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Evidence-Based Emergent

Management Of Bleeding
Disorders
Abstract

hildren with both congenital (eg, hemophilia or von Willebrand


disease) and acquired (eg, immune thrombocytopenia [ITP])
bleeding disorders frequently present to the emergency department
(ED) with a wide variety of bleeding-related problems ranging from
petechiae to intracranial hemorrhage (ICH).In many instances, such
as hemophilia or von Willebrand disease, the bleeding disorder has
been previously diagnosed because of an abnormal family history or
bleeding in infancy. However, in other instances, a patient may present with abnormal bleeding symptoms (such as a patient with ITP),
and it is the role of the emergency clinician to facilitate the diagnosis
and initiate therapy.
This Pediatric Emergency Medicine Practice article provides up-todate guidelines and an evidence-based review of the most common
bleeding disorders and management of specific bleeding emergencies in the ED.

Case Presentation
A 5-year-old girl with type 3 von Willebrand disease presents to the ED
with epistaxis after a forceful sneeze. It has not resolved after 30 minutes of
direct pressure. You recall that most patients with von Willebrand disease
have mild symptoms such as easy mucosal bleeding, but this patient is
still bleeding profusely out of both nares and is beginning to look pale with
AAP Sponsor
Martin I. Herman, MD, FAAP, FACEP
Professor of Pediatrics, UT College
of Medicine, Assistant Director of
Emergency Services, Lebonheur
Childrens Medical Center,
Memphis, TN

Medicine, University of Medicine


and Dentistry of New Jersey;
Director, Pediatric Emergency
Medicine, Childrens Medical
Center, Atlantic Health System;
Department of Emergency
Medicine, Morristown Memorial
Hospital, Morristown, NJ

Volume 8, Number 8
Authors
Katherine Fullerton, MD
Department of Emergency Medicine, Inova Fairfax Hospital
for Children, Falls Church, VA; Assistant Professor of
Emergency Medicine, Virginia Commonwealth University
School of Medicine, Richmond, VA
Rick Place, MD
Pediatric Medical Director, Department of Emergency
Medicine, Inova Fairfax Hospital for Children, Falls Church,
VA; Assistant Professor of Emergency Medicine, George
Washington University School of Medicine, Washington, DC
Peer Reviewers
Jennifer B. Dean, MD
Assistant Professor of Pediatrics, George Washington
University School of Medicine, Childrens National Medical
Center, Washington, DC
Madeline Matar Joseph, MD, FAAP, FACEP
Associate Professor of Emergency Medicine and Pediatrics,
Assistant Chair for Pediatrics - Emergency Medicine
Department, Chief - Pediatric Emergency Medicine Division,
Medical Director - Pediatric Emergency Department,
University of Florida Health Science Center Jacksonville, FL
Ghazala Q. Sharieff, MD, FACEP, FAAEM, FAAP
Associate Clinical Professor, Childrens Hospital and
Health Center University of California San Diego; Director
of Pediatric Emergency Medicine, California Emergency
Physicians, San Diego, CA
Paula Whiteman
Medical Director, Pediatric Emergency Medicine, EncinoTarzana Regional Medical Center, Tarzana, CA; Attending
Physician, Cedars-Sinai Medical Center, Los Angeles, CA
Prior to beginning this activity, see Physician CME
Information on page 28.

Chair for Pediatrics - Emergency


Tommy Y. Kim, MD, FAAP
Medicine Department, Chief Assistant Professor of Emergency
Pediatric Emergency Medicine
Medicine and Pediatrics, Loma
Division, Medical Director - Pediatric Linda Medical Center and
Emergency Department, University
Childrens Hospital, Loma
of Florida Health Science Center
Linda, CA
Jacksonville, FL
Brent R. King, MD, FACEP, FAAP,

Alson S. Inaba, MD, FAAP,


Ran D. Goldman, MD
PALS-NF
Associate Professor, Department
Pediatric Emergency Medicine
Jeffrey R. Avner, MD, FAAP
of
Pediatrics,
University
of
Toronto;
Attending Physician, Kapiolani
Professor of Clinical Pediatrics
Division of Pediatric Emergency
Medical Center for Women &
and Chief of Pediatric Emergency
Medicine and Clinical Pharmacology
Children; Associate Professor of
Medicine, Albert Einstein College
and Toxicology, The Hospital for Sick
Pediatrics, University of Hawaii
of Medicine, Childrens Hospital at
Children,
Toronto,
ON
John A. Burns School of Medicine,
Montefiore, Bronx, NY
Honolulu, HI; Pediatric Advanced
T. Kent Denmark, MD, FAAP, FACEP Mark A. Hostetler, MD, MPH
Life Support National Faculty
Clinical Professor of Pediatrics and
Medical Director, Medical Simulation
Representative, American Heart
Emergency Medicine, University
Center; Associate Professor of
Association, Hawaii and Pacific
of Arizona Childrens Hospital
Emergency Medicine and Pediatrics,
Island Region
Division of Emergency Medicine,
Loma Linda University Medical
Phoenix, AZ
Andy Jagoda, MD, FACEP
Center and Childrens Hospital,
Professor and Chair, Department
Loma Linda, CA
Madeline Matar Joseph,
of Emergency Medicine, Mount
MD, FAAP, FACEP
Michael J. Gerardi, MD, FAAP,
Sinai School of Medicine; Medical
Associate Professor of Emergency
FACEP
Director, Mount Sinai Hospital, New
Medicine and Pediatrics, Assistant
Clinical Assistant Professor of
York, NY

Editorial Board

August 2011

Gary R. Strange, MD, MA, FACEP


Professor and Head, Department
of Emergency Medicine, University
of Illinois, Chicago, IL
Christopher Strother, MD
Assistant Professor,Director,
Undergraduate and Emergency
Simulation, Mount Sinai School of
Medicine, New York, NY

FAAEM
Professor of Emergency Medicine
and Pediatrics; Chairman,
Adam Vella, MD, FAAP
Department of Emergency Medicine, Assistant Professor of Emergency
The University of Texas Houston
Medicine, Director Of Pediatric
Medical School, Houston, TX
Emergency Medicine, Mount Sinai
Robert Luten, MD
School of Medicine, New York, NY
Professor, Pediatrics and
Michael Witt, MD, MPH, FACEP,
Emergency Medicine, University of
FAAP
Florida, Jacksonville, FL
Medical Director, Pediatric

Ghazala Q. Sharieff, MD, FAAP,


Emergency Medicine, Elliot Hospital
FACEP, FAAEM
Manchester, NH
Associate Clinical Professor, Childrens
Hospital and Health Center/University Research Editor
of California, San Diego; Director
Lana Friedman, MD
of Pediatric Emergency Medicine,
Fellow, Pediatric Emergency
California Emergency Physicians, San
Medicine, Mount Sinai School of
Diego, CA
Medicine, New York, NY

Accreditation: EB Medicine is accredited by the ACCME to provide continuing medical education for physicians. Faculty Disclosure: Dr. Fullerton, Dr. Place, Dr. Dean, Dr. Joseph, Dr. Sharieff, Dr.
Whiteman, and their related parties report no significant financial interest or other relationship with the manufacturer(s) of any commercial product(s) discussed in this educational presentation.
Commercial Support: This issue of Pediatric Emergency Medicine Practice did not receive any commercial support.

mild tachycardia. Youre surprised by the severity of the


patients presentation and wish you were more familiar
with the types of von Willebrand disease.

Your next patient is an 18-month-old boy with
hemophilia brought to the ED after falling down 6 steps.
He has an occipital scalp hematoma but is otherwise well
appearing. His family is new to the area and does not have
a primary care provider currently.

Your colleague signs out a 4-year-old child with
presumed ITP who is receiving WinRho in room 7 in an
effort to manage the child on an outpatient basis. Shortly
after your colleague leaves, you are called to the room
because the patient has rigors and a temperature of 104F
(40C).

Society of Hematology (http://www.hematology.


org/PracticeGuidelines) and British Society for Hematology (http://www.bcshguidelines.com) were
consulted.

Although the body of literature examining the
risks and management of emergent bleeding disorders is large, published data is primarily from
case series and prospective and retrospective cohort
observational studies. Multiple consensus guidelines are available for more common disorders (eg,
hemophilia A and B, von Willebrand disease, and
ITP), but many of the recommendations are based
on expert opinion.1-11 (See Table 1.) While several
randomized controlled trials have compared specific therapies or compared an individual therapy to
observation or placebo,12-17 much of the data supporting individual therapies for hemophilia and von
Willebrand disease are derived from open-label prospective cohort studies. These outcome measures are
often subjective, such as the assessment of therapeutic response as excellent, good, or poor.18-43

Similar limitations may be found within the
body of evidence regarding management of ITP.
Investigations of ITP often use platelet count as a
surrogate marker of effective therapy. However, no
study adequately demonstrates a specific platelet
count that is directly correlated with bleeding risk
and clinical outcome. As with other bleeding conditions, the preponderance of the evidence is derived
from prospective cohorts and case series. A few welldesigned randomized trials have provided direct
comparisons between therapeutic options, but these
suffer from small sample sizes.44-52

Critical Appraisal Of The Literature


Ovid MEDLINE and PubMed were searched for
literature (published from 1960 to the present) on
bleeding disorders with a focus on pediatric patients. Terms used in the search included but were
not limited to: bleeding disorder, coagulation disorder,
ITP, idiopathic thrombocytopenia, immune thrombocytopenia, hemophilia, and von Willebrand disease. The
National Guideline Clearinghouse (www.guidelines.gov) and the Cochrane Database of Systematic
Reviews as well as the websites of the American

Table Of Contents
Abstract........................................................................ 1
Case Presentation.......................................................1
Critical Appraisal Of The Literature....................... 2
Epidemiology, Etiology, And Pathophysiology..... 2
Specific Bleeding Disorders...................................... 3
Coagulation Disorders.............................................. 3
Prehospital Care......................................................... 6
Emergency Department Evaluation........................ 6
Diagnostic Studies...................................................... 7
Therapy........................................................................ 9
Clinical Pathway: Emergency Department
Management Of Immune Thrombocytopenia.... 12
Clinical Pathway: Emergency Department
Management Of Hemophilia............................... 13
Clinical Pathway: Emergency Department
Management Of Hemophilia With Inhibitors.... 14
Clinical Pathway: Emergency Department
Management Of Von Willebrand Disease.......... 15
Risk Management Pitfalls In The Emergency
Treatment Of Bleeding Disorders....................... 17
Controversies/Cutting Edge.................................. 18
Cost-Effective Strategies.......................................... 18
Disposition................................................................ 19
Summary................................................................... 19
Case Conclusions..................................................... 19
References.................................................................. 20
CME Questions......................................................... 27
Pediatric Emergency Medicine Practice 2011

Epidemiology, Etiology, And


Pathophysiology
In healthy individuals, hemostasis is achieved by
intricate interrelated mechanisms involving the
vascular endothelium, platelets, and coagulation
factors. The coagulation cascade involves multiple
procoagulant proenzymes circulating in the blood.
These proenzymes are synthesized in the liver and,
in their active forms, help produce thrombin from its
precursor, prothrombin.

The clotting cascade is classically described as
consisting of extrinsic and intrinsic pathways, each
merging into a common pathway. The intrinsic pathway is triggered by contact between blood (factor
XII, kallikrein) and damaged subendothelium (collagen). Activated factor XII cascades through factor
XI and factor IX (with its cofactor, factor VIII) into
the common pathway, converting factor X into factor
Xa. Tissue factor, released by damaged endothelium,
initiates the extrinsic pathway by activating factor
VII, which in turn causes the conversion of factor X
to factor Xa.

In the common pathway, factor Xa (in conjunc2

ebmedicine.net August 2011

tion with its cofactor, factor V) converts prothrombin (factor II) to thrombin. Finally, thrombin cleaves
fibrinogen into fibrin monomers that assemble into
fibrin fibers. Thrombin also facilitates the release of
von Willebrand factor from circulating von Willebrand factor/factor VIII complex, making it available for platelet activation and aggregation. (See
Figure 1.)

