C H A P T E R

29

Approach to the Child with a

Suspected Bleeding Disorder
Brian Branchford and Jorge Di Paola

CHAPTER OUTLINE
INTRODUCTION
CLINICAL EVALUATION
Clinical Presentation of Bleeding
Relevant Clinical History
Age of Onset
Family Bleeding History
Medications

INTRODUCTION
Before initiating the laboratory workup of any patient
with a suspected defect of hemostasis, the hematologist
must first verify that the patient has a clinical history,
signs, and symptoms compatible with a bleeding disorder. This is not an easy task because mild bleeding and
bruising are common in the general population. Furthermore, bleeding, particularly in the outpatient setting,
is difficult to quantify because patient reports may be
biased; the definition of excessive bleeding or bruising
is subjective and varies among individuals. Additionally,
a critical consideration in children is the fact that
many of them have not had specific hemostatic challenges such as surgeries or menarche that might unveil a
bleeding disorder. All these factors contribute to the difficulty in the diagnosis of bleeding in the pediatric
population.
Therefore, an accurate diagnosis is made primarily by
obtaining a thorough personal and family history and
then performing a careful physical examination, which
will lead to an appropriate set of laboratory tests. Once
suspicion for a bleeding disorder is confirmed, the remaining workup items are implemented in a focused manner
with reference to particular differential diagnoses.
Children with suspected bleeding disorders might
present for evaluation in a variety of ways: concerning
signs and symptoms, abnormal presurgical screening
laboratory results, or a known family history of hemostasis defects that requires consultation. The variety in
severity of different bleeding disorders also results in

PHYSICAL EXAMINATION
LABORATORY EVALUATION
Sample Collection and Technique and Preanalytical
Variables
Screening Tests
Global Tests for the Evaluation of Bleeding
BLEEDING IN THE CRITICALLY ILL CHILD

children presenting at different ages. The goal for the

consulting hematologist is to approach the child with a
broad differential diagnosis in mind, narrow the options
by carefully assessing the medical and family history as
well as pertinent physical findings, and order the most
appropriate laboratory tests to reach a diagnosis and
initiate definitive therapy, if indicated.
Although the approach to the bleeding child is often
similar in the outpatient and inpatient setting, the practicing hematologist is sometimes consulted because of bleeding in the critically ill patient. In such cases therapeutic
measures will likely be required immediately and an accurate diagnosis made later.

CLINICAL EVALUATION
The initial clinical evaluation of a child with a suspected
bleeding disorder starts with a series of questions, usually
at a doctors office or clinic, that attempt to summarize
the most important aspects of the clinical presentation
and history of bleeding. Although several standardized
bleeding assessment tools have been used recently in
research projects, their value in clinical practice is still
unproven. Therefore, questions should be designed to
establish certain parameters that would prompt an appropriate laboratory workup. The initial set of questions
should establish the following: (1) the most common site
and type of bleeding (e.g., mucocutaneous versus articular or deep muscle), (2) bleeding on hemostatic challenge
such as surgeries or trauma, and (3) family history of
bleeding.
999

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SECTION IX HEMOSTASIS

TABLE 29-1 Differences in Clinical

Manifestations of Primary Hemostatic Defects and
Clotting Factor Deficiencies
Clinical
Characteristic

Primary Hemostatic
Defect

Clotting Factor
Deficiency

Site of bleeding

Skin, mucous
membranes

Soft tissues, muscles,

joints

Bleeding after
minor cuts

Yes

Rare

Petechiae

Present

Absent

Ecchymosis

Small, superficial

Large, deep, palpable

Hemarthrosis

Rare

Common

Bleeding after
trauma/surgery

Immediate

Delayed

Clinical Presentation of Bleeding

Significant surgical or postoperative hemorrhage, rectal
or genitourinary bleeding, and major muscle or joint
bleeding are easily identified as abnormal, but they represent a minority of new cases. Most often the clinicians
challenge consists in differentiating mild but common
presenting symptoms of bleeding disorders, such as easy
bruising and mucosal bleeding (e.g., epistaxis, menorrhagia, oropharyngeal), from those encountered in
healthy children and then determining when additional
laboratory evaluation is warranted. Large bruises without
previous significant trauma, disseminated petechiae,
intramuscular hematomas, hemarthrosis (joint effusion,
warmth, and pain with passive movement) usually indicate a bleeding disorder. In young children, refusal to
walk is often a sign for an extremity-related bleed and
could represent the first sign of hemarthrosis in a boy
with hemophilia (Table 29-1).
Susceptibility to increased bruising must first be differentiated from nonmedical causes such as abuse, a phenomenon that is, unfortunately, common enough to
warrant its own set of guidelines for evaluation in recent
reports from the American Academy of Pediatrics.1,2
Inflicted trauma is most likely to manifest over the
head, chest, back, and long bones (and may retain the
outlines of the instrument used to inflict harm), whereas
bruises associated with primary hemostasis defects are
usually located over areas of typical childhood trauma,
such as bony protuberances of extremities or spinous
processes.3
Epistaxis is a frequent presenting sign in children with
hemostatic disorders, but it is also a common complaint
among healthy children, usually the result of local aggravating factors (dry nasal mucosa, trauma, allergic rhinitis).4 In a recent study of 248 children referred to the
otolaryngology clinic at Childrens Hospital of Philadelphia for epistaxis, 11% were found to have a bleeding
disorder (type 1 von Willebrand disease [VWD], platelet
aggregation defect, or mild factor VII deficiency), with
clinical predictive factors being younger age or previous
emergency medical care for the epistaxis.5 Other studies,

