice, determination of red cell
survival using Cr51-labeled red cells is seldom required to document an
increased rate of red cell destruction.
Tests Reflecting Increased Red Cell Production
The compensatory bone marrow response to hemolysis results in the
delivery of young red cells in the form of reticulocytes into the circulation.
These young cells contain RNA, which stains supravitally with dyes such as
new methylene blue or brilliant cresyl blue. The normal reticulocyte count
has a range of 0.5% to 2.0%, reflecting the fact that each day
approximately 1% of the red cell mass is destroyed and replaced by young
red cells from the bone marrow, because red cell survival is approximately
120 days.
The reticulocyte count is always elevated in a hemolytic state in which there
is a normal compensatory bone marrow response. However, a more accurate
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assessment of red cell production is required, because the percentage of
reticulocytes may be falsely elevated as the reticulocytes may be diluted into
a lesser number of total circulating red cells. In addition, in response to the
anemia, reticulocytes may leave the bone marrow prematurely and mature
in the circulation for longer than the normal maturation time of 1 day, again
leading to a falsely elevated reticulocyte count. These cells (so-called shift
reticulocytes) are recognizable as large bluish-gray erythrocytes on
Romanowsky (Wright's, Giemsa) stains.
The reticulocyte production index (RPI) corrects the hematocrit to a normal
value of 45% and takes into account the maturation time of the reticulocyte
at a particular hematocrit (approximately 1.0 day at a hematocrit of 45%,
1.5 days at 35%, 2.0 days at 25%, and 2.5 days at 15%).
For example, an RPI of 5.3 is calculated for a patient suspected of having a
hemolytic state with the following indices: hemoglobin, 12.0 g/dL;
hematocrit, 36%; reticulocyte count, 10%; shift cells present. An RPI of
greater than 2.5 to 3.0 is generally regarded as indicative of a hemolytic
state, but it is very important to exclude the presence of hemorrhage in a
particular patient, as this too may lead to an elevated RPI. Although the RPI
is probably the single most useful test to detect a hemolytic state, a
cautionary note is in order, as the test may not be sensitive enough to
detect mild hemolytic states.
There are four main mechanisms of drug-induced immune-mediated
hemolysis that appear to be drug-specific:
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1. Hapten mechanism: The drug forms an antigenic complex with a RBC
membrane protein that is recognized by an antibody. Binding of the
antibody to this complex on the RBC membrane leads to destruction of
the RBC. Hemolysis occurs only when the drug is present.
a. Laboratory studies:
 DAT positive for IgG.
b. Examples: penicillins.
2. Immune complex mechanism: The offending drug, or its metabolite,
forms an antigenic complex with a plasma protein. An anti-drug
antibody (usually IgM) binds to this antigenic complex to form an
immune complex that adheres to RBCs and activates complement,
which leads to hemolysis. It is the most common form of drug-induced
hemolysis.
a. Laboratory studies:
 DAT positive for C3.
b. Examples: quinidine, phenacetin.
3. Autoantibody mechanism: An autoantibody (IgG) is induced by the
offending drug. This autoantibody is usually directed against an Rh
blood group antigen.
a. Laboratory studies:
 DAT is positive for IgG.
 An antibody or a positive DAT can be present in the
absence of hemolysis.
b. Examples: alpha-methyldopa, ibuprofen.
4. Immunogenic drug-RBC complex (in vivo sensitization) mechanism:
An antibody binds to the drug (or a metabolite) that is in an
immunogenic complex that is formed by the drug (or a metabolite)
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associating with a specific RBC membrane antigen. The binding of the
drug to the RBC antigen provides specificity for the anti-drug antibody
to bind to the drug (the antibody does not bind to the RBC antigen).
Thrombocytopenia42-61
Platelets are cell fragments that function in the clotting system.
Thrombopoietin helps control the number of circulating platelets by
stimulating the bone marrow to produce megakaryocytes, which in turn shed
platelets from their cytoplasm. Thrombopoietin is produced in the liver at a
constant rate and its circulating level is determined by the extent to which
circulating platelets are cleared, and possibly by bone marrow
megakaryocytes. Platelets circulate for 7 to 10 days. About one third are
always transiently sequestered in the spleen. The platelet count is normally
140,000 to 440,000/μL. However, the count can vary slightly according to
menstrual cycle phase, decrease during near-term pregnancy (gestational
thrombocytopenia), and increase in response to inflammatory cytokines
(secondary, or reactive, thrombocytosis). Platelets are eventually destroyed
by apoptosis, a process independent of the spleen.
Platelet disorders include 1) an abnormal increase in platelets
(thrombocythemia and reactive thrombocytosis), 2) a decrease in platelets
(thrombocytopenia), and 3) platelet dysfunction. Any of these conditions,
even those in which platelets are increased, may cause defective formation
of hemostatic plugs and bleeding. The risk of bleeding is inversely
proportional to the platelet count and platelet function. When platelet
function is reduced (i.e., as a result of uremia or aspirin use), the risk of
bleeding increases.
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Risk of Bleeding*
Platelet Count
≥ 50,000/μL
Minimal
20,000 - 50,000/μL
Minor bleeding after trauma
< 20,000/μL
Spontaneous bleeding
< 5000/μL
Severe, possibly life-threatening spontaneous bleeding
*Reduced platelet function (i.e., due to uremia or aspirin use) adds to risk of bleeding.
Thrombocytopenia (combination of medical terms, “thrombocyte” [platelet]
and “penia” [deficiency], based upon Greek “thrombos” [clot]; “kytos”
[container, with modern meaning of cell]; and “penia” [poverty]) indicates
reduced platelet count numbers. Depending on its cause, thrombocytopenia
can indicate increased risk of bleeding, thrombosis, and/or mortality. Causes
of thrombocytopenia can be classified by mechanism and include decreased
platelet production, increased splenic sequestration of platelets with normal
platelet survival, increased platelet destruction or consumption (both
immunologic and nonimmunologic causes), dilution of platelets, and a
combination of these mechanisms. Increased splenic sequestration is
suggested by splenomegaly.
A large number of drugs may cause thrombocytopenia, typically by
triggering immunologic destruction. Overall, the most common specific
causes of thrombocytopenia include:

