Pediatr Clin N Am 49 (2002) 1239 – 1256

Approach to the bleeding child

Geoffrey A. Allen, MDa,*, Bertil Glader, MD, PhDb,*
a
Division of Hematology/Oncology, University of North Carolina School of Medicine,
Chapel Hill, NC, USA
b
Division of Hematology/Oncology, Stanford University School of Medicine, Stanford, CA, USA

The challenge for pediatricians in evaluating a child with a potential bleeding

disorder is to ascertain whether the patient’s symptoms are appropriate to the
hemostatic stress or whether further investigation of an underlying hemorrhagic
disorder is warranted. This review describes the elements of the medical history,
physical examination, and clinical laboratory testing that are important in
recognizing clinically significant bleeding disorders. Some of the more commonly
encountered bleeding scenarios also are summarized.

Coagulation overview
The primary phase of hemostasis is the production of the platelet plug. This
process begins immediately after vascular injury as subendothelial tissues are
exposed to circulating blood. Platelet binding to the subendothelium (adhesion) is
mediated by the platelet surface glycoprotein Ib and von Willebrand factor (vWF)
that is produced by endothelial cells. Subsequent to platelet adhesion, there is
platelet activation with release of platelet contents and exposure of yet another
platelet surface glycoprotein (IIb/IIIa). Enlargement of the initial platelet plug
depends on platelet-platelet interaction (aggregation) that occurs by way of
linkage of platelet surface glycoprotein IIb/IIIa and fibrinogen and also potentially
involves vWF [1]. The platelet plug not only offers the first line of defense against
hemorrhage but also provides the phospholipid surface required for some of the
protein-protein interactions necessary for the formation of a fibrin clot.
The secondary phase of hemostasis results in the formation of a cross-linked
fibrin clot. This phase also is initiated by the exposure of extravascular tissues
when tissue factor– bearing cells come in contact with circulating blood. The
coagulation proteins circulate in inactive precursor forms known as zymogens;

* Corresponding authors.
E-mail addresses: allen@med.unc.edu (G.A. Allen), bglader@stanford.edu (B. Glader).

0031-3955/02/$ – see front matter D 2002, Elsevier Science (USA). All rights reserved.
PII: S 0 0 3 1 - 3 9 5 5 ( 0 2 ) 0 0 0 9 1 - 3
1240 G.A. Allen, B. Glader / Pediatr Clin N Am 49 (2002) 1239–1256

however, with the initiation of coagulation, these zymogens are converted to

active forms through limited proteolysis. These activated proteins then further
activate other zymogen factors in a chain reaction, ultimately leading to the
cleavage of fibrinogen to fibrin and formation of the blood clot (Fig. 1) [2,3].
Although the clotting cascade model has undergone significant modification since
its introduction in 1964 and has some physiologic inconsistencies, it is still very
useful for the interpretation of abnormal coagulation test results such as the
prothrombin time (PT) and activated partial thromboplastin time (aPTT).
The interactions of activated platelets and the clotting cascade give rise to a
hemostatic response that is potentially explosive and, unchecked, can lead to
thrombosis and tissue damage. Fortunately, coagulation is modulated by a number
of mechanisms including the removal of activated factors through the reticulo-
endothelial system and the control of activated procoagulants by natural anti-
thrombotic pathways (antithrombin III, protein C, protein S). In addition to these
limiting reactions, there exists the fibrinolytic pathway, which restores vessel
patency following hemostasis. The end product of the fibrinolytic pathway is
plasmin, which is a proteolytic enzyme that degrades fibrin, resulting in the
formation of fibrin degradation products including D-dimers. The generation of
plasmin from plasminogen is stimulated by tissue plasminogen activitor, and the
reactions are limited by a2-antiplasmin and plasminogen activator inhibitor. These
fibrinolytic factors are important because defects that result in increased plasmin
generation can lead to bleeding.

Medical history and clinical examination

The medical history and physical findings should enable the primary care
provider to sort out those patients with a high likelihood of having an underlying
bleeding disorder. Features of abnormal bleeding include a duration or quantity
beyond what would be expected of ‘‘routine’’ bleeding episodes: epistaxis unre-
lieved by 15 minutes of pressure along the entire side of the nose; menstrual periods
lasting longer than 7 days or associated with passage of clots, saturation of pads, or
frequently stained clothing; significant bleeding from dental procedures lasting
beyond the day of the procedure and/or requiring a blood transfusion; ecchymoses
of a size or character inconsistent with the degree of reported trauma. When a child
has had previous surgery or dental extractions without bleeding complications, it is
unlikely there is an underlying congenital hemorrhagic disorder.
In a similar manner, the patient’s family history should be explored for
symptoms of a bleeding disorder. This history is particularly important in
pediatrics because most children have not encountered severe challenges to
their hemostatic system. Also, inherited hemorrhagic disorders in families may
have gone undiagnosed or been misdiagnosed for multiple generations, espe-
cially when mild. Questioning should include all members of the family,
regardless of any early suspicions as to the nature of a diagnosis. For example,
hemophilia, an X-linked disorder that primarily affects males, may also result in
 G.A. Allen, B. Glader / Pediatr Clin N Am 49 (2002) 1239–1256 1241

