V. ANATOMY & PHYSIOLOGY

The Bone Marrow

The Bone marrow is the soft, flexible, vascular tissue found in the hollow interior

cavities and cancellous bone spaces in the center of many bones and which is the

source of erythrocytes (red blood cells) and leukocytes (white blood cells).

There are two main types of bone marrow. Red bone marrow is the center of production

of all blood cells except one type of lymphocyte, which matures in the thymus. Yellow

bone marrow stores fats.

As the source of blood cells, the bone marrow is critical to the health of people. The

disruption of the intricate harmony, such as the production of too many, too few, or

abnormal blood cells, results in diseases, such as leukemia, that can be life-threatening.

Medical procedures have been developed to examine the bone marrow (bone marrow

aspiration and biopsy) of patients and also to transfer normal stem cells from a donor

into a recipient (bone marrow transplantation).

STRUCTURE

Red marrow consists primarily of a loose, soft network of blood vessels and protein

fibers interspersed with developing blood cells. The blood vessels are termed the

vascular component, and the protein fibers and developing blood cells collectively are

referred to as the stroma, or the extravascular component. The protein fibers crisscross

the marrow, forming a meshwork that supports the developing blood cells clustered in

the spaces between the fibers.

Red marrow contains a rich blood supply. Arteries transport blood containing oxygen

and nutrients into the marrow, and veins remove blood containing carbon dioxide and

other wastes. The arteries and veins are connected by capillaries, blood vessels that

branch throughout the marrow. In various places, the capillaries balloon out, forming

numerous thin, blood-filled cavities. These cavities are called sinusoids, and they assist

in blood-cell production.

Yellow marrow is so named because it is composed of yellow fat cells interspersed in a

rich mesh of connective tissue that also supports many blood vessels. While not usually

actively involved in blood formation, in an emergency yellow marrow is replaced by

blood-forming red marrow when the body needs more blood.

Gray's Anatomy illustration of cells in bone marrow. (From New World Encyclopedia)

FUNCTIONS

Red marrow produces all of the body’s blood cells—red blood cells, white blood cells,

and platelets. Red blood cells in the circulatory system transport oxygen to body tissues

and carbon dioxide away from tissues. White blood cells are critical for fighting bacteria

and other foreign invaders of the body. Platelets are essential for the formation of blood

clots to heal wounds.

Within red bone marrow, all blood cells originate from a single type of cell, called a

hematopoietic stem cell. Stimulated by hormones and growth factors, these stem cells

divide to produce immature, or progenitor blood cells. Most of these progenitor cells

remain in the stroma and rapidly undergo a series of cell divisions, producing either red

blood cells or white blood cells. At any one time, the stroma consists largely of

progenitor cells in various stages of development. At the appropriate developmental

stage, the fresh, new cells squeeze through the walls of the capillaries. From there, the

cells leave the bone and enter the body’s circulatory system. Some progenitor cells

migrate to the sinusoids, where they produce platelets, which also travel to the

circulatory system via the capillaries.

Although stem cells are relatively rare—about 1 in every 10,000 marrow cells is a stem

cell—they typically produce the forerunners of an estimated 2 million red cells per

second and 2 billion platelets per day. However, if significant amounts of blood are lost

or other conditions reduce the supply of oxygen to tissues, the kidneys secrete the

hormone erythropoietin. This hormone stimulates stem cells to produce more red blood

cells. To fight off infection, hormones collectively termed colony stimulating growth

factors are released by the immune system. These hormones stimulate the stem cells to

produce more infection-fighting white blood cells. And in severe cases, the body

converts yellow marrow into red marrow to help produce needed blood cells.

THE HEMATOPOIETIC SYSTEM

Hematology is the science of blood and blood forming tissues. It includes both

cellular and non-cellular blood components. Hematologic activities occur in many organs

of the body and have the potential for multiple forms of pathology. Blood itself is

composed of two elements – the liquid component, plasma, and the solid components,

which are mainly erythrocytes, leukocytes, and thrombocytes. These elements are

formed by hematopoiesis.

Hematopoiesis is the continuous, regulated formation of blood cells. There are

three primary functions of hematopoiesis.

