Download Hemophilia And Von Willebrand Disease In Children: Emergency

Hemophilia And Von Willebrand
Disease In Children: Emergency
Department Evaluation And
Management
Abstract
Adam E. Vella, MD, FAAP
Associate Professor of Emergency
Medicine, Pediatrics, and Medical
Education, Director Of Pediatric
Emergency Medicine, Icahn School
of Medicine at Mount Sinai, New
York, NY
Associate Editor-in-Chief
Vincent J. Wang, MD, MHA
Associate Professor of Pediatrics,
Keck School of Medicine of USC;
Associate Division Head, Division
of Emergency Medicine, Children's
Hospital Los Angeles, Los Angeles,
CA
Editorial Board
Jeffrey R. Avner, MD, FAAP Professor of Clinical Pediatrics
and Chief of Pediatric Emergency
Medicine, Albert Einstein College
of Medicine, Children’s Hospital at
Montefiore, Bronx, NY
Steven Bin, MD
Associate Clinical Professor,
Division of Pediatric Emergency
Medicine, UCSF Benioff Children’s
Hospital, University of California,
San Francisco, CA
Richard M. Cantor, MD, FAAP,
FACEP
Professor of Emergency Medicine
and Pediatrics, Director, Pediatric
Emergency Department, Medical
Director, Central New York Poison
Control Center, Golisano Children's
Hospital, Syracuse, NY
Volume 12, Number 9
Authors
Kevin R. Schwartz, MD
Instructor of Pediatrics, Harvard Medical School, Department of
Pediatrics and Department of Emergency Medicine, Massachusetts
General Hospital, Boston, MA
Max Rubinstein, MD
Department of Pediatrics, Massachusetts General Hospital, Harvard
Medical School, Boston, MA
Peer Reviewers
Hemophilia and von Willebrand disease are the most common inherited bleeding disorders encountered in the emergency department.
Evidence suggests that the management of bleeding disorders in
the emergency department is currently suboptimal, and literature to
guide evaluation and management in this setting is limited, though
some guidelines do exist. The emergency clinician must have a high
index of suspicion for new diagnoses, particularly in young patients
with unprovoked bleeding and children with multiple or severe
bleeds. The foundation of hemophilia treatment is urgent clotting
factor replacement, with replacement goals guided by the presenting
complaint. Bleeding in von Willebrand disease may be treated with
products containing von Willebrand factor or with desmopressin.
This review focuses on the epidemiology, pathophysiology, common
presentations, evaluation strategies, and emergency management of
these bleeding disorders.
Editor-in-Chief
September 2015
Ilene Claudius, MD
Associate Professor of Emergency
Medicine, Keck School of Medicine
of USC, Los Angeles, CA
Alson S. Inaba, MD, FAAP
Associate Professor of Pediatrics,
University of Hawaii at Mãnoa
John A. Burns School of Medicine,
Division Head of Pediatric
Ari Cohen, MD
Emergency Medicine, Kapiolani
Chief of Pediatric Emergency Medicine
Medical Center for Women and
Services, Massachusetts General
Children, Honolulu, HI
Hospital; Instructor in Pediatrics,
Harvard Medical School, Boston, MA
Madeline Matar Joseph, MD, FAAP,
FACEP Marianne Gausche-Hill, MD, FACEP,
Professor of Emergency Medicine and
FAAP
Pediatrics, Chief and Medical Director,
Professor of Clinical Medicine,
Pediatric Emergency Medicine
David Geffen School of Medicine
Division, University of Florida Medical
at UCLA; Vice Chair and Chief,
School-Jacksonville, Jacksonville, FL
Division of Pediatric Emergency
Medicine, Harbor-UCLA Medical
Center, Los Angeles, CA
Michael J. Gerardi, MD, FAAP,
FACEP, President
Associate Professor of Emergency
Medicine, Icahn School of Medicine
at Mount Sinai; Director, Pediatric
Emergency Medicine, Goryeb
Children's Hospital, Morristown
Medical Center, Morristown, NJ
Sandip Godambe, MD, PhD
Vice President, Quality & Patient
Safety, Professor of Pediatrics and
Emergency Medicine, Attending
Physician, Children's Hospital of the
King's Daughters Health System,
Norfolk, VA
Stephanie Kennebeck, MD
Associate Professor, University of
Cincinnati Department of Pediatrics,
Cincinnati, OH
Anupam Kharbanda, MD, MS
Research Director, Associate
Fellowship Director, Department
of Pediatric Emergency Medicine,
Children's Hospitals and Clinics of
Minnesota, Minneapolis, MN
Tommy Y. Kim, MD, FAAP, FACEP
Associate Director of Emergency
Medicine and Pediatrics, Loma
Linda University Medical Center and
Children’s Hospital, Loma Linda, CA
Melissa Langhan, MD, MHS
Associate Professor of Pediatrics,
Ran D. Goldman, MD
Fellowship Director, Director of
Professor, Department of Pediatrics,
Education, Pediatric Emergency
University of British Columbia;
Medicine, Yale School of Medicine,
Co-Lead, Division of Translational
New Haven, CT
Therapeutics; Research Director,
Robert Luten, MD
Pediatric Emergency Medicine, BC Professor, Pediatrics and
Children's Hospital, Vancouver, BC,
Emergency Medicine, University of
Canada
Florida, Jacksonville, FL
P. David Sadowitz, MD
Associate Professor of Pediatrics and Emergency Medicine, SUNY
Upstate Medical University, Department of Emergency Medicine
and Pediatrics, Upstate University Hospital, Syracuse, NY
Eric Werner, MD, MMM
Department of Hematology and Oncology, Children’s Cancer
and Blood Disorders Center, Children’s Hospital of The King’s
Daughters, Norfolk, VA
CME Objectives
Upon completion of this article, you should be able to:
1.