abnormal bleeding symptoms in female carriers [4,5]. Questioning must include

inquiries about previous surgical procedures, dental extractions, and transfusions
of all family members, as well as the menstrual and obstetric histories of female
relatives. When questioning about menstrual periods, do not ask whether they are
normal; too many women with menorrhagia have considered their periods to be
normal because their mothers and sisters have had the same history and often the
same bleeding disorder. Make an objective assessment by asking specific ques-
tions. Determine how many total days of flow (usually 7 or less); determine how
many days of heavy flow (usually no more than 3); ask about ‘‘flooding’’ or how
often pads have to be changed during the heavy-flow days. These questions are
important because it is now recognized that up to 20% of girls with menorrhagia
beginning at menarche have an underlying bleeding disorder [6,7].
The type of bleeding manifestations helps guide the evaluation. Mucosal
membrane bleeding (gingival hemorrhage, epistaxis, menorrhagia), petechiae,
and bruising are more typical of quantitative or qualitative platelet disorders and
von Willebrand disease (vWD). Conversely, spontaneous, deep muscle, and joint
bleeding are seen more commonly with bleeding due to coagulation-factor
deficiencies such as in hemophilia.
The time of onset of the symptoms is important. Acute onset over a period of
days to weeks is suggestive of an acquired disorder, such as immune (previously
idiopathic) thrombocytopenic purpura (ITP) or vitamin K deficiency. Symptoms
of a longer duration are indicative of a congenital disorder such as vWD or
coagulation-factor deficiencies. In the case of infants with congenital coagulation
disorders, bleeding manifestations sometimes occur at birth (following circum-
cision), appear in the first months of life (with immunizations) or, most
commonly, present when children become mobile and begin to experience mild
trauma. Mild bleeding disorders may not become apparent until a person
experiences more significant challenges to their hemostatic system, such as
surgery, dental extractions, trauma, or menstruation. In some children, bleeding
with trauma is associated with good initial hemostasis, only to be followed by
persistent oozing due to failure to form a firm clot. This type of bleeding
characteristically is seen with factor XIII deficiency and disorders of the
fibrinolytic pathway.
The overall health of the patient also is a clue to the cause of bleeding.
Congenital bleeding disorders and ITP usually occur in children who are
otherwise well. Conversely, disseminated intravascular coagulation (DIC) occurs
in sick individuals with comorbid conditions. Liver disease often is associated
with bleeding due to impaired production of coagulation factors and, to the extent
that there is significant portal hypertension, thrombocytopenia also can be
contributory. Malabsorbtion and other gastrointestinal disease can lead to impaired
vitamin K absorption and bleeding due to impaired coagulation-factor synthesis.
Renal disease often is associated with abnormalities in platelet function, thereby
leading to defects in primary hemostasis.
The physical examination offers further clues to a diagnosis. Petechiae are
almost pathognomonic of platelet-related bleeding. Involvement of the mucosal
1242 G.A. Allen, B. Glader / Pediatr Clin N Am 49 (2002) 1239–1256

membranes with purpura or hemorrhage may also be present. The nares should
be gently examined in children with a complaint of epistaxis because exco-
riations and damaged vessels may be indicative of trauma (digital or otherwise),
rather than spontaneous bleeding. Ecchymoses in places other than the anterior
shins and elbows, such as the flank, abdomen, or back, may be indicative of a
bleeding propensity. Bruises in any area that appear excessively large for the
degree of trauma or those with underlying palpable hematomas may be seen in
patients with significant bleeding disorders. Swelling or limited range of motion
of any joint without a history of significant trauma is definitely abnormal.
Similarly, deep tissue and intramuscular bleeds are not common in patients with
intact hemostatic systems. Unfortunately, the possibility of physical abuse must
be considered in the evaluation of any child with unusual patterns of bruising
or bleeding.

Laboratory studies to evaluate for a bleeding disorder

The initial laboratory studies to evaluate for a possible bleeding disorder should
include a complete blood count (CBC) with review of the smear, a PT, and an
aPTT. Results of these tests will determine subsequent studies to be obtained.

CBC
The complete blood count offers at least two important pieces of information. It
allows for rapid determination of the platelet count, either confirming or rejecting
a suspected thrombocytopenia. In addition, it may offer clues as to the severity and
duration of the patient’s bleeding. Anemia in association with a history of bleeding
symptoms should raise a red flag. In children with recurrent epistaxis, it is those
with anemia that are most likely to have an underlying bleeding disorder. A
microcytic anemia, indicative of iron deficiency, may represent a history of
prolonged blood loss, not compensated for by normal dietary iron intake.
Alternatively, a normocytic anemia may be seen in cases of recent hemorrhage
with significant amounts of blood loss. Anemia, thrombocytopenia, and leukocyte
abnormalities raise the specter of bone marrow failure syndromes as seen in
leukemia and lymphoma.

Peripheral blood smear

The peripheral blood smear should be examined in any patient with a suspected
platelet disorder. A low platelet count must be confirmed by review of the smear
because clumping of platelets can cause a falsely low automated count, which may
be easily detected on examination of the smear. Clumping of platelets can occur
due to EDTA-dependent antibodies and, if persistent, may require repeat collec-
tion of the blood sample in an alternative anticoagulant such as citrate. On a well-
prepared slide, each platelet in a 100  field contributes approximately 15,000/mL
to the total platelet count. A few fields should be counted and the results averaged
 G.A. Allen, B. Glader / Pediatr Clin N Am 49 (2002) 1239–1256 1243

to yield a platelet estimate [8]. Examination of the smear also allows for
examination of platelet morphology. In the giant-platelet disorders such as
Bernard-Soulier or May-Hegglin anomaly, the majority of platelets will be of a
size similar to or larger than the erythrocytes. On a smear from a patient with the
much more common ITP, both normal and large platelets are seen. Conversely, the
Wiskott-Aldrich syndrome is characterized by smaller-than-normal platelet vol-
ume. The mean platelet volume is often reported as part of an automated complete
blood count but may not accurately reflect the actual platelet size, particularly in
the presence of thrombocytopenia.