1. Oxygen delivery

2. Hemostasis

3. Host defense

Note that some complexity is omitted from the diagram. Lymphocytes come from

"Lymphoid" line, whereas granulocytes, monocytes, megakaryocytes, and erythrocytes

come from "Myeloid" line. Among myeloid cells, granulocytes and monocytes have a

common precursor, "CFU-GM".

Hematopoiesis occurs in the bone marrow. The degree and location of bone

marrow activity varies depending on the age and health status of your patient. Within the

bone marrow there is a pluripotent stem cell. This stem cell is the “Mother Cell” or the

originator of all blood cells. It has the ability to self-renew and create progenitor stem cell

lines. They are naturally limited in number. By reviewing the chart above, you can see

that all cells come from the stem cell. An attack on the stem cell can theoretically affect

all of them similarly. A disease or agent that impacts erythroblasts could impact all the

cell type in that “line,” but not those in a different “line.”

The Blood

Blood is a liquid tissue. Suspended in the watery plasma are seven types of cells

and cell fragments. The Red Blood Cells (RBCs) or erythrocytes , Platelets or

thrombocytes, and five kinds of white blood cells (WBCs) or leukocytes. Three kinds of

granulocytes are as follows: Neutrophils, Eosinophils, Basophils. Two kinds of

leukocytes without granules in their cytoplasm are: Lymphocytes and Monocytes,

Functions of the BloodBlood performs two major functions: transport through the body of : oxygen and

carbon dioxide, food molecules (glucose, lipids, amino acids), ions (e.g., Na+, Ca2+,

HCO3−), wastes (e.g., urea), hormones, heat and defense of the body against infections

and other foreign materials. All the WBCs participate in these defenses.

Red Blood Cells (erythrocytes)

The most numerous type in the blood. Women average about 4.8 million of these

cells per cubic millimeter (mm3; which is the same as a microliter [µl]) of blood. Men

average about 5.4 x 106 per µl. These values can vary over quite a range depending on

such factors as health and altitude. (Peruvians living at 18,000 feet may have as many

as 8.3 x 106 RBCs per µl.) RBC precursors mature in the bone marrow closely attached

to a macrophage. They manufacture hemoglobin until it accounts for some 90% of the

dry weight of the cell. The nucleus is squeezed out of the cell and is ingested by the

macrophage. No-longer-needed proteins are expelled from the cell in vesicles called

exosomes. Thus RBCs are terminally differentiated; that is, they can never divide. They

live about 120 days and then are ingested by phagocytic cells in the liver and spleen.

Most of the iron in their hemoglobin is reclaimed for reuse. The remainder of the heme

portion of the molecule is degraded into bile pigments and excreted by the liver. Some 3

million RBCs die and are scavenged by the liver each second. Red blood cells are

responsible for the transport of oxygen and carbon dioxide.

Hemoglobin

Hemoglobin is a protein that is carried by red cells. It picks up oxygen in the lungs

and delivers it to the peripheral tissues to maintain the viability of cells. Hemoglobin is

made from two similar proteins that "stick together". Both proteins must be present for

the hemoglobin to pick up and release oxygen normally. One of the component proteins

is called alpha, the other is beta. Before birth, the beta protein is not expressed. A

hemoglobin protein found only during fetal development, called gamma, substitutes up

until birth.

In adult humans the hemoglobin (Hb) molecule consists of four polypeptides: two

alpha (α) chains of 141 amino acids and two beta (β) chains of 146 amino acid. Each of

these is attached the prosthetic group heme. There is one atom of iron at the center of

each heme. One molecule of oxygen can bind to each heme.

Like all proteins, the "blueprint" for hemoglobin exists in DNA (the material that

makes up genes). Normally, an individual has four genes that code for the alpha protein,

or alpha chain. Two other genes code for the beta chain. (Two additional genes code for

the gamma chain in the fetus). The alpha chain and the beta chain are made in precisely

equal amounts, despite the differing number of genes. The protein chains join in

developing red blood cells, and remain together for the life of the red cell.

Hemoglobin synthesis requires the coordinated production of heme and globin.

Heme is the prosthetic group that mediates reversible binding of oxygen by hemoglobin.

Globin is the protein that surrounds and protects the heme molecule.