however, have found an incidence as high as 25%6 to

33%7 for coagulopathy among children referred to pediatric hematologists for recurrent epistaxis. Therefore it is
important that epistaxis be taken seriously as a presenting
symptom, particularly in cases that require emergency
medical care, occur in both nostrils, or appear in association with other bleeding signs or a family history of
similar bleeding.
Menorrhagia is also a frequent presenting sign for mild
or moderate bleeding disorders (including VWD, platelet
function disorders, and other coagulopathies)3 and can
quickly lead to severe anemia and decreased quality of
life. The classic definition of menorrhagia (i.e., greater
than 80mL of blood loss per cycle) is rarely used clinically8 because most women describe limitations of their
daily activities as more important than the actual volume
of blood lost.9 A more popular working definition is
excessive cyclic uterine bleeding that occurs at regular
intervals over several cycles, or prolonged bleeding that
lasts for more than 7 days.10 In fact, the American
College of Obstetrics and Gynecology has recommended
that testing for VWD be performed in all adolescents
with severe menorrhagia,11 although a subsequent metaanalysis determined that there may not be adequate data
to support this universal recommendation.12 It is essential
for practitioners to be judicious about laboratory testing
in adolescents with menorrhagia. All adolescents that
present with menorrhagia should be evaluated by a gynecologist; testing for a bleeding disorder is not always
warranted, particularly in the absence of family and personal history or other bleeding manifestations.
Surgical (e.g., circumcision, tonsillectomy) or dental
(e.g., extractions) bleeding also may be associated with
disorders of hemostasis. This type usually manifests as
uncontrolled bleeding during or after the procedure,
bleeding that extends beyond the surgical site, unexpected
need for blood transfusion, or delayed bleeding after a
procedure.3
Hereditary hemorrhagic telangiectasia may also be
manifested as mucosal bleeding, particularly epistaxis.
Profuse bleeding into soft tissues or joints suggests deficiency of a coagulation factor (such as factors VIII or IX).
Umbilical stump bleeding is typically seen with factor
XIII deficiency, but it may also occur with deficiencies of
prothrombin, factor X, and fibrinogen.13
After establishing the possibility of a true bleeding
disorder, the clinician should next consider a broad differential diagnosis for the bleeding child and approach
the history taking and physical examination with the
intent to systematically remove options and pare down
the list to a certain category or group of potential diseases. Briefly, the main categories to be considered should
include anatomic abnormalities, quantitative and qualitative platelet defects affecting platelet plug formation
(primary hemostasis), and quantitative and qualitative
defects of clot propagation (secondary hemostasis). Differentiation also must be made between inherited and
acquired disorders. Common diseases should be considered before rare ones, and diagnoses that are either life
threatening or easy to treat should be prioritized in the
evaluation process.

29 Approach to the Child with a Suspected Bleeding Disorder

Finally, it is clear that the clinical assessment and the

laboratory workup of the bleeding child will vary depending on the emergent nature of the clinical situation. The
practicing hematologist is often consulted in the inpatient
setting regarding bleeding in the intensive care unit or
operating room. The approach in these situations is
sometimes limited by the inability to obtain reliable baseline hemostatic laboratory values because of the presence
of active disease or the fact that most patients receive
hemostatic agents (including blood products) to stop the
hemorrhage. Therefore it becomes difficult to distinguish
congenital bleeding conditions frin acquired ones. Often
the immediate need for treatment supersedes a more thorough evaluation. In these cases it is reasonable to treat
the patient and then, if a baseline defect of hemostasis is
suspected, perform the laboratory evaluation days or
even months after the episode, when the acute process is
resolved.

Relevant Clinical History

Information about the patients previous response to
hemostatic challenges (e.g., surgical procedures, invasive
dental work, traumatic injuries) is an essential part of the
initial evaluation. For example, a congenital hemorrhagic
disorder is unlikely in a patient with a history of surgical
procedures or tooth extractions without any abnormal
bleeding, whereas postoperative transfusion requirements
and iron-responsive anemia often signal hemostatic
defects. In view of the variability of patients perception
of bleeding, as well as the lack of a uniform clinical
measure of bleeding severity, the history may be most
discriminatory when a standardized and validated questionnaire is used and a bleeding score is incorporated
into the diagnosis.14,15 Several such instruments currently
exist, but consensus on a single questionnaire that can
quantitate bleeding optimally is still evolving.16-18 The
International Society of Thrombosis and Hemostasis
(ISTH) Joint Scientific Subcommittee (SSC) on von Willebrand factor (VWF) and Pediatric/Perinatal Bleeding
Disorders recently developed a bleeding assessment tool
to provide more accurate determination of bleeding phenotype in individuals with bleeding disorders and compared them to healthy subjects.19 The main objective of
all the existing bleeding assessment tools is to accurately
diagnose bleeding and predict the risk of bleeding in the
future. However, owing to their high negative predictive
value, it is becoming increasingly clear that these new
instruments are more effective at excluding the likelihood
of a bleeding disorder than predicting future bleeding
risk. Family history is also a key component in establishing both the likelihood of an inherited bleeding disorder
and its specific nature. However, determination of which
family members may have been affected by relying on
testimony from one or more relatives can be difficult.
Therefore the ISTH SSC on VWF has a specific definition
of a positive family history for VWD.20 In summary, a
personal history of bleeding triggers clinical and laboratory evaluation, and a positive family history serves as
supportive evidence for a hereditary bleeding disorder.21
The history of the present illness often provides useful
clues to the diagnosis, including several classic types of

1001

presentation. A sick child with fever, shock, and mucocutaneous purpura may have disseminated intravascular
coagulation (DIC) associated with bacteremia. Hemophilia should be considered in a male toddler who has
just started crawling and exhibits subcutaneous or joint
bleeding, or who bleeds after circumcision. A girl who
has had severe menorrhagia since menarche may have
VWD. A well-appearing child covered with petechiae
likely has immune thrombocytopenia, but if the lesions
are localized to the buttocks, ankles, and feet, and they
present as palpable bruises, Henoch-Schnlein purpura
should be considered.
When applicable, a detailed menstrual history, including age at menarche, duration of menses, interval between
menses, and frequency of pad or tampon replacement
necessary to control the bleeding, should be obtained.
The prevalence of bleeding disorders in women with menorrhagia is as high as 20%, and menorrhagia is a common
initial symptom in women with VWD (approximately
90% of female patients).22-26
It is also important to note whether the patient has an
underlying medical disorder that may affect hemostasis,
such as hepatic or renal disease, malabsorption syndrome,
or Ehlers-Danlos syndrome (EDS) or another connective
tissue disorder.27 Most of the coagulation proteins are
synthesized in the liver, and as a result, liver insufficiency
is a common cause of prolongation of clotting times and
bleeding.28,29 Certain metabolites that accumulate in
uremia can interfere with platelet function,30,31 whereas
low-molecular-weight coagulation proteins (factors IX
and XI) are lost through the kidney in children with
nephrotic syndrome.32 In malabsorption syndrome, levels
of the vitamin Kdependent coagulation factors (II, VII,
IX, and X) may be depleted and lead to excessive bleeding.33,34 A child with cyanotic congenital heart disease and
polycythemia may have petechiae and excessive bleeding
with surgery, in part as a result of thrombocytopenia,
hypofibrinogenemia, or both.35