PT and aPTT
The PT and aPTT are screening tests for the second phase of hemostasis. The
PT evaluates the extrinsic and common pathways of the coagulation cascade,
whereas the aPTT evaluates the intrinsic and common pathways. The PT is often
reported as an international normalized ratio, a standard allowing for the
comparison of results between different laboratories. In the absence of heparin
contamination, prolongation of the aPTT is indicative of a circulating anticoagu-
lant or inhibitor or of a factor deficiency. The factor level at which either the PT or
aPTT becomes prolonged varies but is usually around 40% of normal pooled
plasma levels for any given factor [9].

aPTT and PT mixing studies

An abnormal PT or aPTT should be followed by a mixing study, the results
of which will indicate either the presence of an inhibitor or a factor
deficiency. By mixing equal volumes of a patient’s plasma with normal
plasma, any factor deficiency should be corrected to a minimum of 50%
levels; hence, the normalization of the PT or aPTT following a mixing study
indicates a factor deficiency. Persistent prolongation of the test result after
mixing with normal plasma is indicative of the presence of an inhibitor
(usually an antibody against one or more coagulation factors) [9]. In most
children, these inhibitors are not associated with clinical bleeding but merely
interfere with in vitro testing. A prime example is the inappropriately named
lupus anticoagulant that is associated with a prolonged aPTT; however, there
is no bleeding. Paradoxically, the lupus anticoagulant in adolescents and adults
is clinically associated with a propensity for thrombosis. Bleeding due to a
lupus anticoagulant only occurs when the PT also is prolonged due to
decreased factor II activity. In children, most inhibitors are typically transient
in nature—often associated with viral illness—and usually return to normal in
a few days to weeks.

Coagulation-factor assays
When a factor deficiency is suggested by family history or mixing studies,
specific coagulation-factor assays are indicated. This testing is done with a
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modified form of either the PT or aPTT, depending on the factor being tested; the
result is reported as a percentage of activity seen in normal pooled plasma. When
aPTT mixing studies indicate a factor deficiency, it is necessary to measure factors
VIII, IX, and XI because deficiencies of these factors are associated with clinical
bleeding. Decreased concentration of factor XII, prekallikrein, and high molecular
weight kininogen also can cause a prolongation of the aPTT; however, these
deficiencies are not associated with bleeding.

Fibrinogen measurement
The functional activity of fibrinogen is measured by observing fibrin monomer
formation in the presence of added thrombin [9]. Quantitative measurements
that detect the fibrinogen protein (antigen) also are available. In rare dysfibrino-
genemias, there is discordance in fibrinogen function (low) and immunologic
levels (normal).

Thrombin time
The time required to form a clot when thrombin is added to plasma is a measure
of fibrin formation [9]. When it is prolonged, it signifies low fibrinogen activity,
the presence of fibrin split products, or heparin contamination. The reptilase
clotting time is similar to the thrombin time, except that the coagulation induced
by this enzyme from snake venom is not inhibited by heparin. For this reason,
utilizing aTT and reptilase clotting time together can help clarify whether
abnormal coagulation results are due to heparin contamination.

Screening tests for defects in primary hemostasis

In addition to the coagulation-factor tests described above, it often is important
to screen for abnormalities in primary hemostasis such as vWD or platelet-
function abnormalities. The traditional test used has been the template bleeding
time and often is included as part of initial screening for a bleeding disorder.
Questions regarding the reliability, sensitivity, specificity, and predictability of the
bleeding time, however, have led to a decline in its use [10 –12]. A new laboratory
device, the PFA-100 platelet function screen (Dade Behring, Deerfield, Ill), has
been introduced into clinical practice as a substitute for the bleeding time [13,14].
This instrument is an automated device that simulates primary hemostasis by
aspirating a small amount of citrated whole blood through an aperture in a
membrane coated with collagen and either epinephrine or adenosine diphosphate.
The exposure to platelet agonists and high shear forces result in vWF-dependent
attachment and activation and aggregation of platelets, resulting in occlusion of
the aperture by a stable platelet plug. The time to occlusion is prolonged in patients
with most types of vWD and some platelet disorders. Comparisons indicate that
the PFA-100 is superior to the bleeding time, offering a very good screening test
for most cases of vWD and some platelet function disorders (Fig. 2) [11,15,16].
When there is evidence for abnormalities in primary hemostasis, the initial studies
 G.A. Allen, B. Glader / Pediatr Clin N Am 49 (2002) 1239–1256 1245

should focus on vWD because this is such a common disorder. If the vWD work-
up is conclusively negative, then platelet aggregation studies should be obtained to
identify an abnormality in platelet function. It should be noted that normal
numbers of platelets are needed for primary hemostasis and no functional tests
should be done in patients with thrombocytopenia.

Platelet aggregation studies

Platelet aggregation studies measure the degree and pattern of platelet aggrega-
tion after the addition of platelet agonists (adenosine diphosphate, epinephrine,
collagen, thrombin, arachidonate, ristocetin). The patterns of aggregation
observed can aid in the detection and definition of platelet function disorders
such as storage pool defects, Bernard-Soulier syndrome, or Glanzmann’s throm-
basthenia. The latter two syndromes are characterized by the lack of specific
glycoproteins on the platelet surface. Whereas aggregation studies previously
were the only method of diagnosis, flow cytometry now allows for direct detection
of platelet-surface glycoprotein expression. Platelet aggregation testing and
interpretation is typically performed only in specialized laboratories.