When the vascular endothelium sustains an injury, von Willebrand factor is also secreted. Von Willebrand factor, synthesized in megakaryocytes and
endothelial cells, binds to platelet surface receptors
(Ib) and facilitates platelet activation and adhesion
to exposed subendothelial collagen matrix. Platelets
then undergo shape changes that allow GPIIb/IIIa
receptors on activated platelets to bind to fibrinogen,
resulting in a stable clot.

cause of isolated thrombocytopenia. While ITP is


defined as a platelet count of less than 100,000/mm3,
more than 50% of patients with ITP will present with
platelet counts below 20,000/mm3. Immune thrombocytopenia is thought to be the result of antibodymediated platelet destruction within the reticuloendothelial system (primarily in the spleen). More
recently, impaired platelet production and T-cellmediated platelet destruction have been recognized
as additional contributors.2
Children with ITP most often present with small
petechiae and bruising, but a lesser number may
also have mucosal bleeding such as epistaxis, bleeding from the mouth, or bleeding in the gastrointestinal tract. The number of children presenting with severe bleeding episodes requiring hospital admission
and/or blood transfusions during the first 28 days
of illness has been estimated to be as low as 2.9%.53
Intracranial hemorrhage is the feared complication of ITP, but it has a very low reported incidence
(0.19%-0.78%). Seventy-five percent of patients with
ICH have platelet counts below 10,000/mm3.54,55 The
incidence of ITP peaks around 2 to 5 years of age,
and data from case series demonstrates that over
70% of children with ITP will have recovered within
6 months.54,56-60

Specific Bleeding Disorders


Platelet Disorders
Platelet disorders can be divided into 2 main categories, quantitative thrombocytopenia and functional
platelet dysfunction. (See Table 2 on page 4.) Quantitative thrombocytopenia is defined as a platelet
count less than 150,000/mm3. Thrombocytopenia, in
turn, can be caused by decreased production or increased destruction of platelets. Platelet production
may be impaired by infection, nutritional deficiencies, malignancy, or from rare congenital (genetic)
disorders. Many of these conditions (eg, leukemia)
are associated with abnormalities in other cell lines.

Immune thrombocytopenia is the most common

Coagulation Disorders
Hemophilia
A deficiency of any component of the coagulation
cascade, congenital or acquired, can cause a bleeding
disorder. The most common inheritable conditions

Table 1. Consensus Guidelines For Treatment Of Hemophilia And Von Willebrand Disease
Expert Panel

Subject of Guideline

Website

National Heart, Lung,


and Blood Institute, von
Willebrand Disease
Expert Panel and the
American Society of
Hematology3

The diagnosis, evaluation, and management of


von Willebrand disease

http://www.nhlbi.nih.gov/guidelines/vwd/index.htm

United Kingdom
Haemophilia Center
Doctors Organization
(UKHCDO)5

Guideline on the selection and use of therapeutic


products to treat hemophilia and other hereditary bleeding disorders

http://www.ukhcdo.org/UKHCDOguidelines.htm

United Kingdom
Haemophilia Center
Doctors Organization
(UKHCDO)8

Guidelines for management of patients with


hemophilia A and inhibitors

http://www.ukhcdo.org/UKHCDOguidelines.htm

World Federation of
Hemophilia6

Protocols for the treatment of hemophilia and von


Willebrand disease

http://www.wfh.org/2/docs/Publications/VWD_WomenBleedingDisorders/TOH-14-Protocols-Hemophilia-VWD-Revised2008.pdf

Italian Association of
Haemophilia Centres7

Evidence-based recommendations on the treatment of von Willebrand disease in Italy

Website not available

Association of Hemophilia Clinic Directors of


Canada9

Guidelines for management of patients with


hemophilia A and inhibitors

http://www.ahcdc.ca/documents/InhibitorGuide2010.pdf

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Pediatric Emergency Medicine Practice 2011

are factor VIII deficiency (hemophilia A) and factor IX


deficiency (hemophilia B). These 2 X-linked disorders
have an incidence of 1:10,000 and 1:60,000, respectively.61 Congenital deficiencies of other coagulation
factors (fibrinogen, prothrombin, factor VII, factor
X, factor XI, factor XIII) are autosomal recessive and
are much less common.61 Subsequent discussion will
focus on factor VIII and factor IX deficiencies.

The severity of factor VIII and factor IX deficiencies is determined by the factor activity level: mild
(5%-40%), moderate (1%-5%), and severe (< 1%).62
Severe hemophilia comprises the largest group.63
In the newborn period, children with hemophilia
may present with ICH or with excessive bleeding
after circumcision or heel stick blood sampling.64-66
Children with severe hemophilia are more likely to
experience spontaneous hemarthroses, intramuscular hematomas, and difficult-to-control bleeding
from lacerations or oral lesions.

Most children experience their first significant
bleeding episode during the toddler years. One
prospective study of 37 children observed that approximately 44% of children with hemophilia had
their first bleeding episode of any type by the age
of 1 year and their first episode of hemarthrosis at a
mean age of 1.9 years.67 A retrospective analysis of
126 pediatric ED visits for hemophilia demonstrated
that 48% of visits were for soft-tissue hematomas,
24% for hemarthroses, and 12% for head injuries.68

Recurrent hemarthrosis is the most serious
chronic morbidity. Blood in the joint provokes
an intense inflammatory cascade that results in
synovial revascularization, enhanced vulnerability
to recurrent bleeding, and eventually, cartilage destruction. The ankle is the most commonly affected
joint in children, but other affected joints include
the knee, elbow, and shoulder. Prophylactic factor administration beginning at a young age is an
aggressive approach to interval treatment that has
significantly reduced the development of hemophilic arthropathy.

Intramuscular hematomas can be incredibly


painful and may result in significant neurovascular
morbidity (eg, compartment syndrome, nerve compression). Iliopsoas hematoma may be especially
difficult to diagnose, frequently mimicking acute appendicitis or hip pathology. Pain may be especially
severe if there is compression of the femoral nerve
or sacral plexus. Less common bleeding manifestations include hematuria, intracranial or intraocular
hemorrhage, gastrointestinal bleeding, or intestinal
hematoma.

Intracranial hemorrhage has exceeded HIV as
the leading cause of death in hemophilia patients.63
Intracranial hemorrhage can occur with or without
a history of trauma and is much more likely to occur in patients with severe hemophilia. In a French
study, only 62% of patients younger than 15 years
reported a history of trauma69; diagnosis was delayed in 43% of these patients, and treatment was
delayed in 37%. It is possible that spontaneous
ICH really represents minor, unrecognized trauma
from days before.69

Von Willebrand Disease


Although hemophilia is the most well-known coagulation disorder, von Willebrand disease is far more
common, with an estimated prevalence of 0.8% to
1.3% of the general population.70,71 In contrast to
hemophilia, mucocutaneous bleeding characterizes
von Willebrand disease.3 Patients with clinically
significant von Willebrand disease typically experience heavy menses, recurrent or prolonged epistaxis,
gingival or intraoral bleeding, easy bruising, and
post-procedural bleeding.72-74

Unlike many other coagulation factors, von Willebrand factor has no enzymatic activity. Von Willebrand factor is a large multimeric protein which
functions as a binding protein; it facilitates the binding of activated platelets to exposed subendothelial
collagen as well as platelet-to-platelet clumping
(through the glycoprotein Ib receptor). Von Wil-

Table 2. Platelet Disorders


Impaired Platelet Production

Platelet Destruction

Platelet Dysfunction

Infection with bone marrow suppression


(eg, HIV, parvovirus)
Leukemia
Nutritional deficiencies (eg, vitamin B12,
folate)
Medications (eg, NSAIDs, aspirin)
Congenital disorders (eg, Wiscott-Aldrich
syndrome, thrombocytopenia with absent
radius,)
Infection with bone marrow suppression
(eg HIV, parvovirus

Immune thrombocytopenia
Neonatal alloimmune thrombocytopenia
Sequestration from hypersplenism (eg, malaria)
Platelet consumption (eg, Kasabach-Meritt, disseminated intravascular coagulation, hemolyticuremic syndrome)
Medication (eg, heparin-induced thrombocytopenia, trimethroprim/sulfamethoxazole)

Platelet-vessel wall adhesion defects


(eg, Bernard-Soulier syndrome)
Platelet-platelet interaction defects
(eg, Glanzmanns thrombasthenia)
Acquired platelet dysfunction

Abbreviations: HIV, human immunodeficiency virus; NSAIDs, nonsteroidal anti-inflammatory drugs.

Pediatric Emergency Medicine Practice 2011

ebmedicine.net August 2011

lebrand factor also provides a critically important


function as a carrier protein for factor VIII, slowing
its otherwise rapid clearance from the blood.

Von Willebrand disease can be divided into 3
primary types. Autosomal dominant type 1 affects
about 75% of patients with von Willebrand disease.74
Heterozygous carriers have a mild quantitative
deficiency of von Willebrand factor, resulting in
mild-to-moderate mucocutaneous bleeding. These
patients may have such mild clinical manifestations
that they escape detection throughout their lives.
Type 2 von Willebrand disease consists of a collection of qualitative defects in von Willebrand factor
with variable bleeding severity. Patients with type
2N have impaired binding of von Willebrand factor
to factor VIII, resulting in clinical features similar
to hemophilia A due to rapid clearance of unbound
factor VIII from the blood stream. Type 3, the most
severe form of von Willebrand disease, is rare and
is characterized by an almost complete deficiency
of von Willebrand factor (and extremely low levels
of factor VIII), leading to severe bleeding complications, including ICH in up to 8% of patients.75,76

lungs, and intracranially. Intracranial hemorrhage


accounts for the relatively high morbidity and mortality associated with this condition.78 Late disease
may present between 2 to 12 weeks of age.77 Universal prophylactic neonatal vitamin K supplementation has virtually eliminated this disease except in
patients who decline or miss vitamin K administration for personal reasons such as home deliveries.79

Ingestion of warfarin may cause coagulopathy
by interfering with the hepatic production of vitamin K-dependent coagulation factors. In addition
to its therapeutic use as an anticoagulant, warfarin
and superwarfarins are also contained in commonly
used rodenticides; 87% of the reported 10,157 pediatric warfarin exposures in the United States in 2008
were secondary to rodenticide exposure.80 Fortunately, the majority of rodenticide exposures involve
minimal quantities that do not result in overt coagulation abnormalities.81

In contrast to liver failure, in which coagulation
factors are underproduced, DIC results from rapid
depletion by systemic activation of the coagulation
system. Most commonly associated with sepsis, DIC
can also be caused by a variety of insults, including
trauma, malignancy, Kasabach-Meritt syndrome,
and envenomations.82-86 Diffuse intravascular
thrombosis of small and mid-size vessels results in
end-organ damage and paradoxical hemorrhage
from massive consumption of coagulation factors.