Age of Onset
It is also important to investigate the age of onset of clinical bleeding. Generally, early age of onset correlates with
more severe bleeding and may indicate a congenital cause.
Bleeding that develops later in childhood may indicate
either an acquired problem or a milder congenital bleeding disorder. For example, mild hemophilia may not be
diagnosed until late childhood or adolescence, when
participation in contact sports presents an increased
hemostatic challenge.36,37 Postcircumcision hemorrhage,
umbilical stump bleeding, cephalohematomas, and subgaleal hemorrhage are cardinal manifestations of underlying bleeding disorders and should be evaluated
thoroughly. The incidence of neonatal intracranial hemorrhage among boys with hemophilia is estimated to be
as high as 3% and may be as high as 25% in patients
with FXIII deficiency.3
The neonatal period (first 4 weeks after delivery) is a
time of unique transitional physiology, which includes the
coagulation system. The neonate has physiologically
decreased levels of most procoagulant and anticoagulant
proteins (although levels of acute phase reactants, such

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SECTION IX HEMOSTASIS

as factor VIII and fibrinogen, are normal), and thus the

hemostatic system can be easily overwhelmed, potentially
during the significant head trauma associated with labor
and vaginal delivery. One study reported intracranial
hemorrhage (ICH) after spontaneous vaginal delivery at
a rate of 1 per 1900, whereas the rate of ICH in babies
delivered by vacuum-assisted delivery was 1 in 860.38 In
addition, 15% to 30% of patients with inherited bleeding
disorders have bleeding manifestations in the neonatal
period,39 and certain disorders, such as neonatal alloimmune thrombocytopenia (NAIT), are unique to the neonatal period. Furthermore, the neonate is significantly
affected by the state of maternal health and medications
used during labor. Because of the small blood volume in
a neonate, a relatively small degree of blood loss can have
major hemodynamic consequences.
When evaluating bleeding in a neonate, the hematologist must first assess whether the baby is healthy or has
medical conditions that may have precipitated hemorrhage. It is important to inquire about prolonged rupture
of membranes, chorioamnionitis, and fetal distress during
labor. Additional details about the mothers state of
health, including infections, autoimmune disease, and
platelet count, should be obtained. Vitamin K administration to the baby should be confirmed. The neonate should
be examined, with particular attention directed to the
presence of birth trauma, bruises, and petechiae and evidence of flank masses (renal vein thrombosis), which can
cause thrombocytopenia. The presence of hepatosplenomegaly may suggest disseminated intrauterine infection.
When blood is obtained for various coagulation tests,
particular attention should be paid to the patients hematocrit concentration and the volume of the sample. Additionally, all laboratory results should be compared with
normal values for different gestational ages.40,41
Isolated thrombocytopenia in a healthy infant may be
seen in NAIT, in maternal autoimmune thrombocytopenia, or in cases of decreased platelet production such
as amegakaryocytic thrombocytopenia or the syndrome
of thrombocytopenia with absent radii. Rarely, type 2B
VWD may be manifested as thrombocytopenia in a well
infant. Thrombocytopenia in sick neonates is often due
to the underlying cause, such as infection or DIC. Isolated
prolongation of the prothrombin time (PT) or activated
partial thromboplastin time (APTT) in a healthy baby
may be caused by a specific clotting factor deficiency in
the extrinsic or intrinsic pathway, respectively, and prolongation of both the PT and APTT suggests either a
common pathway clotting factor deficiency or vitamin K
deficiency (hemorrhagic disease of the newborn). The
so-called early vitamin K deficiencyassociated bleeding
usually presents in the first week of life and is associated
with nutritional deficiencies or failure to administer
vitamin K at birth, whereas late vitamin K deficiency
bleeding occurs between 3 and 8 weeks after birth and
may manifest as intracranial hemorrhage or severe gastrointestinal bleeding.42

known or suspected bleeding problems in other family

members, including any specific diagnoses. If the family
history is positive for bleeding, the hematologist should
note the type and severity of bleeding (e.g., joint bleeding,
epistaxis, menorrhagia), age at onset, and the relationship
of the affected family member or members to the patient.
An X-linked recessive inheritance pattern (maternal
cousins, uncles, and grandfather) suggests a diagnosis of
hemophilia A or B,43 whereas an autosomal dominant
pattern would be more consistent with VWD or hereditary hemorrhagic telangiectasia. Most other clinically
relevant clotting factor deficiencies are inherited in an
autosomal recessive manner, and the family history is
frequently negative for bleeding, although consanguinity
may be noted.
Approximately one third of infants and young children with newly diagnosed hemophilia have a negative
family history,3 consistent with the Haldane hypothesis
for the fraction of new mutations in all lethal X-linked
recessive disorders.44,45 For VWD, considerable variation
in symptoms may be noted among affected family
members because of the incomplete penetrance (i.e., not
every person that inherits the mutation will exhibit an
abnormal phenotype) and variable expressivity (i.e.,
family members with the same mutation have a variable
phenotype) that are hallmarks of this disease. Bleeding
manifestations may be very mild in some and give the
misleading impression of a negative family history.
Factor XI deficiency, an autosomal trait most often (but
not exclusively) seen in persons of Ashkenazi Jewish
descent, may be associated with a very mild or moderate
tendency for bleeding. The degree of bleeding manifestations does not correlate well with the level of factor XI
or the APTT, although the patients specific mutation
may be predictive.46,47

Medications
A careful history of medication use should be obtained,
including prescribed medications, over-the-counter drugs,
recreational drugs, and herbal products.48 A number
of drugs are associated with bleeding diatheses, with
mechanisms including induction of thrombocytopenia
(e.g., quinine or quinidine, rifampin, trimethoprimsulfamethoxazole, carbamazepine, cimetidine, ranitidine,
valproic acid)49-52 and platelet dysfunction (nonsteroidal
antiinflammatory drugs [NSAIDs] such as ibuprofen
[reversible effect] and aspirin [irreversible]).53,54-57 In the
case of medications that cause platelet dysfunction, it is
important to note that they primarily exacerbate preexisting bleeding disorders rather than cause clinically relevant
bleeding by themselves. In addition, prolonged antibiotic
use may lead to lower vitamin K levels and induce
bleeding secondary to acquired deficiency of vitamin K
dependent factors. Table 29-2 lists medications, compounds, and herbal supplements known to be associated
with bleeding.

