Download Chapter X.12. Lymphangiomas John J. Chung, MS, MPH This

Chapter X.12. Lymphangiomas John J. Chung, MS, MPH
This newborn male infant was born to a 30 year old G1P1 mother at 40 weeks gestation via cesarean
section. Prenatal ultrasonography performed at 32 weeks gestation revealed a 1 cm x 1 cm x 1 cm
hypoechoic but nonseptated mass in the posterior neck. An encephalocele or meningocele were deemed
unlikely and the infant was suspected of having a cystic hygroma (a type of lymphatic malformation). No
evidence of fetal hydrops or other congenital anomalies were noted. The pregnancy is closely monitored
with detailed serial ultrasounds for the duration of the pregnancy. At term, the hypoechoic lesion is 2 cm x
1 cm x 2 cm. While there is still no indication of hydrops fetalis by ultrasonography, a cervical cystic mass
could obstruct a vaginal delivery and the mother is advised to undergo a cesarean section.
Upon delivery, Apgar scores are 8 and 9 at 1 and 5 minutes. VS T 37.5, HR 110, R 60, BP 51/25, weight
3.3 kg (50th %ile), length 51cm (50th %ile). His head is normocephalic with no evidence of additional
cystic masses. Eyes, ears, nose and mouth are all normal. A 2 cm wide mass is noted in the posterior neck.
Heart, lung, abdomen, extremity, skin and neurologic examinations are normal.
He begins to breast feed normally. Imaging studies fail to demonstrate any other cysts. Because nuchal
cysts can grow to obstruct the trachea or esophagus, most of the cyst is surgically excised. Histology of the
cyst shows only lymphatic tissue, confirming the diagnosis of a cystic hygroma. Because of its proximity to
nerves, the cystic hygroma tissue could not be completely removed. By 12 months of age, local recurrence
of the cystic hygroma is evident. Options for recurrent and unresectable lymphangiomas, such as drug
sclerotherapy, were discussed with his parents. They are also informed of the possibilities of infection,
hemorrhage, and continual recurrence despite treatment.
Lymphangiomas or lymphatic malformations (LM) are defined as isolated regions of lymphatic tissue
which are thought to occur after the 6th week of gestation, when developing lymphatic tissue fails to
properly anastomose (1,2,3). Lymphatic tissue can also improperly anastomose with capillaries, veins, and
arteries (4). These isolated regions of lymphatic tissue function to absorb interstitial fluid and enlarge as
lymph fluid continues to accumulate with time (3). Depending on their location and size, lymphatic
malformations can be benign and asymptomatic or they can press against nerves, organs, or obstruct
circulation (4). For example, lymphangiomas in the head and neck can cause airway obstruction, and alter
speech and/or mastication (3).
The true incidence rate for lymphatic malformations is uncertain, since small ones may not be very evident.
The most common lymphatic malformation, cystic hygromas, have an estimated incidence of 1:875 among
miscarriages (3). By comparison, hemangiomas are much more common and occur in as many as 10% of 1
year olds (5). Lymphatic malformations are found equally in boys and girls (5). Lymphatic malformations
are commonly diagnosed in infancy with more than half of the cases identified prenatally or postpartum
and more than 90% diagnosed by the 2nd or 3rd year of life (4,6). Lymphatic malformations rarely regress
after birth but can remain asymptomatic until later in life when trauma or infections can cause lymphatic
malformations to rapidly grow and interfere with other structures (7).
Seventy-five percent of lymphatic malformations are found in the head and neck but lymphatic
malformations can occur anywhere (1). Generally, the most common sites are in the head and neck,
mediastinum, axilla, and abdomen (1). Lymphangiomas that are microcystic superficial lesions of the skin
or mucous membranes have many names: lymphangioma simplex, lymphangioma circumscriptum,
capillary lymphangioma and angiokeratoma circumscriptum (4,9). Deeper lymphangiomas can be either
microcystic (cavernous lymphangiomas), macrocystic (lymphangioma cystoides, cystic hygromas, or cystic
lymphangiomas), or mixed microcystic- macrocystic (4,9).
The etiology of lymphangiomas is unknown (10). However, cystic hygromas have been found to be
associated with chromosomal abnormalities such as Turner syndrome and Down syndrome (2,3).
Chromosomal abnormalities are usually associated with other congenital findings such as mental or
developmental retardation, heart defects, or alterations in the development of sexual characteristics at
puberty.
Diagnosis is principally made on the basis of clinical appearance and imaging. For example, capillary
lymphangiomas or lymphangioma simplex are superficial white, purple, or red papules that appear wartlike (9). Such superficial lymphangiomas are usually asymptomatic but can become infected. They can
occasionally bleed when the superficial lymphangioma is in communication with ruptured blood vessels.
Lymphangioma circumscriptum are superficial clusters of papules that are said to look like frog eggs (9).
Lymphangioma circumscriptum is also found in skin or mucous membrane but extend deeper into the
dermis than lymphangioma simplex (9). Cavernous lymphangiomas usually involve the skin or mucous
membranes but they extend deeper into muscle where they form small, thin-walled, lymph fluid filled
spaces referred to as microcysts (9).
Cystic lymphangiomas or cystic hygromas are large, well-circumscribed, loculated, lymph fluid-filled
spaces (macrocysts) (3,9). Large loculated cysts tend to occur in areas where expansion is possible such as
the deep lymph vessels in the neck and head or near other organs. These deep lymphangiomas can be
asymptomatic or they can present with signs and symptoms associated with serious complications. Cystic
hygromas, usually identified prenatally or antenatally, are especially serious. Considerable lymphedema
can accompany growing cystic hygromas which can sometimes lead to hydrops fetalis and intrauterine fetal
demise (IUFD) or early perinatal neonatal death (early PND) due to circulatory failure (3). Additionally,
the size and position of the cyst may complicate vaginal delivery (3).
When aspirated, the cystic space fluid includes proteinaceous fluid with few lymphocytes (1). MRI findings
are important in distinguishing between lymphangiomas and other vascular malformations (1). Arterial or
venous vascular malformations enhance with contrast during MRI contrast studies, while lymphatic
malformations do not. CT scans can also help differentiate venous malformations from lymphangiomas as
well as help identify hemorrhages. Plain film radiographs can identify associated skeletal deformities.
Ultrasound imaging is particularly useful during the perinatal/neonatal period (4).
Specimen biopsies of superficial lesions show typical lymphatic vessels lined by well differentiated, flat,
endothelial cells (3,8). Deeper lesions show dilated and interconnected lymph vessels that can form
loculations (3).
The differential diagnosis includes lymphadenitis, other congenital vascular malformations (hemangiomas,
branchial cleft cyst, cellulitis, dermoid cyst), and tumors. Bloody lymphangiomas are often easily confused
with hemangiomas or Kaposi's sarcoma (4). Because of the variable location of lymphangiomas, the
differential diagnosis should also include site-specific pathologies. For example, the differential diagnosis
of a nuchal cystic hygroma should include encephalocele or meningocele, and tumors of the head and neck
(3).
Small superficial lymphangiomas are generally left untreated if asymptomatic (1). Cystic hygromas
identified in a fetus are especially concerning. The fetus is assessed for additional abnormalities that would
increase the risk of fetal death or poor postpartum prognosis such as chromosomal abnormalities, hydrops
fetalis, and large cyst volumes (2). These factors are important in whether or not the fetus is aborted or
delivered vaginally or by cesarean section. In the U.S., deep lymphangiomas such as cystic hygromas and
larger superficial lymphangiomas are surgically excised (1,3,6). However, surgical excision is difficult
because of the delicate nature of thin- walled lymphatic tissue and the close proximity of lymphatic
malformations to nerves, organs, and blood vessels (3,6). As a consequence, complete excision is possible
in less than a third of the cases (6). Incomplete excision does eliminate the space occupying effects of the
lesion but are complicated by a high risk of recurrence and infection (3).
In sclerotherapy, drugs including bleomycin, OK-432 (derivative of low virulence Group A streptococcus
pyogenes), and fibrin adhesives are used to stimulate sclerosis and regression (6). In the U.S,. sclerotherapy
is generally reserved for recurrent or unresectable lymphangiomas but, in some small studies, sclerotherapy
agents have been used in place of surgical excision with good results (3,6). Sclerotherapy complications
include ulcers, scarring, and recurrence of lymphangiomas (3,7). Other treatment options include
interferon- alpha treatment (7), laser ablation or radiation treatment. Radiation treatment carries a number
of complications and is usually reserved as a treatment of last resort (7).
Chapter XI.1. Anemia Darryl W. Glaser, MD
A 22 month old boy presents to your office with a chief complaint of pallor. A visiting relative who has not
seen the child for 5 months told his mother that the boy appears pale. The mother brings him in for a
checkup even though she notices no change in his coloring (he has always been fair skinned). On review of
symptoms you find that he is an active toddler, with no recent fatigue, exercise intolerance, or increase in
sleeping. He has had no blood in his diapers and no black or tarry stools. He is a picky eater, taking small
amounts of chicken, pork and some vegetables, but loves milk and drinks six to eight bottles of whole milk
per day.
Family history reveals a distant aunt who had anemia when she was pregnant but which subsequently
resolved. There is no history of splenectomy, gall stones at an early age, or other anemia in the family.
Page - 407
Exam: VS: T 37.5, BP 90/52, P 145, RR 16, Height 85.5 cm (50th %ile), Weight 13.2 kg (75th %ile).
General appearance: He is a pale appearing, active toddler, holding a bottle, tearing and eating paper from
Chapter
XI.1.Eyes:
Anemia
your
exam table.
No scleral icterus. Pale conjunctiva. Mouth: Dental caries. Chest: Clear. Heart: Mild
Darryl
W.
Glaser,
MD II/VI systolic ejection murmur heard best over the upper left sternal border.
tachycardia as above, grade
Abdomen:
Nomonth
hepatosplenomegaly.
Rectal:
Dark
brown,
soft stool,
negative
forrelative
occultwho
blood.
A 22
old boy presents to your
office with
a chief
complaint
of pallor.
A visiting
has not seen the child for 5
months told his mother that the boy appears pale. The mother brings him in for a checkup even though she notices no change in his
coloring
(he6,100,
has always
skinned).
On review
symptomsMCV
you find
is an active
with no recent
fatigue,
CBC:
WBC
Hgbbeen
6.2fair
g/dl,
Hct 19.8%,
Pltof589,000,
54that
fL,heRDW
17%.toddler,
Reticulocyte
count
is exercise
intolerance,
increase microcytosis,
in sleeping. He has
had no blood inmild
his diapers
and no black
tarry stools. He is There
a picky is
eater,
1.8%.
The laborreports
hypochromia,
anisocytosis
andorpolychromasia.
no taking small
amounts of chicken, pork and some vegetables, but loves milk and drinks six to eight bottles of whole milk per day.
basophilic
stippling.
Family
history reveals a distant aunt who had anemia when she was pregnant but which subsequently resolved. There is no history
of splenectomy, gall stones at an early age, or other anemia in the family.
Exam: diagnose
VS: T 37.5,iron
BP 90/52,
P 145, RR
16, Height
cmiron
(50thand
%ile),
Weight
(75th %ile).
appearance:
He is a
You correctly
deficiency
anemia,
start85.5
oral
limit
his 13.2
milkkgintake.
YouGeneral
see him
in 3
pale
active toddler,and
holding
a bottle,is
tearing
paper from yourcount
exam 17%.
table. Eyes:
scleral
Pale in
conjunctiva.
days
toappearing,
assure compliance
his RDW
27%and
andeating
his reticulocyte
WhenNoyou
seeicterus.
him back
Mouth: Dental caries. Chest: Clear. Heart: Mild tachycardia as above, grade II/VI systolic ejection murmur heard best over the upper
twoleft
weeks
mother
is amazed
at his new interest
in table
Hgb negative
is now for
8.5occult
g/dl,blood.
and his MCV
sternalhis
border.
Abdomen:
No hepatosplenomegaly.
Rectal:
Darkfoods.
brown, His
soft stool,
64 fL. Two
months
later
his
hemoglobin
has
completely
normalized,
and
you
continue
iron
CBC: WBC 6,100, Hgb 6.2 g/dl, Hct 19.8%, Plt 589,000, MCV 54 fL, RDW 17%. Reticulocyte counttherapy
is 1.8%. for
The lab reports
microcytosis,
hypochromia, mild anisocytosis and polychromasia. There is no basophilic stippling.
three
more months.
You correctly diagnose iron deficiency anemia, start oral iron and limit his milk intake. You see him in 3 days to assure compliance
and his RDW is 27% and his reticulocyte count 17%. When you see him back in two weeks his mother is amazed at his new interest in
Anemia
occurs when the red blood cell mass or hemoglobin content is too low to meet a person's
table foods. His Hgb is now 8.5 g/dl, and his MCV 64 fL. Two months later his hemoglobin has completely normalized, and you continue
physiologic
In children,
iron therapydemands.
for three more
months. "normal" levels vary with age, gender, and geographic location (height
above sea level). A summary of normal values is listed below (1):
Anemia occurs when the red blood cell mass or hemoglobin content is too low to meet a person's physiologic demands. In children,
"normal" levels vary with age, gender, and geographic location (height above sea level). A summary of normal values is listed below (1):
Table 1. Lower limit (3rd %ile) of normal hemoglobin (Hgb column) and lower (3rd %ile) and upper (97th
%ile)
limit
of normal
MCV
andhemoglobin
sex (1) (M=males,
Table
1. Lower
limit (3rd
%ile)by
ofage
normal
(Hgb column)F=females).
and lower (3rd %ile) and upper (97th %ile) limit of normal MCV by
age and sex (1) (M=males, F=females).
Age
1-4
5-7
8 - 10
12 - 14
15 - 17
Over 18
Hgb (g/dl)
11.2
11.5
11.8
12
12 (F), 13 (M)
12 (F), 14 (M)
Lower
MCV limit
72
75
76
76
78
80
Upper
MCV limit
85
87
89
89
92
95
Signs of anemia include pallor of the skin, conjunctiva, and mucus membranes, tachycardia, orthostatic hypotension, heart murmur
and of
edema.
Symptoms
may
include
headache,
dizziness and
and dyspnea.
Other signs andtachycardia,
symptoms depend
on the cause for anemia,
Signs
anemia
include
pallor
offatigue,
the skin,
conjunctiva,
mucus membranes,
orthostatic
such as jaundice,
urine, orand
splenomegaly
in hemolytic may
anemias
(2). fatigue, headache, dizziness and dyspnea.
hypotension,
heartdark
murmur
edema. Symptoms
include
When the diagnosis of anemia is suspected based on signs and symptoms, it can quickly be confirmed by laboratory evaluation.
Other
and symptoms
dependthe
onetiology,
the cause
forcan
anemia,
such asdue
jaundice,
darkofurine,
splenomegaly
Thesigns
more difficult
task is determining
which
appear daunting
to the myriad
causesor
of anemia
in children. Testing
in hemolytic
anemias
(2).
for all these causes at once would be inefficient, time consuming, and expensive. It is, in fact, unnecessary because the differential
diagnosis can be narrowed significantly by careful history, thorough examination, and use of various classification schemes.
When the diagnosis of anemia is suspected based on signs and symptoms, it can quickly be confirmed by
History
laboratory
evaluation. The more difficult task is determining the etiology, which can appear daunting due to
1) Has there been a sudden onset of pallor, fatigue, or exercise intolerance? Rapid onset of symptoms suggests a more acute
the anemia,
myriadwhile
of causes
anemia
in children.
Testing
forchronic
all these
causes
at once
would
inefficient,
time
anemia of
without
symptoms
may indicate
a more
process,
allowing
the body
morebe
time
to compensate
for the low
hemoglobinand
levels.
Note that the
presence
of symptoms
does because
not necessarily
reflect the level
of anemia.can
A child
whose Hgb drops from
consuming,
expensive.
It is,
in fact,
unnecessary
the differential
diagnosis
be narrowed
14 to 10 overby
one
week may
be quitethorough
symptomatic,
while the child
in our
presentation
was virtually asymptomatic
significantly
careful
history,
examination,
and
usecase
of various
classification
schemes. dropping to a Hgb
of 6.2 over a period of months. Pallor unrecognized by the patient's day to day caretaker also suggests a gradual process.
2) Any history of blood loss? Obtain a menstrual history. Prolonged, heavy periods are a source for acute blood loss. Over time
chronic loss can lead to iron deficiency, especially when superimposed on poor dietary iron intake.