Erythrocytes and Related Values

Red Blood Cell (RBC)Normal Range: 4.6-6.3 X106/mm3 (males)4.2 -5.4 X106/mm3 (females)

Erythrocytes, or red blood cells, originate from a stem cell. Vitamin B12, folic acid, iron,

and copper are essential in the formation of erythrocytes. Erythropoietin is released by

kidneys in response to hypoxemia which stimulates the bone marrow to produce red

blood cells. Typically, red blood cells live approximately 120 days. When the red blood

cells become old and damaged, the liver, spleen, and bone marrow cleanse them from

the blood.

Reticulocyte CountNormal Range: 0.5-2.5% of RBCsWhen released from the bone marrow red blood cells are slightly immature and are

known as reticulocytes. Reticulocytes mature into red blood cells within a few days.

HemoglobinNormal Range: 14-18 g/dL (males)12-16 g/dl (females)Hemoglobin is a protein-iron compound in red blood cell that carries oxygen. This

laboratory value is used to evaluate the oxygen-carrying capacity of the blood. Red

blood cells and hemoglobin go hand in hand. One unit of packed red blood cells

generally equals one whole number increase in your hemoglobin value. For example:

If your patient’s hemoglobin is 7.0 g/dl, and you give him one unit of packed red blood

cells, your patient’s hemoglobin should come up to 8.0 g/dl.

HematocritNormal Range: 42-52% (males)37-57% (females)Hematocrit is an expression of the total percentage of blood volume that is composed of

red blood cells. It is also known as the packed cell volume of your blood (Sherwood,

1997).

IronNormal Range: 50-150 mcg/dLAs mentioned earlier, iron is necessary for the formation of hemoglobin, an essential part

of the red blood cell. Iron is absorbed from the small intestine into the blood and binds

with transferrin. Transferrin transports iron tothe bone marrow where it is used to make

hemoglobin.

Total Iron Binding CapacityNormal Range: 250-410 mcg/dlThe amount of iron that can still bind with transferrin (to be transported to bone marrow

to make hemoglobin) is known as the total iron binding capacity or TIBC. Think of your

TIBC as the total amount of people that can get on a bus. The iron is the people and the

bus is transferrin. When your serum iron levels increase, your TIBC decreases. When

you serum iron levels decrease, then your TIBC increases.

FerritinNormal Range: 20 - 300 ng/mL (males)20 - 120 ng/mL (females)Ferritin is a protein that binds to iron. Most of the iron stored in the body is attached to

ferritin. Ferritin is found in the liver, spleen, and bone marrow. Only a small amount is

found in the blood. Like the TIBC, the amount of ferritin in the blood may help indicate

the amount of iron stored in your body.

White Blood Cell Count (WBC) and Differential

White blood cells, or leukocytes, are classified into two main groups:

granulocytes and nongranulocytes (also known as agranulocytes). The granulocytes,

which include neutrophils, eosinophils, and basophils, have granules in their cell

cytoplasm. Neutrophils, eosinophils, and basophils also have a multilobed nucleus. As a

result they are also called polymorphonuclear leukocytes or "polys." The nuclei of

neutrophils also appear to be segmented, so they may also be called segmented

neutrophils or "segs." The nongranuloctye white blood cells, lymphocytes and

monocytes, do not have granules and have nonlobular nuclei. They are sometimes

referred to as mononuclear leukocytes.

The lifespan of white blood cells ranges from 13 to 20 days, after which time they

are destroyed in the lymphatic system. When immature WBCs are first released from the

bone marrow into the peripheral blood, they are called "bands" or "stabs." Leukocytes

fight infection through a process known as phagocytosis. During phagocytosis, the

leukocytes surround and destroy foreign organisms. White blood cells also produce,

transport, and distribute antibodies as part of the body's immune response.

LeukocytesTotal WBCNormal Range: 5,000 -10,000/microliter

Leukocytes, or white blood cells, protect the body from bacteria and infection.

The white blood cell count is expressedas the number of leukocytes per microliter of

blood. The total WBC count increases in response to infection or trauma.