Family Bleeding History

PHYSICAL EXAMINATION

The family history is essential for assessing differential

diagnoses. The hematologist should inquire about any

A thorough physical examination must begin with an

evaluation of the vital signs, with particular emphasis on

29 Approach to the Child with a Suspected Bleeding Disorder

1003

TABLE 29-2 Compounds that Decrease Platelet Number and/or Function

Effect

Compound Class

Examples

Mechanism

Platelet
dysfunction

COX-1 inhibitors

Aspirin, ibuprofen, naproxen

Thienopyridines

Clopidogrel, prasugrel, ticagrelor, cangrelor

Phosphodiesterase
inhibitors
GPIIb/IIIa inhibitors

Dipyridamole, cilostazol

-Lactam antibiotics

Cephalosporins, penicillins (esp. in high doses)

SSRIs

Fluoxetine, olanzapine, citalopram, sertraline,

escitalopram
Ginkgo (Ginkgo biloba)
Garlic (Allium sativum)
Bilberry (Vaccinium myrtillus)
Ginger (Zingiber officinale)
Dong quai (Angelica sinensis)
Feverfew (Tanacetum parthenium)
Asian ginseng (Panax ginseng)
American ginseng (Panax quinquefolius)
Siberian ginseng/eleuthero (Eleutherococcus senticosus)
Turmeric (Curcuma longa)
Meadowsweet (Filipendula ulmaria)
Willow (Salix alba)
Black tree fungus (Auricularia polytricha)
Alcohol
Amitriptyline, imipramine, chlorpromazine, cocaine,
lidocaine, isoproterenol propranolol, penicillin,
ampicillin, cephalothin, promethazine,
diphenhydramine, carbenicillin
Furosemide, verapamil, hydralazine, cyclosporine,
hydrocortisone
Caffeine, dipyridamole, aminophylline, theophylline,
vinblastine, vincristine, colchicine, papaverine

Inhibit conversion of AA to
thromboxane A2
Inhibit ADP-induced platelet
activation
Increased cAMP decreases
agonist-induced activation
Inhibit integrin activation and
conformational change
Inhibit epinephrine- and ADPinduced aggregation and granule
release. Also, interference with
platelet-VWF interaction
Decrease platelet serotonin

Herbs and foods

Alcohol
Other

Thrombocytopenia

Antiepileptic drugs
Glycoprotein IIB/IIIa
inhibitors
Anticoagulants
Foods

Abciximab, tirofiban, eptifibatide

Various

Decrease P-selectin exposure

Interfere with platelet membrane

Inhibit prostaglandin pathways

Inhibit platelet phosphodiesterase

Phenytoin, valproate, carbamazepine

Abciximab

Unclear
Drug-dependent antibody

Unfractionated heparin (more common)

low-molecular-weight heparin (less common)
Quinine, white lupin, tahini, jui herbal tea

Drug-dependent antibody
Various

AA, Arachidonic acid; A2, annexin 2; ADP, adenosine diphosphate; cAMP, cyclic adenosine monophosphate; COX, cyclooxygenase-1;
GP, glycoprotein; SSRI, selective serotonin reuptake inhibitors; VWF, von Willebrand factor.

potential signs of severe bleeding-related anemia or intravascular volume loss, such as tachycardia (early finding)
or hypotension (late finding). Next, a global overview
should be undertaken to observe the pattern of bleeding
stigmata. Petechiae are small capillary hemorrhages and
characteristically develop in crops in areas of increased
venous pressure, such as dependent parts of the body or
those compressed by elastic waistbands, sock tops, or
straps (e.g., from backpacks, purses, luggage). They are
painless, nonpalpable, and nonblanching and must be
distinguished from small telangiectases and angiomas. In
general, the presence of petechiae indicates a defect in
primary hemostasis (platelet number or function or vascular integrity). Ecchymoses are palpable purplish lesions
induced by subcutaneous bleeding and usually indicate
a defect in secondary hemostasis (clot propagation),
such as deficiency of a coagulation factor. Additionally,
hemarthrosis, associated with severe coagulation factor

deficiency, should be evaluated for joint size, swelling,

and range of motion limitations. Identification of hepatomegaly and splenic enlargement may point toward
coagulopathy associated with systemic disorders such as
leukemia or hepatocellular disease.
Knowledge of the bleeding manifestations of certain
syndromes can help the hematologist efficiently evaluate
children with known syndromes. Conversely, the hematologists identification of a particular bleeding pattern
may pave the way to an important syndrome diagnosis
that can guide other system-based evaluation or interventions earlier than would otherwise be possible. For
example, it is important for the hematologist to know
that patients with Noonan syndrome can have thrombocytopenia, platelet function defects, and prolonged APTTs
secondary to abnormalities of the intrinsic pathway (deficiencies of FVIII, FIX, FXI).58,59 Another example is the
importance of recognizing bleeding related to skin or

1004

SECTION IX HEMOSTASIS

vascular fragility as a potential manifestation of heritable

connective tissue disorders such as EDS.27 The molecular
basis for bleeding in these syndromes is not well understood, but the clinical association between these syndromes and excessive hemorrhage is strong enough to
warrant a careful investigation.