3) Did the child have jaundice in the newborn period or episodes of jaundice in the past? Glucose-6-phosphate dehydrogenase
deficiency (G6PD) and hereditary spherocytosis will cause recurrent episodes of jaundice and anemia, especially following illness or
stress.
4) Describe the child's diet. When did he start whole milk? How much milk does he drink now? Excessive milk intake with
inadequate dietary iron is a common cause of iron deficiency anemia in toddlers. Does he eat anything unusual (paper, dirt) or chew on
ice? Pica suggests iron deficiency and can predispose to lead poisoning.
History
1) Has there been a sudden onset of pallor, fatigue, or exercise intolerance? Rapid onset of symptoms
suggests a more acute anemia, while anemia without symptoms may indicate a more chronic process,
allowing the body more time to compensate for the low hemoglobin levels. Note that the presence of
symptoms does not necessarily reflect the level of anemia. A child whose Hgb drops from 14 to 10 over
one week may be quite symptomatic, while the child in our case presentation was virtually asymptomatic
dropping to a Hgb of 6.2 over a period of months. Pallor unrecognized by the patient's day to day caretaker
also suggests a gradual process.
2) Any history of blood loss? Obtain a menstrual history. Prolonged, heavy periods are a source for acute
blood loss. Over time chronic loss can lead to iron deficiency, especially when superimposed on poor
dietary iron intake.
3) Did the child have jaundice in the newborn period or episodes of jaundice in the past? Glucose-6phosphate dehydrogenase deficiency (G6PD) and hereditary spherocytosis will cause recurrent episodes of
jaundice and anemia, especially following illness or stress.
4) Describe the child's diet. When did he start whole milk? How much milk does he drink now? Excessive
milk intake with inadequate dietary iron is a common cause of iron deficiency anemia in toddlers. Does he
eat anything unusual (paper, dirt) or chew on ice? Pica suggests iron deficiency and can predispose to lead
poisoning.
5) Has anyone in the family ever had anemia or low blood counts, or ever been on iron? This may suggest a
hereditable cause of anemia, but is not diagnostic. A positive response may simply reflect dietary patterns
in siblings. It is quite common for families to recall at least one relative who was anemic at some time,
especially during pregnancy. Ask if they are still receiving treatment or if the condition resolved. Also
remember that a negative family history does not exclude an inherited anemia.
6) Has anyone in the family ever had their spleen taken out or had gallstones at an early age? Surprisingly,
not all patients know the reasons for past procedures, or may have been too young when they occurred. A
positive response suggests a family history of a hemolytic anemia (such as hereditary spherocytosis). A
negative response does not rule out these causes.
7) What is the child's ethnic origin? Hemoglobinopathies (e.g., sickle cell anemia), thalassemias, and G6PD
deficiency are more common in certain ethnic groups.
Physical Examination
Compare the child's color to his siblings or both parents. Is he active and playful or fatigued? Tachycardia
and heart murmur are common in children with anemia, but look for signs of heart failure including
tachypnea, rales, hepatomegaly or edema. Splenomegaly may indicate immune hemolytic anemia or
hereditary spherocytosis. Look for any skeletal abnormalities as can be seen with the congenital bone
marrow failure syndromes.
Two classification schemes are frequently employed to narrow down the differential diagnosis in anemia.
The first uses the MCV to classify the size of the red blood cell as microcytic, normocytic, or macrocytic.
Although it can be quite helpful, the system is imperfect. Since MCV values in children vary with age, the
age specific MCV values must be used (See Table 1). Even so, certain conditions do not fit neatly into one
category. The anemia of inflammation/chronic disease and of lead poisoning can be microcytic or
normocytic, and the anemia seen with liver failure can be normocytic or macrocytic.
Microcytic anemias include iron deficiency, thalassemia, chronic inflammation, lead poisoning, and
sideroblastic anemia.
Normocytic anemias include acute blood loss, immune hemolytic anemia, hereditary spherocytosis, G6PD
deficiency, sickle cell anemia, renal disease, and transient erythroblastopenia of childhood (TEC).
Macrocytic anemias include folate deficiency, B12 deficiency, liver disease, hypothyroidism, neoplasms
and bone marrow failure syndromes such as aplastic anemia, Diamond-Blackfan anemia (DBA) and
congenital dyserythropoietic anemia (CDEA)
The second classification scheme categorizes anemia by its mechanism. If a patient's hemoglobin is low, it
is due to one of three basic reasons: he/she is either not making adequate amounts (decreased production),
destroying it (increased destruction), or losing it from somewhere (blood loss). This system is more
intuitive and more reliable, but is more difficult to categorize in some cases. A high reticulocyte count
indicates that the patient is able to adequately make red cells and is trying to compensate for the anemia,
suggesting the cause to be blood loss or destruction. A low reticulocyte count suggests decreased
production. Signs of destruction include jaundice, elevated bilirubin, dark urine, splenomegaly, schistocytes
and microspherocytes on peripheral smear, and low serum haptoglobin.
Decreased production results from iron, folate, or B-12 deficiency, lead toxicity, thalassemia, aplastic
anemia, chronic inflammation, neoplasms, TEC, DBA, renal disease, hypothyroidism, CDEA (congenital
dyserythropoietic anemia), and sideroblastic anemia.
Blood loss results from acute hemorrhage, dysfunctional uterine bleeding (heavy and/or prolonged
menstrual periods), pulmonary hemosiderosis (pulmonary hemorrhage), Goodpasture's disease, and
gastrointestinal blood loss (peptic ulcer disease, other GI conditions).
Increased destruction results from immune hemolytic disease, hereditary spherocytosis, G6PD deficiency,
sickle cell disease, thalassemia, DIC (disseminated intravascular coagulation), mechanical heart valves,
burns, PNH (paroxysmal nocturnal hemoglobinuria), and hypersplenism.
Iron deficiency is the most common cause of anemia in childhood (2). Prevalence of iron deficiency ranges
from 5% to 29% of the population, with higher numbers seen in inner city and socioeconomically deprived
populations (3,4). It is most common in toddlers and in the adolescent age groups (periods of rapid growth
and higher potential for inadequate dietary iron) (5).
In infants, early introduction (at age 6 or 8 months) of whole cow's milk into the diet is clearly associated
with iron deficiency anemia, and patients consuming larger amounts of milk are at higher risk of anemia
(3). This is due to three factors: 1) Cow's milk exerts a direct toxic effect on the intestinal mucosa of
infants, leading to prolonged microscopic blood loss in the stools. 2) The caloric value of whole cow's milk
is high due to fat content, decreasing the appetite and leading to less intake of potential iron-rich foods. 3)
The bioavailability of iron in cow's milk is low (6). Accordingly, the American Academy of Pediatrics
recommends that cow's milk not be used in the first year of life. Infants should receive breast milk or iron
fortified formulas for the first year of life, and iron-fortified cereal should be added at the age of four to six
months (6). Infants with appropriate diets and older children and adolescents with iron deficiency anemia
must be evaluated for a source of chronic blood loss. Abnormal uterine bleeding and blood loss from the GI
tract are common. Blood loss in the urine is rare, and from the lungs (idiopathic pulmonary hemosiderosis)
is exceedingly rare. Hemolytic anemias generally do not lead to iron deficiency because the body reuses the
freed iron. Iron deficiency has conclusively been linked to behavioral changes (6) and to lower cognitive
achievement in school aged children and adolescents (7). Thus it should be recognized early and treated
adequately.
Presenting signs and symptoms may be mild because of the gradual onset and the body's ability to
compensate for low hemoglobin concentration. Pallor, fatigue, exercise intolerance, headache, or dizziness
may be present. Physical exam may reveal pale mucus membranes and skin, especially of the palms,
tachycardia with or without heart murmur, and orthostatic hypotension. Laboratory evaluation reveals a low
MCV, low hemoglobin and hematocrit, low reticulocyte count, and often an elevated platelet count. The
red cell distribution width (RDW), a measure of the difference in size between the smallest and largest
RBCs in circulation, may be elevated, denoting a dual population of cells: small (microcytic) iron deficient
cells and some normocytic cells with adequate iron. Evaluation of the blood smear reveals microcytosis and
hypochromia. Serum iron is low, and total iron binding capacity (TIBC) is elevated with low % saturation.
Erythrocyte protoporphyrin is increased. Low serum ferritin is diagnostic of iron deficiency, but normal
levels can be misleading because ferritin is an acute phase reactant and can be falsely elevated in
inflammation (5). Low-normal ferritin values must be interpreted in light of clues from the history,
physical, and other laboratory studies. A bone marrow sample stained for iron shows no iron stores. This
test is most definitive, but generally unnecessary and invasive.
Treatment with multivitamins containing iron is inadequate once the child is anemic. Oral ferrous sulfate,
available in liquid or pill form, at a dose of 3 mg/kg of elemental iron for mild anemia or 6 mg/kg for
severe anemia should be instituted. It should be continued for two to three months after normalization of
blood counts to replete the total body iron stores. The liquid can stain the teeth so it should be given in juice
rather than dropped directly into the mouth. Avoid giving it with milk as milk interferes with its absorption.
Lead poisoning is less common today with the federally mandated removal of lead from gasoline, canned
food sealants, and paint intended for household use in 1977. Since then, there has been a 90% decrease in
the number of children defined as "lead intoxicated" (8). Nationwide, 4.4% of children aged one to five
meet this criteria with blood levels above 10 mcg/dL (9). The primary source of lead in children's blood
today is from lead based paint in older households. Most is ingested as household dust, with only a minor
contribution from paint chips (8). Children under 2 years of age are at highest risk due to exploring
behavior and the practice of bringing paint dust- coated fingers and toys to the mouth. Not surprisingly, the
age and state of disrepair of the home is an important risk factor. Children in an older but well-maintained
home have less exposure than those in an old home with cracked and peeling paint (10).
Most lead poisoning is now found through lead screening. The American Academy of Pediatrics
recommends that a risk assessment survey be given at health maintenance visits, and if any questions are
answered "yes" or "not sure", blood lead levels should be drawn.
The survey should be adapted for known
lead risks in each community, but should include at least the following three questions (10):
1) Does your child live in or regularly visit a house or childcare facility built before 1950?
2) Does your child live in or regularly visit a house or childcare facility built before 1978 that is being or
recently has been renovated or remodeled?
3) Does your child have a sibling or playmate who has or did have lead poisoning?
In communities where more than 27% of housing was built before 1950 or where more than 12% of 1 and 2
year olds have elevated blood lead levels, all children should have lead levels drawn at age 9-12 months
and age 2 years (10).
Acute signs and symptoms of lead intoxication are now rarely seen. Vomiting, abdominal pain, and
constipation are nonspecific and common in this age group. Because of prevention, screening, and the use
of chelating agents as treatment, encephalopathy, seizure, and coma associated with extremely high lead
levels are almost unheard of today. Chronic effects of lead poisoning are more ominous, and include
possibly permanent behavioral and cognitive deficits, including decrease in IQ points (11,12). Complete
blood counts are often normal in children with low to moderately elevated lead levels. Basophilic stippling,
seen as fine blue specks in the RBC membrane under light microscopy, can be prominent. Erythrocyte
protoporphyrin is elevated (13). Anemia results from lead's inhibition of enzymes required for hemoglobin
synthesis (4), but the microcytic anemia of lead poisoning reported in the past is most likely due to
concomitant iron deficiency. Iron deficiency leads to pica which increases risk of lead ingestion, and iron
deficiency leads to increased absorption and retention of lead from the GI tract.
Treatment depends on the blood lead level (BLL) in mcg/dL (10):
I. BLL <10 requires no action.
II. Levels of 10-20 require education and action to decrease lead exposure, including frequent hand
washing, frequent dusting and mopping, and ideally repair or repainting, followed by repeat BLL in 2-3
months.
III. Levels of 20-44 require a detailed history to identify sources of lead exposure, including hobbies
(ceramics), vocations (repair of bridges or boats, plumbing, home building/renovating), and contact (car
batteries, contaminated soil). Corrective action must be taken to decrease exposure. Consider a home visit
or a referral to the local health department for a detailed environmental investigation and referrals for
support services.
IV. Levels of 45-69 require all of the above plus initiation of chelation therapy.
V. Levels of 70 or higher require hospital admission for close observation of mental status and immediate
IV chelation.
The anemia of inflammation, also called anemia of chronic disease, is the second most common cause of
anemia in children after iron deficiency (14). Initially recognized in patients with chronic inflammatory
conditions, it has now been shown to occur in the acute setting, accompanying mild self-limiting illnesses
such as otitis media or upper respiratory infections (15). The mechanism of anemia is multifactorial,
primarily from decreased RBC production (impaired iron utilization and decreased erythropoietin
production and response) but also from decreased RBC survival (16). The degree of anemia is usually mild,
with hemoglobin concentrations of 10 to 11 g/dl, but can be moderate with hemoglobins of 8 to 9 g/dl. The
red blood cells are usually normocytic but can be microcytic (15). Reticulocyte counts are low. Iron studies,
if done, show low serum iron, high serum ferritin, and low TIBC. Bone marrow evaluation would show
abundant iron stores. Anemia associated with acute inflammation is usually benign and self-limited,
resolving 1-2 months after the infection resolves (15). Children with chronic diseases such as rheumatoid
arthritis have a more protracted course; even so, the anemia is rarely significant enough to require
treatment. High doses of erythropoietin can correct the anemia in those rare cases (14).
Folate and vitamin B12 deficiency are rarely seen in children. They cause a macrocytic anemia which may
be accompanied by granulocytopenia and thrombocytopenia. Hypersegmented neutrophils may be seen on
peripheral smear of patients with B12 deficiency. The diagnosis is confirmed by low serum concentration
of the vitamins (4). B12 deficiency requires a Schilling test to determine the cause of the B12 deficiency
(intrinsic factor deficiency, malabsorption due to inflammatory bowel disease, etc.). B12 deficiency is also
associated with neuropathic symptoms.
The thalassemias are a group of inherited disorders of hemoglobin synthesis that cause a microcytic
anemia. Aberrant hemoglobins have shortened lifespans, so the anemia may be caused by both decreased
RBC production and increased destruction. Thalassemia is fully discussed in a separate chapter.
Anemia from bone marrow failure is usually macrocytic. Causes can be congenital (Diamond-Blackfan
anemia, congenital dyserythropoietic anemia) or acquired (aplastic anemia, transient erythroblastopenia of
childhood). These are discussed in detail in a separate chapter. Replacement of normal bone marrow by
malignancy (leukemia or metastatic tumor) can lead to failure of normal red blood cell production, as can
restriction of the marrow space by bone in osteopetrosis.
Destruction of red blood cells, or hemolysis, causes release of intracellular contents into the plasma.
Consequently, indirect (unconjugated) bilirubin, LDH, and AST (SGOT) may be elevated. The urine may
be dark due to excreted hemoglobin or bilirubin. The reticulocyte count is elevated (18). Haptoglobin, a
protein that binds free hemoglobin, decreases. A low serum haptoglobin is diagnostic of hemolysis. If the
red cells are destroyed in the spleen (extravascular hemolysis) red cell fragments are not seen, and the
peripheral smear shows polychromasia and microspherocytes.
Hereditary Spherocytosis (HS) is the most common cause of hemolytic anemia in children. It is inherited in
an autosomal dominant
patternin75%ofcases,butfamilyhistoryisnotalwayspositivebecauseofvariationsinseverityevenamongfamilym
embers. Abnormal membrane proteins cause a loss of portions of the cell membrane, resulting in a rigid red
blood cell with a spherical shape. These cells are trapped in the spleen and destroyed, resulting in hemolytic
anemia (17). Patients present with jaundice, anemia, and splenomegaly. The reticulocyte count is elevated,
and the MCV is normal. An elevated MCHC strongly suggests HS, as it is rarely elevated in any other
condition but is high in 50% of those with HS (18). The peripheral smear usually shows spherocytes, but
the degree is variable and depends on smear quality. One cannot rule out HS by a lack of spherocytes
reported on a peripheral blood smear. The definitive diagnostic test is the incubated osmotic fragility assay,
which shows increased hemolysis to osmotic stress.