Gestational thrombocytopenia

Drug-induced thrombocytopenia due to immune-mediated platelet
destruction (commonly, heparin, trimethoprim/sulfamethoxazole)

Drug-induced thrombocytopenia due to dose-dependent bone marrow
suppression (i.e., chemotherapeutic agents)
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
Thrombocytopenia accompanying systemic infection

Immune thrombocytopenia (ITP, formerly called immune
thrombocytopenic purpura)
Classification of Thrombocytopenia
Cause
Conditions
Diminished or
absent
megakaryocytes in
bone marrow
Aplastic anemia
Leukemia
Myelosuppressive drugs (i.e., hydroxyurea, interferon alfa-2b,
chemotherapy drugs)
Paroxysmal nocturnal hemoglobinuria (some patients)
Diminished platelet
production despite
the presence of
megakaryocytes in
bone marrow
Alcohol-induced thrombocytopenia
Bortezomib use
HIV-associated thrombocytopenia
Myelodysplastic syndromes (some)
Vitamin B12 or folate (folic acid) deficiency
Platelet
sequestration in
enlarged spleen
Cirrhosis with congestive splenomegaly
Gaucher disease
Myelofibrosis with myeloid metaplasia
Immunologic
destruction
Connective tissue disorders
Drug-induced thrombocytopenia
HIV-associated thrombocytopenia
Immune thrombocytopenia
Lymphoproliferative disorders
Neonatal alloimmune thrombocytopenia
Post transfusion purpura
Nonimmunologic
destruction
Certain systemic infections (i.e., hepatitis, Epstein-Barr virus,
cytomegalovirus, or dengue virus infection)
Disseminated intravascular coagulation
Pregnancy (gestational thrombocytopenia)
Sepsis
Thrombocytopenia in acute respiratory distress syndrome
Thrombotic thrombocytopenic purpura–hemolytic-uremic syndrome
Dilution
Massive RBC replacement or exchange transfusion (most RBC
transfusions use stored RBCs that do not contain many viable
platelets)
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When faced with a thrombocytopenic patient, the clinician's key question will
need to be: what is the probable cause of the patient's thrombocytopenia?
The answer will point to the appropriate prognostic and therapeutic
considerations.
Drug-induced Thrombocytopenia
Drug-induced thrombocytopenia (DIT) is a relatively common clinical
disorder. It is imperative to provide rapid identification and removal of the
offending agent before clinically significant bleeding or, in the case of
heparin, thrombosis occurs. DIT can be distinguished from idiopathic
thrombocytopenic purpura (ITP), a bleeding disorder caused by
thrombocytopenia not associated with a systemic disease, based on the
history of drug ingestion or injection and laboratory findings. DIT disorders
can be a consequence of decreased platelet production (bone marrow
suppression) or accelerated platelet destruction (especially immunemediated destruction).
The best-known drug associated with thrombocytopenia is heparin, which
can cause mild to moderate thrombocytopenia (platelet count 50-150x109
per liter). Occurring in the first 5-10 days, this reaction involves a complex
immune reaction; the diagnosis is made by one or more clinical events and
antibody detection. Heparin should be immediately discontinued, and
medical consult sought.
A more severe and serious heparin-induced thrombocytopenia, which occurs
in around 2 per cent of patients, is linked to thrombotic events such as
myocardial infarction (MI) and strokes. Glycoprotein IIb/IIIa inhibitors, such
as abciximab, have also been associated with thrombocytopenia. Betalactam antibiotics have been associated with a seven-fold increase in risk for
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thrombocytopenia, by either an immune mediated mechanism or bone
marrow suppression. However, others have suggested this may be a result
of confounding by indication – where the infection that the antibiotic is used
to treat is an early manifestation of a blood disease. A number of other
drugs have been associated with thrombocytopenia, including cotrimoxazole, acetazolamide, chlorpropamide, furosemide, diazepam,
methyldopa, sodium valproate, thiazide diuretics, tolbutamide and
trimethoprim.
Clinical Features
Clinically, these patients will present with moderate to severe
thrombocytopenia (defined as a platelet count of less than 50x109/L) and
spontaneous bleeding varying from simple ecchymoses, petechiae and
mucosal bleeding to life-threatening spontaneous intracranial hemorrhage.
Exclusion of other causes of thrombocytopenia (such as congenital disorders
and inflammatory processes), anamnestic analysis (such as a temporal
relationship between the administration of the putative drug and the
development of thrombocytopenia), recurrence of thrombocytopenia
following reexposure to the drug and laboratory investigation (such as, total
blood count and platelet serology tests) are all important factors for the
differential diagnosis. Moreover, pseudothrombocytopenia, an artifactual
clumping of platelets in vitro without clinical significance, should also be
ruled out.
The frequency of DIT in acutely ill patients has been reported to be
approximately 19–25%. Generally, platelet count falls rapidly within 2–3
days of taking a drug that has been taken previously, or 7 or more days
after starting a new drug. When the drug is stopped, the platelet count rises
rapidly within 1–10 days of withdrawal. Thus, the primary treatment for
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drug-induced thrombocytopenia is to discontinue the suspected causative
agent. Patients experiencing life-threatening bleeding may benefit from
intravenous immunoglobulin (IVIG) therapy, plasmapheresis, or platelet
transfusions. Corticosteroids seem inefficient in the treatment of DIT.
Etiology
Hundreds of drugs have been implicated in the pathogenesis of DIT. As
noted, DIT disorders can be a consequence of decreased platelet production
or accelerated platelet destruction. A decrease in platelet production is
usually attributable to a generalized myelosuppression, a common and
anticipated adverse effect of cytotoxic chemotherapy. In addition, it has
been reported that some chemotherapeutic agents can induce
thrombocytopenia secondary to an immune-mediated mechanism.
Selective suppression of megakaryocyte production, mediated by thiazide
diuretics, ethanol and tolbutamide, could lead to isolated thrombocytopenia.
However, thiazides can also induce severe thrombocytopenia secondary to
an immune-mediated mechanism. Accelerated platelet destruction in the
presence of the offending drug is most often of immune origin. Non-immune
platelet destruction, associated to a small number of antineoplastic agents
such as bleomycin, can occur in thrombotic microangiopathy (TMA) and its
variant form, hemolytic uremic syndrome (HUS), Immune-mediated platelet
consumption is associated with a large number of drugs leading to druginduced immunologic thrombocytopenia (DITP) by a number of different
mechanisms.
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Mechanisms Of Drug-Induced Immunologic Thrombocytopenia
Drug-induced immunologic thrombocytopenia (DITP) is a relatively common
and sometimes a serious clinical disorder characterized by drug-dependent
antibodies (DDAbs) that bind to platelets and cause their destruction.
Antibodies associated with DITP are unusual in that they typically bind to
glycoproteins (GPs) on the cell membrane of the platelets only in the
presence of the provocative drug.
In the past twenty years, much has been learned about the pathogenesis of
DITP. However, knowledge of the molecular nature of the immune response
is far from complete. It is also unknown how drugs induce the development
of such antibodies. Following the observation that drug-dependent
antibodies bind to platelets via their Fab regions, subsequent studies have
documented the mechanisms of drug-dependent antibody formation.
Hundreds of drugs have been implicated in its pathogenesis, among those,
drugs most often associated with DITP are: heparin, cinchona alkaloid
derivatives (quinine and quinidine), penicillin, sulfonamides, non-steroidal
anti-inflammatory drugs (NSAIDs), anticonvulsants, antirheumatic and oral
antidiabetic drugs, gold salts, diuretics, rifampicin and ranitidine; several
other drugs are occasionally described in case reports of thrombocytopenia.
Quinidine and quinine appear to cause this condition more often than other
medications, with the exception of heparin. Commonly used drugs that
occasionally induce thrombocytopenia include:

Heparin

Quinine

Trimethoprim/sulfamethoxazole

Glycoprotein IIb/IIIa inhibitors (i.e., abciximab, eptifibatide, tirofiban)

Hydrochlorothiazide
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
Carbamazepine

Acetaminophen

Chlorpropamide

Ranitidine

Rifampin

Vancomycin
Hapten-Induced
Antibody
Karl Landsteiner’s pioneering studies in the in the field of
immunochemistry in the 1930's, showed that small molecules, such
as drugs, organic compounds, peptides and oligosaccharides with a
molecular weight of less than 2–5 kDa are not capable of inducing
an immune response. Conversely, these small molecules, called
haptens, could induce an immune response when covalently
attached to a carrier protein. Penicillin and penicillin derivatives are
an example of this category.
Penicillins constitute a large family of compounds whose common
structural basis is a beta-lactam ring condensed to a thiazolidine
ring. In the presence of free amino groups of proteins the betalactam ring opens up and the penicilloyl group covalently links to
epsilon-amino groups of lysine residues of proteins. Covalent
linkage of the drug to the protein can perturb in different ways the
antigen processing of proteins, therefore eliciting an immune
response.
Hapten-dependent immune hemolytic anemia is a well-documented
occurrence during therapy with penicillin. However
thrombocytopenia induced by the “hapten” mechanism is a rare
event.
Drug-Dependent
Antibody
(“Compound” or
“ConformationalDependent”
Antibody)
Antibody binding to the platelets is the causative mechanism. These
antibodies are heterogeneous and directed toward different
epitopes on major platelet membranes glycoproteins (GPs), most
often GPIb/IX, GPV and GPIIb/IIIa and platelet-endothelial cell
adhesion molecule-1 (PECAM-1) only when drug is present in
soluble form.
Remarkably, antibodies in an individual patient are often highly
specific for a single GP. Quinine and quinidine are the most
common causative drugs, but many other medications, including
sulfonamide antibiotics and drug metabolites are implicated in the
pathogenesis.The target of these antibodies appears to be either a
“compound” epitope, made of the drug bound noncovalently (drugs
are easily dissociated from platelets by in vitro washing procedures.
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Demonstration of drug-dependent antibodies requires the continual
presence of the suspected drug during the reaction) to one or
multiple site of the platelet GPs, or a conformational change
elsewhere on the GP molecule that is created in the presence of the
offending drug in soluble form. An alternative, but perhaps less
likely possibility, is that the drug may react first with an existing
antibody to induce a conformational change in the antibody binding
site itself. Finally, the existence of a drug-specific antibody has
been recently reported that directly recognizes quinine itself in a
subset of patients experiencing quinine-induced immune
thrombocytopenia.
The epitopes recognized by antibodies from patients with quinineand sulfonamide-induced thrombocytopenia have been
characterized for selected target molecules. Precise localization,
however, has been achieved only for a limited number of quininedependent antibodies shown to bind to a restricted 70 amino acid
domain of GPIIIa located just N-terminal from a well-defined
disulfide-bonded region that is resistant to protease digestion and
further restricted to a 17-amino acid sequence (AA residues 50–
66).
The binding site of a quinine-dependent antibody specific for GPIb
(alpha subunit) has been mapped to an 11 amino acid sequence
(AA residues 283–293) of the glycoprotein. Furthermore, it has
been reported that Arg110 and Gln115 of GPIX are important in the
formation of the quinine-dependent anti-GPIX antibody-binding
site. There is also evidence that within GPIX there exists a site that
is favored not only by quinine but also by rifampicin- and ranitidineinduced antibodies. Platelet-reactive antibodies induced by
sulfonamide antibiotics were reported to react almost exclusively
with epitopes displayed only on the intact GPIIb-IIIa complex.
Overall, the immunologic specificity appears not to be important in
the explanation and/or prediction of the pathogenesis and gravity of
DITP.
GPIIb-IIIa
Inhibitors
Thrombocytopenia associated with GPIIb/IIIa inhibitors, such as
tirofiban, eptifibatide and abciximab is a well-recognized entity.
Thrombocytopenia is even more common with the oral GPIIb/IIIa
inhibitors.
Tirofiban and eptifibatide are synthetic compounds that mimic or
contain the Ang-Gly-Asp (RGD) motif and bind tightly to the RGD
recognition site in GPIIb/IIIa (ligand-mimetic GPIIb/IIIa inhibitors);
abciximab is a Fab fragment, of the chimeric human-murine
monoclonal antibody 7E3, specific for an epitope on GPIIIa.
The onset of acute thrombocytopenia within hours of the first
exposure to a GPIIb-IIIa inhibitor suggested that nonimmune
factors might be responsible. However, it has been shown that
tirofiban- and eptifibatide-induced thrombocytopenia is due to
antibodies specific to ligand-induced binding sites (LIBS) exposed
after conformational changes in the GPIIb/IIIa molecule following
binding of these ligand-mimetics.
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Such DDAbs may develop following previous tirofiban (or
eptifibatide) exposure or may indeed be naturally occurring and
thus be associated with acute thrombocytopenia on first exposure
to the drug. Similarly, severe immune-mediated thrombocytopenia
can be observed within hours of a patient’s first exposure to
abciximab. Delayed onset of thrombocytopenia can be ascribed to
the persistence of platelet-bound abciximab for several weeks after
treatment, rendering platelets susceptible to destruction by newly
formed antibody.
It has been proposed that antibodies from patients with abciximabinduced thrombocytopenia recognize either murine sequences