Describe the deficiencies that result in hemophilia A, hemophilia
B, and von Willebrand disease.
2. Identify the bleeding manifestations of hemophilia and apply
the appropriate diagnostic workup.
3. Demonstrate appropriate emergency management of
hemophilia and von Willebrand disease.
4. Assess how the presence of clotting factor inhibitors modifies
management for patients with hemophilia.
Prior to beginning this activity, see “Physician CME Information”
on the back page.
Garth Meckler, MD, MSHS
AAP Sponsor
Associate Professor of Pediatrics,
Martin I. Herman, MD, FAAP, FACEP
University of British Columbia;
Division Head, Pediatric Emergency Professor of Pediatrics, Attending
Physician, Emergency Medicine
Medicine, BC Children's Hospital,
Department, Sacred Heart
Vancouver, BC, Canada
Children’s Hospital, Pensacola, FL
Joshua Nagler, MD
International
Editor
Assistant Professor of Pediatrics,
Harvard Medical School; Fellowship Lara Zibners, MD, FAAP
Director, Division of Emergency
Honorary Consultant, Paediatric
Medicine, Boston Children’s
Emergency Medicine, St Mary's
Hospital, Boston, MA
Hospital, Imperial College Trust;
James Naprawa, MD
Associate Clinical Professor
of Pediatrics, The Ohio State
University College of Medicine;
Attending Physician, Emergency
Department, Nationwide Children’s
Hospital, Columbus, OH
EM representative, Steering Group
ATLS®-UK, Royal College of
Surgeons, London, England
Pharmacology Editor
James Damilini, PharmD, MS, BCPS
Clinical Pharmacy Specialist,
Emergency Medicine, St. Joseph's
Hospital and Medical Center,
Phoenix, AZ
Joshua Rocker, MD
Assistant Professor of Emergency
Medicine and Pediatric, Hofstra
North Shore-LIJ School of Medicine, Quality Editor
Hempstead, NY; Associate Director,
Steven Choi, MD
Division of Pediatric Emergency
Medicine, Cohen Children's Medical Medical Director of Quality, Director
of Pediatric Cardiac Inpatient
Center, New Hyde Park, NY
Services, The Children’s Hospital at
Steven Rogers, MD
Montefiore; Associate Vice President,
Assistant Professor, University of
Montefiore Network Performance
Connecticut School of Medicine,
Improvement; Assistant Professor of
Attending Emergency Medicine
Pediatrics, Albert Einstein College of
Physician, Connecticut Children's
Medicine, Bronx, NY
Medical Center, Hartford, CT
CME Editor
Christopher Strother, MD
Assistant Professor, Emergency
Deborah R. Liu, MD
Medicine, Pediatrics, and Medical
Assistant Professor of Pediatrics,
Education; Director, Undergraduate
Keck School of Medicine of USC;
and Emergency Department
Division of Emergency Medicine,
Simulation; Icahn School of Medicine
Children's Hospital Los Angeles,
at Mount Sinai, New York, NY
Los Angeles, CA
Case Presentations
tion factors VIII and IX, respectively. The overall
incidence of hemophilia is 1 per 5000 male births.
Hemophilia A is significantly more common than
hemophilia B, representing 80% of all hemophilia
cases.2 Significant and often life-threatening bleeding (either spontaneous or trauma-induced) is the
hallmark of this disease.3 Historically, hemophilia
was associated with a dismal prognosis, with most
patients dying at a young age of uncontrolled hemorrhage.3 However, life expectancy has increased
dramatically in the past 50 years with the advent
of plasma-derived and recombinant clotting factor concentrates for treatment of hemophilia. Life
expectancy for hemophilia patients in developed
countries with comprehensive longitudinal care now
approaches that of the general male population.4,5
Von Willebrand disease is significantly more
common than hemophilia; however, bleeding in
vWD is generally much less severe than that seen in
hemophilia. Epistaxis, menorrhagia, oral bleeding,
easy bruising, and greater-than-expected postsurgical bleeding are typical presentations of vWD
compared to hemophilia, in which more-severe
joint, intracranial, and intramuscular hemorrhages
are observed.6 Unlike hemophilia, vWD affects men
and women equally, with a prevalence as high as
1% of the population, although significantly fewer
people will be symptomatic from the disease.7 Von
Willebrand disease is not an X-linked disorder, and
multiple genetic inheritance patterns exist. Among
these, autosomal dominant is the most common
pattern. Von Willebrand disease is caused by quantitative or qualitative deficiencies in von Willebrand
factor (vWF), a glycoprotein important for platelet
aggregation and adhesion to sites of vessel injury.8
Together, vWD and hemophilia A and B represent
the vast majority of clinically significant inherited
bleeding disorders. Other inherited bleeding disorders
do exist and include functional or quantitative deficiencies in clotting factors II, V, VII, X, XI, and XIII, as well as
fibrinogen deficiencies. However, these deficiencies,
collectively known as the rare bleeding disorders, represent only 3% of all bleeding disorders and each occur
with a prevalence of 1 in 500,000.9 Therefore, they will
not be addressed in detail within this review. Acquired
bleeding disorders also will not be reviewed here.