Patients with HS can have a "hyperhemolytic crisis", which is an acceleration of the rate of hemolysis
brought on by infections. They typically present with increased jaundice, pallor, and hemoglobins in the 58 g/dl range during or just after a nonspecific viral illness. Blood transfusions may be required. An "aplastic
crisis" can occur following infection with human parvovirus B19, the cause of Fifth disease (erythema
infectiosum) (18). This virus stops all red cell production in the marrow. The reticulocyte count falls to 0,
and in the face of continued RBC destruction without RBC production, the hemoglobin falls precipitously
to levels of 3-6 g/dl. Timely blood transfusions can get these patients through this one time complication.
HS patients whose siblings contract Fifth disease must be followed closely. Treatment consists of educating
the family about the disease and instructing them to come in for examination and blood work at the first
signs of pallor, increased jaundice, or fatigue. Splenectomy is curative but because of the risk of postsplenectomy sepsis, especially in those under age five, the surgery is reserved for those with more severe
disease. Indications include frequent hyperhemolytic episodes, symptomatic anemia leading to limitation of
lifestyle, gallstones, or growth retardation.
G6PD deficiency is the most common of the RBC enzyme defects. The enzyme deficiency causes the red
blood cells to be more sensitive to oxidative stress (17). Hemolysis ensues, resulting in jaundice and
anemia. It is an X-linked disorder and so it mostly affects males, but females can be variably affected due
to random inactivation of one X chromosome or they can be homozygous (mother is a carrier and father
has G6PD deficiency). The clinical course is marked by episodic jaundice. Prolonged neonatal jaundice is
sometimes seen. Older patients may have a history of jaundice, pallor and anemia that accompanies
infections or certain drugs or foods. Different individuals and different ethnic groups (Asian, African,
Mediterranean) may have different mutations which result in differing G6PD deficiency severities, so the
patients may have different susceptibilities to severe neonatal jaundice, kernicterus and acute hemolytic
reactions. Laboratory evaluation reveals a normocytic anemia with variable evidence of hemolysis such as
increased bilirubin, decreased haptoglobin, and hemoglobinuria. The blood smear shows fragmented cells,
schistocytes, and may show characteristic "bite" cells or "ghost" cells. Special stains for Heinz bodies,
denatured hemoglobin, may be positive. A specific G6PD assay is available, and if low, is diagnostic. The
test may be falsely elevated to normal levels during or just after acute hemolysis due to a high reticulocyte
count, so it should be repeated several weeks after the hemolytic event if the diagnosis appears likely (18).
Patients can make auto-antibodies against red blood cell antigens due to autoimmune syndromes,
medications, infections (EBV, mycoplasma, or nonspecific viruses), or unknown reasons. The presentation
is variable, but characteristic findings of hemolytic anemia are the norm. Blood smears show
microspherocytes but schistocytes are not seen. The direct Coombs test is positive. Treatment with
corticosteroids usually results in resolution of the hemolytic anemia (4,17). Intravenous immune globulin
(IVIg) and splenectomy have been used with success in cases refractory to corticosteroids.
Maternal antibodies against infant red blood cell groups can cross the placenta and cause varying degrees
of hemolysis (alloimmune hemolytic disease of the newborn). The clinical picture ranges from mild
hyperbilirubinemia to hydrops and death, but is most often benign and self-limited. Observation alone or
treatment with phototherapy is usually adequate.
With intravascular hemolysis, as seen in disseminated intravascular coagulation (DIC), hemolytic-uremic
syndrome and burns, mechanical injury to red blood cells causes hemolysis within the blood vessel rather
than in the spleen. Red blood cell fragments (schistocytes) are therefore commonly seen on peripheral
blood smears (4). Treatment involves correction of the underlying condition. Because the defect is extrinsic
to the red cell, transfused blood is hemolyzed as quickly as is the patient's, and so transfusion is only a
temporizing measure.
Sickle cell anemia is a hemoglobinopathy common in African, Caribbean, Middle Eastern, and
Mediterranean peoples. A mutation in the hemoglobin molecule causes red cells to take on a rigid sickled
shape, causing obstruction of flow through the microvasculature. Complications due to tissue hypoxia and
hemolytic anemia can be profound. Sickle cell anemia is discussed fully in a separate chapter.
Chapter XI.2. Thalassemia Kelley A. Woodruff, MD
A 12 month old female of Hawaiian, Chinese, Portuguese and Japanese ethnicity is noted to have a
hemoglobin of 9.1 g/dl with an MCV of 58 on a routine CBC screen at her one year well child check up.
She is otherwise healthy and has no complaints. PE is normal. On a review of this child's medical record,
you note the presence of Hemoglobin Barts on her newborn screen.
Thalassemia is one of the most confusing of the hemoglobinopathies, mostly due to confusing
nomenclature, lack of easy diagnostic tests, and its similarity to iron deficiency anemia. Whereas both
thalassemia and iron deficiency anemia are characterized by microcytic hypochromic anemias, iron
deficiency anemia is easily corrected with iron supplementation, but iron supplementation does not correct
the anemia due to thalassemia. In any anemic state, there is increased gut absorption of iron. Even in nontransfused patients, iron overload is often noted in the more severe forms of thalassemia. Since thalassemia
is not an iron deficiency problem, it is not be corrected by additional iron. In fact, in thalassemia over time,
the body becomes iron overloaded, and iron is "stored" in the organs (liver, endocrine organs and heart),
which can cause significant morbidity and mortality.
There are two basic types of thalassemia: alpha thalassemia and beta thalassemia. They have nothing to do
with one another. Alpha thalassemia usually results from the deletion of any number of the 4 genes
necessary to make alpha globin chains. Occasionally, an alpha globin gene is abnormal instead of being
completely deleted. Beta thalassemia usually results from an abnormal gene in one or both of the genes
necessary for beta globin chain production. Occasionally, the entire gene (on one allele) is actually deleted.
The alpha and beta genes are located on different chromosomes and therefore, abnormalities of each are
inherited separately.
Beta thalassemia usually occurs from abnormal beta genes, or less commonly, a deletion of a beta gene. In
beta thalassemia, there is a large lack of normal beta chain production, thus causing a relative excess
amount of alpha chains, which clump together. This abnormal hemoglobin is very unstable, and leads to
erythrocyte death in the bone marrow.
Beta thalassemia minor occurs when only one gene is affected, causing a moderate, lifelong anemia. This
typically requires no treatment other than recognition for the purposes of patient education, to avoid
supplemental iron, and for genetic counseling.
Beta thalassemia major, historically called Cooley's Anemia, occurs when both genes necessary for beta
globin production are affected. Since beta chains are not present in fetal hemoglobin, beta thalassemia does
not manifest itself in newborns. Beta thalassemia presents at 6 months of age when adult hemoglobin has
replaces fetal hemoglobin. Peripheral anemia, caused by the disease, sends signals to the bone marrow to
increase production of erythrocytes (e.g., via erythropoietin), however, erythrocyte production is abnormal
(ineffective). This process is called "ineffective erythropoiesis". With time, the marrow cavities (skull
bones, facial bones, and ribs) expand, leading to the classical facial features and skull X-ray findings ("hair
on end" in untreated patients due to excessive extramedullary hematopoiesis). Erythrocytes that do enter the
circulation are noted to be abnormal by the reticuloendothelial system (spleen and liver), and are taken up
by these organs with ensuing enormous hepatosplenomegaly. In untreated patients, death usually occurs by
the end of the second decade of life from anemia and congestive heart failure.
Currently, part of the standard treatment for beta thalassemia major is lifelong transfusions given every 2-4
weeks. The intent of these transfusions is to keep their hemoglobin trough above 9 or 10 gm/dl. This will,
in effect, shut off the patient's own erythropoiesis and stop the vicious cycle of anemia stimulating
"ineffective erythropoiesis". With each milliliter of transfused packed red blood cells, the patient receives
one milligram of elemental iron. Iron, in addition to being relatively difficult to absorb, is also not easily
excreted. Thus, such transfused patients quickly become iron overloaded. Untreated, iron overload will be
fatal. Regularly transfused patients need to be on lifelong chelation therapy to help their bodies excrete the
excess iron. There are no effective oral iron chelation agents. Currently, most regularly transfused
thalassemia patients receive their chelation as a subcutaneous infusion of deferoxamine over 10 hours each
night (lifelong). With the combination of transfusion and chelation therapy, life expectancy can to be
normal.
A form of alpha thalassemia occurs when any number of the four genes that control alpha globin
production are missing, thereby causing an excess of non-alpha globin chains. The various forms of alpha
thalassemia with their genetic correlate are listed below:
A. 4 normal alleles (normal)
B. 3 normal / 1 missing gene (silent carrier)
C. 2 normal / 2 missing genes (thal trait)
D. 1 normal / 3 missing genes ("Hemoglobin H disease")
E. 4 missing genes (results in hydrops fetalis)
Silent carriers are 1 missing alpha gene. They have no clinical abnormalities. Their hemoglobin, and
hemoglobin electrophoresis are normal and their MCV is borderline normal.
Those with alpha thalassemia trait are clinically normal, but their hemoglobin is slightly low and their
hemogram demonstrates microcytic indices. Their hemoglobin electrophoresis is normal unless it is done in
the newborn period at which time Hemoglobin Barts is present (recall this finding in the case example at
the beginning of the chapter).
Traditionally, people with alpha thalassemia trait are taught that they have a benign condition and no
further education is provided. However, it should be emphasized that although the anemia is benign,
supplemental iron must be AVOIDED to prevent harmful iron buildup. There is suspected sustained
morbidity in persons with thalassemia trait, who are on repeated, or continued iron supplementation.
Additionally, such iron supplementation is generally useless, even in menstruating females, as their stores
are readily replenished by a greater degree of absorption of dietary iron from the gut. The extra iron is
stored in the organs, leading to end organ dysfunction. Additionally, parents with this, so called, "benign"
alpha thalassemia trait, can produce offspring with fatal hydrops fetalis if both parents pass on alleles with
two defective alpha genes.
The name Hemoglobin H disease is a misnomer. In developed countries with otherwise good medical care,
it is not a disease, but rather a condition. People with Hemoglobin H condition can live healthy, long lives.
They are not transfusion dependent, as are those with beta thalassemia major. There are some rare variants,
such as Hemoglobin H Constant Springs, (the Constant Springs is an abnormal gene, rather than a deletion,
named after a U.S. city where it was first identified), that can be dependent on lifelong monthly
transfusions. These people are missing 2 genes from one allele, and have the severely dysfunctional
Constant Springs gene on the other allele. People with Hemoglobin H need to avoid all forms of
supplemental iron, and pregnant women need very close prenatal care for their own health matters. Since
the bone marrow of thalassemia patients requires excess folic acid (due to erythroid hyperplasia), most
clinicians advise lifelong supplementation of 1 milligram daily of folic acid to avoid relative folate
deficiency. During times of severe illness, or in pregnancy, the hemoglobin may drop significantly below
baseline in Hemoglobin H disease, and a transfusion may be recommended. Again, iron is generally not
deficient and, thus iron supplementation is not helpful, nor is it appropriate.
When four beta chains clump together, Hemoglobin H is formed. In infants, gamma chains predominate
over beta chains, and Hemoglobin Barts (four gamma chains) is formed. Hemoglobin H and Hemoglobin
Barts are both useless, with no effective oxygen carrying capacity. There has been a lot of confusion
between this abnormal Hemoglobin H (4 beta chains clumped together) and the clinical condition in which
3 alpha genes are missing, called "Hemoglobin H disease or condition". The abnormal Hemoglobin H
exists (in varying amounts) in all 4 clinical alpha thalassemia categories. Similarly in newborns,
Hemoglobin Barts exists in varying amounts in all alpha thalassemia categories.
Hemoglobin H and Hemoglobin Barts do not cause the degree of ineffective erythropoiesis seen in beta
thalassemia. Therefore, the classical "thal facies", "hair on end" skull X-rays, and enormous
hepatosplenomegaly, all typical of beta thalassemia, are not seen to such degree in severe alpha
thalassemia.
Hemoglobin E results from a single amino acid substitution on the beta globin chains. It is very common in
the golden triangle of Laos, Cambodia, and Thailand. In the heterozygous form, it affects one out of three
persons in this region. Heterozygous Hemoglobin E by itself is not harmful and causes no anemia.
However, when combined with beta thalassemia minor, significant anemia develops over time. Such people
usually become transfusion dependent later in the first decade of life, and if treatment is not sought or
maintained, early death is most likely. The effects of Hemoglobin E on Hemoglobin H are not clear.
Homozygous Hemoglobin E usually causes mild microcytic hypochromic anemia, which resembles alpha
thalassemia trait.
Chapter XI.5. Newborn Hematology Robert W. Wilkinson, MD
This is a newborn female born to a 17 year old gravida 1, para 0, B+, mother at 39 weeks gestation.
Maternal risk factors include a kidney infection in the second trimester. All other risk factors are negative.
After an uneventful vaginal delivery, the infant is discharged at two days of life breast feeding at home. On
the third day of life, moderate jaundice is noted and a bilirubin in the primary care doctor's office is 18.
Home phototherapy is started, but on day six, the bilirubin is 22.9 with the direct component of 0.4. She is
hospitalized for inpatient phototherapy. Her hemoglobin was 15.7 earlier, and it has now dropped to 13.4.
The bilirubin continues to rise to 25.6 in spite of phototherapy. A G6PD is normal and the reticulocyte
count is 3.1. Stools are negative for occult blood. The blood smear shows moderate aniso and
poikilocytosis.
She is transferred to a tertiary pediatric center where she is noted to be normal except for marked jaundice.
Her mother is of German decent and her father is Caucasian and Puerto Rican. Her mother was treated for
newborn jaundice due to presumed ABO incompatibility. Others in her family also had neonatal jaundice.
The father's history is unremarkable. No other family member had neonatal jaundice or anemia or
gallstones.
Upon admission, vital signs are normal. She is visibly jaundiced and a spleen tip is palpable. Labs show a
bilirubin of 25, white count of 17.5, platelets of 230,000 and an unremarkable differential. The hemoglobin
is now down to 10.7 in spite of a reticulocyte count of 4%. In addition, the smear now shows moderate
schistocytes with burr cells and moderate spherocytes. Blood type is B+ and the Coombs is negative. She is
transfused and phototherapy continues until the bilirubin falls to 12. The infant has an otherwise uneventful
course in the hospital and the final diagnosis is hyperbilirubinemia and anemia due to hereditary
spherocytosis. In addition, alpha thalassemia trait is found on her newborn screen. Incubated red cell
osmotic fragility studies on the mother and other maternal family member are consistent with hereditary
spherocytosis.
At the moment of birth, the physician can be confronted with complex hematologic problems seen at no
other time in life. Newborn red cells are much different than in older children and white cell and platelet
disorders can be quite unique. Coagulation factors are abnormal and hemostasis can be markedly altered.
Normal values for most newborn blood tests are different compared to children and adults. Interpretation of
results in term and premature newborns can be critical.
Significant red cell disorders in the newborn period may be associated with a family history of anemia,
jaundice, falling hemoglobin and reticulocytosis in addition to abnormal RBC morphology. The presence of
surface antibodies (e.g., anti-A and/or anti-B) may be helpful or the deficiency of intraerythrocytic enzymes
(e.g., G6PD deficiency). Finally hemoglobinopathies and thalassemia may offer an almost infinite
combination of symptoms and signs in the newborn. Virtually all red cell problems are isolated and the rest
of the hemogram is normal. Marrow failure resulting in pancytopenia with associated infections and altered
hemostasis is vary rare. Definitive studies on red cells can be delayed for three months when the infant is
well and their blood volume is larger. As in the above case, studies of maternal family members
subsequently confirmed the diagnosis of hereditary spherocytosis. It is important to remember that in the
perinatal period (28 weeks gestation to 28 days after birth) there are normal physiologic changes occurring
in red cells. Some of these changes include switching from fetal to adult hemoglobin production, a 30%
drop in hemoglobin, a fall in mean red cell volume (MCV) as well as changes in membrane pliability and
intracellular enzyme levels. RBC survival is further impacted by acquired infections, medications, and
other high-risk conditions. Repeated monitoring of hemoglobin and reticulocyte counts is warranted in the
sick and unstable newborn.
Hydrops fetalis results from severe intrauterine hemolysis and anemia necessitating emergency exchange
transfusion. The cause is usually due to severe alpha thalassemia, red cell surface antibodies or congenital
infections. Rh incompatibility usually presents with rapid hemolysis and varying degrees of anemia and
jaundice (depending on the extent of maternal sensitization and antibody production).