LABORATORY EVALUATION
Sample Collection and Technique and
Preanalytical Variables
A properly drawn blood sample is crucial for adequate
interpretation of coagulation test results.60,61 Many laboratories develop independent ranges, controlling for preanalytic variables (patient posture, medical condition,
lipid levels, hormones, mental and physical stress, activity
before blood draw, tourniquet time, proper tube filling,
specimen processing, and transport conditions).62 Preferably, subjects should be fasting and should have refrained
from smoking, caffeine, or alcohol ingestion, and they
should not have taken any medications known to affect
platelet function (see Table 29-2) on the day of testing;
for some medications, such as aspirin and NSAIDs, the
period of abstinence should be at least 2 weeks.63 Herbal
remedies, garlic, and alcohol may also cause acquired
mild platelet dysfunction.53 Blood for coagulation assays
should be obtained by venipuncture performed by an
experienced phlebotomist using a 19- to 21-gauge
needle.60,61 Drawing samples from an indwelling catheter
often results in sample contamination with heparin or
intravenous fluids and spuriously abnormal values.
Improper sample collection is one of the most common
reasons for falsely prolonged clotting times.64-66 The total
tourniquet time should be less than 3 minutes.67
The initial 1 to 2mL of blood should be drawn into
a waste tube to prevent activation of the test sample by
tissue factor. Then blood is collected into citrated anticoagulant in an evacuated sample tube containing a fixed
amount of buffered sodium citrate (3.2% preferred over
3.8% for coagulation assays) as anticoagulant in the ratio
of one part citrate to nine parts whole blood.63,68,69 A
clinically significant difference between glass and plastic
tubes has not been identified.70 If the patient is polycythemic (hematocrit 55%), the amount of plasma in the
tube would be reduced in proportion to the citrate,
thereby leading to falsely abnormal coagulation test
results. In such circumstances the amount of citrated
anticoagulant should be reduced proportionate to the
high hematocrit.71,72 Conversely, anemia (hematocrit
<25%) does not seem to significantly affect the accuracy
of coagulation tests,73 but it does have an effect on some
global assays of hemostasis such as the Platelet Function
Analyzer (PFA-100) in which hemoglobin should be
greater than 10mg/dL (and platelets should be
>100,000/L) to provide proper biorheologic effect to
bring platelets in contact with the agonist-coated peripheral section of the device.63 For infants and children, small
3-mL tubes (2.7mL blood to 0.3mL citrate) are available. Tubes of all sizes should be filled to at least 90% of
the expected fill volume to prevent false elevation of clotting times from a disproportionately high citrate level.

When tubes with various anticoagulant types are used,

the citrate tubes should be collected before ethylenediaminetetraacetic acidcontaining or heparin-containing
tubes to avoid the potential for carryover.69
Once the tube is filled, the anticoagulated blood should
be gently mixed by inversion three to four times, sent to
a special coagulation laboratory without delay, and tested
within 2 hours of collection if maintained at room temperature or within 4 hours if kept cold. Samples with
visible hemolysis or clots should be discarded. Plasma
samples must be frozen if they are not tested within this
time frame. When they are to be analyzed, frozen samples
should be rapidly thawed at 37 C and tested immediately. Normal values differ from one laboratory to another
and between instruments and reagents. Thus the values
obtained should be compared with the age-appropriate
normal range for that particular laboratory.

Screening Tests
A focused history and physical examination may lead the
physician to obtain certain assays immediately, in order
to identify common disorders, life-threatening situations,
or easily treated conditions. However, if the initial evaluation does not suggest a specific disorder, a panel of
screening tests should be ordered, including a complete
blood count with evaluation of platelet number, size,
morphology, PT, APTT, and thrombin time (TT) to help
in the process of differential diagnosis. Although screening tests represent a very important part of the initial
laboratory evaluation, they are usually neither predictive
nor confirmatory of bleeding. Therefore, if a specific
bleeding disorder is suspected, the laboratory evaluation
should be directed to that specific disorder. These principles are illustrated in Figure 29-1, which provides an
algorithm representing the general approach to working
up clinically significant mucocutaneous bleeding.
Prothrombin Time
The PT is performed by adding a thromboplastin reagent
that contains calcium chloride to the citrated plasma
sample. The time required for clot formation is recorded
with an automated instrument that signals the end point,
as defined by optical or electromechanical change. The
normal (reference) range varies depending on the laboratory (its instrumentation and the lot of thromboplastin),
but it is generally 10 to 11 seconds. The PT measures the
activities of factors I (fibrinogen), II (prothrombin), V,
VII, and X. Prolongation of the PT beyond the reference
range is not generally seen until the functional level of
one of these factors is less than 30% or until fibrinogen
is less than 100mg/dL. Isolated prolongation of the PT
may reflect factor VII deficiency. Though rare, the PT can
also be prolonged by a circulating inhibitor to one of the
involved clotting factors or by the presence of abnormal
fibrinogen molecules or fragments in the circulation.
The PT is also quite useful for monitoring the effect
of coumarin-type anticoagulants. When the PT is used
to monitor a patient taking warfarin, differences in
the sensitivities of different thromboplastin preparations
in different laboratories need to be taken into account.
This consideration has led to the development of a

29 Approach to the Child with a Suspected Bleeding Disorder

1005

Clinically Significant Mucocutaneous Bleeding

CBC with differential

Blood smear
aPTT, PT, Fibrinogen

Low Platelet Count

High MPV

Low MPV

Wiskott Aldrich
Syndrome
X-linked
thrombocytopenia

Normal MPV

ITP
Bernard-Soulier
Other GP1b-IX-V
Syndromes
Giant Platelet Syndromes
GATA1
Platelet type VWD
If VWF low, Type
2BVWD

Scott syndrome
Other causes of bleeding
Glanzmanns
Thrombasthenia

Drug Induced,
Malignancy/
Metabolic
FDP/AML
CAMT
Paris Trousseau
TAR
THC2

Hermansky-Pudlak
Chediak-Higashi
Storage Pool Defect
Signal Transduction Defect
R/O Aspirin Effect

Mixing studies correct,

consider studying other
coagulation factor
deficiencies (Factor XI
deficiency can present with
mucocutaneous bleeding)

If normal labs and high

clinical suspicion of VWD
order VWF levels
Normal Platelet Count
(and no other abnormal
labs including normal
VWF levels)

Abnormally low
levels of VWF
Normal
VWD

Normal
Absent
(except ristocetin)

Platelet Aggregation
ADP receptor P2Y12
TXA2 receptor
ADP/ATP receptor P2X1

If PT, aPTT
prolonged perform
mixing study

Abnormal to
ADP & TXA2

Second wave
Absent/ secretion

Type 1 VWD
VWF:Ag low
VWF:Rco low
FVIII:C low or normal
Multimers: Normal
distribution
VWF:Rco/VWF:Ag ratio  1

Type 3 VWD
VWF:Ag absent
VWF:Rco absent
FVIII:C very low ( 5%)
Multimers: absent
VWF:Rco/VWF:Ag
ratioN/A

Type 2 VWD
VWF:Ag low
VWF:Rco very low
FVIII:C low or normal
Multimers: Loss of HMWM (or
normal)
VWF:Rco/VWF:Ag ratio normal to low