In patients diagnosed with hemophilia, ED visits
are frequent. Not surprisingly, the majority of these
visits are for acute bleeding, where prompt and appropriate intervention by an emergency clinician is
critical in mitigating morbidity and mortality.10,11 In
some cases, a new diagnosis of a bleeding disorder
may be first identified in the ED.11,12 However, several lines of evidence indicate that many emergency
clinicians have little experience and lack familiarity
in evaluating and managing patients with the common inherited bleeding disorders.1,10 Expert guidelines for the evaluation and management of patients
with inherited bleeding disorders exist,13-15 but such
A 7-year-old boy with a history of severe hemophilia B, who
receives scheduled prophylactic factor IX 3 times a week,
presents to the emergency department after rolling off a bed
3 feet from the ground and striking his head. He complains
of a mild headache at this time. On examination, there is no
palpable scalp hematoma, and the neurologic examination
is entirely normal. The patient’s last prophylactic factor
infusion was 2 days ago. Given his normal examination at
this time, is head imaging indicated? Should he receive a
factor IX infusion? If so, when should it be administered,
and how much should be given? The patient uses AlphaNine® SD brand factor IX for his factor replacement at
home, but your emergency department only stocks BeneFIX® brand factor IX. Is it okay to switch factor products?
Are there risks to doing so?
A 17-year-old adolescent boy with a history of severe
hemophilia A with a high-titer inhibitor presents to the
emergency department with pain and swelling in his
right knee that developed at school that day. There is no
history of antecedent trauma. Examination of the affected
knee reveals a large effusion and pain with flexion > 90°.
Are there laboratory studies or imaging that could aid in
diagnostic decision-making? Should you perform arthrocentesis either diagnostically or therapeutically? Should
you treat with a factor VIII concentrate? How does the
presence of a high-titer inhibitor change your management? Your ED stocks both FEIBA and recombinant
factor VIIa as bypassing products. Is one better than the
other for this patient? Can this patient be discharged from
the emergency department after treatment or does the
presence of inhibitors preclude home management?
A 16-year-old girl presents to the emergency department with a 1-month history of menorrhagia. Her
primary care physician has seen her for this complaint
previously and has sent laboratory tests, including a
complete blood count and prothrombin time/partial
thromboplastin time, which were normal. Her von
Willebrand panel was significant for a low von Willebrand factor antigen level (vWF:Ag) of 20 IU/dL
and a low ristocetin cofactor activity level (vWF:RCo)
of 22 IU/dL. She has not started any treatment. What
is her likely diagnosis, and what treatment options
are available for this patient to decrease menorrhagia?
Should she receive oral contraceptive pills, desmopressin, and/or aminocaproic acid? What risks are associated with these therapies? Should her family members
seek testing for bleeding disorders?
Introduction
Hemophilia and von Willebrand disease (vWD)
represent the most common inherited bleeding
disorders, and, consequently, those most likely to
be encountered in the emergency department (ED).1
Hemophilia A and B are X-linked recessive disorders
caused by the deficiency or absence of coagulaCopyright © 2015 EB Medicine. All rights reserved.
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Defining vWD has been challenging for the purpose of creating cohorts of subjects.7 Many patients
with abnormal testing on von Willebrand laboratory
panels have no clinical manifestations of bleeding, and, yet, some patients with equivocal testing
on von Willebrand panels are significantly symptomatic.8 These complications have made accurate
identification of a study population more challenging. Because of the rational basis for giving factor
concentrates in cases of acute bleeding in pediatric
patients, the relatively low risk of doing so in the
era of recombinant factor concentrates, and excellent
infection screening for plasma-derived products, a
randomized trial withholding factor concentrates
for patients with acute bleeds is not feasible, nor is it
appropriate.
recommended standards are often not met in the ED
care of patients with hemophilia.16 Thus, evidencebased knowledge of ED evaluation and management
of inherited bleeding disorders is critical.
Critical Appraisal Of The Literature
A literature search was performed in PubMed using
the search terms hemophilia, factor VIII deficiency,
factor IX deficiency, Christmas disease, children, and
pediatric. This search yielded 5999 results that were
evaluated by the authors, with 118 papers deemed
relevant to this review of hemophilia A and B. A
separate search was conducted using the search
terms von Willebrand disease, children, and pediatric.
This search yielded 1132 results which were reviewed, identifying 30 relevant references for vWD.
The Cochrane Database of Systematic Reviews was
searched using the key terms hemophilia and von
Willebrand disease. This search yielded 12 results, 3 of
which were relevant to this ED-focused review.