Acquired factor inhibitors can result in a significant bleeding diathesis.87 IgG4 autoantibodies that
bind and inactivate factor VIII have been the most
studied and occur most commonly in patients who
receive multiple factor replacement infusions (which
are subsequently recognized as foreign antigens).88,89
Inhibitors may also be seen with autoimmune and
collagen vascular disease, malignancy, and viral
infection.87 Antibody formation to other coagulation
factors may also occur in acquired von Willebrand

Acquired Coagulopathies
A variety of conditions may result in secondary
(or acquired) coagulopathies, including vitamin K
deficiency, warfarin ingestion, liver disease, disseminated intravascular coagulation (DIC), and acquired
factor inhibitors. (See Table 3.)
Hemorrhagic disease of the newborn (HDN), a
result of severe vitamin K deficiency, is seen in the
neonatal period.77 Because vitamin K is essential for
the production of functioning coagulation factors
II, VII, IX, and X, vitamin K deficiency can cause a
severe bleeding diathesis. Newborns are at particular risk of vitamin K deficiency because they have
low stores of vitamin K and receive only minimal
amounts via breast milk. Bleeding can occur from
multiple sites within 2 to 5 days of delivery, including the umbilicus, mucus membranes, circumcision,

Table 3. Differential Diagnosis Of Common


Bleeding Disorders
Figure 1. Coagulation Cascade

Platelet Problems

Inherited Coagulation Disorder*

Acquired Coagulation Disorder

Thrombocytopenia
Platelet dysfunction

Hemophilia
A (factor VIII
deficiency)
Hemophilia
B (factor IX
deficiency)
Von Willebrand
disease
Fibrinogen
deficiency

Vitamin K deficiency
Toxic ingestions
(eg, warfarin)
Liver disease
Disseminated
intravascular
coagulopathy
Acquired factor
inhibitors

* Congenital gene mutations of any factor (including factors II, VII, VIII,
IX, X, XI, XII) in the coagulation cascade may result in phenotypic
expression as a coagulation disorder

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Pediatric Emergency Medicine Practice 2011

disease which is seen in patients with lymphoproliferative disorders, neoplasia (ie, Wilms tumor), and
autoimmune disorders.90,91

drug-induced thrombocytopenia in addition to


therapeutic anticoagulation. Presumably, patients
with toxic warfarin or rodenticide ingestion will
provide this information.
Current medical problems such as known
liver failure or renal insufficiency can help identify
patients at risk for bleeding diathesis. Immunodeficient patients are at risk for sepsis and DIC. Oozing
from umbilical or circumcision sites may be a clue to
severe vitamin K deficiency in neonates born outside
of the hospital. Any bite by an unidentified snake
should be considered to pose a risk of venom-mediated coagulopathy.
Identifying patients with a previously undiagnosed bleeding disorder who require further hematologic evaluation can be difficult. Children with recurrent, moderately severe epistaxis and normal labs
(ie, prothrombin time [PT]/partial thromboplastin
time [PTT]) and adolescent females presenting with
menorrhagia are potential candidates for a hematology referral and further work up. A history of heavy
or prolonged menses, easy bruising, or excessive
bleeding after dental procedures will help to guide
the emergency clinician towards subspecialty referral. Specific historical elements that are predictive of
a bleeding disorder are listed in Table 5.

Prehospital Care
Prehospital care of the patient with a bleeding disorder should focus on the management of life-threatening problems. Direct pressure should be placed on
lacerations or other sites of potential exsanguination,
and injured extremities should be immobilized. Ideally, prehospital providers will identify what therapeutic agents each individual patient might require
such as specific factor replacement products. This
information will expedite care in the ED, and many
patients are able to provide these products prior to
transport.

Emergency Department Evaluation


History
In a patient with a known bleeding disorder, it is
critical to accurately identify the disorder before administering therapeutic agents. This may seem selfevident, but a patients family may not be perfectly
clear about which factor is deficient. If a patient has
hemophilia, ask if they know which replacement
product they usually receive. They will often bring
their factor concentrate with them to the ED, since
many hematologists will prescribe doses of the proper replacement agent in advance.

Patients with bleeding disorders may present
with a wide variety of acute complaints. (See Table
4.) Spontaneous hemarthrosis is the most common
nontraumatic bleeding condition in hemophilia,
and initial premonitory symptoms are not clinically overt. Burning, tingling, or prodromal stiffness
should be taken seriously, should be considered
early evidence of joint hemorrhage, and should
prompt urgent factor replacement, regardless of the
clinical examination. Likewise, limb pain without
the clear presence of joint pathology should prompt
the consideration of intramuscular hematoma.
Iliopsoas (and retroperitoneal) bleeding can be difficult to diagnose clinically. Discomfort may mimic
acute appendicitis or renal colic with radiation to the
flank. Compression of the femoral or sacral nerve
plexus by iliopsoas hematoma may produce radicular radiation down the lower extremity.

Significant headache, even in the absence of
clear head trauma, must be taken seriously as ICH is
the number one life-threatening condition for hemophiliacs.

A careful medication history may identify
medicines such as aspirin or nonsteroidal anti-inflammatory drugs that can cause significant platelet
dysfunction in predisposed individuals. Current
or recent heparin administration is known to cause
Pediatric Emergency Medicine Practice 2011

Physical Examination
The initial focus in the patient with a known or
suspected bleeding disorder is on vital signs and
circulatory status. Tachycardia, with or without
hypotension, is a sign of hypovolemia and shock in
an actively bleeding patient. The presence of altered
mental status must be determined quickly to determine whether the patient has signs of advanced
shock or unrecognized ICH. Fever may be a clue to
underlying sepsis and DIC.
Patients with various bleeding disorders will ex-

Table 4. Common Acute Complaints

Complaint

Etiology

Abdominal or flank pain

Retroperitoneal bleeding, iliopsoas hematoma

Muscle pain

Intramuscular hematoma

Premonitory symptoms: warmth,


burning, stiffness or tingling
in joint

Hemarthrosis

History of minor head trauma,


altered mental status

Intracranial hemorrhage

Headache without trauma

Intracranial bleeding

Epistaxis

Anterior or posterior nosebleed

Bleeding from mouth

Bleeding from oral mucosa

Rash/skin problem

Petechiae, ecchymoses

Eye pain, visual changes

Intraocular bleeding

Back pain, weakness

Intraspinal hematoma

Dark urine

Hematuria

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perience complications that vary by system, identifiable on examination. A careful head and neurologic
examination is critical for any patient who has any
history of head injury or headache. Any external
evidence of head injury in the presence of altered
mental status or headache is of great concern.94
Additionally, altered mental status with a history of
minor head trauma, even with an otherwise normal
examination, should be considered ICH until proven
otherwise.94 For the patient with epistaxis, the location of bleeding (anterior versus posterior) should be
identified. For any patient with a suspected bleeding
disorder and history of trauma, any swelling in the
oropharynx or neck must be addressed immediately
because hemorrhage and expanding hematomas
may cause airway compromise.94
An abnormal pulmonary examination may be
due to pulmonary hemorrhage and is most likely
to be seen in entities such as HDN.78 The presence
of hepatosplenomegaly in a patient with thrombocytopenia suggests a diagnosis other than ITP.11
Abdominal tenderness and or distension may be
seen in such bleeding-related conditions as intestinal
hematoma or iliopsoas hematoma.94-96 However, it
is important to recognize that patients with coagulation defects can also suffer from more common
conditions, such as acute appendicitis.94
The presence of swollen or tender joints or
muscles or pain with range of motion suggests the
presence of hemarthrosis or muscular hematoma.68
Pain elicited with movement of the extremity but
without visible joint effusion is suggestive of muscular hematoma. However, a normal examination
should not dissuade the clinician from providing
factor replacement for hemarthrosis in children with
suggestive complaints. Pain with hip extension without concurrent, equivalent pain with hip rotation
suggests iliopsoas hematoma rather than pathology
within the hip joint.64

The skin examination may provide clues as
to the presence of a coagulation defect in patients
without a preceding formal diagnosis. Petechiae
(pinpoint, unraised, round, non-blanching, red spots
under the skin) suggest platelet problems such as
thrombocytopenia or platelet dysfunction.2,60 In

well-appearing patients, purpura (small palpable


hemorrhages in the skin) may be indicative of a vasculitic disorder (eg, Henoch-Schnlein Purpura) but
may also be found with platelet problems such as
ITP.2 Large ecchymoses or prolonged bleeding from
lacerations and abrasions are more commonly noted
in patients with coagulation defects such as von
Willebrand disease or hemophilia. In ill-appearing
patients, the diagnosis of possible severe sepsis and
DIC must be aggressively pursued.

Diagnostic Studies
It is important to initiate therapy in patients with
acute symptoms and not wait for diagnostic studies.
Replacement therapy should be rapidly administered prior to sending the patient for radiographic
studies.

Laboratory Testing
Laboratory testing in the ED must focus on tests that
produce results quickly and inform the emergent
management of the patient. In the ED, this generally
means a complete blood count (CBC) with peripheral smear, PT and activated partial prothromboplastin
time (aPTT), and type and screen (when indicated).3

A CBC will determine whether a quantitative
platelet problem is present. Of note, ethylenediaminetetraacetic acid (EDTA)-related pseudothrombocytopenia can occur when blood samples from
predisposed individuals are stored with EDTA.97,98
This phenomenon has no in-vivo clinical significance
except that it may misdirect the unaware practitioner.
The hemoglobin and hematocrit will provide evidence
of anemia and also establish a baseline for a patient
with ongoing bleeding. In actively bleeding patients,
values may lag behind clinical severity and should
be interpreted with care.1 Abnormalities in more than
1 cell line may indicate the presence of a malignancy
such as leukemia or lymphoma, even in the absence of
diagnostic blasts on the peripheral smear.2

The PT and aPTT will test for gross abnormalities in the coagulation pathways. (See Table 6 on
page 8.) Isolated elevation of the aPTT is the sine
qua non of hemophilia; functional defects of the
intrinsic arm of the coagulation cascade, proximal to
the common pathway, will manifest as an elevated
aPTT in the face of a normal PT. Both factor VIII
and factor IX deficiencies should demonstrate this
pattern. Less commonly, isolated elevation of the PT
suggests an abnormality of the extrinsic pathway,
such as factor VII. Simultaneous elevation of both
tests suggests a defect in the common pathway such
as factors II and X or severe derangements in the entire coagulation cascade, such as DIC. Patients with
DIC will often have alterations in other tests such as
a platelet count of < 100,000/mm3 and the presence
of fibrin-degradation products.99

Table 5. Historical Predictors Of Potential


Bleeding Disorder3,88,89








Presence of bleeding disorder in a family member


Abnormal bleeding after trauma (not including birth)
Post-surgical bleeding
Prolonged bleeding after tooth extraction
Menorrhagia
Prolonged bleeding after circumcision
Cephalohematoma at time of birth
Hematuria (macroscopic or microscopic)
History of transfusions, recent chemotherapy

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Pediatric Emergency Medicine Practice 2011


A type and screen should be sent on any patient
with a suspected or known bleeding disorder who
may require a transfusion of blood products. In
patients with ITP, Rh testing is necessary in patients
who might receive anti-Rho(D) antibodies as part of
their treatment. Further testing including renal function tests, liver function tests, and thyroid function
tests may be useful to determine causes of bleeding
disorders such as uremia, liver failure, and thyroid
disease.100 Fibrinogen and fibrinogen degradation
product tests are part of the DIC panel. A urine
analysis may be useful to confirm suspected microscopic or macroscopic hematuria.

Additional testing, including a von Willebrand
disease screen (consisting of factor VIII levels, von
Willebrand factor antigen and ristocetin cofactor
assay [ristocetin mediates von Willebrand factorplatelet binding in vitro]) may be useful to facilitate
diagnosis. Additionally, hematologists may request
evaluation for the presence of factor inhibitors in
patients who do not have the expected response to
therapy. However, these tests will not be available at
the time of the visit and should only be ordered in
consultation with a hematologist who can interpret
and follow-up results.

der or swollen limb.