Clinical scenarios encountered in patients being evaluated for

bleeding disorders
The presentation of the bleeding patient can be quite variable and all instances
are not addressed in this article. The common hemorrhagic problems associated
with leukemia and aplastic anemia are not discussed here, except to mention that
bruising and petechiae frequently are present at diagnosis and are often the reason
the child is first brought to medical attention. The presence of anemia, leukocyte
abnormalities, adenopathy, and/or hepatosplenomegaly, however, signifies dis-
tinct differences from other bleeding disorders and immediately changes the focus
of inquiry. The most commonly encountered bleeding scenarios are discussed
below. Table 1 lists the differential diagnoses and potential follow-up studies that
are indicated by the results of the initial laboratory screening.

A child with a significant bleeding history, normal PT, normal aPTT, and normal
platelet count
The important consideration here is the clinician’s impression that the bleeding
history is significant. That being the case, despite the normal screening test results,
further work-up is warranted. This scenario could be due to vWD, factor XIII
deficiency, defects in fibrinolysis, or platelet function disorders.
vWD is the most common congenital bleeding disorder. It is an autosomal
condition that affects 1% to 3% of the population and affects both genders and all
races and ethnicities [17 – 20]. vWD is due to a quantitative or qualitative defect in
vWF, a multimeric plasma protein with two important roles in hemostasis. Large
vWF multimers aid in the formation of the initial platelet plug. In addition, vWF
1246 G.A. Allen, B. Glader / Pediatr Clin N Am 49 (2002) 1239–1256

Table 1
Common laboratory scenarios in children with bleeding disorders
Test results Differential diagnosis Possible follow-up laboratory studies
PT normal von Willebrand disease PFA-100
aPTT normal Platelet function disorder von Willebrand studies
Platelet count normal Factor XIII deficiency Platelet aggregation studies
Fibrinolytic defect Urea clot lysis test
Euglobulin clot lysis
Alpha-2-antiplasmin, PAI-1, TPA

PT normal PTT inhibitor PTT mixing study

aPTT prolonged von Willebrand disease Factor assays (VIII, IX, XI)
Platelet count normal Hemophilia A or B von Willebrand studies
Factor XI deficiency Thrombin time/reptilase time
Heparin contamination

PT prolonged PT Inhibitor PT mixing study

aPTT normal Vitamin K deficiency Factor assays (II, VII, IX, X)
Platelet count normal Warfarin
Factor VII deficiency

PT prolonged Circulating inhibitor PT/PTT mixing studies

aPTT prolonged Liver dysfunction Thrombin time/reptilase time
Platelet count normal Vitamin K deficiency Fibrinogen
Factor deficiency Factor assays
(II, V, X, or fibrinogen)
Dysfibrinogenemia

PT prolonged DIC Thrombin time

aPTT prolonged Liver dysfunction Fibrinogen
Platelet count low Kasabach-Merritt syndrome Factors assays
D-dimers

PT normal Acute ITP —

aPTT normal
Platelet count low Chronic ITP Antinuclear antibodies
Collagen vascular disease Anticardiolipin antibodies
Early bone marrow Direct antiglobulin test
failure syndrome Serum immunoglobulin levels,
Serum complement levels
Tests for helicobacter pylori
von Willebrand factor multiermeric
analysis
Bone marrow aspirate
Marrow chromosomal analysis
Abbreviations: aPTT, activated partial thromboplastin time; DIC, disseminated intrasvascular
coagulation; ITP, immune thrombocytopenia purpura; PAI-1, plasminogen activator inhibitor-1; PT,
prothrombin time; TCT, thrombin clot time; TPA, tissue plasminogen activator.
 G.A. Allen, B. Glader / Pediatr Clin N Am 49 (2002) 1239–1256 1247

acts as a carrier protein for coagulation factor VIII, stabilizing and prolonging its
half-life in the circulation. There are three major types of vWD. Type I vWD is due
to a quantitative defect, represents a partial deficiency in the amount of circulating
vWF, and accounts for approximately 80% of all cases of vWD. Type II vWD,
which accounts for most of the remaining cases, is due to functional defects in
vWF and is further divided into four subtypes: IIA (decreased formation of the
high molecular weight vWF multimers that are most important for hemostasis);
IIB (decreased vWF large multimers due to an increased affinity for platelets); IIM
(decreased affinity of vWF for glycoprotein 1b); and a very rare variant, IIN
(decreased binding of factor VIII due to a point mutation on vWF). Type III vWD,
accounting for 2% to 5% of cases, is due to a near-total absence of vWF, associated
with greatly reduced levels of factor VIII. This is considered to represent
homozygosity or compound heterozygosity for two vWF mutations [19]. The
diagnosis of vWD is suggested by the clinical history. The condition is charac-
terized by mucocutaneous bleeding symptoms (ie, epistaxis, oral bleeding, and
easy bruising). In females, menorrhagia and postpartum hemorrhage may also be
seen [5,6,22,23]. In some cases of type III vWD, the very low factor VIII levels
may be associated with ‘‘hemophilia-type bleeding’’ into joints and muscles. The
complete blood count usually is entirely normal unless there is anemia as a
consequence of bleeding. Significant thrombocytopenia may be observed in some
patients with type IIB vWD and is a consideration when evaluating a child with
chronic ITP (see later discussion). Coagulation tests are typically normal or the
aPTT may be variably prolonged, depending on the magnitude of concomitant
factor VIII deficiency. Tests of primary hemostasis (the PFA-100) usually are
abnormal (Fig. 2). The specific laboratory diagnosis of vWD is established by a
panel of tests including vWF antigen, ristocetin cofactor activity (a functional
marker of vWF), factor VIII activity, and vWF multimeric analysis (Table 2).
Normal results (false negative) frequently are encountered in patients with a
significant bleeding history and type I vWD. Moreover, many physiologic
activities (stress, hormones, exercise) and drugs (oral contraceptive pills) can