White blood cell abnormalities may be asymptomatic and incidental or associated with fever, infection, and
altered host resistance. Wide fluctuation in the WBC count can be noted depending on marrow production
of granulocytes. Infection, antibodies, and medications call all affect the circulating neutrophil pool. This is
the pool of granulocytes sampled with a venipuncture. Interpretation of a peripheral WBC count can be
difficult when trying to determine the risk of infection or underlying pathophysiology. A bone marrow
examination can be very helpful in assessing granulocyte production and the risk of infection. Most WBC
aberrations are secondary or reactive to a disease process, but occasionally rare hereditary disorders can
present in the neonate. These are usually associated with an increased risk of infection (e.g., chronic
granulomatous disease) or as part of a recognizable syndrome (e.g., Jobs syndrome). Congenital leukemia
is extremely rare but striking leukemoid reactions can occur. Of note is the transient myeloproliferative
condition or pseudoleukemia that may be observed in neonates with Down syndrome. Of prime importance
when evaluating infants with any white cell aberration is the real risk of infection and the need for
antimicrobials.
Platelet problems in the newborn present almost exclusively with thrombocytopenia and bleeding.
Thrombocytopenia can be isolated or associated with other cytopenias. A low platelet count results from
either decreased production or peripheral consumption of platelets. By examining the bone marrow and/or
the mean platelet volume (MPV usually higher in younger platelets seen in consumptive disorders), the
underlying pathophysiology can usually be identified. Most thrombocytopenias are consumptive and due to
maternal antiplatelet antibodies, congenital infections, or part of complex DIC seen in sick newborns. It is
paramount to compare the amount of clinical bleeding to the degree of thrombocytopenia in order to
quickly make the right diagnosis and determine the need for transfusion or other therapy.
Hemorrhagic disease of the newborn is usually seen from day 2 to 4 of life resulting from vitamin K
deficiency and the subsequent failure to produce clotting factors II, VII, IX and X. The prothrombin time is
markedly prolonged and serious life threatening hemorrhaging can occur in many organ systems. This
transient deficiency of vitamin K is thought to result from poor placental transfer, marginal content in
breast milk, inadequate intake of breast milk and a sterile gut (lack of vitamin K producing GI flora).
Hemorrhaging can be prevented by the intramuscular administration of prophylactic vitamin K shortly after
birth.
Chapter XI.6. Bleeding Disorders
Desiree Medeiros, MD
This 4 year old female is referred to the hematology department with a chief complaint of acute onset of
easy bruising and "rash" for 3 days. She has not had epistaxis, oral bleeding, gross blood in urine or stools.
She has never had palpable bruises, hemarthroses or deep muscle bleeds in the past. She has no history of
fever or appetite changes. She had upper respiratory infection symptoms approximately 2 weeks ago. There
is no travel history. She has 2 older brothers, neither of whom have had bleeding symptoms. Family history
is negative for frequent nosebleeds, oral bleeding, menorrhagia or excessive bleeding with surgery or
trauma. There is no history of malignancies, or autoimmune disorders.
Exam: VS are normal. Height and weight are at the 50th percentile. She is a healthy appearing, cooperative
girl in no acute distress. HEENT exam demonstrates no signs of bleeding or bruising. Heart and lung exams
are normal. Her abdomen demonstrates no hepatosplenomegaly. A diffuse petechial rash is noted on her
neck, trunk, extremities and groin. Nonpalpable ecchymoses of varying ages are present on shins and arms.
Her neurologic examination demonstrates no deficits.
CBC shows Hgb 12.8, Hct 38.5, WBC 6,000 with a normal differential. Platelet count is low at 5,000. PT
and PTT 12.0 and 32 seconds, respectively. Review of the peripheral smear shows normal morphology of
red and white blood cell lines. The platelets are reducedinnumberandthemajorityofthemareincreasedinsize.
Abonemarrowaspirateisnotperformed.
She is diagnosed with immune thrombocytopenic purpura. She is followed closely with weekly CBCs. Her
bruises and petechiae fade by her next visit and her platelet count returns to 240,000 one month later.
Bleeding disorders can either be inherited or acquired and are due to defects in either primary or secondary
hemostasis. While evaluating a child with a bleeding tendency, the history and physical examination should
be directed at differentiating between these. An appropriate history can be more helpful in evaluating these
children than any laboratory test. Bruising with or without preceding trauma can be due to a defect in either
primary or secondary hemostasis although deep palpable bruises are usually due to a clotting factor defect.
Petechiae are usually due to a platelet or blood vessel defect. One should ask about a history of mucosal
bleeding (including epistaxis, oral bleeding, gastrointestinal, genitourinary and menstrual bleeding),
bleeding from injury or following procedures such as circumcision and tonsillectomy, and deep tissue or
musculoskeletal bleeding. Age of onset, frequency and severity of each bleeding complaint should be
determined and an extensive family history and medication history should be obtained.
The child should be examined for signs of bleeding, such as petechiae, bruising, mucosal bleeding, and
oozing from venipuncture sites. Differentiate between superficial bruises and deep palpable ecchymoses,
making note of their location. Special attention should be made to the joints and large muscle areas, looking
for deep tissue bleeding.
Laboratory studies assist in confirming suspicions raised from the history and physical. Routine screening
laboratory studies should include complete blood count (CBC) with a platelet count, prothrombin time (PT)
and activated partial thromboplastin time (PTT).
Further specific testing should be performed based on the
working diagnosis. These include a PTT mixing study (which helps differentiate a factor deficiency from
an acquired inhibitor), bleeding time, factor assays, von Willebrand studies, and platelet aggregation tests.
The bleeding time is an uncommonly ordered test during which a standardized small laceration is created
on the patient's forearm and the time for the bleeding to stop is measured and compared to standard times.
This test is prolonged in conditions of thrombocytopenia and platelet dysfunction. Platelet aggregation
studies are special studies that can be done to test the aggregation of platelets in response to several known
agents which induce platelet aggregation in vitro such as adenosine diphosphate (ADP), epinephrine and
collagen.
Page - 421
The more commonly encountered bleeding disorders are discussed in further depth in this chapter.
I. Primary Hemostasis (platelets)
A. Quantitative (thrombocytopenia)
1. ITP
2. Hemolytic uremic syndrome (HUS)
3. Thrombotic thrombocytopenic purpura (TTP)
4. Medications
5. Marrow failure (leukemia, aplastic anemia)
6. Platelet sequestration, consumption and dilution
B. Qualitative (poor platelet function)
1. Inherited platelet aggregation defect
2. Drug effect
II. Secondary Hemostasis (coagulation)
A. Congenital factor deficiency
1. Hemophilia A and B
2. von Willebrand disease
3. Other factor deficiencies (rare)
B. Acquired factor deficiency
1. Vitamin K deficiency
2. Liver failure
C. Antiphospholipid antibody
Defects in Primary Hemostasis
Quantitative
disorders result in thrombocytopenia, either due to decreased bone marrow production or increased platelet
Defects in
Primary platelet
Hemostasis
destruction.
Quantitative
platelet disorders
result in thrombocytopenia, either due to decreased bone marrow production
Immune Thrombocytopenic
Purpura
or increased
platelet
destruction.
Immune
or idiopathic
thrombocytopenic purpura (ITP) is one of the most common acquired bleeding disorders of childhood.
Usually, it is a benign, self-limited disease that occurs in previously healthy children. The typical course in an untreated child is resolution
of bleeding symptoms 3 to 10 days after diagnosis, regardless of the platelet count and an increase in the platelet count within 1 to 3 weeks.
Immune
Thrombocytopenic Purpura
The platelet count returns to normal in 4 to 8 weeks in approximately half of patients and two thirds of children have resolution by 3
months after diagnosis. By 6 months, platelet counts have returned to normal (>150,000 per cubic mm) in 80% of patients. The remainder
are defined
having chronic
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children.
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(>150,000
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HIV infection. These children appear well except for bruises and petechiae. A minority of patients have mucous membrane hemorrhage,
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such asfollow
menorrhagia,
gastrointestinal
bleeding
or oral ITP,
blood in
blisters.
not havecounts
jaundice,
hepatosplenomegaly.
recover as
above. Adults
more
commonly
follow a of
course
chronic
which
thecount is
Thenoted
most important
laboratory
assessment
in the evaluation
ITP is consistent
the CBC and with
peripheral
bloodITP,
smear.inThe
platelet
typically
very low
cubic mm) and
therethrombocytopenia
is appreciable bleeding,
the hemoglobin
concentration
normal
as is the
platelet
counts
are (<20,000
usually per
moderately
low,unless
but the
persists
for long
periods ofistime
and
leukocyte
count.
The peripheral
smear shows
morphology
of allconsequences
cell lines except from
the platelets
are reduced
in number
often
for life.
If patients
with chronic
ITPnormal
sustain
significant
recurrent
bleeding,
a and tend to be
large. PT and PTT are normal and do not need to be performed. The bleeding time is predictably prolonged and unnecessary in the
splenectomy
to raise
their
platelet
count.
evaluation ofisa sometimes
child with ITP.necessary
When indicated
by the
medical
history
and physical examination, evaluation for HIV, systemic lupus
erythematosus, or Evan's syndrome should be considered. Bone marrow aspiration should be considered in patients with
hepatosplenomegaly,
abnormalities
on the
CBC.
ITPlymphadenopathy,
is an immune-mediated
disorderorinother
which
circulating
antiplatelet
antibodies target epitopes on the
Management of ITP in a child includes education and reassurance of the child's parents. The child's activities should be limited, and
platelet membrane (1). The antibody-coated platelets are subsequently destroyed by macrophages in the
aspirin and NSAID containing medications should not be used. Children without significant clinical bleeding may be closely observed
reticuloendothelial
system.
Children
with
ITPcount
present
with
suddenit onset
bruising,
petechiae
anduntil it returns to
with CBCs once or twice
weekly.
Once the
platelet
begins
to increase,
may beof
measured
every
2 to 3 weeks
occasionally
epistaxis.
There
may count
be a has
history
of a preceding
infection
orplatelet
a recent
live-virus
normal (>150,000).
Once
the platelet
normalized,
recurrence isviral
rare and
follow-up
counts
are unnecessary (1,2). A few
children with ITP
bleeding
significant
enough to warrant
medical
management.
Standard
therapy options include
oral or IV
immunization
(1).have
There
should
be no evidence
of other
disorders
causing
thrombocytopenia,
such as
corticosteroids (which block the reticuloendothelial system's destruction of antibody-coated platelets and reduce synthesis of antiplatelet
systemic
lupus erythematosus or HIV infection. These children appear well except for bruises and
antibodies), IVIG (IV gamma globulin which inhibits Fc receptors on phagocytes, allowing antibody-coated platelets to circulate and alters
petechiae.
A minority
of B-cell
patients
haveand
mucous
as(which
menorrhagia,
T-lymphocyte
subsets and
function
reduces membrane
autoantibody hemorrhage,
production), andsuch
Anti-D
is the anti-serum against the Rh(D)
gastrointestinal
bleeding
blood
blisters.
do notit have
jaundice,
pallor, or hepatosplenomegaly.
antigen on erythrocytes
andor
byoral
coating
Rh(D)
positive They
erythrocytes,
decreases
platelet destruction).
uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP)
TheHemolytic
mostHUS
important
laboratory assessment in the evaluation of ITP is the CBC and peripheral blood smear.
and TTP are closely related disorders caused by microvascular occlusion of arterioles and capillaries producing ischemia of
Themultiple
platelet
countHUS
is typically
very low
(<20,000 per cubic
mm) andhemolytic
unless there
is and
appreciable
organs.
is a combination
of thrombocytopenia,
microangiopathic
anemia,
acute renal bleeding,
failure (4). It occurs
the mostly
hemoglobin
concentration
normal
as is TTP
the is
leukocyte
count.
The peripheral
smearinclude:
showsthrombocytopenia,
normal
in children
and has a fairlyisgood
prognosis.
characterized
by a pentad
of features which
microangiopathic
neurologic
disturbances,
renal dysfunction
and and
fevertend
(4). Ittooccurs
in young
and teenagers
morphology
of allhemolytic
cell linesanemia,
except
the platelets
are reduced
in number
be large.
PTadults
and PTT
are and
carriesand
a high
and notThe
treated.
Table 1 time
compares
both disorders.
normal
do mortality
not needif unrecognized
to be performed.
bleeding
is predictably
prolonged and unnecessary in the
evaluation of a child with ITP. When indicated by the medical history and physical examination, evaluation
for HIV, systemic lupus erythematosus, or Evan's syndrome should be considered. Bone marrow aspiration
should be considered in patients with lymphadenopathy, hepatosplenomegaly, or other abnormalities on the
CBC.
Management of ITP in a child includes education and reassurance of the child's parents. The child's
activities should be limited, and aspirin and NSAID containing medications should not be used. Children
without significant clinical bleeding may be closely observed with CBCs once or twice weekly. Once the
platelet count begins to increase, it may be measured every 2 to 3 weeks until it returns to normal
(>150,000). Once the platelet count has normalized, recurrence is rare and follow-up platelet counts are
unnecessary (1,2). A few children with ITP have bleeding significant enough to warrant medical
management. Standard therapy options include oral or IV corticosteroids (which block the
reticuloendothelial system's destruction of antibody-coated platelets and reduce synthesis of antiplatelet
antibodies), IVIG (IV gamma globulin which inhibits Fc receptors on phagocytes, allowing antibodycoated platelets to circulate and alters T-lymphocyte subsets and B-cell function and reduces autoantibody
production), and Anti-D (which is the anti-serum against the Rh(D) antigen on erythrocytes and by coating
Rh(D) positive erythrocytes, it decreases platelet destruction).
Hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP)
HUS and TTP are
closely related disorders caused by microvascular occlusion of arterioles and capillaries producing ischemia
of multiple organs. HUS is a combination of thrombocytopenia, microangiopathic hemolytic anemia, and
acute renal failure (4). It occurs mostly in children and has a fairly good prognosis. TTP is characterized by
a pentad of features which include: thrombocytopenia, microangiopathic hemolytic anemia, neurologic
disturbances, renal dysfunction and fever (4). It occurs in young adults and teenagers and carries a high
Page - 422
mortality if unrecognized and not treated. Table 1 compares both disorders.
Table 1: Comparison of HUS and TTP
Feature
HUS
TTP
Course
Age usually <3 yr
M=F
Prodrome: infection, diarrhea
Recurrence rare
Age usually 3rd decade
F>M
Prodrome less common
Recurrence common
Diagnosis
Triad
Acute renal failure
Thrombocytopenia
Microangiopathic anemia
Pentad
CNS disturbance
Thrombocytopenia
Microangiopathic anemia
Renal dysfunction
Fever
Etiologic factors
E. coli, Shigella gastroenteritis, Pregnancy, autoimmune disease,
pneumococcus
malignancy, drugs
Treatment
Renal dialysis
Corticosteroids - no help
Transfuse only if necessary
Plasma exchange
Corticosteroids
AVOID transfusions
Prognosis
Good
Poor
A variety of drugs have been reported to cause thrombocytopenia either by drug-induced platelet destruction or bone marrow
suppression.
Heparin
emphasis
because
it is so commonly used.
Heparin
does not inhibit platelet
function but it may
A variety
of drugs
havemerits
beenspecial
reported
to cause
thrombocytopenia
either
by drug-induced
platelet
sometimes cause thrombocytopenia. There are two types of heparin-induced thrombocytopenia (HIT). The first occurs 2 to 5 days after
destruction
or bone marrow suppression. Heparin merits special emphasis because it is so commonly used.
initiation of heparin. Platelet counts rarely fall below 100,000 per cubic mm and normalize within 1 to 5 days. This type is thought to
Heparin
inhibit
platelet
function
it heparin
may sometimes
cause
thrombocytopenia.
areafter
twothe initiation of
resultdoes
from not
platelet
aggregation
secondary
to abut
direct
effect (4). The
second
type of HIT occurs 3 There
to 15 days
typesheparin
of heparin-induced
thrombocytopenia
(HIT).
The first
occurs
to mechanism
5 days after
initiation
of heparin.
(4). Platelet counts
fall below 40,000. Arterial
thrombosis
may
occur. 2The
is immune
mediated.
Treatment involves
discontinuation
of heparin.