Figure 29-1 A providers guide to the staged workup of clinically significant mucocutaneous bleeding. ADP, Adenosine diphosphate; aPTT, activated partial thromboplastin time; ATP, adenosine triphosphate; CAMT, congenital amegakaryocytic thrombocytopenia; CBC, complete blood
count; FDP/AML, familial platelet disorder with predisposition to acute myelogenous leukemia; ITP, immune thrombocytopenia; MPV, mean platelet
volume; PT, prothrombin time; Rco, ristocetin cofactor test; TAR, thrombocytopenia with absent radii syndrome; TXA2, thromboxane A2; VWD,
von Willebrand disease; VWF, von Willebrand factor.
standardized method of expressing the prolongation as
an international normalized ratio.
Activated Partial Thromboplastin Time
The APTT is performed by adding a partial thromboplastin reagent, which is a source of phospholipids
without tissue factor, to the patients citrated plasma
sample, plus introducing controlled activation of the
contact factors (factors XI and XII, prekallikrein, and
high-molecular-weight kininogen) by preincubation with
a surface-activating reagent (e.g., Celite, kaolin, silica, or
ellagic acid).74 This mixture is incubated for 2 to 5 minutes
before calcium chloride is added, and the time required
for clot formation is recorded. As for the PT, automated
instruments are generally used. The APTT measures
factors I (fibrinogen), II (prothrombin), V, VIII, IX, X,
XI, and XII; prekallikrein; and high-molecular-weight
kininogen. Deficiency of any of the latter three factors
can result in a markedly prolonged APTT in the absence
of clinically significant bleeding. Isolated prolongation of
the APTT in a patient with clinical bleeding is likely to
result from a deficiency of factor VIII, IX, or XI. It should

be noted that the sensitivity and reproducibility of the

APTT are highly dependent on the specific reagents used
(particularly the activator in the partial thromboplastin
reagent). With most APTT reagents, the APTT will not
be prolonged until the amount of factor VIII is less than
35% (0.35U/mL). The laboratory should establish a reference range for each new lot of reagent and each new
method of clot detection. The reference range will generally be approximately 26 to 35 seconds for children and
adults but longer (30 to 54 seconds) in term infants (and
often even longer in premature infants).
The APTT is somewhat less sensitive than the PT to
deficiency of the vitamin Kdependent factors (so mild
deficiencies could be missed), but it is more sensitive to
the presence of circulating anticoagulants and heparin.
The APTT can detect circulating anticoagulants (e.g.,
lupus anticoagulants) and is routinely used to monitor
standard heparin therapy.75 Among hospitalized infants
or children, unintentional contamination of patient
samples with heparin is a common cause of an unexpected prolongation of the APTT that does not correct
on mixing.

1006

SECTION IX HEMOSTASIS

Thrombin Time
The TT measures the thrombin-induced conversion of
fibrinogen to fibrin and is performed by adding bovine
thrombin to the patients citrated plasma and recording
the clotting time. The TT measures the amount and the
clotting function of fibrinogen and is also prolonged in
the presence of heparin or circulating fibrin degradation
products (FDPs). An extremely prolonged TT usually
indicates a heparin effect. Reptilase, a snake venom protease, clots fibrinogen in the presence of heparin and thus
can be used to identify heparin as the cause of a prolonged TT. Thus in the presence of heparin the TT is
prolonged, whereas the reptilase time is normal. Alternatively, it is possible to test for heparin activity by its
antifactor Xa activity or with the use of commercial
heparinase. The sensitivity of the TT can be increased by
dilution of the thrombin to give a control TT of 16 to 18
seconds.
Platelet Count
The normal platelet count (for all ages) ranges from
150,000 to 450,000 per microliter. Review of the platelets on a well-prepared stained blood smear should give
a visual estimate that matches the laboratorys printed
value. A spuriously low automated platelet count (pseudothrombocytopenia) may result from ethylenediaminetetraacetic acid anticoagulant plus an IgG or IgM
platelet antibody, platelet cold agglutinins, unexpectedly
large platelet size (e.g., as seen in idiopathic thrombocytopenia purpura) in which the cell counter is unable
to distinguish the platelets from other cell types, or
platelet clumping from a partially clotted sample. Electric particle counters also often provide a mean platelet
volume and platelet volume (size) distribution. In the
setting of thrombocytopenia, increased platelet size may
suggest increased platelet turnover. Large platelets are
also seen in many hereditary platelet syndromes, and
very small platelets are characteristic of Wiskott-Aldrich
syndrome.
Bleeding Time
The bleeding time (BT), a measurement of length of time
that bleeding continues after a standardized wound is
made on the forearm or ear lobe, is no longer in clinical
use in the United States or United Kingdom, primarily
because of its poor reliability and parental perception of
the test as overly invasive. It is, however, inexpensive and
uses moderately accessible materials, and therefore it is
still used in developing countries as a global hemostasis
assay.
PFA-100
Current platelet function tests are often viewed as inaccurate and unreliable (BT) or labor intensive and time
consuming (platelet aggregation studies). Recently, a
range of new instruments have been developed that
attempt to simulate in vivo platelet adhesion and aggregation. The PFA-100 (Dade Behring, Marburg, Germany)
is a commercially available instrument that uses test cartridges containing collagen/adenosine diphosphate- or

collagen/epinephrine (CEPI)-coated membranes with

a small aperture (150m). Citrated blood is aspirated
under high shear (5000 to 6000/sec) from the sample
reservoir through a capillary tube onto the membrane,
and blood flow is monitored through the aperture. Platelets begin to adhere and aggregate primarily through
interactions with collagen under high shear, thereby
resulting in closure of the aperture. The instrument monitors the drop in flow rate with time as the aperture gradually occludes and records the final closure time (CT) with
either cartridge. Although the test is reproducible between
cartridge lots and instruments, each laboratory should
establish normal control times. Citrate samples have been
shown to be stable for up to 4 hours after sample collection, but transport through a pneumatic vacuum transport or tube system is not recommended.
The test is sensitive to the platelet count, hematocrit
concentration, platelet function, and VWF level and function. Generally, a platelet count of less than 80 to 100
9
/L or a hematocrit concentration of less than 30% leads
to a prolonged CT.76 The PFA-100 CT is inversely proportional to the VWF levels and has been used by some
as a screening test for VWD.77 In congenital platelet disorders, PFA-100 CT depends on the severity of the disorder. Severe platelet function defects in glycoprotein
Ib/V/IX (Bernard-Soulier syndrome or platelet-type
VWD) and glycoprotein IIb/IIIa (Glanzmann thrombasthenia) result in a markedly prolonged CT. In plateletdense granule deficiency or secretion defects, the
prolongation in CT is variable and is often seen in the
CEPI cartridge. Thus, although the PFA-100 CT is abnormal in some forms of platelet disorders, the test does not
have sufficient sensitivity or specificity to be used as a
screening tool for platelet disorders in general.78 It is most
consistently abnormal in severe platelet function disorders, in which clinical symptoms alone are significant
enough to suggest the diagnosis. Additionally, PFA-100
CT may be altered by drugs that affect platelet function.
Aspirin and other NSAIDs prolong the CEPI CT. The role
of the PFA-100 in therapeutic monitoring is currently
being investigated.78 Despite its wide use, the PFA-100
has not demonstrated great overall efficacy as a screening
tool for mild to moderate bleeding disorders.
Specific Tests
Specific Coagulation Factors. Each of the coagulation
factors of the intrinsic pathway (prekallikrein, highmolecular-weight kininogen, and factors VIII, IX, XI,
and XII) can be measured by one-stage, APTT-based
methods. A specific factor assay measures the clotting
time of a mixture of diluted test plasma and a specific
factor-deficient substrate plasma that supplies all factors
except the one being measured.79 Though seldom performed in U.S. clinical laboratories, a chromogenic substrate assay kit for factor VIII (as well as chromogenic
kits for certain other clotting factors) that is based on
measuring the generation of factor Xa is also commercially available.
Each of the extrinsic and common pathway coagulation factors (V, VII, and X) can be measured by specific
one-stage assays based on the PT. The patients diluted