Table 2
Diagnostic results in testing for von Willebrand’s disease
Type vWF:Ag vWF:RCo Multimers VIII Platelets
I Low Low All present Low or normal Normal
IIA Low Very Low Decreased HMW Low or Normal Normal
& IMW forms
IIB Low or Normal Low or Normal Decreased HMW Low or Normal Low
forms
IIM Normal Very Low Normal Normal Normal
IIN Normal Normal Normal < 25% Normal
III Extremely Low Extremely Low All extremely < 10% Normal
or Absent or Absent decreased or absent
Abbreviations: vWF:Ag, von Willebrand antigen; vWF:RCo, ristocetin cofactor activity; HMW
multimeters, high molecular weight multimeters; IMW, intermediate molecular weight multimeters.
1248 G.A. Allen, B. Glader / Pediatr Clin N Am 49 (2002) 1239–1256

increase vWF, thereby confounding the diagnosis. As a general rule, abnormally

low results suggestive of vWD usually are correct. In individuals very suspect of
having a bleeding disorder but having normal vWF antigen and ristocetin cofactor
levels, however, it often is necessary to repeat testing on other occasions in order
to make the diagnosis. Just as oral contraceptive pills can mask the diagnosis of
vWD, normal nonpregnant hormonal cycles also can influence factor levels: the
lowest vWF levels are observed in the early part of the follicular phase (days 4– 7,
the time when menstrual flow is ceasing) [5,24,25].
Factor XIII deficiency is characterized by delayed or prolonged bleeding and
because the PT and aPTT do not assess this factor activity, the screening
coagulation tests are normal [26,27]. Following activation by thrombin, factor
XIII serves to cross-link the fibrin monomers, stabilizing a newly formed clot and
making it more resistant to fibrinolysis. This factor deficiency is inherited in an
autosomal-dominant pattern, with heterozygotes having approximately 50% of
normal levels and those with the homozygous state having almost no factor.
Because very small amounts of factor XIII are required for hemostasis, symptoms
only occur with severe deficiency. The clots formed in such individuals are quite
friable and may result in delayed and prolonged bleeding episodes that are either
spontaneous or associated with minimal trauma. The classic presentation of the
homozygous state is prolonged bleeding from the umbilical stump in the newborn
or post circumcision. Patients with a severe factor XIII deficiency have been
reported to have a high incidence of intracranial bleeding, up to 30% in some
series, with a significant number of fatalities [26]. Other clinical manifestations of
factor XIII deficiency are poor wound healing and, in neonates, delayed separation
of the umbilical cord. Laboratory testing demonstrates an abnormally rapid lysis of
the patient’s clot in either 5 mol/L urea or 1% monochloroacetic acid, which is
corrected with the addition of normal plasma.
Defects of the fibrinolytic system are associated with bleeding due to abnor-
mally rapid dissolution of the fibrin clot. Although rare, excessive bleeding has
been described in association with deficiencies of a2-antiplasmin and plasminogen
activator inhibitor – 1 and excess of tissue plasminogen activator [28]. The
identification of such defects requires a high index of suspicion but should be
considered in patients with prolonged bleeding following trauma; in particular,
rebleeding following initial hemostasis. The screening laboratory investigation of
these defects utilizes the euglobulin clot lysis time, a marker of plasmin activity. If
the euglobulin lysis time is shortenend, the investigation should proceed with
assays of the individual components of the fibrinolytic system. These tests usually
are performed in specialized laboratories and the work-up of patients with potential
fibrinolytic disorders should be coordinated with hematology consultation.

A child with bleeding history and isolated prolongation of the aPTT

An isolated prolongation of the aPTT can be due to an inhibitor, heparin
contamination, or deficiency in the intrinsic pathway of coagulation, excluding
those factors in the common pathway (factors V, X, prothrombin, and fibrinogen).
 G.A. Allen, B. Glader / Pediatr Clin N Am 49 (2002) 1239–1256 1249