Platelet
counts rarely
fall below 100,000 per cubic mm and normalize within 1 to 5 days. This type is
thought to result from platelet aggregation secondary to a direct heparin effect (4). The second type of HIT
Decreased numbers of platelets result from impaired platelet production due to leukemia, aplastic anemia or bone marrow
occurs
3 to 15 due
days
the initiation
heparin
(4). Platelet
counts
fall below
40,000.
Arterial
thrombosis
suppression
to after
viral infection
or drugs.ofThese
are discussed
in separate
chapters.
May-Hegglin
anomaly
is characterized
by mild to
may moderate
occur. The
mechanismand
is immune
mediated.
Treatment
involves discontinuation
of heparin.
thrombocytopenia
the presence
of Dohle bodies
in the leukocytes.
Kasabach-Merritt (giant
hemangioma) syndrome is due to
localized intravascular coagulation from low blood flow through the abnormal vascular tissue and is associated with thrombocytopenia (4).
Foreign bodies in the circulation (central venous catheters and prosthetic valves) are sites for platelet consumption. Platelet loss also
results from extracorporeal circulation and exchange transfusions. Massive plasma and blood transfusions lead to a dilutional
thrombocytopenia. Finally, platelet counts may be low as a result of sequestration when the spleen is enlarged.
Qualitative platelet disorders (defects in platelet aggregation) are very rare. Most are inherited as autosomal recessive traits.
Patients present with bleeding similar to that seen with thrombocytopenia. They complain of skin and mucous membrane bleeding,
recurrent epistaxis, gastrointestinal bleeding, menorrhagia, and prolonged bleeding with injury or surgery (5). Aspirin (ASA) and non-
Etiologic factors
E. coli, Shigella gastroenteritis, Pregnancy, autoimmune disease,
pneumococcus
malignancy, drugs
Treatment
Renal dialysis
Corticosteroids - no help
Transfuse only if necessary
Plasma exchange
Corticosteroids
AVOID transfusions
Prognosis
Good
Poor
Decreased numbers of platelets result from impaired platelet production due to leukemia, aplastic anemia or
A variety
of drugs have
been
to cause thrombocytopenia
either
drug-induced
destruction
or bone
marrow
bone marrow
suppression
due
toreported
viral infection
or drugs. These
arebydiscussed
in platelet
separate
chapters.
Maysuppression. Heparin merits special emphasis because it is so commonly used. Heparin does not inhibit platelet function but it may
Hegglin
anomaly
is characterizedThere
by mild
to types
moderate
thrombocytopenia
and the(HIT).
presence
of Dohle
sometimes
cause thrombocytopenia.
are two
of heparin-induced
thrombocytopenia
The first
occurs 2bodies
to 5 days after
in the
leukocytes.
Kasabach-Merritt
hemangioma)
syndrome
due to localized
initiation
of heparin.
Platelet counts rarely(giant
fall below
100,000 per cubic
mm andisnormalize
within 1 to 5intravascular
days. This type is thought to
result from from
plateletlow
aggregation
secondary
to a direct
heparin effect
(4). The tissue
second type
occurs 3 to
15 days after the initiation of
coagulation
blood flow
through
the abnormal
vascular
and of
is HIT
associated
with
heparin (4). Platelet(4).
counts
fall below
40,000.
thrombosis(central
may occur.
The mechanism
immune
mediated.valves)
Treatment
thrombocytopenia
Foreign
bodies
in Arterial
the circulation
venous
cathetersis and
prosthetic
areinvolves
discontinuation of heparin.
sites for platelet consumption. Platelet loss also results from extracorporeal circulation and exchange
transfusions.
Massive
plasma
and result
bloodfrom
transfusions
lead production
to a dilutional
thrombocytopenia.
platelet
Decreased
numbers
of platelets
impaired platelet
due to leukemia,
aplastic anemiaFinally,
or bone marrow
suppression
duelow
to viral
or drugs.
These are when
discussed
separateischapters.
May-Hegglin anomaly is characterized by mild to
counts
may be
as ainfection
result of
sequestration
theinspleen
enlarged.
moderate thrombocytopenia and the presence of Dohle bodies in the leukocytes. Kasabach-Merritt (giant hemangioma) syndrome is due to
localized intravascular coagulation from low blood flow through the abnormal vascular tissue and is associated with thrombocytopenia (4).
Qualitative
platelet
in platelet
very
Most
areconsumption.
inherited asPlatelet
autosomal
Foreign bodies
in thedisorders
circulation (defects
(central venous
cathetersaggregation)
and prosthetic are
valves)
arerare.
sites for
platelet
loss also
recessive
traits.
Patients present
with
similar to that
seen
withand
thrombocytopenia.
They
complain
results from
extracorporeal
circulation
and bleeding
exchange transfusions.
Massive
plasma
blood transfusions lead
to a dilutional
thrombocytopenia.
plateletbleeding,
counts mayrecurrent
be low as aepistaxis,
result of sequestration
when thebleeding,
spleen is enlarged.
of skin
and mucousFinally,
membrane
gastrointestinal
menorrhagia, and
prolonged bleeding with injury or surgery (5). Aspirin (ASA) and non- steroidal anti-inflammatory drugs
Qualitative platelet disorders (defects in platelet aggregation) are very rare. Most are inherited as autosomal recessive traits.
(NSAIDs)
are common
causes
of to
temporary
platelet
dysfunction.
Laboratory
usually
Patients present
with bleeding
similar
that seen with
thrombocytopenia.
They
complain ofevaluation
skin and mucous
membrane bleeding,
demonstrates
a normal
platelet count,
bleeding
time bleeding
and abnormal
platelet
aggregation
recurrent epistaxis,
gastrointestinal
bleeding,prolonged
menorrhagia,
and prolonged
with injury
or surgery
(5). Aspirinstudies.
(ASA) and nonsteroidal anti-inflammatory
drugs (NSAIDs)
are common
temporary
platelet
dysfunction.
Laboratory
evaluation
Coagulation
studies (PT, PTT)
are usually
normal.causes
The of
most
common
platelet
aggregation
defects
are usually
demonstrates
a normal
platelet count, prolonged bleeding time and abnormal platelet aggregation studies. Coagulation studies (PT, PTT)
described
in table
2 below.
are usually normal. The most common platelet aggregation defects are described in table 2 below.
Table 2: Platelet aggregation defects
Platelet
aggregation studies
Platelet
count
Glanzmann
thrombasthenia
Abnormal to all agonists
Normal
Bernard-Soulier
syndrome
Abnormal to ristocetin
Decreased
Giant platelets
Storage pool defect
(Dense body deficiency,
Gray platelet syndrome)
Abnormal 2nd phase
of aggregation
Normal
Abnormal platelet granules
on electron microscopy
ASA/NSAID
Abnormal to arachidonic acid
and abnormal secondary
aggregation to ADP and
epinephrine.
Normal
Drug induced enzyme effect
inhibiting platelet granule release
This is the most common cause
of platelet dysfunction
Condition
Other
Defects in Secondary Hemostasis
Hemophilia
Hemophilia is an X-linked inherited bleeding disorder transmitted from female carriers to
their male children. It is due to a deficiency of factor VIII (Hemophilia A or "Classic hemophilia") or factor
IX (Hemophilia B or "Christmas disease"). Hemophilia A is more common, occurring in 1/5000 male
births while hemophilia B occurs in 1/15,000 (6). Signs and symptoms vary depending on the severity of
the hemophilia. Severity is defined by baseline factor levels: severe <1%, moderate 1-5%, mild >5% (6,7).
Children with severe hemophilia usually present in the first year of life with a history of extensive deep
palpable ecchymoses. There may be a history of bleeding from the circumcision. After the age of 2 years,
they begin to develop spontaneous hemarthroses or deep muscle bleeds. They can have mucosal bleeds,
such as oral bleeding with procedures and hematuria. The bleeding is usually not catastrophic. Instead, it is
prolonged and continuous without therapy. A head injury is considered an emergency since it is potentially
life threatening if not treated appropriately. Children with milder forms of hemophilia may present later in
life with a history of easy bruising or prolonged bleeding following injury. They usually do not have
spontaneous bleeding. Laboratory findings include a markedly prolonged PTT (>100 seconds) and a
decreased factor VIII or IX activity. Other screening tests (PT, platelet count and bleeding time) should be
normal.
The mainstay of therapy is replacing the deficient clotting factor with factor VIII or IX concentrate (6,7).
Page - 423
Defects in Secondary Hemostasis
Hemophilia
Hemophilia is an X-linked inherited bleeding disorder transmitted from female carriers to their male children. It is due to a
deficiency of factor VIII (Hemophilia A or "Classic hemophilia") or factor IX (Hemophilia B or "Christmas disease"). Hemophilia A is
Bothmore
human
derived and recombinant factor concentrates are available. In the past, factor replacement
common, occurring in 1/5000 male births while hemophilia B occurs in 1/15,000 (6). Signs and symptoms vary depending on the
carried
a risk
of hemophilia.
transmission
of viral
infections,
especially
hepatitis
andmoderate
C, and 1-5%,
HIV.mild
This>5%
risk(6,7).
has Children
been with
severity
of the
Severity
is defined
by baseline
factor levels:
severe B
<1%,
reduced
current
viralpresent
inactivation
techniques
andawith
the
recombinant
factor.
unit
severewith
hemophilia
usually
in the first
year of life with
history
of availability
extensive deepof
palpable
ecchymoses.
ThereEach
may be
a history of
bleeding
from
the increase
circumcision.
theVIII
age oflevel
2 years,
to develop
spontaneous
or deep
muscle
bleeds. They
of factor
VIII
will
the After
factor
bythey
2%begin
and has
an 8 to
12 hour hemarthroses
half-life. Each
unit
of factor
can have
mucosal
such
oral bleeding
The bleeding
is usually
not depends
catastrophic.
IX will
increase
thebleeds,
factor
IXaslevel
by 1% with
and procedures
has an 18and
to hematuria.
24 hour half-life
(6,7).
Dosing
on Instead,
the it is
prolonged and continuous without therapy. A head injury is considered an emergency since it is potentially life threatening if not treated
location
and severity
of with
the milder
bleed.forms
In addition
to factor
replacement,
hemophilia
benefit
from bleeding
appropriately.
Children
of hemophilia
may present
later in lifemales
with awith
history
of easy bruising
or prolonged
supportive
often require
intervention.
acidPTT
is an
followingmeasures,
injury. Theyphysical
usually dotherapy
not haveand
spontaneous
bleeding.orthopedic
Laboratory findings
include Aminocaproic
a markedly prolonged
(>100 seconds)
a decreased factor
VIII
or be
IX activity.
Other screening
plateletmembrane
count and bleeding
time) Mild
shouldfactor
be normal.
oraland
antifibrinolytic
and
can
used adjunctively
to tests
treat(PT,
mucous
bleeding.
VIII
mainstay
of be
therapy
is replacing
the deficient clotting
factorconcentrated
with factor VIIIintranasal
or IX concentrate
(6,7). Both human derived and
deficient The
patients
may
treated
with intravenous
or highly
desmopressin
recombinant factor concentrates are available. In the past, factor replacement carried a risk of transmission of viral infections, especially
(DDAVP)
a release
VIIIviral
stores.
Thesetechniques
boys need
be the
cautioned
toof recombinant
hepatitis which
B and C,causes
and HIV.
This riskin
hasendogenous
been reduced factor
with current
inactivation
andtowith
availability
avoid
contact
such VIII
as tackle
football,
boxing
wrestling.
is an
nationally
recognized
thatunit
hemophilia
factor.
Eachsports
unit of factor
will increase
the factor
VIIIor
level
by 2% andIthas
8 to 12 hour
half-life. Each
of factor IX will
increasecenters
the factorhave
IX level
by 1% and
an 18 to 24of
hour
half-lifewith
(6,7).hemophilia.
Dosing depends
on the location
and severity
of have
the bleed. In
treatment
improved
thehasprognosis
patients
Patients
and their
families
addition
to factor
replacement,
males with
hemophiliapromptly
benefit fromatsupportive
measures,
physical
therapy
and often require
orthopedic
a home
supply
of factor
and infuse
themselves
the earliest
sign of
a bleed.
Prophylaxis
has been
intervention. Aminocaproic acid is an oral antifibrinolytic and can be used adjunctively to treat mucous membrane bleeding. Mild factor
instituted
in most
severely
affected
individuals
they
infuse themselves
regularly (DDAVP)
two to three
VIII deficient
patients
may be
treated with
intravenouswhere
or highly
concentrated
intranasal desmopressin
whichtimes
causesaa release in
week
and/or prior
a sports
order
tocautioned
prevent tospontaneous
bleeds.
This
has reduced
muchorofwrestling.
the
endogenous
factorto
VIII
stores. activity
These boysinneed
to be
avoid contact sports
such
as tackle
football, boxing
It is
nationally
recognizedinthat
treatment
centers
have improved
the prognosis
of patients
with hemophilia.
Patients
chronic
arthropathy
thishemophilia
population.
Today,
young
people with
hemophilia
can lead
independent
and and their
families
havelives.
a home supply of factor and infuse themselves promptly at the earliest sign of a bleed. Prophylaxis has been instituted in
nearly
normal
most severely affected individuals where they infuse themselves regularly two to three times a week and/or prior to a sports activity in
order to prevent spontaneous bleeds. This has reduced much of the chronic arthropathy in this population. Today, young people with
von hemophilia
Willebrand
(vWD)and
is the
most
common
candisease
lead independent
nearly
normal
lives. inherited bleeding disorder. It affects 1% to 2% of the
population. Von Willebrand factor is a cofactor for platelet adhesion and a carrier protein for factor VIII
vonThe
Willebrand
Disease form is transmitted as an autosomal dominant trait. Severity of bleeding
(8,9).
most common
von Willebrand disease (vWD) is the most common inherited bleeding disorder. It affects 1% to 2% of the population. von
symptoms
depends
on the type and subtype. Types 1 and 3 result in quantitative defects of the von
Willebrand factor is a cofactor for platelet adhesion and a carrier protein for factor VIII (8,9). The most common form is transmitted as an
Willebrand
protein
(i.e.,
while symptoms
Type 2 isdepends
due toona the
qualitative
defect Types
in the1 von
autosomal dominant trait. deficiency)
Severity of bleeding
type and subtype.
and 3Willebrand
result in quantitative defects of
the von
Willebrand
proteinare
(i.e.,
deficiency)
while
protein.
The
vWD types
listed
in table
3. Type 2 is due to a qualitative defect in the von Willebrand protein. The vWD types are
listed in table 3.
Table 3 - von Willebrand disease subtypes
Type
Defect
Bleeding symptoms
Type 1 (common)
Quantitative: Decreased vWF
Mild
Type 2 (uncommon)
2A
2B
2N
2M
Qualitative: Normal vWF levels
vWF not "sticky" enough
vWF too "sticky"
Lacking receptor for factor VIII binding
Lacking receptor for platelet binding
Variable
Potentially severe
Similar to hemophilia
Fairly mild
Type 3 (rare)
Quantitative absent vWF
Severe
Patients with vWD often have a positive family history of bleeding and easy bruisability in addition to the personal bleeding history.
The bleeding
symptoms
be similar
to that family
seen withhistory
thrombocytopenia
or platelet
dysfunction
and usually
involve the
Patients
with vWD
oftencanhave
a positive
of bleeding
and easy
bruisability
in addition
tomucous
the
membranes
and patients
present
complaints
of recurrent
oral bleeding
and menorrhagia. In
personal
bleeding
history.
Thewith
bleeding
symptoms
canepistaxis,
be similar
to that with
seendental
withcare,
thrombocytopenia
oraddition, they
often have a history of easy or spontaneous bruising and post-operative bleeding. More rarely, one may elicit a history of gastrointestinal
platelet
dysfunction and usually involve the mucous membranes and patients present with complaints of
or genitourinary bleeding. Types 2N and 3 may also have deep tissue bleeding, similar to the bleeding seen in moderate or severe
recurrent
epistaxis, oral bleeding with dental care, and menorrhagia. In addition, they often have a history
hemophiliacs.
of easy orThe
spontaneous
bruisingtests
andinpost-operative
bleeding.
More
rarely,
one
elicit
a history
of activity
most useful screening
patients with suspected
vWD are
bleeding
time,
PTTmay
and von
Willebrand
factor
(ristocetin cofactor).
Ristocetin cofactor
is a functional
of the
protein.
least bleeding,
one of thesesimilar
screeningtotests will be
gastrointestinal
or genitourinary
bleeding.