A search of The National Guideline Clearinghouse (www.guideline.gov) yielded 2 sets of
guidelines for hemophilia from the World Federation of Hemophilia and the British Committee for
Standards in Haematology, and 1 guideline for vWD
from the National Heart, Lung, and Blood Institute
of the National Institutes of Health. Most recommendations regarding acute treatment of inherited
bleeding disorders contained within the hemophilia
guidelines are level IV (based on case series/historically controlled studies), with the exception of
recommendations for factor prophylaxis, which have
stronger evidence (level II, based on randomized
controlled trials). For vWD, recommendations are
largely derived from case series and retrospective
reports (almost all grade C recommendations with
level IV evidence).
The absence of a significant number of large
randomized trials for hemophilia is multifactorial.
Modern hemophilia care began with the development of plasma-derived factor concentrates in the
1960s. Subsequent research was confounded by
the staggering number of patients with hemophilia
who were affected by HIV infections contracted via
plasma-derived clotting factor infusions in the late
1970s and early 1980s.17 A 1998 study by Rosenberg
and Goedert estimated that nearly half of all patients
with hemophilia living in the United States were
infected with HIV.18 Despite being the most common inherited clotting factor deficiency, hemophilia
remains a rare disease, and randomized controlled
trials generally require multicenter participation
to accrue an adequate number of patients. Modern
national registries for patients with hemophilia have
aided in consolidating retrospective information on
these patients, but they have not effectively facilitated a large number of prospective multicenter trials.19
September 2015 • www.ebmedicine.net
Etiology And Pathophysiology
Hemostasis And The Coagulation Cascade
Before discussing the specific pathophysiology underlying vWD and hemophilia, an overview of the
normal bleeding cessation and clot formation process is useful. Hemostasis is generally divided into
primary and secondary responses. Primary hemostasis involves the formation of a platelet plug, whereas
secondary hemostasis involves the coagulation cascade and fibrin reinforcement of the primary platelet
plug.20 The primary hemostatic response begins
with local vasospasm to decrease hemorrhage. Next,
circulating platelets adhere to newly exposed vascular collagen and to each other, a process that is mediated by vWF. This is followed by platelet activation
and platelet aggregation. The end result of primary
hemostasis is a platelet plug over the site of vascular
injury. Unfortunately, this plug is short-lived and is
easily sheared when normal blood flow returns.20,21
Therefore, secondary hemostasis is required. This
step utilizes the coagulation cascade, which includes
a variety of proenzymes and their cofactors interacting on damaged endothelium or platelets. The
cascade occurs in 3 phases: initiation, amplification,
and propagation. Initiation occurs with the release
of tissue factor (TF) from damaged endothelium.
TF binds to factor VII, and this complex, in turn,
activates factor X and factor IX. Factor X combines
with factor V, which converts prothrombin to thrombin (factor II). However, this process only activates
a small amount of thrombin. In order to produce
more thrombin, a positive feedback loop known as
the amplification phase is initiated by thrombin itself.
In this phase, thrombin activates the production of
more factor V, factor VIII, factor IX binds with factor
VIII, which, in turn, activates the production of even
more factor X-factor V complex. This leads to an
even greater amount of thrombin. In addition to the
roles just described, thrombin converts fibrinogen
to fibrin. Factor XIII covalently crosslinks the fibrin
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strands, strengthening the thrombus and completing
the coagulation cascade.20
cases per 1 million patients. It is caused by a severe
quantitative defect in vWF, with undetectable levels
of vWF leading to markedly decreased levels of factor
VIII. These patients have bleeding phenotypes similar
to hemophilia A.6 In addition to the various subtypes
of vWD, there exists a subset of patients with vWF:Ag
or vWF:RCo in an intermediate range (30-60 IU/dL)
who will have clinical bleeding symptoms. These
patients are sometimes referred to as “low vWF,” and
they are potentially eligible for the same treatments
administered for vWD.
Pathophysiology Of Von Willebrand Disease
Von Willebrand disease is the most common bleeding disorder in the United States. However, its clinical manifestations vary greatly, and it is thought that
only 10% of patients with laboratory-defined vWD
will have symptomatic disease.22 Von Willebrand
disease is defined by a qualitative or quantitative defect in vWF. This glycoprotein is synthesized in endothelial cells and megakaryocytes, and it is secreted
into circulation, where it participates in hemostasis
in 3 ways: (1) vWF binds to platelet glycoprotein
receptor GPIb/IX, which initiates platelet adhesion
to injured subendothelium; (2) vWF interacts with
the GPIIb/IIIa receptor on platelets, which facilitates
platelet aggregation; and (3) vWF binds and stabilizes factor VIII in circulation, preventing it from being
degraded by protein C.8,21
Three categories of vWD exist, and they vary in
pathophysiology and phenotype. Type 1 vWD accounts for 80% of patients with vWD and is defined
by a quantitative defect in vWF.21 There is much
debate about the precise cut point for diagnosis, but
expert opinion suggests a vWF antigen (vWF:Ag)
level, a quantitative measure of vWF, of < 30% to
40% of normal, along with a history of bleeding
symptoms. Such patients will also generally have
decreased performance on the vWF ristocetin cofactor
(vWF:RCo) activity assay (< 30), a measure of vWF
function. Type 2 vWD is due to a qualitative defect of
vWF, of which there are 4 subtypes. Type 2A occurs
in 10% of patients with vWD, and it is caused by a
mutation in vWF and the subsequent inability of vWF
to form high-molecular-weight multimers. These
multimers are necessary for the optimal functionality
of vWF. Patients with type 2A vWD have decreased
performance on vWF:RCo assay, but may have a normal quantity of vWF as measured by vWF:Ag. Type
2B disease is caused by a gain of function mutation in
the GPIb binding site on vWF, such that it binds with
too much avidity to platelets. This decreases highmolecular-weight multimers and leads to platelet
agglutination, and, occasionally, thrombocytopenia,
as platelets precipitate from the blood. A decreased
vWF:RCo is observed in these patients. Type 2M
vWD is a family of vWF abnormalities that cause
structural defects in the molecule that decrease its
multimeric size. These defects may lead to altered
vWF binding to platelets or to adhesive proteins such
as type 3 collagen. Type 2N vWD is caused by the inability of vWF to bind to factor VIII. Therefore, factor
VIII is easily degraded in circulation, and patients will
have decreased factor VIII levels. As a consequence,
they typically present with symptoms similar to a
patient with hemophilia A. The third subtype of vWD
is type 3. This subtype is quite rare, with only 1 to 2
Copyright © 2015 EB Medicine. All rights reserved.