LymphocytesNormal Range: 16-46%

There are several kinds of lymphocytes (although they all look alike under the

microscope), each with different functions to perform . The most common types of

lymphocytes are B Lymphocytes ("B cells"). These are responsible for making

antibodies. T lymphocytes ("T cells"). There are several subsets of these: Inflammatory

T-cells that recruit macrophages and neutrophils to the site of infection or other tissue

damage. Cytotoxic T-Lymphocytes (CTLs) that kill virus-infected and, perhaps, tumor

cells. Helper T-cells that enhance the production of antibodies by B cells.

Although bone marrow is the ultimate source of lymphocytes, the lymphocytes

that will become T cells migrate from the bone marrow to the thymus where they mature.

Both B cells and T cells also take up residence in lymph nodes, the spleen and other

tissues where they encounter antigens; continue to divide by mitosis; mature into fully

functional cells. Lymphocytes mature in the lymph nodes. They live approximately 100-

300 days. The total lymphocyte count represents total T and B lymphocytes. T

lymphocytes are killer cells. They tell B lymphocytes to make antibodies. Lymphocytes

increase in viral illnesses, such as measles, mumps, chicken pox, influenza, viral

hepatitis, mononucleosis, and in acute transplant rejection.

MonocytesNormal Range: 0-12%

Monocytes leave the blood and become macrophages. Macrophages are large,

phagocytic cells that engulf foreign material (antigens) that enter the body dead and

dying cells of the body. They ingest cellular debris at the area of infection or

inflammation. They increase after several days of active infection or inflammation. They

are like your body’s garbage truck: they are a little slow, but they pick up all the

“garbage” or cellular debris and take it away.

NeutrophilsNormal Range: 40-70%

The most abundant of the WBCs. This photomicrograph shows a single

neutrophil surrounded by red blood cells. Neutrophils squeeze through the capillary walls

and into infected tissue where they kill the invaders (e.g., bacteria) and then engulf the

remnants by phagocytosis. This is a never-ending task, even in healthy people: Our

throat, nasal passages, and colon harbor vast numbers of bacteria. Most of these are

commensals, and do us no harm. But that is because neutrophils keep them in check.

However, heavy doses of radiation, chemotherapy, and many other forms of stress can

reduce the numbers of neutrophils so that formerly harmless bacteria begin to

proliferate. The resulting opportunistic infection can be life-threatening. Leukocyte types

are counted and expressed as a percentage. Neutrophils are the predominant type of

granulocytes. Neutrophils are special soldiers in your body’s immunity army. Their main

responsibility is to kill bacteria, destroy bacteria’s ability to reproduce, and destroy

bacteria’s ability to produce endotoxins.

BandsNormal Range: 0-8%

Neutrophil’s primal cell type is bands. Bands are adolescent neutrophils. It is

abnormal to have elevated bands in your blood stream. When the percent of bands is

increased you have a “shift to the left.” Historically, the diagram of the hematopoietic

system was read from left to right, not top to bottom as it does today. Thus, if you had an

increase in a cell type, moving left to the progenitor cell – you would have a shift to the

left.

EosinophilsNormal Range: 0-7%

The number of eosinophils in the blood is normally quite low (0–450/µl).

However, their numbers increase sharply in certain diseases, especially infections by

parasitic worms. Eosinophils are cytotoxic, releasing the contents of their granules on

the invader. Eosinophils are responsible for fighting parasites, and are increased in

allergic or autoimmune disorders. For example, eosinophils increase when a patient has

hives due to allergic reaction.

BasophilsNormal Range: 0-1%

The number of basophils also increases during infection. Basophils leave the

blood and accumulate at the site of infection or other inflammation. There they discharge

the contents of their granules, releasing a variety of mediators such as: histamine,

serotonin, prostaglandina and leukotrienes which increase the blood flow to the area and

in other ways add to the inflammatory process. The mediators released by basophils

also play an important part in some allergic responses such as hay fever and an

anaphylactic response to insect stings. Histamine and heparin and increase only in the

healing process.

Leukocytosis, a WBC above 10,000, is usually due to an increase in one of the

five types of white blood cells and is given the name of the cell that shows the primary

increase. Neutrophilic leukocytosis = neutrophilia, Lymphocytic leukocytosis =

lymphocytosis, Eosinophilic leukocytosis = eosinophilia, Monocytic leukocytosis =

monocytosis, Basophilic leukocytosis = basophilia.