29 Approach to the Child with a Suspected Bleeding Disorder

test plasma is incubated with commercially available

plasma that is deficient in either factor V, VII, or X; a
mixture of tissue factor and calcium chloride is added,
and the clotting time is determined.79
For each clotting factor assay based on the APTT or
PT, the clotting times of serial dilutions of a plasma
sample representing a pool obtained from a large number
of normal individuals is used to construct a standard
curve. The concentration of the specific factor in each of
the several dilutions of patient plasma is determined from
the standard curve and is used to calculate the level of
that clotting factor in the patients undiluted plasma.79 In
most laboratories, automated instruments are used to
perform the assays, and many of these instruments are
preprogrammed with a statistical package for plotting the
data. The reference pooled normal plasma should be
calibrated with a commercial or national standard that
has been assayed against an international standard when
available.80
Covalent stabilization of fibrin by factor XIIIa is essential for normal hemostasis (see Chapter 27). Factor XIIIa
catalyzes the formation of covalent cross-links between
the and chains of fibrin, which results in increased
mechanical stability of the fibrin clot and resistance to its
degradation by plasmin. None of the routine screening
tests (PT, APTT, or BT) detect factor XIII deficiency.81
Screening for factor XIII deficiency can be performed
with the clot solubility test: solubility of the patients
recalcified plasma clot in 5mol/L urea or monochloroacetic acid is assessed after 30 minutes and periodically
at 1, 2, 4, and 24 hours. Clots from patients with less
than 1% factor XIII activity are soluble. Quantitation of
factor XIII can be done with specific amine incorporation
assays, although these tests are generally performed only
in specialized research laboratories.81
Recommended tests for VWD include APTT, factor
VIII assay, ristocetin cofactor assay to measure VWF
activity, VWF antigen assay, and ABO blood group
typing. If these tests suggest VWD, VWF multimer analysis should be performed. Treatment of VWD depends on
accurate subtype diagnosis (see Chapter 31).
Fibrinogen. The concentration of fibrinogen in plasma
can be measured immunologically (fibrinogen antigen) or
by a chemical method in which the ability of fibrinogen
to clot does not influence the assay. Normal fibrinogen
antigen levels are between 200 to 400mg/dL. Fibrinogen
is an acute phase reactant, and elevated levels are commonly seen in stress or acute illness.
The level of functional fibrinogen or fibrinogen activity
can also be measured. The von Clauss kinetic assay uses
a dilute solution of patient plasma and an excess of
thrombin, which makes fibrinogen the rate-limiting step
in the clotting reaction.82 The resulting clotting time in
seconds is compared with a standard dilution curve to
determine the concentration of clottable fibrinogen.
Fibrinogen is decreased in congenital afibrinogenemia,
hypofibrinogenemia, and consumptive states such as
DIC. The assay is also sensitive to abnormalities in fibrinogen function (dysfibrinogenemia) or the presence of
inhibitors of fibrin formation such as FDPs.

1007

Euglobulin Clot Lysis Time. The euglobulin clot lysis

time (ECLT) is a screening test for excessive fibrinolysis.
It is performed by using the plasma euglobulin fraction
prepared from fresh, citrated, platelet-poor plasma. After
clot formation, lysis is measured. The normal ECLT is 60
to 300 minutes. It is shortened in conditions characterized by increased fibrinolysis (e.g. 2-antiplasmin deficiency, plasminogen activator inhibitor 1 deficiency, or
systemic fibrinolysis).
Platelet Function Tests. When ordering tests of platelet
function, the physician must be aware that a wide variety
of drugs can affect the platelet count and alter test results.
Drugs such as aspirin irreversibly affect platelet function
for the entire life span of the platelet (10 to 11 days).
Thus tests of platelet function should be scheduled at a
time when the individual has not taken any relevant drugs
for at least 10 days.
The most common test of platelet function is platelet
aggregometry. Platelet aggregation can be performed in
whole blood by impedance technique or in plateletrich plasma (PRP) by the turbidimetric technique.
Whole blood platelet aggregation can be combined with
release of adenosine triphosphate by using a lumiaggregometer. A variety of platelet agonists (ristocetin,
epinephrine, collagen, adenosine diphosphate (ADP),
and arachidonic acid) can be added to an aliquot of the
patients sample. The rapidity and extent of platelet
agglutination are detected by changes in optical density
(PRP) or impedance (whole blood) and are graphically
recorded for each agonist used.83 In Glanzmann thrombasthenia, the patients platelets will agglutinate normally with ristocetin but not at all with the addition of
ADP, epinephrine, collagen, or arachidonic acid. In
Bernard-Soulier syndrome, platelet agglutination will
occur normally on addition of each of these agonists
except ristocetin.83