Pathophysiology Of Hemophilia
Hemophilia is an X-linked recessive disorder, and it
is divided into hemophilia A and B. Hemophilia A is
defined by a deficiency in factor VIII, and it occurs in
1 in 5000 males. Hemophilia B is due to a deficiency
in factor IX, and it occurs in 1 in 30,000 males.20 Hemophilia has no racial or geographic predilection.23
One-third of hemophilia cases are caused by de novo
mutations, and, therefore, a patient with this diagnosis may not have a family history of the disease.24 The
absence of factor VIII or IX leads to the inability to activate factor X and the subsequent inability to activate
thrombin. Therefore, both hemophilia A and B have
similar phenotypes and, on laboratory testing, present
with prolonged partial thromboplastin time (PTT).
Both diseases are further characterized by their
severity, which is defined by the level of clotting factor activity. Patients with severe disease have < 1% of
normal clotting factor activity, patients with moderate disease have 1% to 5% of normal clotting factor
activity, and patients with mild disease have 5% to
40% of normal clotting factor activity. Patients with
mildly decreased levels of factor VIII or IX with > 40%
of normal clotting factor activity are unlikely to be
symptomatic, and they are not generally considered
to have a clinical diagnosis of hemophilia.23
In hemophilia A, 35% of patients have severe
disease, 15% have moderate disease, and 50% have
mild disease. In contrast, 60% of patients with hemophilia B have severe disease.14 The severity of disease
helps predict the bleeding phenotype. Patients with
severe disease often have multiple bleeding episodes
per month, usually in joints and soft tissues, and
they can also have spontaneous bleeds. Patients with
moderate disease typically bleed 4 to 6 times per year
and will bleed with mild trauma. Mild disease does
not generally cause frequent bleeding episodes, and
these patients may only hemorrhage with surgery
or significant trauma, though correlation of bleeding
symptoms with baseline factor levels is not consistent,
and some patients with baseline factor levels > 1%
will nonetheless have severe bleeding.25
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Differential Diagnosis
mophilia and vWD should invoke consideration of
these diagnoses in the undiagnosed patient.
The most common screening tests for a patient with
a suspected bleeding disorder include a complete
blood count (CBC), prothrombin time (PT), and PTT.
Typically, hemophilia A and B both cause isolated
prolongation of the PTT with a normal PT and platelet count. When a prolonged PTT is noted in a male
patient with significant bleeding, assays for levels of
factor VIII and IX should be ordered. The differential
diagnosis for isolated prolongation of PTT includes
laboratory or sampling errors (such as inadequate
specimen volume in a sample tube or a partially clotted sample), the presence of heparin in the patient,
in the line from which the sample was drawn, or in
the tube in which the sample was sent, and factor XI
deficiency (sometimes called hemophilia C, which is
extremely rare). In addition, factor XII deficiency and
the presence of the lupus anticoagulant will result
in a prolonged PTT on laboratory testing, but do not
result in a clinical bleeding phenotype. An isolated
PT prolongation is caused by factor VII deficiency.
Prolongation of both PT and PTT results from factor
V, factor X, fibrinogen, or prothrombin deficiencies.25
Depending on the severity and the degree to
which factor VIII levels are affected, vWD may or
may not result in prolonged PTT. Platelet count will
generally be normal, though studies of platelet function (eg, PFA-100 or platelet aggregation studies)
will be abnormal.21 Table 1 presents the differential
diagnosis for bleeding disorders based on abnormalities in PT and PTT studies.