Sonography may be useful when evaluating
a patient with a bleeding disorder and suspected
intraocular hemorrhage, hemarthrosis, and/or
soft-tissue hematomas.102,103 Although not specifically studied in hemophilia, ultrasonography allows
for noninvasive and rapid assessment of vitreous
hemorrhage.104,105 Ultrasonography can also be used
to identify joint effusions (eg, hip) and provides an
alternative to computed tomography (CT) scan for
the evaluation of patients with potential iliopsoas
hemorrhage, although data on this subject is limited
to case series and retrospective reviews.95,96
A CT scan is an excellent modality to assess iliopsoas hemorrhage or other retroperitoneal lesions
and may be necessary when ultrasound findings are
equivocal or unavailable.106,107 A CT scan of the abdomen/pelvis should be considered in any patient
with a bleeding disorder and lower abdominal or
hip pain.
The diagnosis of ICH in children with bleeding
disorders can be facilitated by a CT scan. However,
in the well-appearing child with a normal examination, there are no clear guidelines on when a head
CT is clinically indicated. Even among pediatric
hematologists, there is wide variation regarding the
use of head CT imaging for a well-appearing hemophiliac who has sustained a minor head injury.108
One retrospective cohort of 97 pediatric patients
with hemophilia (A and B) found that of 295 head
CT scans performed for minor head injury, 9 cases
of ICH were identified; a lack of symptoms and a
normal neurologic examination did not exclude
ICH.109 Another review of 43 patients followed over
9 years, with 73 presentations of patients suspected
to have ICH upon arrival in the ED, demonstrated
4 risk factors for ICH: severe phenotype, absence
of maintenance prophylaxis, presence of a factor
inhibitor, and altered level of consciousness at presentation.110 In particular, the authors found that the
absence of altered consciousness had a 98% negative
predictive value for ICH (67% positive predictive
value). Unfortunately, these findings have not been
confirmed in other patient groups and have not been
reproduced prospectively. In the ED, a conservative
approach should be taken: after emergent factor
replacement, a CT scan should always be performed
on patients with any neurologic examination abnormality or alteration in consciousness, with strong
consideration for imaging children with hemophilia
who present with minor head injury. The threshold
for what constitutes a severe enough minor head
injury to warrant imaging is obviously a matter of
clinical judgment.
Also, because of the susceptibility to spontaneous or traumatic ICH, a head CT should be performed on any patient with ITP, low platelets, and
headache with abnormal neurologic examination,

Radiologic Testing
While joint radiographs may demonstrate chronic
changes of hemophilic arthropathy, such as joint
space narrowing, epiphyseal overgrowth, and widened intercondylar notches, they are unnecessary in
the acute management of spontaneous hemarthrosis.
While hemarthrosis should be treated clinically,101
radiographs may help to differentiate acute fracture
from hemarthrosis or muscular hematoma in a ten-

Table 6. Interpretation Of PT And aPTT


Results
PT and aPTT

Specific Bleeding
Disorders

Coagulation Pathway

Normal PT
Normal aPTT

Von Willebrand
disease, platelet
function problem

Not a problem with


coagulation cascade

Normal PT
# aPTT

Factor deficiency
(VIII, IX, XI, or XII),
lupus anticoagulant

Intrinsic pathway

# PT

Factor VII deficiency

Extrinsic pathway

DIC, sepsis, liver


disease, KasabachMerritt syndrome,
heparin, factor
deficiency (II, V,
X), fibrinogen deficiency

Both intrinsic and


extrinsic pathways or
common pathway

Normal aPTT

# PT
# aPTT

Abbreviations: DIC, disseminated intravascular coagulation; PT, prothrombin time; aPTT, activated partial prothromboplastin time

Pediatric Emergency Medicine Practice 2011

ebmedicine.net August 2011

and/or minor head injury. One case-control study


and several case series and retrospective analyses
have been performed that examine risk for ICH.55,111114
Psaila et al conducted a nationwide survey over
13 years and estimated a population-based incidence
of ICH of 0.19% to 0.78%.55 Of the children with
ICH, 90% had platelet counts less than 20,000/mm3,
and 75% had platelet counts less than 10,000/mm3.55
Any concomitant bleeding other than petechiae
and ecchymosis was predictive of ICH. A retrospective investigation performed by Elalfy et al of 1840
patients with ITP identified 10 cases of ICH. Of these
10 patients, 7 had platelet counts of less than 1,000/
mm3.112 Only 1 patient had a history of head trauma.
A second retrospective analysis by Choudhary et al
of 750 patients with ITP, aged 10 months to 18 years,
identified 17 cases of ICH.113 Only 4 cases were precipitated by head trauma. The median platelet count
in these patients was 12,000/mm3 (range: 2000/mm3
- 50,000/mm3).
Magnetic resonance imaging should be used to
assess suspected spinal epidural hematomas in patients with hemophilia but only after factor replacement is given.94,115-18 Magnetic resonance imaging
is also excellent for detecting abnormal changes
associated with hemarthroses but is not indicated for
this purpose in the emergency setting.101,119

disease, both factor VIII and von Willebrand factor is


often given, but other adjuncts such as intravenous
or intranasal desmopressin and epsilon aminocaproic
acid are also commonly administered.

Historically, cryoprecipitate and FFP were the
first products used to replace coagulation factors and
treat hemophilia A and B, respectively. Beginning in
the 1970s, prothrombin complex concentrates (PCCs)
were developed to treat hemophilia B but were also
useful for replacement of other vitamin K dependent
factors (II, VII, IX, and X). A relatively high risk of
thrombosis dampened enthusiasm for its use.120
Plasma-derived, specific factor concentrates
were then developed as an effective therapy for hemophiliacs requiring factor VIII or IX replacement.
Prior to contemporary screening methods, many
patients contracted hepatitis C and HIV. However,
current virucidal techniques and donor screening
have minimized the risks of viral transmission from
human plasma-derived products.121-3
Recombinant clotting factors are now the most
commonly used products for replacement therapy
in hemophiliacs because of their efficacy and superior safety profile. Recombinant products are now
recommended as first-line therapy for patients with
hemophilia A and B requiring factor VIII or factor IX
replacement.5,6
Three generations of recombinant factor VIII
(rFVIII) have been developed with continued improvement in purity and risk of infection. The first
generation used human serum albumin for stabilization. The second-generation products were albuminfree and did not include the B-domain of the factor
VIII gene. Third generation recombinant factor
concentrates do not contain any human or animal
proteins in the manufacturing process or final preparation. Multiple prospective open-label investigations have demonstrated that recombinant products
are efficacious and do not cause more inhibitor
formation than plasma-derived factor replacement
products.12,18-24,124
Historically, PCCs were used for factor IX
replacement. Subsequently, plasma-derived factor IX concentrates were developed and found to
be much less thrombogenic than PCCs.13,25-7,125127
Over the past few decades, the purity of the
factor IX concentrates has improved greatly; high
purity and ultrapure products are now available.
However, as with factor VIII deficiency, these
have given way to recombinant factor IX (rFIX),
which is just as efficacious as plasma-derived
products and also eliminates any risk of infectious disease transmission.5,28-31

Therapy
Emergent Therapy For Congenital Bleeding
Disorders
Emergency management of hemorrhage for patients with a congenital bleeding disorder centers on
increasing the circulating levels of deficient clotting
factors. This discussion focuses on the treatments of
factor VIII and IX deficiencies and von Willebrand
disease. Many clinical trials have been performed, but
almost all of these are open-label and non-randomized. In addition, no head-to-head comparisons of the
most commonly used therapeutic agents have been
published. In a large number of studies examining
factor replacement products, the primary outcome
was the investigators (subjective) assessment of
whether the patients response was excellent/good.
Several guidelines based on evidence and expert
consensus have been published to assist with the
management of hemorrhage in patients with congenital bleeding disorders.3-7 All of these guidelines highlight that rapid correction of deficient clotting factors
is tantamount. Specific replacement products should
be used if available and are discussed in the following
section. If unavailable, cryoprecipitate (for factor VIII
deficiency) or fresh frozen plasma (FFP) (for factor IX
deficiency) may be used as a last resort. The goal of
factor replacement is generally considered to be 40%50% for minor bleeds and 80%-100% for major hemorrhages.6 For patients with severe von Willebrand
August 2011 ebmedicine.net

Principles Of Factor Replacement In


Hemophilia
Treatment of hemophilia revolves around using the
safest product available in the quantity necessary to
9

Pediatric Emergency Medicine Practice 2011

effectively control the bleeding condition and minimizing further morbidity. Depending on the condition, this may range from a single infusion in the ED
for mild hemarthrosis to a continuous infusion in the
intensive care unit for intracranial bleeding.
Factor replacement for hemophilia is dosed on a
unit per kilogram basis; 1 unit is considered to be the
amount of clotting activity found in 1 mL of normal
plasma. Dosing differs somewhat between factor
VIII and factor IX deficiency.
One unit/kilogram of factor VIII concentrate
will increase factor VIII activity by 2%; therefore,
to achieve 100% correction, 50 U/kg must be
administered.6
One unit/kilogram of factor IX concentrate will
only increase factor IX activity by 1%; therefore,
twice as much factor IX must be administered
for the same effect: 100 U/kg are necessary to
achieve 100% correction.6
These dosing guidelines are accurate only in the
absence of an inhibitor.
The opposite relationship exists in terms of the
timing of redosing between these 2 factors. Factor VIII has a half-life of 8 to 12 hours and needs
to be dosed twice as frequently (about every 12
hours) as factor IX, which has a longer half-life
of about 24 hours.6

hematologist can), but the presence of an undiagnosed inhibitor should be suspected when patients
fail to respond to routine therapy.
Until recently, the only option was to use large
doses of factors VIII and IX to overwhelm inhibiting antibodies. Currently, recombinant activated
factor VII (rFVIIa) (Novoseven) and activated
prothrombin complex concentrates (aPCCs) (factor eight inhibitor bypass activity [FEIBA]) are
available.136 A Cochrane Review comparing rFVIIa
concentrate with aPCCs found no difference in
effectiveness between the 2 products and no difference in safety as defined by tolerability and clotting
complications.15,137 Two studies of the economic
impact of FEIBA versus rFVIIa use found that the
cost per episode when treating acute bleeding and/
or peri-operative prophylaxis was less with the use
of FEIBA than with rFVIIa.138,139
In the United States, rFVIIa is currently approved
for the treatment of bleeding episodes in hemophiliacs (A or B) with inhibitors and patients with congenital factor VII deficiency. Several prospective openlabel multi-center trials (study sample sizes ranging
from 15 to 84 patients) have investigated the ideal
dosing of rFVIIa, and a wide range of effective bolus
doses were found; continuous and bolus interval dosing were found to be equivalent.140-143 See Table 7 for
FDA-approved dosing recommendations.144
Several investigations of rFVIIa in patients with
inhibitors in hemophilia have demonstrated that
rFVIIa is effective in the treatment of intracranial
and extracranial hemorrhage.145-7 Recombinant
activated factor VII is also effective therapy for
limb-threatening and severe abdominal bleeding in
patients with inhibitors.148-50 Off-label use of rFVIIa
includes treatment of patients with massive bleeding without a bleeding disorder.151 In addition,
case reports suggest that patients with severe von
Willebrand disease with inhibitors or refractory to
standard treatment may also benefit from the use of
rFVIIa.152-3
Factor eight inhibitor bypass activity, an
activated prothrombin complex concentrate, is an
alternate bypassing agent for patients with hemophilia and inhibitors. Unlike rFVIIa, FEIBA is a
pooled blood product and has a small risk of disease
transmission. Factor eight inhibitor bypass activity
is approved for the control of spontaneous bleeding
episodes or presurgical prophylaxis in patients with
hemophilia A and B and inhibitors.154 Recommended dosing ranges from 50 to 100 units/kg every 12
hours. Dosing should continue until signs of clinical
improvement are achieved. Several retrospective
and one open-label prospective cohort trial found
that 81% to 93% of bleeding episodes achieved
excellent/good hemostasis with FEIBA.33,34,155,156
In 2010, the FDA added a black box warning for
FEIBA emphasizing the risk of thrombotic and


Factor concentrate does not come in predefined
doses; each lot will have the number of units listed
on the vial. An important principle in the administration of factor concentrate is to round up the dose
so as not to waste factor from a partially used vial.6

Bypassing Agents: Treatment Of Patients


With Factor Inhibitors
Patients with hemophilia can develop inhibitory
antibodies to factor replacement products, rendering these products ineffective and complicating the
management of acute bleeding disorders.8,9,128,129
These IgG4 antibodies bind and inactivate circulating factor. The degree of inhibition is measured in
Bethesda units, where one unit decreases factor activity by 50%. An estimated 3.6% to 17.5% of patients
with hemophilia (A or B) have inhibitors.130 A population study of 3435 hemophilia patients in France
found that for all patients with hemophilia A, 7%
had inhibitors but for patients with severe disease,
12.8% had inhibitors.130 In the same study, inhibitors
were found in 2% of all patients with hemophilia B
and 4% of patients with severe disease.130 Of note,
the presence of inhibitors in patients with hemophilia B may be associated with a risk of anaphylaxis.129
Multiple variables increase an individuals likelihood of developing inhibitors, including earlier age
at first exposure, use of prophylaxis, and frequency
of factor use.131-135 Most patients with inhibitors
should be able to provide this information (or their
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Adjunct Therapies

thromboembolic events similar to other aPCCs as


discussed previously. Factor eight inhibitor bypass
activity is contraindicated for patients with a
known normal coagulation (ie, a non-hemophiliac
with traumatic hemorrhage), for the treatment of
bleeding episodes from coagulation factor deficiencies in the absence of inhibitors, and in patients with
DIC.157

Desmopressin (DDAVP, Stimate, Minirin) has


been used since the late 1970s as an adjunct therapy
for patients with both mild hemophilia A (ie, with
some residual endogenous VIII activity) and von
Willebrand disease.164 (See Table 8 on page 16.) Desmopressin, a synthetic analog of vasopressin, stimulates the release of von Willebrand factor and factor
VIII from storage sites in the vascular endothelium,
thus allowing many patients with minor bleeding
episodes to avoid blood products and/or costly
factor replacement infusions.165,166 Desmopressin
is most effective for patients who have measurable
levels of von Willebrand factor and factor VIII, and
it can be administered via intravenous, intranasal,
and subcutaneous routes.17,36,37,167,168 (Subcutaneous desmopressin is not currently available in the
US.) Individual responses are quite variable, and
many hematologists will conduct a desmopressin
challenge to determine whether a patient with von
Willebrand disease or mild hemophilia is responsive
to desmopressin therapy.7,169 These results should
guide ED management.