PhysiologyIn response to an acute infection, trauma, or inflammation, white blood cells

release a substance called colony-stimulating factor (CSF). CSF stimulates the bone

marrow to increase white blood cell production. In a person with normally functioning

bone marrow, the numbers of white blood cells can double within hours if needed. An

increase in the number of circulating leukocytes is rarely due to an increase in all five

types of leukocytes. When this occurs, it is most often due to dehydration and

hemoconcentration. In some diseases, such as measles, pertussis and sepsis, the

increase in white blood cells is so dramatic that the picture resembles leukemia.

Leukemoid reaction, leukocytosis of a temporary nature, must be differentiated from

leukemia, where the leukocytosis is both permanent and progressive.

Therapy with steroids modifies the leukocytosis response. When corticosteroids

are given to healthy persons, the WBC count rises. However, when corticosteroids are

given to a person with a severe infection, the infection can spread significantly without

producing an expected WBC rise. An important concept to remember is that,

leukocytosis as a sign of infection can be masked in a patient taking corticosteroids.

Leukopenia occurs when the WBC falls below 4,000. Viral infections,

overwhelming bacterial infections, and bone marrow disorders can all cause leukopenia.

Patients with severe leukopenia should be protected from anything that interrupts skin

integrity, placing them at risk for an infection that they do not have enough white blood

cells to fight. For example, leukopenic patients should not have intramuscular injections,

rectal temperatures or enemas.

Leukocytes: critical low and high values

A WBC of less than 500 places the patient at risk for a fatal infection. A WBC

over 30,000 indicates massive infection or a serious disease such as leukemia. When a

patient is receiving chemotherapy that suppresses bone marrow production of

leukocytes, the point at which the count is lowest is referred to as the nadir.

Blood ClottingPlateletsNormal Range: 150,000 – 400,000/microliter

Platelets are cell fragments produced from megakaryocytes. Blood normally

contains 150,000–350,000 per microliter (µl) or cubic millimeter (mm3). This number is

normally maintained by a homeostatic (negative-feedback) mechanism. If this value

should drop much below 50,000/µl, there is a danger of uncontrolled bleeding because

of the essential role that platelets have in blood clotting. Some causes: certain drugs and

herbal remedies; autoimmunity.

When blood vessels are cut or damaged, the loss of blood from the system must

be stopped before shock and possible death occur. This is accomplished by solidification

of the blood, a process called coagulation or clotting. A blood clot consists of a plug of

platelets enmeshed in a network of insoluble fibrin molecules. Platelets are small,

colorless cells that have a lifespan of seven to ten days. They perform three major roles:

1) decreasing the luminal size of damaged vessels to decrease blood loss, 2) forming

blockages in injured vessels to decrease blood loss, and 3) with plasma providing the

correct ingredients needed to accelerate blood coagulation.

THE CLOTTING CASCADEThe end result of the clotting cascade is fibrin clots, fibrin, and thrombin. When

the clotting cascade is activated, usually due to vessel injury or damage, platelets are

one of the first responders. They stick to the damaged vessel and recruit more platelets

to the site. This aggregation of platelets forms a temporary plug that safeguards the

vessel wall from further bleeding. Simultaneously, additional proteins from the clotting

cascade are activated in a specific order that lead to the formation of fibrin. Fibrin is a

very sticky substance and acts as glue at the site, securing the platelet plug. Finally, the

clot must be dissolved in order for normal blood flow to resume following tissue repair.

The dissolution of the clot occurs through the action of plasmin. Plasmin is a protein that

is responsible for digesting fibrin. Eventually, scar tissue forms completing the healing of

the injured vessel (Sherwood, 1997).

PlasmaPlasma is a straw-colored, clear liquid that is ninety percent water. It is essential

for the transport of our blood components. Besides water, plasma also contains

dissolved electrolytes responsible for membrane excitability, plasma proteins that

maintain the osmotic distribution of fluid and substances capable of buffering pH

changes (Sherwood, 1997). Plasma transports materials needed by cells and materials

that must be removed from cells: various ions (Na+, Ca2+, HCO3−, etc.; glucose and

traces of other sugars; amino acids; other organic acids; cholesterol and other lipids;

hormones; urea and other wastes. Most of these materials are in transit from a place

where they are added to the blood (a "source") exchange organs like the intestine and

depots of materials like the liver to places ("sinks") where they will be removed from the

blood, every cell and exchange organs like the kidney, and skin.