Hemarthrosis
Hemarthrosis is the classic manifestation of hemophilia and the most common bleeding symptom
in patients with hemophilia. It can occur up to 20
to 30 times per year in patients with severe hemophilia.28 Patients generally report mild pain in the
affected joint that progresses to severe pain, swelling, warmth, and decreased range of motion, with
the ankles, knees, and elbows being most commonly
affected.3 While hemarthrosis is not the most common initial presenting symptom of hemophilia,
spontaneous joint bleeding should trigger workup
for a bleeding disorder.26,29
Hematomas/Soft-Tissue Bleeds
Hematomas are a common initial presentation in hemophilia. Cohort studies suggest that 17% to 40% of
infants with hemophilia, particularly mild to moderate hemophilia, may present with large soft-tissue
hematomas.30 Features that may suggest a bleeding
disorder include hematoma formation after minimal trauma and slow resolution of the lesions.26,31
Muscle hematomas are the second most common
bleeding manifestation in hemophilia, behind only
hemarthroses, and they are a more common initial
presentation of the disease. These bleeds generally
present with muscle swelling, decreased range of
motion, pain, a decrease in hemoglobin, and possible nerve entrapment.32
Mucosal Bleeding
Both patients with vWD and patients with hemophilia can present with prolonged or severe mucosal
bleeding. Adolescent females with vWD classically
Timing Of Diagnosis
While children with hemophilia and vWD can have
classical clinical presentations, it is important to
recognize that young children and children with
milder disease may not carry a diagnosis at the time
of presentation to the ED. In a German cohort of
children with severe hemophilia A, only 44% had a
bleeding episode during the first year of life. A few
children did not have a bleed until after age 4 years,
with an average age of diagnosis of 1.2 years.26 A
retrospective cohort study of 55 patients calculated
an average age of diagnosis of 5.3 years in children
with mild hemophilia and no known family history
of disease.27 A British survey of the caregivers of 12
children with hemophilia suggested that patients
often seek medical attention multiple times (either in
the ED or from their primary care physician) before
receiving a diagnosis.12 Accurate diagnosis of the
underlying bleeding disorder is important both in
acute management and in the prevention of longterm morbidity and mortality.
Table 1. Differential Diagnosis For Bleeding
Disorders By Abnormality In Prothrombin
Time/Partial Thromboplastin Time Studies
Typical Presenting Symptoms Of Inherited
Bleeding Disorders At Diagnosis
The following typical bleeding presentations of heSeptember 2015 • www.ebmedicine.net
Laboratory Finding
Differential Diagnosis
Prolonged PT only
• Factor VII deficiency
• Liver failure
Prolonged PTT only
•
•
•
•
Prolonged PT and
PTT
•
•
•
•
•
Factor VIII, IX, XI, or XII deficiency
Lupus anticoagulant
Heparin in sample
von Willebrand disease (with low factor
VIII)
• Specimen integrity problems
Factor V or X deficiency
Fibrinogen or prothrombin deficiency
Disseminated intravascular coagulation
Lupus anticoagulant
Specimen integrity problems
Abbreviations: PT, prothrombin time; PTT, partial thromboplastin time.
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present with menorrhagia (defined as bleeding for
> 7 days or loss of > 80 mL of blood per menstrual
cycle).9 Younger children with vWD can have excessive or prolonged bleeding from mucous membranes (such as occurs in epistaxis or in bleeding
after dental procedures). Children with hemophilia
may also present with similar symptoms, but they
can also have more-severe mucosal bleeding, such as
gastrointestinal hemorrhage.21
crutches for weight-bearing joints) to help prevent
further damage.16 If blood loss is significant, volume
should be repleted with crystalloid. Most hematologists recommend initiating factor replacement
within 1 hour of bleeding. Therefore, if home factor
infusions cannot be completed, the patient should be
taken to a treatment center expeditiously.38
Intracranial Hemorrhage
Intracranial hemorrhage (ICH) is the most serious
complication in children with bleeding disorders.
ICH has been reported to have 20% mortality in the
hemophilia population, though this rate is lower in
patients aged < 19 years. Among surviving patients,
25% to 75% sustain permanent disability.33 ICH is 20
to 50 times more frequent in males with hemophilia
than in males without. ICH is a less-frequent complication in patients with vWD, but no large studies
have been conducted on this subject. Case series
suggest that patients with the rare type 3 subtype
of vWD are at higher risk for ICH.34 While ICH is
certainly seen in patients without inherited bleeding disorders, ICH with minimal or no antecedent
trauma raises the suspicion of an underlying bleeding disorder, and screening laboratory testing should
be considered in these patients.35
The child with a bleeding disorder requires a unique
approach in the ED, and enlisting the support of a
hematologist is very important. However, not all patients with a primary coagulation defect come to the
ED with a known diagnosis. As stated previously,
one-third of all patients with hemophilia have a de
novo mutation, and have no known family history.
In fact, a British study of 25 patients with hemophilia without a known family history suggested that
the mean age of diagnosis is 29.5 months.12 Patients
with milder bleeding disorders tend to be diagnosed
later in life. In older children, menorrhagia may be
the first or only sign of vWD.1 Therefore, it is important to have a high index of suspicion in children
with multiple episodes of easy bruising or bleeding.
The initial evaluation is driven by vital signs and
pertinent presenting symptoms and examination
findings. The appropriate resuscitative measures
take precedence over disease-specific measures.
Perhaps the only variation on the secondary survey
is immobilization of any bleeding joint to prevent
further injury.16 It is only once the child is stabilized
that bleeding disorder evaluation and management
should be prioritized.
There is no universally agreed-upon algorithm
for evaluating a patient with a bleeding disorder.
However, there are guidelines from the United Kingdom Haemophilia Centre Doctors' Organisation that
can help guide the initial assessment.16 (See Table 2,
page 7.) After a complete history is taken (including
the elements noted in Table 2) and a complete physical examination is completed, diagnostic studies can
be considered.