In responsive patients, desmopressin will cause
a 3- to 5-fold rise in factor levels, peaking at 30 to
60 minutes for intravenous infusions and 90 to 120
minutes for intranasal administration. The plasma
half-life is 5 to 8 hours for stimulating the release of
factor VIII and 8 to 10 hours for von Willebrand factor.165 A common mistake is to substitute DDAVP
nasal spray for Stimate nasal spray (both are desmopressin products), but the products have different
concentrations and are not interchangeable. Stimate is administered by intranasal spray (150 mcg
intranasally for patients < 50 kg, 300 mcg for patients > 50 kg). Intravenous desmopressin is dosed at
0.3 mcg/kg intravenously over 30 minutes. Patients
often experience tachyphylaxis from repeated dosing
within short time intervals.38 Adverse effects include
tachycardia, flushing, cramping, headache, nausea,
vomiting, and a risk of significant hyponatremia if

Factor Replacement Products For Von


Willebrand Disease
Some patients with more severe von Willebrand
disease (or mild disease with more severe bleeding
episodes) will require infusions of specific factor
replacement products. Depending on the type of von
Willebrand disease, these patients are often deficient
in functioning factor VIII as well as von Willebrand
factor. In contrast to patients with hemophilia, for
which the products of choice are usually of high
purity, concentrates containing von Willebrand factor continue to be plasma-derived. In the US, the 3
most commonly used combination products with
factor VIII and von Willebrand factor are HumateP, Alphanate, and Wilate.158-160 Each product
contains different concentrations of factor VIII and
von Willebrand factor; therefore, dosing is calculated
in the units of von Willebrand factor ristocetin cofactor (RCo) and is best determined by consulting the
package insert.

Evidence supporting the use of factor VIII/von
Willebrand factor concentrates consists of multiple
prospective and retrospective cohort analyses, but
there have been no direct comparisons of the efficacy
of the 3 products currently available in the US.3943,161-3
Factor VIII/von Willebrand factor replacement therapy is recommended for significant bleeding events or major surgery for patient with types 2
and 3 von Willebrand disease and patients with type
1 von Willebrand disease who are unresponsive to
desmopressin.3

Table 7. Dosing Recommendations For Inhibitor Bypassing Agents


Bypassing Agent

Type Of Hemorrhage

Initial Dose

Notes

Recombinant
activated factor VII
(rFVIIa)

Mild/moderate bleed

90 mcg/kg every 2 hours

Until hemostasis achieved or response judged to be inadequate144

Severe bleed

90 mcg/kg every 2 hours

Continue dosing at 3 to 6 hour intervals after hemostasis achieved to


maintain the hemostatic plug

Joint

50 units/kg every 12 hrs

May increase to 100 units/kg/dose

Mucous membrane

50 units/kg every 6 hrs

May increase to 100 units/kg as needed (max 200 units/kg/day)

Soft tissue (severe)

100 units/kg every 12 hrs

Maximum 200 units/kg/day

Central nervous system

100 units/kg every 12 hrs

May increase to every 6 hours dosing interval

Factor eight inhibitor


bypass activity
(FEIBA)

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Pediatric Emergency Medicine Practice 2011

Clinical Pathway: Emergency Department Management Of Immune


Thrombocytopenia
Immune thrombocytopenia*

Thrombocytopenia without
evidence of moderate/severe
hemorrhage

History and Physical: no hepatosplenomegaly


Laboratory tests: Complete blood count, reticulocyte count
peripheral smear, type and screen (Rh)

ED management of stable patient


with immune thrombocytopenia

Platelets < 20,000/mL and mucous membrane bleeding or <


10,000/mL and minor purpura

Strongly consider admission (Class III) for monitoring of


symptoms and side effects [at least 8 hours for Rho(D)]

Platelets > 20-30,000/mL and


asymptomatic or minor purpura
only

Choose one of the following therapies

Discharge home with close followup and observation

Thrombocytopenia with life- or


organ-threatening hemorrage

ED management of unstable
patient with immune thrombocytopenia

Platelet transfusions (Class III) 2


to 3 times usual amount
Give intravenous immunoglobulin,
methylprednisolone, or Rho(D)
concurrently (Class II-III)

Bleeding not
controlled

Intravenous
immunoglobulin
(Class II)
0.8-1g/kg IV

If Rh+,
intravenous
Rho(D) (Class
II)
50-75 mcg/
kg x 1

Prednisone
(Class II)
1-2 mg/kg/day
by mouth x 14
days or 4 mg/
kg/day by mouth
x 3 days

Emergent
splenectomy
(Class III)

Bleeding
controlled

Admit to intensive care unit

*These actions should be taken in consultation with a hematologist

Class Of Evidence Definitions


Each action in the clinical pathways section of Pediatric Emergency Medicine Practice receives a score based on the following definitions.
Class I
Always acceptable, safe
Definitely useful
Proven in both efficacy and
effectiveness

Level of Evidence:
1 or more large prospective
studies are present (with rare
exceptions)
High-quality meta-analyses
Study results consistently positive and compelling

Class II
Safe, acceptable
Probably useful

Level of Evidence:
Generally higher levels of
evidence
Non-randomized or retrospective studies: historic, cohort, or
case control studies
Less robust RCTs
Results consistently positive

Class III
May be acceptable
Possibly useful
Considered optional or alternative treatments

Level of Evidence:
Generally lower or intermediate
levels of evidence
Case series, animal studies,
consensus panels
Occasionally positive results

Indeterminate
Continuing area of research
No recommendations until
further research

Level of Evidence:
Evidence not available
Higher studies in progress
Results inconsistent, contradictory
Results not compelling
Significantly modified from: The
Emergency Cardiovascular Care
Committees of the American
Heart Association and represen-

tatives from the resuscitation


councils of ILCOR: How to Develop Evidence-Based Guidelines
for Emergency Cardiac Care:
Quality of Evidence and Classes
of Recommendations; also:
Anonymous. Guidelines for cardiopulmonary resuscitation and
emergency cardiac care. Emergency Cardiac Care Committee
and Subcommittees, American
Heart Association. Part IX. Ensuring effectiveness of communitywide emergency cardiac care.
JAMA. 1992;268(16):2289-2295.

This clinical pathway is intended to supplement, rather than substitute for, professional judgment and may be changed depending upon a patients individual
needs. Failure to comply with this pathway does not represent a breach of the standard of care.
Copyright 2010 EB Medicine. 1-800-249-5770. No part of this publication may be reproduced in any format without written consent of EB Medicine.

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Clinical Pathway: Emergency Department Management Of Hemophilia

Hemophilia*

No inhibitors

Known inhibitors

Suspected hemorrhage:
CNS, abdominal/GI tract,
compartment syndrome,
ocular trauma or unstable vital signs?

See Clinical Pathway on


page 14.

YES

NO

ED management of
unstable patient

ED management of
stable patient

Minor bleeding: renal, oral, nasal, intramuscular


(except iliopsoas), or lacerations

Suspected
Hemarthrosis

Factor replacement to
100% physiological
level before imaging

Factor replacement to
100% physiological
level**

Factor replacement to
50% physiological level

Hemophilia A

Hemophilia B

Hemophilia A

Hemophilia B

rFVIII (Class II) 50 IU/kg

rFIX or high purity FIX


(Class II) 100-150 IU/
kg***

rFVIII (Class II) 25 IU/kg

rFIX or high purity FIX


(Class II) 50-75 IU/
kg***

Bleeding controlled?

Diagnostic imaging and consider admission to intensive


care unit.

NO
*These actions should be taken in consultation with a hematologist.
**For pediatric patients. For adults, factor replacement is to 50%.
***Consult package insert for product-specific dosing.
See page 12 for Class of Evidence definitions.

Actions to consider:

Replace factor to
100%

Desmopressin
(Class II) if pretested

Amicar (Class III)

Admission if bleeding uncontrolled

Abbreviations: CNS, central nervous system; GI, gastrointestinal.

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13

YES

Discharge with close


follow-up with hematologist.

Pediatric Emergency Medicine Practice 2011

Clinical Pathway: Emergency Department Management


Of Hemophilia With Inhibitors
Hemophilia with inhibitors

Mild bleeding**

Inhibitor level < 5 BU/


mL***

Low responder***

High dose rFVIII (Class


III) or FEIBA (Class III)
or rFVIIa (Class III)

Severe life- or limb-threatening bleeding

Inhibitor level > 5 BU/


mL***

Inhibitor level < 5 BU/


mL***

Inhibitor level > 5 BU/


mL***

Unconfirmed but suspected inhibitors

High responder***

FEIBA (Class II) or


rFVIIa (Class III)

High dose rFVIII (Class


III) or FEIBA (Class III)
or rFVIIa (Class III)

FEIBA (Class III) or rFVIIa (Class III) or plasmapheresis and rFVIII (Class III)

Bleeding well controlled?

YES

NO

Discharge home with


close follow-up with
hematologist

Admit for further management

Consider admission to intensive care unit.

*These actions should be taken in consultation with a hematologist. Consider inhibitors in patients
who do not respond as expected to traditional factor replacement.
**For patients with mild Hemophilia A and mild bleeding. DDAVP may be a useful first-line therapy.
***Low responders are patients with inhibitor levels < 5 BU/ml and do not develop an amnestic
response following exposure to FVIII.
See page 12 for Class of Evidence definitions.
Abbreviation: BU, bethesda unit.

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Clinical Pathway: Emergency Department Management


Of Von Willebrand Disease
Von Willebrand disease*

History and physical and


initial stabilization

Type 2B, 2N, or 3 von


Willebrand disease?
NO

YES

Cryoprecipitate
(Class III)****

Only if concentrate
not available

FVIII concentrate rich in


von Willebrand factor**
(Class II)

Major life- or organthreatening bleeding?

YES

NO

Major life- or organthreatening bleeding?

NO

YES

Admit to intensive care


unit.

Bleeding controlled?
NO

Desmopressin (Class II)



Intravenous: 0.3 mcg/kg

Intranasal (Stimate*):

1 spray: age > 5
years, weight <
50 kg

2 sprays: age >
5 years, weight >
50 kg

YES
Adjunct therapies***
Amicar (Class III)
Topical thrombin
(Class III)

Bleeding well
controlled

Bleeding not controlled

Admission
Consider: FVIII with von
Willebrand factor infusion

Discharge home with close follow-up


with hematologist

*These actions should be taken in consulatation with a hematologist.