IV. THE PATIENT AND HIS ILLNESS

A.PATHOPHYSIOLOGY (BOOK CENTERED)

Predisposing Factors: Race ( White race )Gender (Male)Age (increases with age)Heredity/Familial Tendency

Affectations in different committed cells

Mutant leukemia cells proliferate and fill the bone marrow

Compete and infiltrate hematopoeisis &

Precipitating Factors:Antecedent HematologicDisordersCongenital DisorderEnvironmental Exposures (high doses of radiation, chemicals like benzene, tobacco Smoke)Prior Exposure To Chemotherapeutic Agents For Another Malignancy

Disruption of pluripotent stem cells

Disruption of specific genes

Bone Pain

PetechiaeEcchymosis

Gingival bleedingepistaxis

Bleeding Tendencies

pallorAnemia

Wt. loss Malaise

Easy fatigability

Erythroblasts

Proliferation of immature

phagocytes

Decreased production of normal RBC

Megakaryoid Committed Cells

Megakaryoblast

Proliferation of immature

megakaryocytes

Myeloid Committed Cells

Myeloblasts

Proliferation of immature

myelocytes

Lymphoblasts

Proliferation of immature

lymphocytes

Affectations of B lymphocytes

& T-lymphocytes

Erythroid Committed Cells

Risk for infection

Affectations in different committed cells

Monoblasts

Proliferation of immature

monocytes

Lymphoid Committed Cells

Affectations in WBC cells components

NeutrophilsBasophils

Eosinophils

Inability to protect body against

invasion

Leukoblast

a. SYNTHESIS OF THE DISEASE

GENERAL DESCRIPTION

The underlying pathophysiology consists of a maturational arrest of bone marrow

cells in the earliest stages of development. The mechanism of this arrest is under study,

but in many cases, it involves the activation of abnormal genes through chromosomal

translocations and other genetic abnormalities. This developmental arrest results in 2

disease processes. First, the production of normal blood cells markedly decreases,

which results in varying degrees of anemia, thrombocytopenia, and neutropenia.

Second, the rapid proliferation of these cells, along with a reduction in their ability to

undergo programmed cell death (apoptosis), results in their accumulation in the bone

marrow, blood, and, frequently, the spleen and liver.

b. RISK FACTORS

PRE-DISPOSING FACTORS:

RACE - AML is more common in whites than in other populations.

SEX - AML is more common in men than in women. The difference is even more

apparent in older patients. Some have proposed that the increased prevalence of AML in

men may be related to occupational exposures.

AGE - Prevalence increases with age. The median age of onset is 65 years. However, this disease affects all age groups.

FAMILIAL TENDENCY - Germ-line mutations in the gene AML1 (RUNX1, CBFA2) occur

in the familial platelet disorder with predisposition for AML, an autosomal-dominant

disorder characterized by moderate thrombocytopenia, a defect in platelet function, and

propensity to develop AML. Some hereditary cancer syndromes, such as Li-Fraumeni

syndrome, can manifest as leukemia.

PRECIPITATING FACTORS:

ANTECEDENT HEMATOLOGIC DISORDERS - Unknown etiology that occurs most

often in older patients and manifests as progressive cytopenias that occur over months

to years. Other that predispose patients to AML include aplastic anemia, myelofibrosis,

paroxysmal nocturnal hemoglobinuria, and polycythemia vera.

CONGENITAL DISORDERS - Some congenital disorders that predispose patients to

AML include Bloom syndrome, Down syndrome, congenital neutropenia, Fanconi

anemia, and neurofibromatosis. More subtle genetic disorders, including polymorphisms

of enzymes that metabolize carcinogens, also predispose patients to AML.

ENVIRONMENTAL EXPOSURES -Several studies demonstrate a relationship between

radiation exposure and leukemia. Early radiologists (prior to appropriate shielding) were

found to have an increased likelihood of developing leukemia. Patients receiving

therapeutic irradiation for ankylosing spondylitis were at increased risk of leukemia.