incorporated into abciximab or conformational changes induced by
abciximab in GPIIb/IIIa when abciximab binds. Conversely,
antibodies found in healthy individuals, that recognize enzymatic
cleavage sites in human immunoglobulins, appear not capable of
causing thrombocytopenia in patients who have received the drug.
Drug-Induced
Autoantibody
During the exposure to a medication, some patients make drugdependent antibody and drug-independent antibodies
(autoantibodies) simultaneously. Usually these autoantibodies are
transient. On rare occasions, these autoantibodies can persist for a
long period of time leading to a chronic autoimmune
thrombocytopenic purpura (AITP) as it could be the case during the
exposure to gold salts. The underlying mechanism of this immuneresponse is unknown. A possibility, is that the drug might alter the
processing of platelet GPs in such a way that one or more peptides
not ordinarily seen by the immune system, "neoantigens", are
generated, thus “conventional” and “cryptic” GP-derived peptides
could be presented to T cells in the context of Class II HLA.
Generation of such "cryptic" peptides through various mechanisms
is an important theme in autoimmunity. In murine models, heavy
metal ions such as Hg++ and Au+++ have been shown to alter
processing of proteins, leading to presentation of cryptic (and
immunogenic) peptides. It has been speculated that sensitivity
reactions (including thrombocytopenia) seen in patients with
rheumatoid arthritis who are treated with gold salts may be related
to this mechanism, although other possibilities have been
suggested. In several human models, protein-specific antibodies
and other ligands perturb protein processing, leading to the
generation of cryptic peptides recognized by T cells.
Immune
Complex
It was hypothesized that antibodies causing DITP recognize
circulating drug directly to form immune complexes somehow
reacting with platelets as "innocent bystanders" to cause their
destruction. However, the putative immune complexes were never
demonstrated experimentally and it was later shown that DDAbs
bind to platelets via their Fab rather than Fc receptors.
Indeed, a peculiar immune complex mechanism is responsible for
the thrombocytopenia occurring in heparin-induced
thrombocytopenia (HIT).
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HIT differs from most other forms of drug-induced immune
thrombocytopenia in that the responsible antibodies bind to
complexes resulting from non-covalent interaction of a platelet
alpha granules releasate, the CXC chemokine platelet factor 4 (PF4;
CXCL4), and heparin to produce immune complexes that engage
with the Fc gamma RIIA receptor on platelets and induce platelet
activation, rather than merely binding to platelets to promote their
destruction in the reticuloendothelial system. Paradoxically, about
10% of patients with HIT also experience life-threatening
thrombosis.
Drug-induced thrombocytopenia occurs typically when a drug bound to the
platelet creates a new and foreign antigen, causing an immune reaction. This
disorder is indistinguishable from ITP except for the history of drug
ingestion. When the drug is stopped, the platelet count typically begins to
increase within 1 to 2 days and recovers to normal within 7 days.
Laboratory Diagnosis
The diagnosis of drug-induced thrombocytopenia is often empirical. In
patients exposed only to a single drug, recovery after its discontinuation
provides circumstantial evidence that the thrombocytopenia was caused by
drug sensitivity. In vitro documentation of platelet-bound immunoglobulins,
in the presence of the putative drug, provides direct evidence for the
involvement of the tested drug in causing in vivo platelet destruction.
Many different methods have been used to detect the presence of DDAbs.
These include the use of radiolabeled or fluorescein-labeled (platelet
immunofluorescence test; PIFT) anti-IgG to detect platelet-bound
immunoglobulin, enzyme-linked immunospecific assay (ELISA), flow
cytometry and immunoprecipitation-Western blotting (IP-WB). ELISA and IPWB allow assessing both the presence and specificity of DDAbs. Because the
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formation of the target for DDAb occurs when the drug noncovalently
associates with a specific protein, the drug must be constantly present in
every step of the assay, including washing buffer. The specificity of the
reaction is assessed by comparing the reactivity of the serum or plasma
sample in the presence and in the absence of drug.
Flow cytometry is a rapid and highly sensitive technique for the detection of
platelet-reactive antibodies induced by several drugs, including, but not
limited to, quinine, quinidine and sulfamethoxazole. As noted, the ELISA
techniques, while not as sensitive, facilitates identification of the target
molecules with which DDAb react; these include the antigen capture ELISA
assay, in which a monoclonal antibody specific for a platelet membrane
glycoprotein is plated onto microtiter wells and used to capture the specific
membrane glycoproteins from a platelet lysate (ACE, MAIPA) and a modified
antigen capture ELISA in which the drug-dependent antibodies are first
incubated in the presence or absence of drug with intact platelets, the cells
containing bound antibodies then lysed in Triton X-100, and the lysate
applied to a monoclonal antibody coded ELISA well.
Factors that should be considered for the failure to demonstrate DDAbs
include poor solubility in an aqueous medium of some drugs; the possibility
that the sensitizing agent can be a structurally modified form of the
sensitizing drug resulting from in vivo metabolism; and a possible
requirement that autologous cells be used for testing.
Treatment
The treatment includes stopping drugs that impair platelet function, and
rarely, platelet transfusions. In patients with thrombocytopenia or platelet