Emergency Department Evaluation
Postsurgical Bleeding
Prolonged or excessive bleeding after minor surgical
procedures is a cardinal feature of both hemophilia
and vWD, and it is often the presenting symptom at
diagnosis.36 Many boys with hemophilia are diagnosed when they have significant bleeding after
circumcision. It is important to realize, however, that
this will not always occur in patients with hemophilia and will occur only very rarely in patients with
vWD. In a cohort of boys with severe hemophilia A,
50% underwent circumcision without any bleeding
complications.26
Prehospital Care
Diagnostic Studies
Optimizing home treatment in patients with bleeding disorders has been shown to decrease total
factor concentrate utilized and subsequent cost to
the healthcare system.37 Unfortunately, there is little
research on prehospital care in this population, and
current recommendations are based primarily on
expert opinion.38
Most patients with severe hemophilia receive
prophylactic factor infusions in the home to prevent bleeds. Additional doses are administered in
response to bleeding symptoms. Other prehospital
care might include ice, compression, and elevation
for joint or soft-tissue bleeds.39 In cases of hemarthrosis, the joint should be protected (eg, using
Copyright © 2015 EB Medicine. All rights reserved.
Most recommendations for imaging and diagnostic
studies in a child with a bleeding disorder are based
upon expert consensus, given the relative dearth of
data. In the ED, the workup is primarily dependent
upon the presenting complaint and the patient’s mental status and vital signs.
Laboratory Studies
Order a blood type and crossmatch and a CBC to
assess hemoglobin and platelets in children with
severe bleeds and/or alterations in vital signs.
Coagulation studies (PT, PTT, and fibrinogen) can
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be useful if the diagnosis of a bleeding disorder
is being considered. However, these studies will
not detect patients with qualitative platelet disorders, many forms of vWD, and the rare factor XIII
deficiency. For patients with low platelet levels
and normal PT/PTT levels, consider and work
up systemic causes of thrombocytopenia, such as
idiopathic thrombocytopenic purpura, hemolytic
uremic syndrome, autoimmune disorder, bone marrow disease, etc.
In patients with hemophilia, baseline factor levels
(factor VIII in hemophilia A, factor IX in hemophilia
B) can help emergency clinicians determine goal treatment levels; however, the results of these tests will
generally not be available while the patient is in the
ED, and cannot be used to guide treatment. Therefore, factor dosing must be chosen empirically. If the
patient has a known diagnosis of factor VIII or factor
IX deficiency but the severity is unknown, it is reasonable to assume that the patient has severe disease for
the purpose of factor dosing. If a baseline level has
not been established and/or the patient has received
treatment for the disorder, order a factor VIII level in
patients with vWD and symptoms of severe bleeding.40 Inhibitor titers in the ED setting are not useful
in acute management, as results are generally not
available while the patient is in the ED, but they may
help guide ongoing therapy if the patient is suspected
of having new development of inhibitors.
Factor levels can be measured 30 to 60 minutes
after factor infusion to determine the patient’s response to the infusion. If there is little increase in the
measured factor level, an inhibitor is likely present.
The utility of vWD screening in the ED is limited,
as vWF is an acute phase reactant and any measurements of vWF antigen during acute illness can be
potentially misleading. In patients in whom vWD is
suspected based on clinical or family history, consider a vWF:Ag level, vWF:RCo activity level, and a
factor VIII activity level. However, these should be
interpreted with caution as false negatives are common in the setting of acute bleeding or illness and
estrogen or corticosteroid use. Patients with negative
tests in whom the index of suspicion remains high
should have repeat testing in the outpatient setting.
Imaging Studies
Regardless of the need for imaging, the process of
obtaining imaging should not delay factor replacement.
Head Imaging
There are no consensus guidelines as to which patients with head trauma require imaging and which
patients can be safely observed.41 Two retrospective cohort studies have been completed looking at
the use of head computed tomography (CT) scans
in patients with hemophilia with concern for ICH.
One study at the Children’s Hospital of Philadelphia found 9 cases of ICH. In 5 of these 9 cases, the
patients were asymptomatic at presentation, leading
the authors to suggest that early, more liberal use of
head CT scans may be justified.42 However, another
retrospective cohort study at The Hospital for Sick
Children in Toronto identified 11 cases of ICH in
children with hemophilia. In all 11 cases, the patients
presented with altered mental status or signs of increased intracranial pressure.43 Given this conflicting
evidence, it seems reasonable to obtain a head CT or
magnetic resonance imaging (MRI) scan in patients
with severe hemophilia after any head trauma,
particularly in infants, patients with severe disease,
or patients with inhibitors. All patients with altered
mental status or an abnormal neurological examination require emergent head imaging. If possible, an
MRI is preferred, given its ability to better visualize
the posterior fossa.43
In considering ICH in vWD, a retrospective
cohort study was performed in children with vWD
and head trauma. The study identified 6 children
with ICH, all of whom presented with signs of
elevated intracranial pressure and/or altered consciousness. Therefore, it seems reasonable to reserve
Table 2. Summary Of The United Kingdom
Haemophilia Centre Doctor’s Organisation
Evaluation Guidelines16
1. The patient should be assessed within 15 minutes of arrival. Treatment, if indicated, should be initiated within 30 minutes of arrival.
2. Emergency clinicians should know or have immediate chart access to the patient’s diagnosis and the severity of the bleeding disorder. The clinician should also know if the patient has inhibitors.