Types assay
2N and
3 von
mayWillebrand
also have
deep At
tissue
abnormal in 97% of patients with vWD (10). Other useful studies include platelet count, von Willebrand factor (vWF) antigen and factor
the bleeding
seen in moderate or severe hemophiliacs.
VIII activity. Once the diagnosis of vWD is made, the vWF multimeric assay and platelet aggregation studies will determine the type of
vWD. With deficient or defective von Willebrand factor, there will be abnormal platelet aggregation to ristocetin. Other platelet
Theaggregation
most useful
screening
in patients with suspected vWD are bleeding time, PTT and von Willebrand
studies
should betests
normal.
It is important
to keep
in mind that
vWF is an cofactor
acute phaseisreactant
and therefore,
vWD
can be affected
by cigarette
factor activity
(ristocetin
cofactor).
Ristocetin
a functional
assaystudies
of theforvon
Willebrand
protein.
smoking, stress, exercise, pregnancy, corticosteroids, birth control pills, etc. In addition, people who are blood group O have a lower
At least one of these screening tests will be abnormal in 97% of patients with vWD (10). Other useful
normal range for vWF antigen and ristocetin cofactor activity. When there is a strong suspicion that a patient has vWD, the laboratory
studies
include
count,
von
evaluation
mayplatelet
need to be
repeated
upWillebrand
to 3 times. factor (vWF) antigen and factor VIII activity. Once the
diagnosisInofmost
vWD
is ofmade,
thebleeding
vWF multimeric
and platelet
aggregation
studies
determine
cases
vWD the
symptoms areassay
quite mild,
and therapy
includes education
andwill
measures
for localthe
control of
Aminocaproic
acid isor
useful
in treating
mucous
membrane
bleeding.
Desmopressin
(DDAVP)platelet
causes a release of factor VIII
typebleeding.
of vWD.
With deficient
defective
von
Willebrand
factor,
there
will be abnormal
and vWF from
storage sitesOther
and is useful
in treating
bleedingstudies
symptoms
in patients
with mild (type 1) vWD. Patient with severe forms of
aggregation
to ristocetin.
platelet
aggregation
should
be normal.
vWD (type 3) or a qualitative defect of the vWF (types 2A, 2B, 2N) may need replacement with Humate-P (a factor VIII product
It is important to keep in mind that vWF is an acute phase reactant and therefore, studies for vWD can be
affected by cigarette smoking, stress, exercise, pregnancy, corticosteroids, birth control pills, etc. In
addition, people who are blood group O have a lower normal range for vWF antigen and ristocetin cofactor
activity. When there is a strong suspicion that a patient has vWD, the laboratory evaluation may need to be
repeated up to 3 times.
In most cases of vWD the bleeding symptoms are quite mild, and therapy includes education and measures
for local control of bleeding. Aminocaproic acid is useful in treating mucous membrane bleeding.
Desmopressin (DDAVP) causes a release of factor VIII and vWF from storage sites and is useful in treating
bleeding symptoms in patients with mild (type 1) vWD. Patient with severe forms of vWD (type 3) or a
qualitative defect of the vWF (types 2A, 2B, 2N) may need replacement with Humate-P (a factor VIII
product containing vWF) (8,9). Once diagnosed and followed and treated in a comprehensive hemophilia
treatment center, people with vWD can lead normal lives.
Other Factor Deficiencies
Deficiencies in other fluid factors are much more rare than deficiencies in
factors VIII, IX or vWF. Factor XI deficiency presents with variable bleeding and a prolonged PTT.
Bleeding symptoms do not correlate with the factor level (11). It is more common in the Ashkenazi Jewish
population. Deficiencies of the contact factors (factor XII-Hageman factor, high molecular weight
kininogen, and prekallikrein) are associated with a significantly prolonged PTT without bleeding symptoms
(11). Deficiencies of factors II, V, VII, X and XIII are very rare. For most of these, bleeding symptoms
occur in those whose factor levels are <5% to 10% (11). Factor VII deficiency should be considered with
isolated prolongation of the PT. Factors II, V, and X are common pathway factors and present with
prolongation of both PT and PTT. Factor XIII deficiency is associated with bleeding from the umbilical
stump and intracranial hemorrhage with a normal PT and PTT. It is only symptomatic in patients whose
level is <1%. Treatment consists of replacement of the deficient factor with fresh frozen plasma or, if
available, specific factor concentrate (11).
Acquired Defects of Secondary Hemostasis
Vitamin K is needed for the synthesis of factors II, VII, IX
and X. Vitamin K is vital to the carboxylation of glutamic acid residues which is needed for the calcium
and phospholipid-dependent activation of these factors (1). The most common circumstance in which
vitamin K deficiency leads to bleeding is hemorrhagic disease of the newborn. Without vitamin K
supplementation, significant GI and cutaneous hemorrhage may develop within a few days (1). After the
newborn period, vitamin K is absorbed from the GI tract. Deficiency may then result from nutritional
deficits, malabsorption, or alteration in intestinal flora. Treatment must be directed at the underlying
disorder and vitamin K supplementation.
Decreased synthesis of coagulation proteins occurs in severe liver disease. Abnormalities in the liver's
capacity to synthesize one or more clotting factors may result in problems with hemostasis. Treatment
involves replacement of the decreased factor(s) with fresh frozen plasma. Liver disease may also lead to
portal hypertension and platelet sequestration in the spleen.
Disseminated intravascular coagulation (DIC) occurs in patients who are critically ill and therefore, rapid
diagnosis is essential. Fever, hypotension, acidosis, oliguria, or hypoxia may be present. In addition,
petechiae, purpura, and oozing from wounds and venipuncture sites may develop. Although not always
clinically evident, microvascular and large vessel thrombosis may occur. The platelet count is typically
decreased due to consumption and platelet destruction. The PT and PTT are prolonged from depletion of
factors V, VIII, IX, and XI. Fibrinogen is decreased. Fibrin degradation products and the D-dimer assay are
increased. The mainstay of therapy is to treat the underlying disease. However, this may not always be
enough to correct serious bleeding or thrombosis. Additional therapy consists of replacing clotting factors
and platelets and possibly the use of heparin and antifibrinolytic agents (1).
Circulating inhibitors such as heparin and the lupus anticoagulant (antiphospholipid antibody) often lead to
abnormalities in screening coagulation laboratory values. These cause a prolonged PTT which is not
corrected with 1:1 dilution with normal plasma (the PTT mixing study). If the patient has a factor
deficiency such as hemophilia, adding normal plasma to the patient's plasma, will partially correct the
factor deficiency and the PTT will normalize. If the PTT does not normalize by adding normal plasma, this
implies that an anticoagulant is present in the patient's plasma. The term “lupus anticoagulant” is
misleading because it can occur in many clinical settings other than in SLE and the anticoagulant effects
plasma. Liver disease may also lead to portal hypertension and platelet sequestration in the spleen.
Disseminated intravascular coagulation (DIC) occurs in patients who are critically ill and therefore, rapid diagnosis is essential.
Fever, hypotension, acidosis, oliguria, or hypoxia may be present. In addition, petechiae, purpura, and oozing from wounds and
venipuncture sites may develop. Although not always clinically evident, microvascular and large vessel thrombosis may occur. The
platelet count is typically decreased due to consumption and platelet destruction. The PT and PTT are prolonged from depletion of factors
V, VIII, IX, and XI. Fibrinogen is decreased. Fibrin degradation products and the D-dimer assay are increased. The mainstay of therapy
is to treat the underlying disease. However, this may not always be enough to correct serious bleeding or thrombosis. Additional therapy
consists of replacing clotting factors and platelets and possibly the use of heparin and antifibrinolytic agents (1).
Circulating inhibitors such as heparin and the lupus anticoagulant (antiphospholipid antibody) often lead to abnormalities in
arescreening
only observed
vitro with
of the PTT,
but isnot
excessive
bleeding.
Instead,
when
coagulationin
laboratory
values.prolongation
These cause a prolonged
PTT which
notwith
corrected
with 1:1 dilution
with normal
plasma
(the it
PTT mixing
study). itIf may
the patient
has a factor deficiency
such as hemophilia,
adding normal
plasma to the patient's plasma,
partially
occurs
in adults,
be associated
with spontaneous
abortion,
and thromboembolism.
In thewillpediatric
correct the factor
deficiency
and the in
PTT
will normalize.
If the PTT
does notoften
normalize
by adding anormal
implies
that an
population,
it usually
occurs
otherwise
healthy
children,
following
viralplasma,
illnessthisand
is transient
anticoagulant is present in the patient's plasma. The term “lupus anticoagulant” is misleading because it can occur in many clinical settings
with
rare
clinical
sequelae
(1).
other than in SLE and the anticoagulant effects are only observed in vitro with prolongation of the PTT, but not with excessive bleeding.
Instead, when it occurs in adults, it may be associated with spontaneous abortion, and thromboembolism. In the pediatric population, it
usually occurs in otherwise healthy children, often following a viral illness and is transient with rare clinical sequelae (1).
A summary of laboratory studies for bleeding disorders is listed below. Routine tests are commonly
orderedAby
non-hematologists.
tests
are not
ordered
are onlyordered
ordered
(most commonly
summary
of laboratory studiesSpecial
for bleeding
disorders
is listed
below. routinely
Routine testsand
are commonly
by non-hematologists.
tests are not ordered
routinely
and are only ordered
(most
commonly by
hematologists
and other
subspecialists) when a bleeding
bySpecial
hematologists
and other
subspecialists)
when
a bleeding
disorder
is highly
suspected.
disorder is highly suspected.
Tests for:
Abnormal in:
Disorders of platelet quantity
ITP, HUS, TTP, thrombocytopenia due to bone marrow suppression,
platelet consumption.
PT
Extrinsic and common coagulation
Pathway (factors I, II, V, VII, X)
Factor deficiency (I, II, V, VII, X), liver failure, vitamin K deficiency,
coumadin, warfarins.
PTT
Intrinsic and common pathway
(factors I, II, V, X, VIII, IX, XI, XII)
Factor deficiency (I, II, V, X, VIII, IX, XI, XII), heparinization,
circulating anticoagulants, vWD
Circulating anticoagulants.
PTT corrects with factor deficiency, but it does not normalize with
circulating antibodies/anticoagulants.
Bleeding time
Platelet function
ASA, NSAIDs, platelet function disorders (see table 2), vWD
Platelet aggregation
Platelet function
ASA, NSAIDs, platelet function disorders (see table 2), vWD
Ristocetin cofactor
vWF function
vWD
vWF antigen
vWF quantity
vWD
Routine tests:
Platelet count
Special tests:
PTT mixing
study
vWF multimeric assay Defines type of vWD
vWD
Chapter XI.7. Transfusion Medicine Kelley A. Woodruff, MD
A 7 year old boy is being worked up for profound pancytopenia. He was well until one week ago when his
grandparents noted pallor. He has had no recent history of fever, and is otherwise well. He was initially
seen yesterday in the hematology clinic, where a CBC showed a hemoglobin of 5.3 g/dl, WBC 1.9 K/ml
with 96% lymphocytes, and a platelet count of 4,000. He has a bone marrow aspirate scheduled for
tomorrow. He is brought back in to the clinic today, because he has epistaxis, which has been ongoing for 1
hour now. He states he feels weak and dizzy.
Exam: He is afebrile, BP 110/40, HR is 186 with a mild gallop. Weight is 26 kg (75%ile). He is lying
down, with a tissue to his nose, and bright red blood is dripping out. He is alert and oriented, nontoxic, and
comfortable. He is pale appearing, conversing appropriately, and no other overt bleeding is noted. His
abdomen is benign.
CBC today shows hemoglobin 5.1, WBC 1.3, and platelet count 5,000. After IV access is obtained, he is
given a fluid bolus and a "type and hold" for blood status is ordered.
The start of transfusion medicine occurred during World War II when the major blood types A, B, AB and
O, and Rh factor were identified. Type A persons have A antigen on the membrane of their red blood cells.
They develop anti-B antibodies shortly after birth without any prior antigenic stimulation, thus these
antibodies are called natural antibodies. Type B persons have B antigen on the membranes of their red
blood cells, and such persons naturally have anti-A antibodies in their plasma. Type AB persons have both
A and B antigens, and no anti-A or anti-B antibodies in their plasma. Type O persons, who lack these major
red cell membrane antigens, have both anti-A and anti-B antibodies. When crossmatching a unit of blood
for a transfusion, the biggest concern is to avoid giving the patient antigen that would react with their own
antibodies. Thus, people with type O blood are considered to be universal donors, with regard to red blood
transfusions, since there are no major (A or B) antigens on their red blood cells.
Most transfusions of red blood are given as packed red blood cells (PRBCs) that have most of the plasma
removed. Each unit of PRBCs is about 250 ml, depending on the type of preservative used, and each ml
provides 1 milligram of elemental iron. The fastest rate of transfusing a patient should be 5 ml/kg/hour.
Generally, a transfusion is ordered as 10-15 ml/kg given over 2 to 3 hours.
The advent of platelet transfusions in the early 1970's changed the survival rate for many diseases. Today,
single donor platelets are usually considered the optimal product for most platelet transfusion needs. A
single donor unit of platelets is based on the adult dose and contains about 225 ml per unit. It is obtained
via pheresis from one donor and takes about 4 hours to donate, compared to 30 minutes to donate one pint
of whole blood. Platelets extracted from a unit of whole blood (called random platelets) contain about 50
ml per unit. Usually about 6-8 random units (i.e., 6-8 different donor exposures!) need to be pooled
together to equal the volume of one unit of single donor platelets. Single donor platelet transfusions are
usually given over 1 hour.
A hemolytic transfusion reaction results when an antibody-antigen reaction causes (donor) red cell lysis. It
is most severe when a patient has circulating antibody that reacts with donor antigen (RBCs). Some
antigens produce stronger hemolytic reactions than others. For example, transfusion reactions involving A
and B antigens will cause a brisk, severe hemolysis, leading to fatalities from renal failure. The Duffy and
Kell antigens also cause significant hemolysis. The Lewy antigen leads to a mild hemolysis that is not
usually fatal (remembered by the mnemonic Duffy dies, Kell kills, and Lewy lives). There are many other
less common antigens, natural and acquired, that are screened for in the direct antibody test (DAT) during
crossmatching. A patient having a hemolytic transfusion reaction may present with lower back pain, and
hemoglobinuria. The treatment consists of supportive care, especially intravenous hydration to help protect
the kidneys from damage. Corticosteroids may also be beneficial.
Another type of transfusion reaction is associated with urticaria, or less commonly, fevers. These reactions
are typically caused by extraneous donor proteins, which are foreign to the recipient. These proteins are
usually carried in the plasma of the donor product. Therefore, such reactions are usually seen more often
with platelet transfusions than with red cell transfusions, since the platelet products carry more plasma than
the packed red cell units. Urticaria reactions are usually mild, and treated with diphenhydramine and
sometimes IV corticosteroids. Epinephrine is only rarely required. Fevers are usually mild and self-limited,
and can be managed with acetaminophen.
Irradiation of blood products will inhibit the replication of nucleated cells (e.g., WBCs) in the donor
product, by damaging their DNA. This radiation dose will not kill common organisms known to
contaminate blood products. All transfusion products have donor stray white blood cells, which, in theory,
could replicate when transfused into an immunocompromised host. This would cause a graft versus host
(GVH) situation, which, when arising from a blood transfusion, is often fatal. Therefore, all blood products
given to infants, oncology patients, or other immunocompromised hosts should be irradiated. The
exception, of course, is a stem cell product for a stem cell (bone marrow) transplant. If these stem cells
were irradiated, the new graft would not grow, and there would be no transplant.
Infusion filters should be used for all transfusions of packed red blood cells and platelets. The only
exception to this is the infusion of a stem cell product for any type of stem cell transplant. There are many
types of filters. Their main purpose is to filter out either extraneous white blood cells or large foreign
proteins. The use of a filter during a transplant of stem cells would filter out the very stem cells that are
intended for the patient! Since filters will not dependably remove all white blood cells, filters cannot
replace irradiation to prevent graft versus host disease.
Infections acquired from transfusions are rare due to improved screening methods by blood banks.