dysfunction, drugs that further impair platelet function, particularly
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aspirin and other NSAIDs, should not be given. Patients who are already
taking such drugs should consider alternative drugs, such as acetaminophen,
or simply stop using them.
Patients may require platelet transfusion, but transfusions are given only in
limited situations. Prophylactic transfusions are used sparingly because they
may lose their effectiveness with repeated use due to the development of
platelet alloantibodies. In platelet dysfunction or thrombocytopenia caused
by decreased production, transfusions are reserved for patients with active
bleeding, severe thrombocytopenia (i.e., platelet count < 10,000/μL), or in
need of invasive procedures. In thrombocytopenia caused by platelet
destruction, transfusions are reserved for life-threatening or CNS bleeding.
Heparin-Induced Thrombocytopenia
Studies have shown that between 1% and 5% of hospital patients exposed
to heparin for 1 to 2 weeks develop HIT. Of patients diagnosed with HIT,
approximately one-third will develop overt thrombosis and of these, about
one-third will suffer amputation or death. Hence, the overall chance of
serious morbidity or mortality as a result of a course of heparin therapy is
about 3 per 1000. Early recognition and appropriate treatment may reduce
these numbers.
Heparin is a widely used anticoagulant that can be administered
intravenously (IV) or subcutaneously (SC) both to prevent thrombosis in
high-risk patients and to limit progression of established thrombosis. It is
also used as a flush to keep IV lines open. Heparin is often used to prevent
clotting in extracorporeal circulation such as that in heart–lung bypass
machines, where it is infused or even present as the anticoagulant coating
within the tubing system.
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Heparin-induced thrombocytopenia is characterized by an unexplained
decrease in platelet count, occurring 5 or more days after the initiation of
heparin therapy. This lag is consistent with an immune response related to
heparin administration, unless the patient has been previously exposed to
heparin.
Nomenclature seen in the literature regarding this syndrome can be
confusing. Over the years, various names have been used for this syndrome,
such as heparin-induced thrombocytopenia with thrombosis syndrome
(HITTS) and HIT type II. These terms have been used to distinguish
immune-mediated HIT from the mild, non–immune-mediated
thrombocytopenia, which may occur within the first few days of heparin
administration. This nonimmune (also called HIT type I) thrombocytopenia
resolves spontaneously and does not increase the risk for thrombosis. For
the rest of this section, when the term HIT is used, it signifies the immunemediated disorder in which there is a risk of thrombosis.
Heparin-induced thrombocytopenia may occur even when very-lowdose heparin (i.e., used in flushes to keep IV or arterial lines open) is used.
The mechanism is usually immunologic. Bleeding rarely occurs, but more
commonly platelets clump excessively, causing vessel obstruction, leading to
paradoxical arterial and venous thromboses, which may be life threatening
(i.e., thromboembolic occlusion of limb arteries, stroke, acute
MI). Heparin should be stopped in any patient who becomes
thrombocytopenic and develops a new thrombosis or whose platelet count
decreases by more than 50%.
All heparin preparations should be stopped immediately and presumptively,
and tests are done to detect antibodies to heparin bound to platelet factor.
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Anticoagulation with nonheparin anticoagulants (i.e., argatroban, bivalirudin,
fondaparinux) is necessary at least until platelet recovery. Low molecular
weight heparin (LMWH) is less immunogenic than unfractionated heparin but
cannot be used to anticoagulate patients with HIT because most HIT
antibodies cross-react with LMWH. Lepirudin is no longer available.
Warfarin should not be substituted for heparin in patients with HIT and, if
long-term anticoagulation is required, should be started only after the
platelet count has recovered.
Although HIT may present with simultaneous thrombocytopenia and
thrombosis, or sometimes with thrombosis preceding thrombocytopenia, the
first manifestation of HIT is usually an unexplained decrease in platelet count
of 30% to 50% or to less than 100 × 109/L, occurring 5 or more days
(usually 5 to 8 days) after the initiation of heparin therapy. The platelet
count rarely decreases to 15 × 109/L or less. The mean nadir has been
reported to be approximately 60 × 109/L.
Heparin-induced thrombocytopenia can cause both venous and arterial
thrombosis, but venous thrombosis occurs about four times more often.
DVT, PE, lower limb arterial thrombosis, and coronary arterial thromboses
may occur. Other sequelae can also be seen. Thromboses may be multiple.
The occurrence of multiple arterial thromboses is sometimes referred to as
white clot syndrome, because the thrombi formed in high-flow vessels have
a high platelet and fibrin content and relatively few red blood cells.
Accurate diagnosis of HIT requires a high degree of suspicion on the part of
the medical provider caring for the heparin-exposed patient.
Recommendations for monitoring platelet counts vary, but it seems prudent
to check a baseline platelet count at the initiation of heparin therapy and to
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repeat platelet counts at intervals of several days. Because of the timing of
the onset of HIT, particular vigilance around day 4 after initiation of heparin
(day 0 being the first day of heparin administration) and for 10 days
thereafter is particularly crucial. Patients who have had previous exposure to
heparin may have an amnestic response and develop HIT rapidly after