**Use home supply if possible; use entire vial. Examples of FVIII concentrate with von Willebrand factor are Humate P, Koate DVA, Alphanate SD, and Wilate. See package inserts for product specific dosing.
***Adjunct therapies may be administered at same time as replacement products or desmopressin.
****Amount of von Willebrand factor and FVIII in cryoprecipitate is variable (at least 80 IU/bag of FVIII). Dosing is based on FVIII component.
See page 12 for Class of Evidence definitions.

August 2011 ebmedicine.net

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Pediatric Emergency Medicine Practice 2011

subsequent water intake is not carefully monitored


(particularly in younger children).170,171

Anti-fibrinolytic therapies such as epsilon-aminocaproic acid (EACA)Amicarare often used
as adjuncts to factor replacement in both hemophilia
and von Willebrand disease. This agent inhibits
plasminogen and has antiplasmin activity, aiding in
initial hemostasis and preventing rebleeding, particularly orally, where enzymatic activity produces an
inherently fibrinolytic environment.172 Amicar can
be dosed as follows: loading dose 100 to 200 mg/
kg (maximum 10 grams) followed by a maintenance
dose of 50 to 100 mg/kg (maximum 5 grams) orally
every 6 hours.173

Epsilon-aminocaproic acid has been studied extensively for perioperative use in patients without
bleeding disorders and to a lesser extent in patients
with bleeding disorders.174,175 Two case series determined that EACA may be useful in patients with
hemophilia with inhibitors and may have an antiinhibitor effect separate from its anti-fibrinolytic
action.176,177

In addition, topical thrombin or fibrin glue is
often used concomitantly for local control.6 The evidence supporting their use is also based primarily
on case series.178-180

cally significant bleeding, such as ICH, is low with


platelet counts above 10,000 to 20,000/mm3 but is
obviously devastating when it occurs.

The 3 standard therapies for the treatment of ITP
are glucocorticoids, intravenous immune globulin
(IVIG), and Rho(D) immune globulin [Rho(D)], each
with different safety and efficacy profiles which are
discussed in detail below. Most patients with severely depressed platelet counts will be hospitalized
for initiation of therapy.
Glucocorticoids
Historically, low dose oral steroids served as firstline therapy for ITP. Glucocorticoids have the
advantage of lower cost and excellent safety profile
when compared to other therapies. However, in
recent years, with the advent of IVIG and Rho(D),
many hematologists deem glucocorticoids to be a
second-line therapy. Prednisone (1-2 mg/kg/day)
was continued until the platelet count recovered
(but not necessarily normalized). Multiple investigators conducting unblinded, randomized clinical
trials have determined that glucocorticoids are more
efficacious than placebo in improving platelet counts
during the first week of therapy.181-187 For patients
with life-threatening bleeding and platelets less than
50,000/mm3, high dose oral prednisone (4-8 mg/
kg/day) or intravenous methylprednisolone 10 to 30
mg/kg/day should be administered.188

Steroids should never be started unless the
diagnosis is unequivocal (and this diagnosis should
probably be made by a hematologist). Any features
that are inconsistent with this diagnosis, such as
hepatosplenomegaly (more than one affected cell
line) or the presence of systemic symptoms such
as fever, necessitate a bone marrow biopsy prior to
the introduction of steroids. The risk of introducing steroids in patients with an equivocal diagnosis
is masking and delaying diagnosis of malignancy.
Adverse effects of systemic glucocorticoids are not
benign and include hypertension, behavioral abnormalities, and hyperglycemia.172

Emergent Therapy For Immune


Thrombocytopenia
The vast majority of patients with isolated, severe
thrombocytopenia suffer from ITP. Unlike oncology
patients where transfusions compensate for profoundly inhibited platelet production, therapy for
ITP is focused on interrupting ongoing platelet destruction by the reticuloendothelial system, as noted
earlier in this review.

The primary goal of therapy is not simply to
increase the platelet count; rather, the specific purpose of medical intervention is to prevent bleeding
complications. Therefore, decision thresholds for
intervention depend on these risks. A 2010 International Consensus Report published in the journal
Blood recommends that management of pediatric
patients with ITP be based on the severity of their
symptoms.10 (See Table 8.) However, specific criteria
are largely based on expert consensus. Most authorities recommend instituting therapy for a platelet
count below 10,000 to 20,000/mm3. The risk of clini-

Intravenous Immune Globulin


It is believed that IVIG works by flooding Fc receptors on macrophages in the reticuloendothelial system, eliminating their ability to secure and destroy
opsonized platelets. Intravenous immunoglobulin is

Table 8. Adjunct Agents


Route of Administration

Initial Dose

Infusion Time

Peak Effect

Intravenous desmopressin

0.3 mcg/kg

30 min

30-60 minutes

Intranasal Stimate (150 mcg/spray)

1 spray if weight < 50 kg


2 sprays if weight > 50 kg

N/A

90-120 minutes

Oral Amicar (epsilon-aminocaproic


acid)

100 to 200 mg/kg (max 10 g/dose or 30 g/day)

N/A

45-99 minutes

Pediatric Emergency Medicine Practice 2011

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ebmedicine.net August 2011

equivalent or slightly superior to glucocorticoids at


rapidly increasing platelet counts.181,183-186,189 Standard dosing is 0.8 to 1 g/kg as a single dose (which
may be repeated on subsequent days). Case series in
the 1980s first demonstrated that IVIG can effectively raise platelets (average 50,000/mm3) within 1 to 5
days of administration.190-191 A single meta-analysis
examining data pooled from 10 randomized clinical trials found that glucocorticoids may in fact be
inferior to IVIG with a 0.74 relative ratio of achieving
a platelet count of 20,000/mm3 at 48 hours (number
needed to treat = 4.55).189 The most common side effects of IVIG include fever, nausea, and vomiting.181
These adverse effects can be minimized with premedication with acetaminophen and diphenhydramine. Like other pooled blood products, a theoretical risk of infectious disease transmission exists.


Case series and randomized controlled trials
have both suggested that intravenous Rho(D) is
as effective as IVIG in increasing platelet counts in
patients with ITP.193-6 However, these same studies
found that Rho(D) may cause more significant adverse effects. Rho(D) may produce fever, profound
chills, and acute intravascular hemolysis.197-200
Similarly to IVIG, minor adverse effects of Rho(D)
can be minimized with pre-medication with acetaminophen and diphenhydramine. Post-licensure
surveillance has identified cases of hemolysis resulting in profound anemia requiring transfusions and
hemoglobinuria with renal failure and death.197-199
Although these were rare occurrences (1.5% estimated incidence rate), the severity of the events led the
FDA to add a black box warning to WinRho SDF
in 2010.200 Patients receiving Rho(D) must be closely
monitored for at least 8 hours after administration,
effectively eliminating this as a therapeutic option in
the ED.

Rho(D) Immune Globulin


Rho(D) immune globulin (WinRho SDF) acts by
coating Rh-positive red blood cells, which then provide
competitive interference of reticuloendothelial Fc
receptors, inhibiting platelet sequestration. (There is a
predictable 1 to 2 g/dL decline in hemoglobin levels over the subsequent 2 weeks). Therefore, Rho(D)
is only useful in Rh-positive patients who have not
undergone splenectomy.192 Recommended dose of intravenous Rho(D) is 50 to 75 mcg/kg for a single dose.2

Platelet Transfusions
Rarely, patients with ITP may require intervention
to immediately address active hemorrhage. Previously mentioned therapies merely halt ongoing
destruction and rely on the bone marrow to replace
and increase platelet levels. With clinically significant bleeding (eg, ICH), functional platelets must be

Risk Management Pitfalls In The Emergency


Treatment Of Bleeding Disorders
1. Management without the hematologist. Initiating treatment and workup without consulting
the hematologist results in errors and wasted
resources.
2. Waiting for the hematologist before doing
anything. Even though involvement of the hematologist is critical for these uncommon conditions, waiting for the consultant before initiating
therapy simply allows the condition to progress.
3. Confirming intracranial bleeding before initiating therapy. Treat first; image second.
4. Guessing which factor to give. (The family
may say I think it is B.) Make sure that you
are clear what the patients condition is before
initiating therapy
5. Basing treatment solely on physical examination. If a hemophiliac has discomfort in a joint,
it must be treated before progression to visible
findings.
6. Excessive ED management. Rho(D) and transfusions are best left for inpatient management
unless clinical condition warrants emergent
therapy.
7. Desmopressin is for pretested patients only,
August 2011 ebmedicine.net

8.
9.
10.
11.

12.

17

not the condition itself. Some patients are nonresponders, and therapy should be based on
these results.
Empirically starting steroid therapy for ITP.
Just because you can does not mean that you
should.
Failure to recognize vitamin K deficiency as a
cause of bleeding in the neonate.
With anticoagulant ingestions, treat the patient, not the number.
Disregarding the possibility of a bleeding condition with a normal PT/PTT. Von Willebrand
disease is the most common congenital bleeding
condition and will typically present with normal
screening labs.
Obtaining spurious lab values secondary to
testing error. Patients who have heparinized
indwelling central lines will have elevated PT/
PTT values if the sample blood is drawn from
the line. The laboratory must be instructed to
conduct the test with heparin neutralization. In
addition, coagulation test values may be falsely
elevated if insufficient blood volume is placed in
the sample tubes.
Pediatric Emergency Medicine Practice 2011

Controversies/Cutting Edge

provided immediately, with doses as high as 2 to 3


times normal required to achieve a goal of 100,000/
mm3.2,54,201,202 Due to ongoing platelet destruction,
repeated platelet boluses (or even continuous therapy) may be required until bleeding is controlled.
A recent international consensus guideline also recommends concurrently administering intravenous
methylprednisolone (30 mg/kg; maximum 1 g) and
IVIG (0.8-1 g/kg).10,203

Recombinant activated factor VII is only approved


for use in patients with hemophilia. Because of its
utility as a general hemostatic agent, many physicians are using rFVIIa for off-label purposes, including treatment of hemorrhage associated with
acquired coagulopathies associated with hepatic
failure, DIC, and surgery as well as bleeding associated with prematurity, malignancies, and trauma.210-216 The increasing use of rFVIIa for off-label
purposes was demonstrated by a 2010 multicenter
cohort investigation of 4942 patients that determined
that 74% of patients given rFVIIa were being treated
for off-label indications.210 In the pediatric literature, multiple retrospective analyses and case series
demonstrate that rFVIIa given for massive bleeding
in non-hemophiliac children decreases the need for
blood product administration but is associated with
a significant risk of thrombotic events.211-216

Emergent Splenectomy
Splenectomy is a therapy of last resort for ITP and is
rarely performed emergently.2 Multiple case reports
have demonstrated successful treatment of refractory hemorrhage with emergency splenectomy,
but no controlled trials have been conducted.204-209
Although an effective method of increasing platelet
counts, splenectomy has many potentially serious
complications, including hemorrhage, infection,
thrombosis, prolonged hospitalizations and death.209

Cost-Effective Strategies
1. Routine labs, such as factor levels or a PT/
PTT, in patients with a known coagulopathy
are generally unnecessary. Most patients with
congenital bleeding disorders who present to the
ED are already diagnosed. Laboratory evaluation simply documents what is already known
and consumes unnecessary time and resources.
Unless requested by the hematologist, laboratory studies prior to providing factor concentrate
is generally unnecessary.
2. Factor II levels and a bleeding time are not appropriate testing in the ED. There are a plethora
of tests that can be ordered in patients with a
suspected but undiagnosed bleeding condition.
Beyond the basic screening tests listed above,
targeted testing is best left to the hematologist.
Tests for suspected bleeding conditions, even
one as common as von Willebrand disease, can
be difficult to interpret and are best left to the
specialist. Simply ordering tests to be helpful
and get things started do not improve the timeliness, accuracy, or efficiency of the evaluation.
3. Diagnostic radiographs provide no significant
clinical information in hemophiliacs without
a history of trauma. Spontaneous hemarthroses
are exceedingly common in patients with severe
hemophilia (most hemophiliacs) and x-rays
merely document chronic changes and acute
effusions, neither of which aid in the clinical
management.
Pediatric Emergency Medicine Practice 2011

4. Ordering a type and cross where a type and


screen should be sufficient. It is common to
reflexively order a type and cross when patients
present with a bleeding condition. It is much
more expensive than a type and screen and frequently unnecessary. Avoid ordering a type and
cross unless transfusion is a likely intervention.
5. Use the patients own medications when
possible. Most patients have a supply of their
condition-specific factor and will bring it to the
ED. Using this factor will reduce errors and
will minimize the theoretical risk of increasing
inhibitors with changes in brands of factor.
6. Consider outpatient observation for patients
with low but not dangerous platelet levels
in ITP. Bleeding risk is threshold related. All
patients with ITP do not need admission, only
those at significant risk of life-threatening complications in need of immediate therapy. These
patients will require prompt (1-3 day) follow-up
with a hematologist.
7. Attempt to use adjunct therapy where appropriate before moving on to factor concentrate.
Patients with minor bleeding (oral lesions,
epistaxis) and mild hemophilia A or von Willebrand disease may benefit from adjuncts such
as Amicar or desmopressin without the need
for expensive factor concentrate.