Survivors of the atomic bomb explosions in Japan were at a markedly increased risk for

the development of leukemia. Persons who smoke have a small but statistically

significant (odds ratio, 1.5) increased risk of developing AML. In several studies, the risk

of AML was slightly increased in people who smoked compared with those who did not

smoke. Exposure to benzene is associated with aplastic anemia and pancytopenia.

These patients often develop AML. Many of these patients demonstrate M6 morphology.

PRIOR EXPOSURE TO CHEMOTHERAPEUTIC AGENTS FOR ANOTHER

MALIGNANCY - As more patients with cancer survive their primary malignancy and

more patients receive intensive chemotherapy (including bone marrow transplantation

[BMT]), the number of patients with AML increases because of exposure to

chemotherapeutic agents. Patients with a prior exposure to alkylating agents, with or

without radiation, often have a myelodysplastic phase prior to the development of AML.

The typical latency period between drug exposure and acute leukemia is approximately

3-5 years for alkylating agents/radiation exposure but only 9-12 months for

topoisomerase inhibitors.

C. SIGNS AND SYMPTOMS WITH RATIONALE

1. Anemia, Neutropenia, and Thrombocytopenia – These are due to bone marrow

failure. It results from the fact that as leukemic clone of cells grows, it tends to displace

development of normal blood cells in the bone marrow. There is also decreased

neutrophil levels despite an increased total WBC count.

2. Physical signs of anemia, including pallor and a cardiac flow murmur, are frequently

present – These are due to the increased number of white blood cells displacing or

otherwise interfering with the production of normal blood cells in the bone marrow. The

most common symptom of anemia is fatigue. Patients often retrospectively note a

decreased energy level over past weeks. Other symptoms of anemia include dyspnea

upon exertion, dizziness, and, in patients with coronary artery disease, anginal chest

pain. Myocardial infarction may be the first presenting symptom of acute leukemia in an

older patient.

3.Fever and other signs of infection can occur, including lung findings of pneumonia –

These are due to the lack of normal white blood cell production that makes the patient

susceptible to infections, while the leukemic cells are derived from white blood cell

precursors, they have no infection-fighting capacity. Patients present with fever, which

may occur with or without specific documentation of an infection. Patients with the lowest

absolute neutrophil counts (ie, <500 cells/µL and especially <100 cells/µL) have the

highest risk of infection. Patients also often have a history of upper respiratory infection

symptoms that have not improved despite empiric treatment with oral antibiotics.

4. Abnormal Bleeding ( nosebleeds, gingival bleeding, purpura, ecchymosis, petechiae

–These are due to thrombocytopenia. Patients usually demonstrate petechiae,

particularly on the lower extremities. Petechiae are small, often punctate, hemorrhagic

rashes that are not palpable. Areas of dermal bleeding or bruises (ie, ecchymoses) that

are large or present in several areas may indicate a coexistent coagulation disorder such

as DIC. Purpura is characterized by flat bruises that are larger than petechiae but

smaller than ecchymoses. Potentially life-threatening sites of bleeding include the lungs,

gastrointestinal tract, and the central nervous system.

5. Signs relating to organ infiltration with leukemic cells – The most common sites

of infiltration include the spleen, liver, and gums. These include hepatosplenomegaly

and, to a lesser degree, lymphadenopathy Patients with splenomegaly note fullness in

the left upper quadrant and early satiety. . Occasionally, patients have skin rashes due

to infiltration of the skin with leukemic cells (leukemia cutis). Chloromata are

extramedullary deposits of leukemia. Rarely, a bony or soft-tissue chloroma (solid

leukenic mass or tumor outside of the bone marrow) may precede the development of

marrow infiltration by AML (granulocytic sarcoma).

6. Bone Pain - Patients with a high leukemic cell burden may present this symptom

which is caused by increased pressure in the bone marrow.

7. Signs relating to leukostasis - Patients with markedly elevated WBC counts

(>100,000 cells/µL) can present with symptoms of leukostasis (ie, respiratory distress

and altered mental status). Leukostasis is a medical emergency that requires immediate

intervention.