Global Tests for the Evaluation of Bleeding

Over the last two decades, investigators and clinicians
have attempted to develop global assays of hemostasis
that would eventually be able to predict risk of bleeding
as well as measure therapeutic efficacy of blood products
and clotting factor replacement therapy. As knowledge of
the coagulation system developed in the 1950s, specific
assays were devised to measure the individual clotting
factors. However, it soon became apparent that individual clotting factor assays were inadequate to assess the
true nature of the hemostatic system. It was obvious that
static end point laboratory tests such as the PT or APTT
also did not accurately reflect the patients overall hemostatic status and could not assess the dynamic clotting
cascade. The common clinical observation that patients
with hemophilia have great phenotypic variation in bleeding despite identical factor levels stresses this point. This
has led to a revival of interest in global clotting assays.
In addition, the development of technical innovations and
computer-assisted methods of analysis has improved the
reliability and reproducibility of global assays. Two such
techniques are described here: thromboelastography
(TEG) and thrombin generation assays (TGAs). TEG is

1008

SECTION IX HEMOSTASIS

usually performed on whole blood and quantitatively

measures the dynamics of fibrin formation. TGAs are
generally performed on plasma and measure thrombin
formation.
Thromboelastography
Hartert first described TEG as a global test for blood
coagulation more than 50 years ago.84 TEG monitors the
whole dynamic process of hemostasis from clot formation to its dissolution and also provides information
about platelet function. TEG produces a continuous
profile of the overall rheologic changes occurring during
coagulation while using a small amount of whole blood.
By processing the data, the viscoelastic changes occurring
during whole blood clot formation can be transformed
into a dynamic velocity profile that is then recorded as a
tracing. Currently, reagent-modified TEG with various
activators (tissue factor, kaolin) and inhibitors is used
with the aim of accelerating the coagulation cascade and
obtaining differential diagnostic information.85 The two
commonly used instruments are the TEG (Haemoscope
Corp, Skokie, Illinois) and the rotating thromboelastometer ROTEM (Pentapharm, Munich, Germany).86 Currently used primarily as tools to decrease transfusion
requirements during cardiac87 and hepatic surgery, these
instruments are also being investigated as screening tools
for bleeding disorders.88,89
Thrombin Generation Assays
TGAs have been used extensively in research laboratories
but are cumbersome to perform.90 A more recently

developed test, calibrated automated thrombography

(CAT), may be applicable to the routine clinical laboratory. CAT measures the concentration of thrombin in
clotting plasma by monitoring the splitting of a fluorogenic substrate and comparing the results with known
constant thrombin activity in a parallel nonclotting
sample (control).91 Application of TGAs is currently
being investigated for monitoring of hemophilia treatment and anticoagulation therapy and as a means to
better understand the differing clinical patterns in bleeding disorders.92
Overall, although significant advances have been made
in the development of global assays of hemostasis, and
some of them are widely used in the clinical and surgical
setting, the evidence for making critical diagnostic and
therapeutic decisions based on results obtained from
these assays is still largely premature; caution should be
exercised.

BLEEDING IN THE CRITICALLY ILL CHILD

It is not uncommon for the general pediatric hematologist
to be consulted in the critical care setting for acute bleeding in the presence of abnormally prolonged clotting
tests, thrombocytopenia, or suspected platelet dysfunction. Several clinical situations may lead to the presence
of acquired bleeding in the inpatient setting; when the
underlying cause is resolved, bleeding typically stops
(Table 29-3). Perhaps the most common consult for
excessive bleeding in this setting concerns consumption
of clotting factors and platelets in the presence of DIC.

TABLE 29-3 Acquired Bleeding Disorders

Underlying Bleeding Disorder

Hemostatic Defect

Cause

Overwhelming sepsis

Acute DIC

Initiation of coagulation, damage to the endothelium;

decrease in clotting and anticlotting factors

Liver disease

Multiple coagulation factor deficiency

Decreased hepatic synthesis

Increased fibrinolysis
Decreased clearance of plasminogen activators
Hypercoagulable state
Decreased production of natural anticoagulants
Thrombocytopenia
Hypersplenism

Malabsorption syndrome

Decreased production of factors II, VII,

IX, and X and proteins C and S

Vitamin K deficiency

Cyanotic congenital heart

disease

Mild to moderate thrombocytopenia

Shortened platelet survival

Abnormal platelet function
Acquired defects in platelet aggregation

Acyanotic congenital heart

disease (e.g., ASD, PDA)

Decreased high-molecular-weight VWF

multimers

Consumption

ECMO and CPB platelet

dysfunction

Platelet activation in the oxygenator

and physical damage to the platelet
membrane

Coagulation factor deficiency

Consumption of coagulation factors in the circuit
Hyperfibrinolysis
Increase in tPA and decrease in 2-antiplasmin

Acute promyelocytic
leukemia

Thrombocytopenia
Decreased production in bone marrow
and increased consumption

Disseminated intravascular coagulation

Release of procoagulant material from the leukemic cells
Hyperfibrinolysis
Increased synthesis of plasminogen activators

ASD, Atrial septal defect; CPB, cardiopulmonary bypass; ECMO, extracorporeal membrane oxygenation; PDA, patent ductus arteriosus;
tPA, tissue plasminogen activator; VWF, von Willebrand factor.

29 Approach to the Child with a Suspected Bleeding Disorder

Box 29-1 Conditions Associated with Disseminated

Intravascular Coagulation
Sepsis (particularly gram-negative bacteremia)
Trauma
Massive tissue injury
Head injury
Fat embolism
Malignancy
Acute promyelocytic leukemia
Myeloproliferative disorders
Obstetric accidents
Vascular disorders
Giant hemangiomas (Kasabach-Merritt syndrome)
Aortic aneurysm
Toxins
Snake venom
Drug overdose
Immunologic reactions
Severe anaphylaxis
Acute hemolysis
Acute transplant rejection

DIC is an acquired systemic disorder characterized by

widespread activation of coagulation and deposition of
fibrin leading to the formation of thrombi in the microcirculation accompanied by secondary activation of fibrinolyis.72 DIC can be acute or chronic, compensated or
decompensated, and caused by a wide variety of conditions (Box 29-1). DIC should be suspected in children
with shock and bleeding manifestations. In DIC the PT
and APTT are usually both prolonged, with decreased
fibrinogen, factor VIII, and factor V. A concomitant
decrease in natural anticoagulants (protein C, protein S,
and antithrombin III) may also be seen. Examination of
the peripheral smear usually reveals the presence of schistocytes and thrombocytopenia.93 There is also an increase
in d-dimer and FDPs secondary to the formation of
plasmin. As discussed earlier in the chapter, in most cases
the diagnosis of the cause of bleeding becomes complicated by the need for immediate therapeutic intervention,
which usually requires replacement products.
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