18

ebmedicine.net August 2011

Disposition

asymptomatic or have only minor purpura can be


safely discharged and may not require any treatment
other than repeated laboratory monitoring.11

Hemophilia And Von Willebrand Disease


All patients with a bleeding disorder and clinically
significant or uncontrolled hemorrhage require admission. Patients with hemophilia or von Willebrand
disease and central nervous system bleeding (intracranial or intraspinal), neck injury (tracheal hemorrhage, retropharyngeal hemorrhage), gastrointestinal
or intra-abdominal hemorrhage, suspected compartment syndrome, nerve compression, ocular trauma
(hyphema or vitreous hemorrhage), or severe epistaxis requiring packing and ENT consultation must
be admitted for either continuous or repeated dosing
of factor replacement and monitoring.

The factor replacement goal in all hemophiliacs
with these diagnoses is 100% (not to drop below
50%).94 As stated previously, the half-lives of rFVIII and rFIX are 8 to 12 hours and 18 to 24 hours,
respectively. Patients with von Willebrand disease
who have these types of hemorrhages will also
require admission for repetitive dosing of desmopressin and/or von Willebrand factor/FVIII replacements. Some experts recommend that activity levels
for von Willebrand factor/RCo and FVIII must be
monitored closely with an initial target of 100 IU/dl
and a trough above 50 IU/dL for at least 7-10 days;3
however, other hematologists will follow the clinical
response of the patient instead.

In consultation with the hematologist, patients
with hemophilia or von Willebrand disease who
have well-controlled, non-life threatening hemorrhage usually can be discharged with plans for close
follow-up. Conditions that are often managed on an
outpatient basis include epistaxis, bleeding from the
oral mucosa, small intramuscular hematomas, and
hemarthroses. Some of these patients may require
repeat factor administration on an outpatient basis.

Summary
Children with bleeding disorders frequently present to the ED with a wide variety of complaints
ranging from minor to life threatening. Much of the
morbidity and mortality associated with bleeding
disorders can be prevented by early and aggressive
recognition and intervention. Critical interventions
should be initiated based on the history alone, prior
to the advent of physical examination abnormalities and prior to obtaining diagnostic studies. With
knowledge of the basic evidenced-based principles
of emergency management outlined in this article,
the emergency clinician will be able to successfully
identify and intervene in the emergent presentations
of bleeding disorders.

Case Conclusions
You do a quick literature search of von Willebrand disease
and realize that this patient has a severe type of von Willebrand disease that has no circulating von Willebrand
factor and almost no FVIII. Therefore, her epistaxis will
not likely respond to desmopressin (the most commonly
used therapy in von Willebrand disease). In consultation
with a hematologist, you administer a Humate-P infusion along with the adjunct therapy of oral Amicar. You
pack the nose with gauze and have the mother hold direct
pressure on the area. Approximately 30 minutes later,
all bleeding has stopped. A CBC demonstrates that your
patient now has mild anemia, but her tachycardia resolves
with a normal saline bolus.

You again consult with the hematologist and decide
to send the patient home after several hours of observation, with oral Amicar to be taken every 6 hours and
instructions to follow-up in the hematologists office
tomorrow.

Next, you take care of the 18-month-old boy with
hemophilia and scalp hematoma. While simultaneously
questioning the family and doing a quick physical assessment of the patient, you determine that the patient has
severe hemophilia A. He does not have any known inhibitors. Other than the scalp hematoma, he has a normal
physical examination and, at this time, does not show any
alteration in mental status or neurologic abnormalities.
The family does not think that the patient has a history of
inhibitors, and although they do not have a primary care
provider currently, they did bring a vial of his rFVIII with
them to the ED. You administer 50 IU/kg of rFVIII immediately. A non-contrast CT scan of the brain demonstrates
a small epidural hematoma. You consult neurosurgery
and hematology and transfer the patient to the pediatric
intensive care unit.

Finally, you can focus on the 4-year-old with ITP

Immune Thrombocytopenia
Hospital admission is generally reserved for patients
at risk of clinically significant bleeding.11 All patients with severe, life-threatening bleeding must be
admitted to an intensive care setting. Patients with
platelet counts of < 20,000/mm3 and mucous membrane bleeding or patients with platelet counts of
less than < 10,000/mm3 and minor purpura require
medical therapy with IVIG, Rho(D), or steroids and
are usually admitted for parental medication administration and monitoring.
Discharged patients should have reliable families who have received teaching regarding signs and
symptoms of bleeding and a physician available to
give advice at all times. They must be instructed regarding the avoidance of non-steroidal anti-inflammatory drugs, and the children may not participate
in contact sports or high impact activities. In general,
patients with platelet counts > 30,000/mm3 who are
August 2011 ebmedicine.net

19

Pediatric Emergency Medicine Practice 2011

receiving Rho(D). You realize this patient is most likely


experiencing intravascular hemolysis from the Rho(D)
that is being administered. You recognize that this is a
potentially severe complication of Rho(D) administration
and stop the infusion immediately. Prior to the Rho(D)
administration, you had sent a type and screen to the lab,
but you now send a type and cross because transfusions of
packed red blood cells may be necessary if hemolysis continues. You emergently notify the hematologist and administer a normal saline bolus. The patient is transferred
to the pediatric intensive care unit for close monitoring of
clinical status, hemolytic anemia, and renal function.

10.

11.

12.

References

13.

Evidence-based medicine requires a critical appraisal of the literature based upon study methodology and number of subjects. Not all references are
equally robust. The findings of a large, prospective,
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To help the reader judge the strength of each
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149. Liebman HA, Chediak J, Fink KI, et al. Activated recombinant human coagulation factor VII (rFVIIA) therapy for

24

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abdominal bleeding in patients with inhibitory antibodies to


factor VIII. Am J Hematol. 2000 Mar;63(3):109-113. (Prospective, open-label, cohort; 8 patients)
150. Lusher, JM. Acute hemarthroses: the benefits of early versus
late treatment with recombinant activated factor Vii. Blood
Coagul Fibrinolysis. 2000 Apr;11 Supl:S45-9. (Retrospective;
223 hemarthroses)
151. Hay CR, Negrier C, Ludlam CA. The treatment of bleeding
in acquired haemophilia with recombinant factor VIIa: a
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(Prospective cohort, 28 patients)
152. Ciaverella N, Schiavoni M, Valenzano E, et al. Use of
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two patients with type III von Willebrands disease and an
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153. Friederich PW, Wever PC, Briet E, et al. successful treatment
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156. Smejkal SP, Brabec P, Matyskova M, et al. FEIBA in treatment
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157. FDA Letter to healthcare Professionals. Important Drug
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163. Thompson AR, Gill JC, Ewenstein BM, et al. Successful treatment for patients with von Willebrand disease undergoing
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165. Mannucci PM. Desmopressin (DDAVP) in the Treatment
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patients with mild and moderate hemophilia A and von Willebrands disease to treatment with desmopressin. Ann Intern
Med. 1985 Jul;103(1):6-14. (Prospective; 68 patients)
167. Revel-Vilk S, Blanchette VS, Sparling C, et al. DDAVP challenge tests in boys with mild/moderate haemophilia A. Br J
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168. Gill JC, Ottum M, Schwartz B. Evaluation of high concentration intranasal and intravenous desmopressin in pediatric
patients with mild hemophilia A or mild-to-moderate type
1 von Willebrand disease. J Pediatr. 2002 May;140(5):595599. (Prospective with comparison to historical cohort; 25
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responses to repeated DDAVP infusions in patients with
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170. Dunn AL, Powers JR, Ribeiro MJ, et al. Adverse events during use of intranasal desmopressin acetate for haemophilia
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40 patients. Haemophilia. 2000 Jan;6(1):11-14. (Case report; 1
patient and Retrospective; 40 patients)
171. DDAVP desmopressin acetate solution. Package insert.
Sanofi-Aventis U.S. LLC. (Package insert)
172. Amicar? (Aminocaproic acid). Package insert. Xanodyne
pharmaceuticals, Inc. Rev 09/08 Code 909A00. (Package
insert)
173. Gill JC: Diagnosis and treatment of von Willebrand disease.
Hematol Oncol Clin North Am 2004;18(6):1277-99. (Review)
174. Djulbegovic B, Hannan MM, Bergman GE. Concomitant
treatment with factor IX concentrates and antifibrinolytics in
hemophilia B. Acta Haematol. 1995(94) Suppl 1:43-7. (Retrospective; 19 patients)
175. Djulbegovic B, Marasa M, Pesto A, et al. Safety and efficacy
of purified factor IX concentrate and antifibrinolytic agents
for dental extractions in hemophilia B. Am J Hematol. 2996
Feb;51(2):168-170. (Prospective; 8 patients)
176. Ghosh K, Shetty S, Pathare A, et al. Epsilon-aminocaproic
acid inhibits the activity of factor VIII inhibitors in patients
with severe haemophilia A in vivo an in vitro. Acta Haematol.
2000;103(2):67-72. (Prospective, 6 patients)
177. Ghosh K, Shetty S, Jijina F, et al. Role of episilon amino
caproic acid in the management of haemophilic patients with
inhibitors. Haemophilia. 2004 Jan;10(1):58-62. (Prospective; 10
patients)
178. Rakocz M, Mazar A, Varon D, et al. Dental extractions in
patients with bleeding disorders. The use of fibrin glue. Oral
Surg Oral Med Oral Pathol. 1003 Mar;75(3):280-282. (Prospective; 80 patients)
179. Federici AB, Sacco R, Stabile F, et al. Optimising local
therapy during oral surgery in patients with von Willebrand
disease: effective results from a retrospective analysis of 63
cases. Haemophilia. 2000 Mar;6(2):71-77. (Retrospective, 63
patients)
180. Yilmaz D, Akin M, Ay Y, et al. A single centre experience in
circumcision of haemophilia patients: Izmir protocol. Haemophilia. 2010 Nov ;16(6):888-91. (Retrospective; 50 patients)
181. Blanchette VS, Luke B, Andrew M, et al. A prospective,
randomized rial of high-dose intravenous immune globulin
G therapy, oral prednisone therapy, and no therapy in childhood acute immune thrombocytopenic purpura. J Pediatr.
1993 Dec;123(6):989-995. (Prospective, randomized, openlabel, clinical trial; 53 patients)
182. Bellucci S, Charpak Y, Chastang C, et al. Low doses versus
conventional doses of corticoids in immune thrombocytopenic purpura (ITP): results of a randomized clinical trial
in 160 children, 223 adults. Blood. 1988 Apr;71(4):1165-1169.
(Prospective, randomized, open-label clinical trial; 383
patients)
183. Imbach P, Wagner HP, Berchtold W, et al. Intravenous immunoglobulin versus oral corticosteroids in acute immune

25

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thrombocytopenic purpura in childhood. Lancet. 1985 Aug