Of the remaining factors (high molecular weight kininogen, factors VIII, IX, XI,
and XII), only deficiencies of three (VIII, IX, and XI) result in a bleeding diathesis.
As discussed previously, vWD can present with this scenario, depending on the
magnitude of factor VIII deficiency.
Hemophilia A (factor VIII deficiency) and hemophilia B (factor IX deficiency)
represent the most common inherited factor deficiencies after vWD, with a total
incidence of approximately 1 in 5000 males [17,29]. Factor VIII deficiency
accounts for 85% of the cases, with the remainder being factor IX deficiency. Even
though most cases are familial, a significant number of spontaneous mutations
occur; therefore, a family history of hemophilia may not always be present. Both
are inherited in an X-linked fashion, with males being the most severely affected.
Female carriers may also have lower-than-normal levels of the factor (depending
on the pattern of lyonization) and can have an increased incidence of menorrhagia
and obstetric bleeding [4,7]. Thus, this diagnosis must be considered in any patient
with bleeding symptoms, regardless of gender or family history.
Measurement of plasma factor activity can be used to predict the severity of
bleeding. Severe hemophilia is defined as < 1% of pooled plasma levels. These
patients experience joint and deep tissue bleeding in response to little or no known
trauma. Patients with levels of 1% to 5% of pooled plasma levels are classified as
having moderate hemophilia (with less spontaneous bleeding) but can still have
serious hemorrhages in response to trauma and surgical procedures. Mild
hemophilia is defined as levels > 5% and is associated with bleeding primarily
only in association with trauma.
Hemophilia C (factor XI deficiency) is a rare bleeding disorder, with an
estimated prevalence of 1 in 100,000; however, the carrier rate is quite high in
the Ashkenazi Jewish population (estimated at 8%) [30]. The diagnosis is
suspected in those with bleeding symptoms, prolonged aPTT, normal PT, and
normal factor VIII and IX levels, and is confirmed with activity assays. Factor XI
deficiency differs from the other hemophilias in that it is an autosomally inherited
disorder tending to have milder symptoms, with bleeding episodes typically in
response to trauma or surgery. The spontaneous deep tissue and intra-articular
bleeds characteristic of severe factor VIII or IX deficiency are not typically
observed in patients with severe factor XI deficiency. In addition, the degree of the
clinical symptoms does not correlate with plasma factor levels as well as it does
with factor VIII or IX deficiency. In other words, patients with severe deficiency of
factor XI may have mild bleeding symptoms, whereas severe bleeding has been
reported in patients with levels near the lower limit of normal.

A child with bleeding history and an isolated prolongation of PT

Factor VII is the only factor tested for by the PT that is not part of the common
pathway. In the absence of an inhibitor, isolated prolongation of the PT is consistent
with factor VII deficiency; however, factor VII deficiency is a rare entity and there
are other possibilities that the clinician should consider. Because factor VII has the
shortest half-life of all the clotting factors, plasma levels drop most rapidly in
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situations affecting the production of multiple procoagulants (eg, warfarin inges-

tion or acute liver failure). Thus, prolongation of the PT would be expected acutely,
prior to prolongation of the aPTT. Similarly, in most laboratories, the PT is more
sensitive to deficiencies of the vitamin K – dependent factors (factors II, VII, IX,
and X) than is the aPTT. Thus, an isolated prorogation of the PT also may be due to
mild vitamin K deficiency or antagonism (see later discussion).

A child with bleeding history and prolongation of both PT and aPTT with a
normal platelet count
Prolongation of both the PT and aPTT in a symptomatic patient can be
indicative of deficiency of one or more factors. Deficiency of a single factor in
the common pathway (factor V, X, prothrombin, or fibrinogen) or an abnormally
functioning fibrinogen molecule (dysfibrinogenemia) can prolong both of the
coagulation times; however, such conditions are rare. Deficiency of multiple
factors from both the intrinsic and extrinsic pathways may have a single etiology
and also prolong both the PT and aPTT.
Vitamin K deficiency is the most common cause for this constellation of
findings. Vitamin K is required for the creation of calcium-binding sites on
specific procoagulant factors (factors II, VII, IX, and X) necessary for proper
activity. The absence of vitamin K results in the production of functionally
defective proteins. Bleeding due to vitamin K deficiency can be quite severe, with
a significant incidence of gastrointestinal, deep tissue, and intracranial bleeding.
Vitamin K deficiency may be due to inadequate intake, absorption, or utilization
of dietary vitamin K. In addition, there are a number of compounds that act as
antagonists that can result in symptomatic factor deficiencies. The best known
example of vitamin K deficiency –related bleeding is hemorrhagic disease of the
newborn. Prior to the institution of vitamin K prophylaxis, hemorrhagic disease
of the newborn was a significant problem in the neonatal period, although it still
is seen as a clinical issue in some neonates who do not receive vitamin K. Early
hemorrhagic disease of the newborn presents in the first 24 hours of life and is
typically associated with maternal medications that may affect vitamin K
metabolism (anticonvulsants). Classic hemorrhagic disease of the newborn
occurs between days 2 and 7 of life and is due to a combination of factors:
inadequate stores at birth because the placenta transports lipids poorly, the
neonatal liver is immature with respect to clotting factor synthesis, inadequate
intake (breast milk has low quantities of vitamin K), and the neonatal gut is sterile
during the first days of life. The late form of vitamin K –deficiency bleeding
typically occurs after the first week of life, extending into the first few months of
life. This late form is associated with a number of processes that interfere with
vitamin K stores, including inadequate intake in breast-feeding babies and
inadequate absorption in infants with chronic diarrhea, associated antibiotic
therapy, cystic fibrosis, a1-antitrypsin deficiency, and other gastrointestinal
disorders. The classic form is the most common of the three and is best prevented
by the use of prophylactic vitamin K in the newborn period [31,32].
 G.A. Allen, B. Glader / Pediatr Clin N Am 49 (2002) 1239–1256 1251

Another cause of abnormal vitamin K metabolism is the ingestion of warfarin-

like compounds. Warfarin is a vitamin K antagonist, commonly used therapeuti-
cally as an anticoagulant in both pediatric and adult populations. Patients on
therapeutic warfarin doses have a 1% to 3% annual incidence of significant
hemorrhage. Accidental or intentional ingestion of warfarin by a child may result
in a picture identical to that seen in vitamin K deficiency. The so-called ‘‘super-
warfarins’’ commonly used in rodenticides are an even greater potential hazard.
These compounds are derivatives of warfarin with up to 100 times the biologic
activity of medicinal warfarin, with significantly longer half-lives [33]. The
placement of these poisons in the household may make them readily available to
any mobile child. Although vitamin K –deficiency bleeding responds very quickly
to administration of vitamin K, the increased activity and long half-lives of the
superwarfarins require prolonged courses of high-dose vitamin K therapy and,
when there is significant bleeding, fresh frozen plasma may be required.