Infectious agents that can be transmitted through transfusions include HIV, Hepatitis B, Hepatitis C,
Parvovirus and malaria. Blood is actively screened for all these agents and discarded if contamination is
even suspected. Cytomegalovirus (CMV) infection can also be transmitted through blood transfusions. It is
harbored in a dormant state in the white blood cells of previously infected persons. Since 80% of most adult
populations are positive for past CMV infection, most donated blood is CMV serology positive. CMV
infection can be transmitted to severely immunocompromised persons with no prior infection. Such an
incident might occur during a bone marrow transplant. Since newborns up to age 4 months are considered
immunocompromised and have no previous CMV infection, all newborns receive CMV negative blood.
Clinicians should familiarize themselves with the options for ordering, holding, or preparing for a PRBC
transfusion. A "draw and tag" should be ordered for a patient who might possibly need a transfusion during
the hospital stay (but the probability of this is low). In this case, a blood sample is drawn from the patient
and the patient is tagged with a special blood products identification bracelet which is matched to the
specimen drawn and a set of labels which will be used on any blood products which might be ordered for
the patient in the next few days. If blood products are required for this patient, they can be ordered from the
blood bank. The blood bank will crossmatch the blood using the previously drawn and labeled specimen.
A "type and hold", also called a "type and screen", should be ordered for a patient who has a moderate
likelihood of requiring a transfusion during the hospital stay. The patient is drawn and tagged as in the
"draw and tag" procedure. Additionally, the patient's blood type and Rh are determined and a screening test
is performed for unexpected antibodies and minor compatibility group profiling. Thus, the patient's blood
type and Rh are known which saves some time in case a crossmatch is needed.
A "type and crossmatch" should be ordered when the patient will be getting a transfusion. The patient is
drawn and tagged. The patient's blood type, Rh, and antibody screens are performed. A unit of blood is then
selected for the patient and compatibility testing is performed with the patient's specimen and the donor
unit's PRBCs. This unit is then held for the patient. This unit cannot be used for any other patient, so a
"type and crossmatch" should only be ordered when a transfusion is highly likely.
In a true emergency with a rapidly hemorrhaging and hypovolemic patient, the time required for blood
typing and crossmatching (20 to 30 minutes) may not be available. Transfusing with O negative PRBCs (if
available) is the best emergency option. In the meantime, a type and crossmatch should be in progress.
Type specific blood (the patient's type and Rh are known, but a crossmatch has not yet been performed) is
sometimes useful until a crossmatch is completed.
There are many ethical issues which need to be considered when transfusing patients. Because of the rare
possibility of morbidity and mortality from transfusions, written and informed consent must always be
obtained before a transfusion is given. The patient (or patient's guardian) must be fully informed of the rare
possibilities of infectious agents and transfusion reactions. Full consideration must be given to the necessity
of a transfusion. In short, if spontaneous resolution of the problem (anemia, thrombocytopenia, or other
morbidity in which a transfusion is thought to be beneficial) can be expected, or if alternative treatments
exist, the transfusion should be avoided. When considering a transfusion, the actual morbidity and mortality
from the underlying problem itself, without a transfusion, must be weighed against the rare problems that
may result from the transfusion itself. Adult patients may refuse a transfusion for themselves, regardless of
their reasons, even in the face of death (e.g., Jehovah's Witness patients). A parent may also refuse a
transfusion for their child. However, if a physician strongly believes that a child has a life-threatening
condition that can only be effectively treated with a transfusion of a blood product, the physician is
obligated to take legal action.
Chapter XII.2. Leukemia and Lymphoma Bruce T. Shiramizu, MD
This is a 10 year old boy who presents to the emergency department with a chief complaint of fever and
increasing tiredness. He was well until 2 weeks ago when he had an upper respiratory illness (URI). He has
been tired with decreased activity since the URI, and has missed school and sports practices for 2 days. He
has a decreased appetite and has lost 2 pounds over the last 2 weeks. He has some shortness of breath when
he climbs stairs, but his parents deny cough, fever, nausea, emesis, bruising, headache, or visual problems.
His past medical health, including birth history, immunizations, and other medical problems is
unremarkable. He lives with his two parents and 6 year old brother, all of whom are healthy. The sibling
and parents had similar URI symptoms 2 weeks ago, but everyone else is back to normal activity levels.
There is no family history of relevant medical problems.
Exam: VS T 38.5 degrees C, P 120, R 32, BP 110/56. Height & weight at the 80th percentile. He is alert,
tired and slightly pale appearing, but in no apparent distress. His head is normocephalic without scalp
lesions. His hair texture is normal. His ear canals and TMs are normal. Pupils are equal and reactive to
light. Conjunctivae are pale. His fundi are normal. His nasal passages are clear. His mucous membranes are
dry and pale. His posterior pharynx is erythematous without lesions and no tonsillar enlargement. His
dentition and gums are normal. No nuchal rigidity is present. He has bilateral cervical nodes, posterior
cervical nodes, axillary nodes, and inguinal nodes palpable (about 1-2 cm), mobile and nontender. His chest
exam (breasts, lungs, heart) is normal except for some tachycardia. His abdomen is flat and non-tender with
normal bowel sounds. His liver edge is palpable at the costal margin. His spleen is palpable 4 cm below the
left costal margin. His back is normal. His skin shows no lesions, bruises or petechiae. Upper and lower
extremities are normal. His neurological exam is normal.
Laboratory: CBC Hgb 7, Hct 24, MCV 100, WBC 56,000, Differential 14% lymphoblasts, 80%
lymphocytes, 6% atypical lymphocytes. Platelets 23,000. Chest x-ray shows clear lung fields but a wide
mediastinum.
He is admitted to the hospital and a diagnostic workup including a bone marrow aspirate and biopsy reveals
acute lymphoblastic leukemia.
There are different types of leukemia but the most common leukemia that occurs in children is acute
lymphoblastic leukemia (ALL). ALL is the most common cancer in children representing 23% of cancer
diagnoses among children younger than 15 years of age and occurring at an annual rate of approximately
31 per million (1). Approximately 2,400 children and adolescents younger than 20 years of age are
diagnosed with ALL each year in the USA. There is a sharp peak in ALL incidence among children ages 2
to 3 years. Lymphomas,ingeneral,aredividedintotwobroadcategories,Hodgkin'sdisease(HD)andnonHodgkin'slymphoma(NHL). Asagroup, it is the third most common childhood malignancy with HD and
NHL accounting for approximately 10% of cancers in children less than 20 years of age (2). In the United
States, there are about 800 new cases of NHL diagnosed each year. Incidence is approximately 10 per
1,000,000.
For both ALL and lymphoma (HD and NHL), the signs and symptoms may be similar but non-specific.
The clinical manifestations may present insidiously or acutely, as an incidental finding on a routine
complete blood count analysis or as a life-threatening infection or respiratory distress. Some characteristics
which may present at the time of diagnosis are lethargy, fever, joint pain, bleeding, abdominal pain, CNS
manifestations, and/or difficulty breathing secondary to a mediastinal mass. On physical examination, there
may be pallor, hepatosplenomegaly, petechiae, and/or lymphadenopathy.
Because some rare cases may be difficult to diagnose even with proper diagnostic biopsies, other diagnoses
should be entertained. These include viral infections such as Epstein-Barr virus, cytomegalovirus; other
malignancies such as neuroblastoma; hematological disorders such as aplastic anemia, histiocytosis,
idiopathic (immune) thrombocytopenic purpura (ITP); and juvenile rheumatoid arthritis. In general, the
differential diagnosis between ALL and NHL has been debated for years, and the criteria utilized to
distinguish between the two categories of diseases have been arbitrary. While both entities can be of B-cell
or T-cell phenotype, the distinction between NHL and ALL is currently based on the degree of bone
marrow involvement. Children who have more than 25% infiltration of their marrow with blast cells are
considered to have ALL.
Treatment and management of ALL and NHL are based on proper diagnosis and staging to determine the
extent of disease involvement. Diagnosis is made from either the bone marrow (ALL) or tissue (NHL), and
includes immunophenotyping, cytogenetics, flow cytometry, and/or molecular studies such as gene
rearrangements. Recommended staging studies include a careful physical examination, complete blood
count, bone marrow aspirate or biopsy, lumbar puncture, and radiographic studies including possible
nuclear medicine studies to assess the extent of disease.
Prior to instituting specific therapy, measures should be instituted to treat emergent problems, particularly
in patients with advanced disease and who may have associated airway compression or superior vena cava
obstruction. Measures should also be in place to be able to monitor and intervene for treatment related
problems such as tumor lysis. Tumor lysis can occur spontaneously or as a result of chemotherapy leading
to serious metabolic complications such as hyperuricemia, hyperkalemia, and hyperphosphatemia. This
could ultimately lead to renal failure or cardiac arrest if left untreated.
Successful treatment of children with ALL and NHL requires the control of systemic disease (marrow, liver
and spleen, lymph nodes, etc.) as well as the treatment (or prevention) of extramedullary disease
particularly in the central nervous system (CNS) (1,3). The main goal of therapy is to begin induction
treatment as soon as the diagnosis is made in order to obtain remission. After inducing remission, the next
goal is to maintain remission. In general, therapy is based on cytotoxic drugs affecting the rapidly dividing
cells during the cell cycle. Multiple drugs are used because each class of drugs acts on a different part of
the cell cycle with the intent of interrupting cell division in the majority of malignant cells. The concept of
inducing remission initially is to try and rapidly destroy the majority of malignant cells within the first 30
days of treatment. Ongoing and subsequent treatment strategies are based on the concept that malignant
cells that "escaped" the induction phase will enter the cell cycle over a period of time and will then be
affected by the drugs. Most of the drugs are administered orally, intravenously, or intramuscularly. CNS
treatment and/or prophylaxis is administered via a lumbar puncture (intrathecal). Occasionally, emergency
treatment has to be considered for life-threatening situations such as airway compression, spinal cord
compression, etc. This can be accomplished with the use of radiation to the involved sites. The immune
system is compromised throughout the duration of therapy. Therefore one must be attentive to any signs or
symptoms of septicemia. Additionally, exposure to infectious agents including live vaccines should be
avoided.
In general, there are clinical and laboratory findings present at the time of diagnosis which may correlate
with prognosis. A high tumor burden, whether assessed by total white blood cell count for ALL or high
stage disease in NHL (or elevated serum LDH) has been consistently found to be an important prognostic
factor. Other factors might include specific chromosome abnormalities, age, race, or gender. Recently, the
rapidity of response to induction therapy or the presence of residual disease has been examined as a
predictor of outcome.
Approximate 75-80% of children and adolescents with ALL and NHL will survive at least 5 years with
modern chemotherapy although outcome is variable depending on a number of factors. Since nearly all
children will achieve remission with proper treatment, one of the main obstacles today is how to effectively
treat bone marrow or CNS relapses. Other challenges are the result of successful treatment and related to
screening and treating long term complications from therapy. These include CNS sequelae affecting
cognition and learning, growth failure, reproductive sequelae, cardiac sequelae, and secondary
malignancies.
Chapter XII.3. Solid Tumor Childhood Malignancies Christina Keolanani Kleinschmidt
An 18 month old female presents to the office for her well-child examination. A third year medical student
is allowed to take the history and perform the initial examination. On a routine ophthalmoscopy exam, the
student notices that the child does not have a red reflex in the right eye. This is reported to the physician
who confirms the exam finding. There is no history of weight loss, anorexia, crossed eyes, fever, or
irritability.
Exam: VS T 37.0, P 110, R 26, BP 92/42. Height, weight, head circumference are all at the 40th percentile.
She is alert and active. Leukocoria is present in the right eye. A normal red reflex observed in the left eye.
Pupils are equal and reactive. The eyes are conjugate. Facial function is good. The remainder of the
physical examination is negative.
Clinical Course: The child is referred to an ophthalmologist. An ophthalmoscopy exam performed under
general anesthesia reveals atumorintheposteriorpoleoftherighteye.
AnorbitalCTdemonstratesthatthetumorisconfinedtotheglobe(i.e.,nospreadoutside the eye). Since the tumor
is small it is treated with laser photoablation. Careful follow ups are scheduled to monitor for recurrences
or development of secondary tumors.
This chapter will cover the four most common malignant solid tumors of childhood: retinoblastoma,
osteosarcoma, neuroblastoma and Wilms' tumor.
Retinoblastoma
Retinoblastoma is a slow growing malignant tumor of the retina that may be confined to
the eye for up to months or even years. In the United States it is the seventh most common pediatric
malignancy (1). About 90% of cases occur before the age of 5. Bilateral tumors occur at an earlier age than
unilateral tumors. The mean age of diagnosis in bilateral tumors is 12 months whereas unilateral tumors
occur at a mean of 24 months of age (2).
The exact molecular pathogenesis has been elucidated for retinoblastoma, which results when there is a
mutation in the retinoblastoma gene found on the long arm of chromosome 13 at band 14 (13q14). The
gene is a tumor suppressor gene that is involved in regulating the cell cycle. In order for retinoblastoma to
manifest, both Rb alleles must be mutated (the essence of the two hit hypothesis). In the hereditary form of
retinoblastoma, the individual inherits a mutant Rb gene from the germ line. Another mutation must occur
in a somatic retinal cell in order for retinoblastoma to manifest itself. In the nonhereditary form, both
mutations must occur in the same somatic retinal cell. When both are mutated, defective intracellular
transcription and unchecked cell proliferation leads to malignant transformation (3).
If it is not detected during the routine ophthalmoscopic exam or suspected due to family history, the first
presenting sign may be a white pupillary reflex called leukocoria, which is frequently noted on flash
photography as a white reflex instead of the usual flash photography "red eye". Parents will often notice
this and bring this to the attention of the child's physician, usually after a significant delay. This sign is
present in approximately 60% of the patients and is attributed to the formation of a central posterior pole
tumor. Another 20% may present instead with strabismus due to tumor involvement of the macula. Retinal
detachment may also be detected. The patient may also present with a red, painful eye, poor vision,
unilateral pupil dilation, heterochromia (the iris color of each eye are not the same), or nystagmus. If the
tumor is in an advanced stage, the patient may present with constitutional symptoms and signs as well as
neurologic defects, orbital mass, proptosis, or blindness (1).
Leukocoria is difficult to detect during a routine exam. If it is not detected during the exam, yet the parent
reports an abnormal pupil, a referral should still be made to an ophthalmologist. Ophthalmoscopy done by a
specialist through dilated pupils is the most important test performed to diagnose retinoblastoma. If the
child is young, this must be done under general anesthesia. Parents and siblings should also have a dilated
ophthalmoscopic examination to rule out unsuspected or dormant tumors (2). A CT scan can also be used
to detect intraocular calcification, optic nerve involvement, and extraocular extension of the tumor (4).
Careful examination is required to rule out any other disorders that resemble retinoblastoma. The
differential for a mass should include astrocytic hamartomas and granulomas of Toxocara canis, Coat's
disease, retinopathy of prematurity, and persistent hyperplastic primary vitreous should be suspected when
there is retinal detachment (1).
Treatment options for retinoblastoma include enucleation, external beam radiation, plaque radiation, laser
photoablation, thermotherapy, cryotherapy, and chemotherapy. The choice of treatment will ultimately
depend on the size, location, and extent of the tumor, whether it is bilateral or unilateral, if there is visual
potential, or if extraocular disease or metastasis is present.
Enucleation is performed on large unilateral tumors that have led to severe visual impairment. Individuals
with optic nerve invasion, secondary glaucoma, and seeding into the pars planta have also undergone
enucleation (5). In the past, enucleation was performed on the eye with the most advanced disease in
bilateral tumors. However, chemotherapy and local therapy have successfully replaced this practice (2).
In the past, standard therapy for the least involved eye in bilateral tumors has been external beam radiation.
However, long term consequences such as cataract formation, radiation retinopathy, optic neuropathy, and
the development of secondary tumors has lead to the search for alternative treatments. Radioactive plaque
therapy (or brachytherapy, in which radioactive seeds are implanted close to the tumor) has since been
employed to restrict the area of the orbit exposed to radiation. This procedure has reduced the harsh
consequences of radiation. Brachytherapy has also been used to treat unilateral tumors. Small tumors have
also responded well to other types of local therapy, in particular cryotherapy and laser photoablation (5).
Chemotherapy is also a common therapy used in the treatment of retinoblastoma. In the past, it was used
basically to treat advanced extraocular disease. Today, it is used when there is extraocular extension,
metastasis, and positive cerebrospinal fluid findings. It is also used if accidental dissemination of tumor
cells has occurred. For example if a previous intraocular procedure was done before the diagnosis of
retinoblastoma was made, the patient may be treated prophylactically with chemotherapy (5).