31;2(8453):464-468. (Prospective, randomized, open-label
clinical trial; 108 patients)
184. Ozsoylu S, Sayli TR, Ozturk G. Oral megadose methylprednisolone versus intravenous immunoglobulin for acute
childhood idiopathic thrombocytopenic purpura. Pediatr
Hematol Oncol. 1993 Oct-Dec;10(4):317-321. (Prospective,
randomized, open-label clinical trial; 20 patients)
185. Albayrak D, Islek I, Kalayci AG, et al. Acute immune
thrombocytopenic purpura: a comparitive study of very
high oral doses of methylprednisolone and intravenously administered immune globulin. J Pediatr. 1994
dec;125(6pt1):1004-1007. (Prospective, randomized, openlabel clinical trial 57 patients)
186. Blanchette V, Imbach P, Andrew M, et al. Randomised trial of
intravenous immunoglobulin G, intravenous anti-D and oral
prednisone in childhood acute immune thrombocytopenic
purpura. Lancet. 1994 Sep 10;344(8924)703-707. (Prospective,
randomized, open-label clinical trial; 146 patients)
187. Buchanan GR, Holtkamp CA. Prednisone therapy for children with newly diagnosed idiopathic thrombocytopenic
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Winter;6(4):355-361. (Prospective, randomized, placebocontrolled clinical trial; 27 patients)
188. De Mattia D, Del Principe D, Del Vecchio GC, et al. Acute
childhood idiopathic thrombocytopenic purpura: AIEOP
consensus guidelines for diagnosis and treatment. Haematologica. 2000;85:420-424. (Expert opinion and consensus
guidelines)
189. Beck CE, Nathan PC, Parkin PC, et al. Corticosteroids versus
intravenous immune globulin for the treatment of acute
immune thrombocytopenic purpura in children: a systematic
review and meta-analysis of randomized controlled trials. J
Pediatr. 2005 Oct;147(4):521-527. (Systematic review)
190. Bussel JB, Goldman A, Imbach P, et al. Treatment of acute
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infusions of gammaglobulin. J Pediatr. 1985 Jun;106(6):886890. (Prospective; 29 patients)
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(Prospective; 7 patients)
192. Scaradavou A, Woo B, Woloski BM, et al. Intravenous anti-D
treatment of immune thrombocytopenic purpura: experience
in 272 patients. Blood. 1997 Apr 15;89(8);2689-2700. (Prospective; 261 patients)
193. Tarantino MD, Madden RM, Fennewald DL, et al. Treatment
of childhood acute immune thrombocytopenic purpura
with anti-D immune globulin or pooled immune globulin. J
Pediatr. 1999 Jan;134(1):21-26. (Retrospective; 33 patients)
194. Tarantino MD, Young G, Bertolone SJ, et al. Single dose of
anti-D immune globulin at 75 microg/kg is as effective as
intravenous immune globulin at rapidly raising the platelet
count in newly diagnosed immune thrombocytopenic purpura in children. J Pediatr. 2006 Apr;148(4):489-494. (Prospective, randomized clinical trial; 105 patients)
195. Kane I, Ragucci D, Shatat IF, et al. Comparison of intravenous immune globulin and high dose anti-D immune
globulin as initial therapy for childhood immune thrombocytopenic purpura. Br J Haematol. 2010 Apr;149(1):79-83.
(Retrospective; 53 patients)
196. El Alfy MS, Mokhtar GM, El-Laboudy MA, et al. Randomized trial of anti-D immunoglobulin versus low-dose
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trial; 34 patients)
197. Gaines AR. Acute onset hemoglobinemia and/or hemoglobinuria and sequelae following Rh(o)(D) immune globulin
intravenous administration in immune thrombocytopenic

Pediatric Emergency Medicine Practice 2011

purpura patients. Blood. 2000 Apr 15;95(8):2523-2529. (Retrospective case series; 15 patients)
198. Rubinstein PG, Chen YH. Delayed hemolysis after intravenous ant-D immune globulin infusion in a patient with
idiopathic thrombocytopenic purpura. Am J Hematol. 2008
Aug;83(8):684-685. (Case report)
199. Gaines AR. Disseminated intravascular coagulation associated with acute hemoglobinemia or hemoglobinuria following Rho(D) immune globulin intravenous administration for
immune thrombocytopenic purpura. Blood. 2005;106:15321537. (Retrospective case series; 6 patients)
200. FDA U.S. Food and Drug Administration. Safety warning:
WinRho SDF (Rho(D) Immune Globulin Intravenous (Human): Risk of Intravascular Hemolysis. 3/10/10. (Safety
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201. Carr JM, Kruskall MS, Kaye JA, et al. Efficacy of platelet
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202. Salama A, Kiesewetter H, Kalus U, et al. Massive platelet
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Thromb Haemost. 2008 Nov;100(5):762-765. (Prospective, 10
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203. Spahr JE, Rodgers GM. Treatment of immune-mediated
thrombocytopenia purpura with concurrent intravenous
immunoglobulin and platelet transfusion: a retrospective
review of 40 patients. Am J Hematol. 2008 Feb;83(2):122-125.
(Retrospective; 40 patients)
204. Zerella JT, Martin LW, Lampkin BC. Emergency splenectomy
for idiopathic thrombocytopeni purpura in children. J Pediatr
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205. Jacobs P, Wood L. Emergency surgery and refractory immune thrombocytopenic purpura. A case report. S Afr Med J.
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206. Wanachiwanawin W, Piankijagum A, Sindhvananda K, et al.
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207. Gural A, Gillis S, Gafanovich A, et al. Massive intracranial
bleeding requiring emergency splenectomy in a patient with
CMV-associated thrombocytopenia. Haemostasis. 1998 SepOct;28(5):250-255. (Case report; 1 patient)
208. Pastore Y, Wacker P, Ozsahin H, et al. Emergency splenectomy in the management of intracranial hemorrhage in childhood immune thrombocytopenic purpura. J Pediatr Hematol
Oncol. 1999 Jul-Aug;21(4):306-307. (Case report; 1 patient)
209. Kojouri K, Vesely SK, Terrell DR, et al. Splenectomy for adult
patients with idiopathic thrombocytopenic purpura: a systematic review to assess long-term platelet count responses,
prediction of response, and surgical complications. Blood.
2004 Nov 1;104(9):2623-2634. (Retrospective; 135 patients)
210. Witmer CM, Huang YS, Lynch K, et al. Offlabel recombinant factor VIIa use and thrombosis in children: A Multi-center Cohort Study. J Pediatr. 2010 Dec 9. [epub ahead of print]
(Retrospective cohort; 3764 patients)
211. Hong I, Stachnik J. Unlabeled uses of factor VIIa (recombinant) in pediatric patients. Am J Health Syst Pharm. 2010 Nov
15;67(22):1909-1919. (Review)
212. Alten JA, Benner K, Green K, et al. Pediatric off-label use of
recombinant factor VIIa. Pediatrics. 2009 Mar;123(3): 10661072. (Retrospective case series; 135 patients)
213. Chuansumrit A, Teeraratkul S, Wanichkul S, et al. Recombinant-activated factor VII for control and prevention of
hemorrhage in nonhemophilic pediatric patients. Blood
Coagul Fibrinolysis. 2010 Jun;21(4):354-362. (Retrospective;
103 patients)
214. Young G, Wicklund B, Neff P, et al. Off-label use of rFVIIa
in children with excessive bleeding: a consecutive study of
153 off-label uses in 139 children. Pediatr Blood Cancer. 2009
Aug;53(2):179-183. (Retrospective)

26

ebmedicine.net August 2011

3. According to this article, severe vitamin K deficiency may lead to which of the following:
a. Hemorrhagic disease of the newborn
b. Bone loss
c. Vision loss
d. Low birth weight

215. Yilmaz D, Karapinar B, Balkan C, et al. Single-center experience: use of recombinant factor VIIa for acute life-threatening bleeding in children without congenital hemorrhagic
disorder. Pediatr Hematol Oncol. 2008 Jun;25(4):301-311.
(Retrospective; 13 patients)
216. Hsia CC, Chin-Yee IH, McAlister VC. Use of recombinant
activated factor VII in patients without hemophilia: a
meta-analysis of randomized controlled trials. Ann Surg.
2008;248(1):61-68. (Systematic review)

4. Emergency clinicians should always use the


hospitals supply of a therapeutic agent instead
of one the patient brought from home.
a. True
b. False

CME Questions
Take This Test Online!

5. Patients with bleeding disorders may present


with which of the following complaints:
a. Abdominal or flank pain
b. Muscle pain
c. Headache without trauma
d. All of the above

Current subscribers receive CME credit absolutely


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6. Which of the following statements are true


with regards to low-dose oral steroids as
therapy for immune thrombocytopenia?
a. They have an excellent safety profile.
b. They cost more than other therapies.
c. With the advent of IVIG and Rho(D), they

are now considered second-line therapies by

many hematologists.
d. Both A and C

1. According to this article, the 2 main categories


of platelet disorders are:
a. Quantitative thrombocytopenia and

functional platelet dysfunction
b. Inherited and acquired
c. Immune and active
d. Emergent and chronic

7. All patients with a bleeding disorder and clinically significant or uncontrolled hemorrhage
require admission.
a. True
b. False

2. According to this article, the most common


inheritable bleeding conditions are:
a. FVIII deficiency (hemophilia A) and FIX

deficiency (hemophilia B)
b. Fibrinogen and prothrombin deficiency
c. FVII deficiency and FXIII deficiency
d. FX deficiency and FXI deficiency

August 2011 ebmedicine.net

27

Pediatric Emergency Medicine Practice 2011

Coming Soon In Pediatric Emergency


Medicine Practice

An Evidence-Based Approach to
Pediatric Carbon Monoxide Poisoning
Author:
Abby M. Williams, MD
Department of Pediatrics, Division of Pediatric
Emergency Medicine, Monroe Carell Jr.
Childrens Hospital at Vanderbilt, Nashville, TN
Carbon monoxide (CO) is an odorless, colorless
gas released from the incomplete combustion
of burning hydrocarbons. CO has been called a
great imitator and silent killer. CO poisoning
is the most common preventable toxic exposure
resulting in death in children 12 years and
younger. In this age group, it is typically an
accidental poisoning. In adolescents, especially
males, CO poisoning may be intentional. It
has also been described as a form of child
abuse by caregivers. Finally, there has been
some evidence that there is a a link between
CO poisoning and sudden unexpected infant
death syndrome (SUIDS); however, one study
retrospectively reported no association in a
series of 50 infants who died unexpectedly.
Further evaluation is necessary to elucidate
a link between SUIDS and CO poisoning.
CO poisoning is frequently associated with
inhalation injuries. When associated with a
thermal burn, it is easier to recognize a carbon
monoxide exposure. However, CO poisoning
may go unrecognized and undetected leading
to morbidity and mortality. Patients with CO
poisoning often present to the emergency
department with a constellation of non-specific
symptoms. Furthermore, CO poisoning is not
detectable on routine drug screens. The clinician
must pay close attention to the details of the
history and have a low index of suspicion in
order to avoid missing this potentially lethal
exposure. This issue of Pediatric Emergency
Medicine Practice is an evidence-based review
of the diagnosis and management of patients
with CO poisoning.

Physician CME Information


Date of Original Release: August 1, 2011. Date of most recent review: July 10, 2010.
Termination date: August 1, 2014.
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Target Audience: This enduring material is designed for emergency medicine physicians,
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Goals: Upon reading Pediatric Emergency Medicine Practice, you should be able to: (1)
demonstrate medical decision-making based on the strongest clinical evidence; (2) costeffectively diagnose and treat the most critical ED presentations; and (3) describe the
most common medicolegal pitfalls for each topic covered.
Objectives: Upon completion of this article, you should be able to: (1) communicate
intelligently with the hematology consultant about patients with hematological conditions
in the ED; (2) manage common bleeding complications in patients with hemophilia; (3)
be familiar with various factor concentrate products and their use; (4) identify and begin
the appropriate evaluation for suspected, previously undiagnosed bleeding conditions,
including immune thrombocytopenic purpura; and (5) recognize less common conditions
associated with coagulopathy.
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