repeat heparin exposure. Many other causes for a decreased platelet count
should be considered before rendering a diagnosis of HIT. Among these are
fever, DIC, splenomegaly, and medications (other than heparin). Of note, in
spite of the thrombocytopenia, HIT patients rarely have a bleeding diathesis.
If suspicion of HIT is high, all sources of heparin exposure should be
discontinued immediately. Continued heparin exposure greatly increases the
risk of thrombosis and LMWH should not be administered, as there is a
cross-reactivity rate of 93%. Assays are available to assist in the diagnosis
of HIT, but discontinuation of heparin should not wait for these results.
Alternative anticoagulant therapy — direct thrombin inhibitors (hirudin
analogs or argatroban) should be considered because of the high risk of
thrombosis even after heparin is discontinued. Platelet count often rises
rapidly after the discontinuation of heparin. The return of the platelet count
to normal within 5 to 7 days of discontinuation of heparin is consistent with
a diagnosis of HIT, although some have been observed to take up to a
month to recover completely. As with most immune reactions, heparin
antibodies may remain in the plasma for extended periods of time. However,
testing should occur within 6 weeks of a thrombocytopenic event.
The risk of HIT appears to be greater in patients exposed to large amounts
of heparin, such as when systemic anticoagulation is required. However,
patients with exposures to very small amounts of heparin, such as that used
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to keep intravenous lines from clotting when not in use, have also developed
HIT.
Two types of assays are commonly used to assist in the diagnosis of HIT:
functional assays and antigen assays. The antigen assays are ELISAs that
use the H-PF4 complex as the target antigen to detect HIT-type
immunoglobulin in the patient's serum. Serologic assays detect IgG, IgA,
and IgM antibodies and have high sensitivity (more than 95%) but the
specificity is low (74% to 86%). In other words, the positive predictive value
of serologic assays is low but the negative predictive value is high.
Functional assays may simply look for platelet aggregation or may be a
variation on a platelet aggregation method that detects products of the
platelet release reaction, such as serotonin or adenosine triphosphate (ATP).
These assays use the patient's serum, heparin, and donor platelets. Either
bovine or porcine heparin may be used in the assays. There is no need for
the laboratory to determine whether the patient has received bovine or
porcine heparin.
It is important to use platelets from donors whose platelets are known to be
reactive to HIT sera. It is unknown why some donors' platelets are reactive
and others are not. Occasional combinations of known HIT sera and known
reactive HIT-reactive platelets do not aggregate. Therefore, it has been
suggested that platelets from two donors whose platelets are known to react
to HIT sera should be used. If platelet aggregation occurs or if there is
evidence of the release reaction only at a low concentration of heparin (0.1
U/mL), this is evidence that the patient's serum contains antibodies that
activate and aggregate platelets in the presence of a therapeutic
concentration of heparin.
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The effective management of patients with HIT is to prevent thrombosis by
limiting platelet activation and thrombin generation. Stopping all heparin
exposure is the most important step in preventing or limiting thrombosis in
patients with HIT. However, even after cessation of heparin, the patient still
has a risk of approximately one in three for developing thrombosis. LMWH
should not be given to patients with HIT because of high cross-reactivity
with PF4-heparin antibodies. Therefore, the use of other anticoagulants
should be considered. In addition, the substitution of another anticoagulant
may be beneficial in patients with an established thrombus.
Because of the risk of venous limb gangrene (distal ischemic necrosis that is
present despite palpable or Doppler-identifiable arterial pulses) the oral
anticoagulant warfarin sodium should not be used in a patient with HIT
unless the patient is also adequately anticoagulated by another nonheparin
anticoagulant for the first few days. The early warfarin-induced reduction of
functioning protein C in the presence of increased thrombin generation seen
in HIT, puts the patient at very high risk for this and other thrombotic
complications. LMWH is also not recommended for the treatment of HIT.
Although it is less likely to induce HIT once a patient has a heparin-induced
antibody, exposure to LMWH carries a risk of thrombosis.
Anticoagulants available for use in HIT patients include heparinoids such as
danaparoid and direct thrombin inhibitors such as hirudin, argatroban, and
bivalirudin, which are discussed subsequently. The adjunctive use of
medications that limit platelet function is also under investigation. Examples
include glycoprotein IIb/IIIa (GPIIb/IIIa) inhibitors such as GPI 562 and ADP
receptor antagonists, clopidogrel and ticlopidine. The current
recommendation for HIT patients is therapy with an alternate anticoagulant
(direct thrombin inhibitors) to be followed by a transition to warfarin. The
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87
warfarin should be started at low doses and given concurrently with direct
thrombin inhibitors for 5 days until a therapeutic INR is achieved for 2 days.
Care should be taken in monitoring INR during this period, as direct
thrombin inhibitors may prolong the INR. Obtaining a chromogenic X assay
may help in transitioning a patient from direct thrombin inhibitors (DTI) to
warfarin. Warfarin is typically continued for 3 to 6 months; however, the
optimal duration of anticoagulation needs further study. Other commonly
associated agents in HIT patients include:

Quinine

Quinidine

Gold Salts

Sulfonamide Antibiotics

Rifampin

Glycoprotein (GP) IIb/IIIa (GPIIb/IIIa) Receptor Antagonists

Heparin
Summary
Medications offer lifesaving treatments for many patients, but they do not
come without risks. Many medications may actually be responsible for
inducing blood dyscrasias. Although medication-induced hematologic
disorders are less common than other types of adverse medication reactions,
they are associated with significant morbidity and mortality. Some agents
cause predictable hematologic disease (i.e., antineoplastics), but others
induce idiosyncratic reactions not directly related to the drugs’
pharmacology. The most common drug-induced hematologic disorders
include aplastic anemia, agranulocytosis, megaloblastic anemia, hemolytic
anemia, and thrombocytopenia.
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The incidence of idiosyncratic drug-induced hematologic disorders varies
depending on the condition and the associated drug. Few epidemiologic
studies have evaluated the actual incidence of these adverse reactions, but
these reactions appear to be rare. Women are generally more susceptible
than men to the hematologic effects of drugs. The incidence varies based on
geography, which suggests that genetic differences may be important
determinants of susceptibility.
The wide spectrum of drug-induced hematologic syndromes is mediated by a
variety of mechanisms, including immune effects, interactions with
enzymatic pathways, and direct inhibition of hematopoiesis. Providing proof
that a drug causes a particular hematologic syndrome is frequently
impossible. Many patients simultaneously receive multiple drugs, making it
difficult to be certain of causality. As medicine advances, older drugs become
obsolete and are replaced by newer formulations. Many drugs formerly
associated with hematologic toxicities are no longer in common use.
However, newer drugs are found to be associated with their own potential
hematologic toxicities. Clinicians from a wide variety of specialties in their
everyday practice need to understand the hematological consequences of
drugs and be prepared for the occurrence and correction of these events in
their patients.
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1. __________ is a lowered threshold to the normal
pharmacological action of a drug.
a.
b.
c.
d.
Dyscrasia
Intolerance
Hypersensitivity
Idiosyncrasy
2. True or False: Idiosyncrasy differs from intolerance in that it is
not an exaggeration of the normal response; it is an abnormal
response per se.
a. True
b. False
3. The development of corneal opacities and retinal damage in
patients treated with chloroquine as an antimalarial or for
arthritis and amebiasis is an example of a drug
a.
b.
c.
d.
side effect.
intolerance.
hypersensitivity.
overdosage.
4. The principal ions necessary for normal cell function include
calcium, sodium, potassium, __________, magnesium, and
hydrogen.
a.
b.
c.
d.
albumin
bilirubin
chloride
heme
5. The main protein constituent of plasma is ________, which is
the most important component in maintaining osmotic
pressure.
a.
b.
c.
d.
intrinsic factor (IF)
bilirubin
heme
albumin
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6. Which of the following is a “secondary effect” of antibiotics?
a.
b.
c.
d.
An anaphylactoid reaction
Avitaminosis
Hepatic damage
Digitalis action
7. A patient with a history of allergies is more likely to be a
candidate for ______________ to a drug than a patient
without a history of allergies.
a.
b.
c.
d.
intolerance
overdosage
hypersensitivity
a secondary effect
8. True or False: The coagulation proteins responsible for
hemostasis circulate in the blood as active enzymes until they
are needed for the coagulation process.
a. True
b. False
9. This process in which blood cells are produced and develop in
the bone marrow is known as
a.
b.
c.
d.
cytopenia.
hematopoiesis.
pancytopenia.
hemostasis.
10. This process in which blood cells are produced and develop in
the bone marrow is known as
a.
b.
c.
d.
cytopenia.
hematopoiesis.
pancytopenia.
hemostasis.
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11. _________ concentration of cellular constituents in the
blood, especially enzymes, can indicate abnormal cell
destruction in a specific organ.
a.
b.
c.
d.
Increased
Decreased
Differentiated
None of the above
12. ___________ contain the vital protein hemoglobin, which is
responsible for transport of oxygen and carbon dioxide
between the lungs and body tissues.
a.
b.
c.
d.
Platelets
Monocytes
Leukocytes
Erythrocytes
13. True or False: The least mature cells are at the periphery of
the erythroblastic island, and the more mature cells are
closest to the center.
a. True
b. False
14. Which of the cellular blood constituents pass through intact
vessel walls to tissues where they defend against invading
foreign pathogens?
a.
b.
c.
d.
Platelets
Hemoglobin
Leukocytes
Erythrocytes
15. Primary lymphoid tissues consist of
a.
b.
c.
d.
thymus and spleen.
lymph nodes.
bone marrow and thymus.
spleen and lymph nodes.
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16. True or False: Primary lymphoid tissues are those in which T