A child with bleeding and prolongation of PT and aPTT and thrombocytopenia

This scenario is most commonly encountered in sick children, with the
bleeding and hematologic abnormalities reflecting DIC or liver failure. A careful
history and physical examination typically provides the data necessary for a
presumptive diagnosis.
DIC is a consumptive coagulopathy secondary to a variety of disorders
including sepsis, trauma, and malignancy [34]. It is characterized by endothelial
perturbation; by initiation of abnormal coagulation in the vasculature, with
resultant deposition of fibrin; and by depletion of multiple clotting factors,
inhibitory proteins, and platelets. Although the diagnosis is a clinical one,
laboratory testing can be used to support the diagnosis of DIC. Typical
laboratory abnormalities include decreased fibrinogen concentration, decreased
factor V and VIII activity, and reduced levels of antithrombin III. Fibrin
degradation products and D-dimers, which are specific for the degradation of
fibrin, usually are elevated.
The liver is the primary site of synthesis for the majority of procoagulant and
fibrinolytic proteins and protease inhibitors. Liver dysfunction due to any number
of diseases results in an imbalance in the hemostatic system, often resulting in a
predisposition toward bleeding in response to trauma or surgical procedures [35].
As in DIC, both the PT and aPTT are typically prolonged due to deficiencies in
multiple factors. In contrast to DIC, factor VIII levels are typically normal or
elevated. Thrombocytopenia may also be present due to portal hypertension and
associated splenic sequestration.

A child with petechiae and/or mucosal bleeding associated with

isolated thrombocytopenia
ITP in children most commonly is acute, but 10% to 15% of children have
chronic ITP. Acute ITP is a self-limited acquired bleeding disorder due to the
1252 G.A. Allen, B. Glader / Pediatr Clin N Am 49 (2002) 1239–1256

production of autoantibodies targeted against the patient’s platelets [36 – 40].

The typical presentation is an otherwise healthy child, with an acute onset of
bleeding symptoms, most often diffuse petechiae and bruising. Less commonly,
epistaxis, oral bleeding, hematuria, and gastrointestinal bleeding may be seen.
Bleeding into the central nervous system is always feared; however, in reality,
this complication is very unusual. There often is a history of a recent viral
illness or immunization preceding the presentation. ITP can occur at any age
but has its peak incidence in the toddler and early school-age years. On
examination, the child appears well, except for symptoms of thrombocytopenia.
Notably, there is no significant lymphadenopathy or hepatosplenomegaly. There
is no evidence of human immunodeficiency viral infection by history or
physical examination. With the ‘‘typical ITP presentation,’’ all that is required
to make the diagnosis usually is a complete blood count and a review of the
peripheral blood smear. Aside from thrombocytopenia, there are no other
hematologic abnormalities, although mild anemia may be present if there has
been any significant antecedent hemorrhage. Review of the smear sometimes
reveals atypical lymphocytes due to recent viral illnesses, but there are no other
leukocyte abnormalities. Both large and normal-sized platelets are seen.
Examination of the bone marrow is not necessary to make the diagnosis of
acute ITP. It is indicated only in those cases associated with other features such
as significant adenopathy, hepatosplenomegaly, macrocytic anemia, or leuko-
cyte abnormalities. The clinical course is variable, but the majority of patients
have recovery of their platelet counts within 2 months of diagnosis; approx-
imately 80% have normal platelet counts within 6 months [40]. These improve-
ments in platelet counts occur with or without therapy.
Chronic ITP exists when low platelet counts persists beyond 6 months from
the time of acute ITP presentation. Although it is not possible to predict those
patients at diagnosis who are destined to have chronic ITP, presenting features
associated with a high risk for chronicity include insidious onset of symptoms,
age greater than 10 years, and female gender. When it is determined that a
patient has chronic ITP, further investigation for underlying disorders is
warranted. In general, the authors obtain these further studies when a younger
child has had ITP for over a year. In teenagers with ITP, however, the authors
usually get this more complete evaluation at the time of initial diagnosis
because of the much higher likelihood of chronic disease. Suggested laboratory
testing for underlying disorders varies but generally includes the following:
antinuclear and antiphospholipid antibody studies, a direct antiglobulin test,
serum complement and immunoglobulin levels, and thyroid function tests [36].
Recently, data have emerged that indicate chronic ITP also may be associated
with Helicobacter pylori infection [21]. Consideration should be given to
testing for type IIB vWD, which is associated with chronic thrombocytopenia.
If there is any concern of an underlying bone marrow failure disorder or
myelodysplasia, chromosomal breakage studies and a bone marrow examination
with cytogenetics are obtained. Testing of family members may reveal evidence
for an inherited thrombocytopenia.
 G.A. Allen, B. Glader / Pediatr Clin N Am 49 (2002) 1239–1256 1253