The extent of optic nerve involvement, extension of the tumor, and choroidal involvement directly
influences mortality. The outcome has been excellent in individuals suffering from unilateral intraocular
tumors. Individuals with optic nerve extension beyond the lamina cribrosa have only a 40% 5 year survival
rate (4). A cure rate of greater than 90% has been seen after enucleation of unilateral intraocular tumors.
The use of local ablation with or without chemotherapy is also usually successful (3).
Patients with a germ line mutation of the Rb gene fare a worse outcome. These are individuals who were
born with one mutant Rb gene and sustained a subsequent spontaneous mutation in a somatic Rb gene.
They have poor survival rates and have a reduced likelihood of salvage of vision. If they survive
retinoblastoma they are at an increased risk for developing a secondary cancer. More than 90% will
develop a secondary cancer within 32 years after treatment (1). This is because the retinoblastoma gene is
linked to nonocular tumors, most notably osteosarcoma (1).
Osteosarcoma
Osteosarcoma is a malignant mesenchymal tumor of bone with resultant osteoid formation.
It is the third most common cancer in
children and adolescents (6). It has a bimodal incidence with the first peak occurring in the second decade
of life and the second peak occurring in the elderly. It is more common in boys than in girls. The common
sites of involvement are the metaphyseal regions of the distal femur, proximal tibia, and proximal humerus
(7).
The exact cause of osteosarcoma is unknown, but it has been linked to a variety of syndromes and genetic
changes. Most notably, it has been strongly correlated with a germ line mutation of the Rb gene. Patients
with retinoblastoma have a significantly increased risk for the development of osteosarcoma. If these
individuals were treated with radiation, their susceptibility increases further (7). Alkylating agents and
other antineoplastic drugs, have also been reported to increase the risk of developing this neoplasm.
Individuals suffering from Li-Fraumeni syndrome, a familial cancer syndrome associated with a germ line
mutation, are also predisposed (8).
Patients usually present with pain and swelling most commonly at the knee. The pain may be intermittent
and most commonly occurs at night causing it to be often dismissed as growing pains. Since individuals
afflicted with this disease are commonly going through their "growth spurt", this conclusion seems rational.
It may further be mistaken by the patient as a sports injury. However, not all patients present with a history
of trauma. Physicians must take care not to make the same assumptions. Additional clinical findings may
help them distinguish this disease from benign growing pains. These findings include a palpable mass,
limited range of motion, tenderness, and warmth (8). However, since none of these findings may be present
initially, an imaging study is often necessary to diagnose osteosarcoma during its earliest stage.
The diagnosis of osteosarcoma can be made on: x-ray of the affected bone, MRI, CT scan, radionuclide
bone scan, and biopsy. Radiographs may display a mixed lytic and blastic lesion. In more advanced cases, a
sunburst pattern of new bone formation and lifting of
thebonycortexmaycreatewhatiscalledaCodmantriangle(4).
AnMRIofthelesionandtheentireboneisdonetoevaluatethetumor's proximity to nerves and blood vessels as
well as its extension into a joint or soft tissue. CT of the chest, and bone scintigraphy detects sites of
metastasis (6). After all of these procedures are done, a biopsy can be performed to make the definitive
diagnosis. Together, these procedures should help to differentiate osteosarcoma from other bone disorders
such as histiocytosis, Ewing's sarcoma, lymphoma, and osteomyelitis (8).
In the past, osteosarcoma was treated with surgery alone. However, the survival rate was poor even for
nonmetastatic cases, since most patients have non-detectable micrometastases at presentation. Surgical
treatment combined with chemotherapy has greatly improved the survival rate. Treatment options available
today include chemotherapy, amputation, and limb salvage procedures (7).
Previously, surgical treatment meant amputation of the affected bone. The bone would be amputated 7 cm
proximal to the proximal border of the tumor to minimize recurrence. The patient would then undergo
chemotherapy. However, with the advent of even more effective chemotherapeutic agents, limb salvage
treatment is the new therapeutic approach to osteosarcoma. The patient undergoes preoperative
chemotherapy to induce primary tumor necrosis and treat micrometastatic disease (6). A block excision of
the tumor and prosthetic replacement is then performed (7). Contraindications for limb salvage therapy
include involvement of a neurovascular bundle by the tumor, immature skeletal age (especially for the
lower limb), infection in the region of the tumor, and extensive muscle involvement that would result in
poor functionality (4).
This multi-agent approach has greatly improved survival rates. Approximately 75% of patients with
nonmetastatic osteosarcoma of the extremity are cured. Even individuals with lung metastases have shown
a 20% to 30% cure rate when treated aggressively with chemotherapy and resection of lung nodules (8).
This is an improvement because pulmonary metastasis has been the major obstacle in curing patients with
osteosarcoma.
Neuroblastoma
Neuroblastoma is a neoplasm of childhood that arises from neural crest cells involved in
the development of sympathetic nervous
tissue. It is the most common extracranial solid tumor of childhood, occurring at a rate of 1 case per 10,000
persons. Young children are the primary targets, with the median age of diagnosis occurring at 2 years of
age. It rarely occurs in children over 10 years of age and it has a slight predilection for boys (2).
The exact cause of neuroblastoma is unknown, but it has been associated with various disorders and
mutations. It has been tied to disorders that involve neural crest development such as Hirschsprung's
disease and neurofibromatosis type I. It has also been linked with several different types of genetic
changes. These changes include n-myc proto-oncogene amplification, chromosome 1p deletion and
chromosome 17q gain (9). It is believed that the 1p deletion and 17q gain are the result of an unbalanced
translocation between these two sites (10). The exact role of these changes in the pathogenesis of
neuroblastoma has not been elucidated.
Neuroblastoma develops from sympathetic neuroblasts anywhere along the sympathetic chain ganglia or in
the adrenal medulla. Spontaneous malignant transformation is believed to occur when sympathetic
neuroblasts fail to differentiate. When there is complete failure of differentiation, a neuroblastoma forms.
Primary tumors occur 50% in the adrenal gland, 30% in retroperitoneal sympathetic ganglia, and 20% in
cervical and thoracic ganglion (9). The patient's clinical presentation depends on the location of the primary
tumor, the size of the tumor, and if it has metastasized. The typical constitutional symptoms of cancer,
fever, general malaise, and pain, are present. Complicating the patient's clinical presentation is the fact that
approximately 75% of patients will present with metastatic disease at the time of diagnosis. Common sites
of metastasis are lymph nodes, bone marrow, liver, skin, orbit, or bone (especially facial bones, skull, and
appendicular bone) (2).
Adrenal and retroperitoneal tumors present as an abdominal mass extending from the flank to the midline
of the abdomen. The mass is usually firm, irregular, and nontender. If the mass begins to enlarge and
extend further in the cavity, abdominal distention, anorexia and weight loss occur. The mass may also be a
result of hepatomegaly due to tumor metastasis, so physicians must take care not to miss this diagnosis.
Retroperitoneal tumors may extend into the paraspinal area and compress on the spinal cord. Thoracic
tumors may compress the spinal cord and cause paraplegia. Lower lumbar tumors may cause cauda equina
syndrome (10).
Thoracic and cervical ganglion may also compress on surrounding structures. Thoracic masses may be an
incidental finding on a chest x-ray done to evaluate dyspnea or other upper respiratory problems. A cervical
tumor presents as a hard, fixed mass associated with Horner's syndrome or tracheal compression (10).
These patients may present with myosis, ptosis, anhydrosis, flushing, and apparent enophthalmos.
On the initial visit, the patient may also present with bone or ocular problems that indicate metastasis to
these regions. The bone metastasis may manifest as bone pain with refusal to walk and reported tenderness,
swelling, or the finding of a localized lump. If the tumor extends into the marrow, bone marrow
suppression may occur. This manifests as anemia and weakness. Periorbital metastasis is associated with
orbital ecchymosis and proptosis, also described as "raccoon eyes" (10).
Clinical manifestations may also be a result of substances released from the tumors. Release of vasoactive
intestinal peptide (VIP) may cause intractable secretory diarrhea leading to hypokalemia and dehydration.
Release of catecholamines from the tumors is rare and may cause hypertension, tachycardia, palpitations,
profuse sweating, and flushing (9). Another mysterious syndrome associated with neuroblastoma is
opsomyoclonus (also called opsoclonus). This syndrome consists of myoclonic jerks and random eye
movements sometimes associated with cerebellar ataxia. It is sometimes called the dancing eyes and
dancing feet syndrome because of its physical presentation. The exact mechanism is unknown but
hypotheses implicate either a peptide produced by the tumor or immunologic cross reactivity between the
tumor and cerebellar neurons (10).
Bone pain may resemble symptoms seen in rheumatoid arthritis, rheumatic fever, osteomyelitis, and acute
leukemia. Abdominal masses are also present in Wilms' tumor, lymphoma, mesenteric cysts,
hydronephrosis, and splenomegaly. Intractable diarrhea may be due to malabsorptive states (11).
If the historical and physical findings lead to the suspicion of neuroblastoma, a complete blood count,
urinalysis, and imaging studies should be done. A CBC may show anemia and thrombocytopenia indicating
extension into the bone marrow. Special urine chemistry may pick up catecholamine metabolites such as
homovanillic acid (HVA) and vanillylmandelic acid (VMA), break down products of the catecholamines
secreted by the tumor. The skeletal survey may discover bone metastases. MRI may also detect bone
metastases as well as intraspinal tumors (11). At initial presentation, ultrasound is useful for diagnosing
intra-abdominal tumors and can display calcifications (11), but ultrasound interpretation requires skilled
expertise. Falsely negative studies are misleading for the clinician unless an alternate imaging study such as
a CT scan is done to make the diagnosis.
The diagnosis must be confirmed by histologic examination. Neuroblastoma is known as one of the small,
blue, round cell tumors of childhood. Histologically, it is characterized by undifferentiated neuroblast
aggregates that are separated by fibrovascular septae. Neuroblastomas that mature into benign
ganglioneuromas due to spontaneous regression or therapy-induced maturation may have a mixture of
undifferentiated and differentiated cells (10). Some neuroblastomas (especially in infants) may undergo
spontaneous regression, even if widely disseminated at initial presentation.
Treatment depends on the stage of the tumor and its histology. Surgical resection is the primary treatment
for those who have a localized tumor that is resectable. This includes patients with tumors that are localized
to one side of the midline or those which cross the midline without encasement of major blood vessels.
Radiation is indicated in those with localized, unresectable tumors that have not responded to initial
chemotherapy. Chemotherapy is used in patients with advanced stages of neuroblastoma (2).
The main prognostic factors for neuroblastoma are the age of the patient, the stage of the disease, presence
of n-myc amplification, and chromosome 1p deletion. Children who are younger than 1 year old and have
favorable histology have better survival rates for all stages than those older than 1 year. For example, a
child older than 1 year with stage 2 disease has an 85% disease-free survival whereas a child younger than
1 year with stage 2 disease has nearly a 95% disease-free survival (10).
Wilms' Tumor
Wilms' tumor is a malignant embryonic neoplasm of the kidney most commonly seen in
young children. It is the second most common abdominal tumor in children (neuroblastoma is more
common). It peaks at ages 1 through 3 years with the median age of diagnosis occurring at 3.5 years in
those with unilateral involvement (13). Bilateral involvement presents at an earlier age than unilateral
involvement.
The exact cause of Wilms' tumor is unknown, but mutations in the short arm of chromosome 11 have been
detected in approximately 30% of the patients (15). The Wilms' tumor suppressor gene (WT1) is located on
locus 11p13 and acts to regulate transcription of other genes during normal renal development (16).
Mutation of WT1 predisposes an individual to nephrogenic rests, benign clusters of blastemal and stromal
cells, which may be subjected to further mutation leading to malignant transformation (2). Deletion of this
locus has been linked to the WAGR (see below) and Denys-Drash syndromes. These are syndromes that
consist of various congenital anomalies in conjunction with Wilms' tumor. Individuals with the WAGR
syndrome present with Wilms' tumor, aniridia, genitourinary malformations, and mental retardation (15).
Those who suffer from Denys-Drash syndrome have Wilms' tumor, nephropathy, and genital abnormalities
(15).
A second locus has recently been discovered at the 11p15 locus. It is denoted as the WT2 gene, but its
exact functions have not been elucidated. Some hypothesize that the gene is actually IGF2 (insulin growth
factor 2), which encodes for a growth factor found in abundance in Wilms' tumor (2). The BeckwithWiedemann syndrome has been linked to this locus. Patients with Beckwith-Wiedemann syndrome display
organomegaly (liver, kidney, adrenal, and pancreas), macroglossia, omphalocele, and hemihypertrophy
(15). Individuals with this syndrome have a 10-20% incidence of tumor development, including Wilms'
tumor (16).
This neoplasm most commonly presents as an asymptomatic abdominal mass discovered by parents during
bathing or by a doctor during a routine exam. The mass is usually smooth, firm and rarely crosses the
midline. Individuals who are symptomatic may present with abdominal pain, fever, anemia, hematuria, and
hypertension. The tumor may compress on the renal artery causing renal ischemia leading to renin secretion
with resulting hypertension (2). Post-streptococcal glomerulonephritis may be mistakenly diagnosed in
cases presenting with hematuria and hypertension. Individuals may also present with abnormalities that
may link them with the syndromes associated with Wilms' tumor (WAGR, Denys-Drash, BeckwithWiedemann). Rarely, a paraneoplastic syndrome may arise in which erythropoietin is released causing
polycythemia (15).
An abdominal mass is linked with a variety of diseases all of which needs to be included in the differential.
Those that are of importance include neuroblastoma, rhabdomyosarcoma, leiomyosarcoma, renal cell
sarcoma, fibrosarcoma, hydronephrosis, polycystic kidney, adrenal hemorrhage, and renal vein thrombosis
(13).
Imaging studies (ultrasound or CT) are required to confirm the presence of a renal mass. Once a Wilms'
tumor is suspected, a complete blood count, liver and kidney function tests, skeletal survey, and chest x-ray
should also be done. Ultrasound or CT helps localize the mass, identifies associated genitourinary
abnormalities, confirms function of the contralateral kidney, and indicates if there is extension to the
inferior vena cava (16). CT scan is better at detecting subtle intra-abdominal abnormalities such as tumor
spread, lymph node enlargement, vascularity, etc. Chest x-rays are done to look for evidence of lung
metastasis. A definitive diagnosis is made based on biopsy results (13).
The National Wilms' Tumor Study Group Staging System is the most common criteria used to stage a
tumor. This system stages tumors according to information gathered by clinicians, surgeons, and
pathologists.
The first line of treatment is surgical resection whenever possible. During the procedure the surgeon should
remove the tumor taking precautions to prevent tumor spillage. While the abdomen is open, the
contralateral kidney should be inspected to detect involvement. The liver should also be inspected for
evidence of metastasis. The renal vein should be checked to see if the tumor has extended to this area.
Lastly, a retroperitoneal lymph node sample should be obtained for histopathology. If the tumor is
inoperable either due to large size or the presence of invasion, a biopsy should be taken and other forms of
therapy started (15). This tumor is sensitive to chemotherapy and radiation so either of these treatment
options are possible therapeutic choices.
If there is bilateral Wilms' tumor, complete resection is not an option since dialysis or a renal transplant
would be required to prevent uremia. Instead, renal sparing surgery is preferred. First, a biopsy must be
done to confirm bilateral involvement and to get histologic data to grade the tumors. Next, preoperative
chemotherapy, appropriate for the stage of the tumor, is begun which lasts for up to six weeks. An
abdominal CT scan is then done to determine if resection is possible. If it looks good, surgical excision is
done. If it does not appear to be resectable, a second-look procedure is done in which another biopsy is
taken and a partial resection is attempted. If a partial resection is not possible, then chemotherapy is utilized
with or without radiation (16).
The prognosis of the patient is based on the histology (grade) and stage of the tumor. A favorable histology
is one in which blastemal, stromal, and epithelial elements may be seen. An unfavorable histology is an
anaplastic one detectable by the presence of gigantic polypoid nuclei within the tumor sample (14). Four
year Wilms' tumor survival (4): Stage I with favorable histology (96%), stage II with favorable histology
(92%), stage III with favorable histology (87%), stage IV with favorable histology (83%), unfavorable
histology (60%).