B. PATHOPHYSIOLOGY (CLIENT-CENTERED)

Predisposing Factors:

Gender (Male)Age (3 years old)

Mutant leukemia cells proliferate and fill the bone marrow

Compete and infiltrate hematopoeisis &

Disruption of pluripotent stem cells

Disruption of specific genes

Precipitating Factors:

Environmental Exposures- Cigarette Smoke- Exposure to certain chemicals (carbonated drinks even before reaching 1-yr of age/ foul-smelling env’t cause by nearby poultry)

• Petechiae* (both palms of the hand)

• Ecchymosis*

• Gingival bleeding*

• Epistaxis (upon admission)

• Hematoma* -Periorbital -in the sole of left foot measuring 6-7 cm diameter

Bleeding Tendencies

Affectations in different committed cells

Erythroblasts

Proliferation of immature

phagocytes

Decreased production of normal RBC

Megakaryoid Committed Cells

Megakaryoblast

Proliferation of immature

megakaryocytes

Myeloid Committed Cells

Myeloblasts

Proliferation of immature

myelocytes

Erythroid Committed Cells

Affectations in different committed cells

Monoblasts

Proliferation of immature

monocytes

Affectations in WBC cells

components

Neutrophils

Lymphocytes

Presence of Blast Cells

Inability to protect body

against invasion

(10-/7/8/14-19-08)

(10-7/8/12/14-19-08)

(10-7/8/12/14-19-08)

10- 3/7/8/12/14/15/17/18/19-08

INFECTION

Signs of infection

• On & off Fever

(10-3/12/13/17/18/19/25- 08)

• Acute

• Organ

Infiltration(distend- ed abdo-

men)

• Leuko-Stasis

• Altered Mental Status

• R

a. SYNTHESIS OF THE DISEASE (CLIENT BASED)

GENERAL DESCRIPTION

The underlying pathophysiology consists of a maturational arrest of bone marrow

cells in the earliest stages of development. This developmental arrest results in 2

disease processes. First, the production of normal blood cells markedly decreases,

which results in varying degrees of anemia, thrombocytopenia, and neutropenia.

Second, the rapid proliferation of these cells, along with a reduction in their ability to

undergo programmed cell death (apoptosis), results in their accumulation in the bone

marrow, blood, and, frequently, the spleen and liver. In AML, the bone

b. RISK FACTORS

PRE-DISPOSING FACTORS:

SEX - AML is more common in men than in women. The difference is even more

apparent in older patients.

AGE- Prevalence increases with age. The median age of onset is 65 years. However,

this disease affects all age groups.

PRECIPITATING FACTORS:

ENVIRONMENTAL EXPOSURES - In several studies, the risk of AML was slightly

increased in people who smoked compared with those who did not smoke.

C. SIGNS AND SYMPTOMS WITH RATIONALE

Pallor*

Malaise/ Fatigue*

(10-7/8/12/14-19-08)

Dyspnea ( RR,

PR)

Anemia*

DEATH

1. Anemia, Neutropenia, and Thrombocytopenia – These are due to bone marrow

failure. It results from the fact that as leukemic clone of cells grows, it tends to displace

development of normal blood cells in the bone marrow. There is also decreased

neutrophil levels despite an increased total WBC count.

2. Physical signs of anemia- including pallor and dyspnea upon exertion.These are

due to the increased number of white blood cells displacing or otherwise interfering with

the production of normal blood cells in the bone marrow. The most common symptom of

anemia is fatigue.

3. Fever and other signs of infection Patients present with fever, which may occur

with or without specific documentation of an infection. These are due to the lack of

normal white blood cell production that makes the patient susceptible to infections, while

the leukemic cells are derived from white blood cell precursors, they have no infection-

fighting capacity.

4. Abnormal Bleeding ( nosebleeds, gingival bleeding, purpura, ecchymosis, petechiae

–These are due to thrombocytopenia.

5. Signs relating to organ infiltration with leukemic cells – The most common sites

of infiltration include the spleen, liver, and gums. These include hepatosplenomegaly

and, to a lesser degree, lymphadenopathy.

6. Bone Pain - Patients with a high leukemic cell burden may present this symptom

which is caused by increased pressure in the bone marrow.

7. Signs relating to leukostasis - Patients with markedly elevated WBC counts

(>100,000 cells/µL) can present with symptoms of leukostasis (ie, respiratory distress

and altered mental status). Leukostasis is a medical emergency that requires immediate

intervention.