Neonatal thrombocytopenia
The platelet count in preterm and term newborns is similar to that of older
children (150,000/mL to 450,000/mL). The significance of a platelet count of
100,000/mL to 150,000/mL is uncertain, but a platelet count of less than 100,000/mL
is definitely abnormal and mandates further investigation. There are many causes
of neonatal thrombocytopenia (Table 3). A useful approach to assessing neonatal
thrombocytopenia is to consider the baby as ‘‘sick’’ or ‘‘well-appearing.’’ Well
babies usually have no major clinical problems other than those related to
thrombocytopenia. Sick infants include those with sepsis, evidence of congenital
infection, abnormal physical findings, presumed genetic disorders, or dysmor-
phic features.
The incidence of thrombocytopenia in sick infants in the neonatal intensive
care unit may be as high as 35% [41]. Thrombocytopenia in newborns with sus-
pected sepsis is even higher [42]. Other clinical conditions known to be associated
with thrombocytopenia include congenital viral infections, asphyxia, respiratory
distress syndrome, and necrotizing enterocolitis. The Kasabach-Merritt syndrome
is a unique disorder in which thrombocytopenia is due to the trapping of platelets
in a giant hemangioma. Most of these giant hemangiomas regress and disappear
within the first few years of life, although some may require treatment with
corticosteroids or interferon [43,44].
Thrombocytopenia in well-appearing children is much less common than in sick
neonates. The most common cause of severe thrombocytopenia in this category is
neonatal alloimmune thrombocytopenia (NAIT), which occurs in approximately
1 in 1800 live births [45 –48]. An isolated thrombocytopenia in the absence of signs
and symptoms of infection may suggest alloimmune thrombocytopenia, in which
passive transfer of maternal antibody directed against the infant’s platelets results in
thrombocytopenia. The pathophysiology of this disorder, analogous to Rh iso-
immunization and hemolytic disease of the newborn, is due to an incompatibility
between maternal and fetal platelet-specific antigens. The mother produces an
antibody against a platelet antigen the fetus inherited from the father. Thrombo-

Table 3
Spectrum of thrombocytopenia in healthy and sick neonates
Sick newborns Well appearing newborns
Infection (bacterial, viral) Alloimmune thrombocytopenia
Hypoxia Maternal autoimmune disease
Respiratory distress syndrome Infection
Pulmonary hypertension Wiskott-Aldrich syndrome
Necrotizing enterocolitis Amegakaryocytic thrombocytopenia
Thrombosis Trisomy 13, 18
Congenital heart disease
Congenital leukemia
Kasabach-Merritt syndrome
TAR syndrome
Abbreviations: TAR, Thrombocytopenia Absent Radii.
1254 G.A. Allen, B. Glader / Pediatr Clin N Am 49 (2002) 1239–1256

cytopenia results in the fetus and this continues on into the newborn period, lasting
a few weeks to months until the maternal antibody is cleared. Unlike Rh
isoimmunization, NAIT often occurs in the first pregnancy. Thus, the first
occurrence of NAIT in a family is often unexpected, occurring in an otherwise
healthy child presenting with petechiae and bruising. The factor distinguishing
NAIT from other forms of neonatal immune thrombocytopenia is the high
incidence of intracranial hemorrhage, up to 20% in some series [46,47]. Almost
half of these episodes of intracranial hemorrhage may occur antenatally, making
rapid diagnosis and treatment crucial. The specific diagnosis of NAIT requires
demonstration of maternal antibodies directed against an antigen on the platelets of
the child and the father. These tests are not readily available at most medical centers
and, usually, a presumptive diagnosis is made while definitive tests are pending.
This presumptive diagnosis is based on isolated thrombocytopenia occurring in a
nonseptic neonate with a normal physical examination (aside from bleeding
manifestations) whose mother has a normal platelet count.
A second cause of thrombocytopenia occurring in well neonates is seen in
infants born to mothers with a history of chronic ITP, some of whom may have
had a prior splenectomy and may be in clinical remission. This is much less of a
neonatal problem than NAIT, and intracranial hemorrhage is rare.

An asymptomatic child with a prolonged aPTT or PT

This scenario is usually encountered when a child has screening coagulation
studies obtained prior to a surgical procedure such as a tonsillectomy. Although the
utility of such screening is debatable, the abnormal studies must be explained. The
causes of prolonged PT and aPTT associated with bleeding have already been
discussed; however, in the child without previous bleeding history and a negative
family history, the approach to diagnosis may take a different path. In one study, the
most common cause of the abnormal results was a circulating inhibitor, ultimately
not associated with bleeding [49]. Other causes of abnormal coagulation screening
tests without a true bleeding disorder include deficiency of the contact factors
prekallikrein, high molecular weight kininogen, or factor XII. Deficiencies of these
factors may prolong the aPTT but do not cause bleeding. On the contrary, factor XII
deficiency is thought to represent a mild risk factor for thrombosis.

Summary
Because bruising and bleeding are normal events of childhood, the pedia-
trician must be able to determine whether a child’s symptoms are normal or
perhaps indicative of a defective hemostasis. A thorough medical history and
physical examination should enable the clinician to choose those patients
warranting further evaluation. Rather than referral to a hematologist at that point
in time, pediatricians should be quite capable of performing the initial laboratory
evaluation and making the correct diagnosis in a majority of cases.
 G.A. Allen, B. Glader / Pediatr Clin N Am 49 (2002) 1239–1256 1255

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