and B cells develop from nonfunctional precursors into
immunocompetent cells.
a. True
b. False
17. Acute blood loss can cause erythropoietic tissue to
temporarily replace
a.
b.
c.
d.
liver function.
fatty tissue.
hematopoiesis.
chronic anemia.
18. Blood-forming tissue located between the trabeculae of
spongy bone is known as
a.
b.
c.
d.
the trabecula.
the spleen.
bone marrow.
platelets.
19. _________ are located on the abluminal surface of the
vascular sinuses and send long cytoplasmic processes into
the stroma.
a.
b.
c.
d.
Fat cells
Reticular cells
Macrophages
Adipocytes
20. Erythroblasts constitute ________ of the marrow cells and
are produced near the venous sinuses.
a.
b.
c.
d.
most
10-20%
half
25–30%
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21. ___________ cells can leave the bone marrow and travel to
the thymus where they mature into T lymphocytes.
a.
b.
c.
d.
Macrophages
Cortical epithelial cells
Lymphoid progenitor
Erythrocytes
22. Cytoplasmic processes of the megakaryocyte form long
proplatelet processes that pinch off to form
a.
b.
c.
d.
macrophages.
hemoglobin.
platelets.
lymphocytes.
23. True or False: Stromal cellular components also provide
cytokines that regulate hematopoiesis.
a. True
b. False
24. Some lymphoid progenitor cells remain in the bone marrow
where they mature into
a.
b.
c.
d.
T lymphocytes.
fat cells.
epithelial cells.
B lymphocytes.
25. Any change in volume of the hematopoietic tissue, as occurs
in many anemias and leukemias, must be compensated for by
a change in the space-occupying
a.
b.
c.
d.
adipocytes.
cortical epithelial cells.
reticular cells.
macrophages.
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26. Myeloproliferative disease, which begins as a hypercellular
disease, frequently terminates in a state of aplasia (absence
of hematopoietic tissue in bone marrow) in which
__________ replaces hematopoietic tissue.
a.
b.
c.
d.
fibrous tissue
fat cells
abnormal cells
dendritic cells
27. Hematopoiesis in the bone marrow is called __________
hematopoiesis.
a.
b.
c.
d.
bilobular
epithelial
abluminal
medullary
28. If _____________ is/are found in the early stages, the
diagnosis of aplastic anemia should be questioned.
a.
b.
c.
d.
cardiopulmonary complications
petechial hemorrhages
splenomegaly
mucosal hemorrhages
29. True or False: The primary purpose of the thymus is to serve
as a compartment in which T lymphocytes mature.
a. True
b. False
30. The best-documented example(s) of drugs causing aplastic
anemia is/are
a.
b.
c.
d.
the antibiotic chloramphenicol.
the anti-inflammatory drug phenylbutazone.
a., and b., above
None of the above
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31. True or False: The spleen is located in the upper-left quadrant
of the abdomen beneath the diaphragm and to the left of the
stomach and is essential to life.
a. True
b. False
32. _____________ using cells collected from bone marrow has
become a relatively common procedure and is curative in
many patients with aplastic anemia.
a.
b.
c.
d.
HSCT (hematopoietic stem cell transplantation)
IST (intensive immunosuppressive therapy)
Cyclosporine
ATG (antithymocyte globulin)
33. People who are taking certain medications such as cancer
(chemotherapeutic) drugs, alkylating agents, anti-thyroid
drugs, and dibenzepin compounds can be at risk for
a.
b.
c.
d.
aplastic anemia.
acquired agranulocytosis.
megaloblastic anemia.
familial neutropenia.
34. A finding of hypersegmented neutrophils is considered highly
sensitive and specific for ____________.
a.
b.
c.
d.
hemolytic anemia.
acquired agranulocytosis.
megaloblastic anemia.
aplastic anemia.
35. A hemolytic state exists when the in vivo survival of red cells
a.
b.
c.
d.
is lengthened.
ceases.
is shortened.
None of the above
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36. True or False: The best-known drug associated with
thrombocytopenia is heparin.
a. True
b. False
37. Heparin is a widely used _________ that can be administered
intravenously (IV) or subcutaneously (SC) both to prevent
thrombosis in high-risk patients and to limit progression of
established thrombosis.
a.
b.
c.
d.
antimalarial
antidepressant
anticoagulant
antifungal
38. In patients with suspected drug-induced thrombocytopenia,
who were exposed only to a single drug, recovery after its
discontinuation is _______ evidence that the
thrombocytopenia was caused by drug sensitivity.
a.
b.
c.
d.
direct
not
absolute
circumstantial
39. Platelet-reactive antibodies may be induced by several drugs,
including, quinine, quinidine and sulfamethoxazole.
a.
b.
c.
d.
sulfamethoxazole.
quinidine.
quinine.
All of the above.
40. Selective suppression of megakaryocyte production, mediated
by thiazide diuretics, ethanol and __________, could lead to
isolated thrombocytopenia sulfamethoxazole.
a.
b.
c.
d.
sulfamethoxazole
tolbutamide
heparin
oral antibiotics
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Correct Answers:
1. b
11. a
21. c
31. b
2. a
12. d
22. c
32. a
3. a
13. b
23. a
33. b
4. c
14. c
24. d
34. c
5. d
15. c
25. a
35. c
6. b
16. a
26. a
36. a
7. c
17. b
27. d
37. c
8. b
18. c
28. c
38. d
9. a
19. b
29. a
39. d
10. b
20. d
30. c
40. b
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