3. It is useful to know what factor product the patient generally
responds to and/or uses at home. Many hemophilia treatment
centers provide their patients with a summary letter that contains
the specific treatment product(s) and dosage recommendations.
4. For patients with vWD or mild hemophilia A, a history of responsiveness or nonresponsiveness to desmopressin should be
obtained.
5. The emergency clinician should determine whether the patient
has had any adverse events due to the bleeding disorder and any
adverse reactions to factor concentrates. In the older patient, it is
useful to know whether the patient has contracted any bloodborne diseases (such as hepatitis C or HIV), as this may broaden
the consideration of potential problems and comorbidities associated with more-severe and more-frequent bleeding sequelae.
6. The emergency clinician should contact the primary hematologist
for any bleeding episode. The primary hematologist will be able to
help guide management decisions and establish follow-up, though
treatment can be initiated prior to discussion with hematology.
7. If a significant bleed is suspected, the patient should be stabilized
and, if possible, transferred to a hemophilia treatment center, as
treatment at these centers is associated with improved outcomes.
Treatment for the bleed should be initiated as soon as possible.
Abbreviations: HIV, human immunodeficiency virus; vWD, von Willebrand disease.
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imaging in vWD only to symptomatic patients or patients with a particularly concerning mechanism of
injury. Exceptions include patients with severe vWD
(type 2N or type 3) whose phenotype is more similar
to hemophilia and who should undergo imaging
more liberally.34
factor IX in the recipient’s plasma by 1% (0.01 IU/mL).3
However, the patient’s individual response may vary,
so peak levels should be confirmed for major or lifethreatening bleeds.
Different types of bleeding require different
dosing and duration of factor infusions to achieve
adequate hemostasis. Factor concentrate vials vary
in the exact number of units of clotting factor contained in each vial. The number of units of factor is
labeled on each vial, and dosing should be rounded
to the nearest number of vials, rounding up when
necessary. Except in young infants, where the available vials of factor concentrates may be limited, it is
unlikely that a partial vial dose would be indicated.
Table 4 (see page 9) provides a quick reference for
dosing and disposition of hemophilia patients by
specific bleeding sites.
Joint And Soft-Tissue Imaging
Hemarthrosis is usually clinically apparent. Therefore, no diagnostic imaging is necessary if a patient
with a known bleeding disorder presents with joint
swelling and pain, particularly in a known target
joint.44 However, ultrasound can be used if the diagnosis is in doubt, and this modality is quite sensitive
for detection of hemarthrosis.45 Plain x-ray films
may be indicated if there is a significant traumatic
mechanism and concern for fracture.
Soft-tissue bleeding may require diagnostic imaging in the ED. Very superficial hematomas are clinically
apparent, and imaging is unnecessary in these cases unless there is concern for underlying bony injury. Deeptissue injuries (such as bleeds into muscles) will often
require imaging for definitive diagnosis and baseline
measurements. Ultrasound is useful for most soft-tissue
hematomas, and CT or MRI can be used if a deeper softtissue bleed is suspected.30,46
Management Of Specific Types Of Bleeding In
Hemophilia
Hemarthrosis
Up to 85% of bleeds in patients with hemophilia occur in joints, and ankles, knees, and elbows are most
commonly affected.3 If a single joint becomes a site of
recurrent hemarthrosis, it is termed a target joint. Over
time, synovitis can occur in such joints and, if uncontrolled, this can lead to cartilage destruction and
significant functional impairment from hemophilic
arthropathy.55 Therefore, significant effort should be
directed toward minimizing bleeding into joints with
the goal of preservation of long-term joint function as
well as averting short-term pain and disability.
In the setting of acute hemarthrosis, consensus
guidelines recommend early factor infusion with an
anticipated goal factor VIII or IX level of 40% to 60%,
based on predicted response to factor infusion as well
as symptom improvement, although postinfusion
Treatment
Treatment Of Bleeding From Hemophilia
Treatment for hemophilia is directed toward replacement of the missing clotting factor (factor VIII
replacement for patients with hemophilia A and factor IX replacement for patients with hemophilia B).
There are 2 general types of clotting factor concentrates available: (1) Plasma-derived factor concentrates, made up of pooled human donor plasma;
these have been available since the 1960s; and (2)
recombinant factor concentrates, which are manufactured in mammalian cell culture systems, and have
been available since the 1980s.17
Both recombinant and plasma-derived factor
concentrates have been shown to be highly effective
in achieving hemostasis, with a success rate of ≥ 90%
after 1 to 2 doses of factor concentrates for typical
bleeding episodes.47,48 There are no quality studies
proving that switching from one type of factor product to another or among different brands of factor
products increases the risk of inhibitor development;
however, this should generally be avoided, if possible.49,50 Therefore, in situations where a patient’s
specific brand of factor is unavailable, and urgent
treatment is necessary, another brand of factor can be
utilized.51 Table 3 details the currently available factor
replacement products.
In general, 1 unit/kg of factor VIII will increase
factor VIII in the recipient’s plasma by 2% (0.02 IU/
mL), whereas 1 unit/kg of factor IX will increase the
Copyright © 2015 EB Medicine. All rights reserved.
Table 3. Available Factor Replacement
Products52
Factor VIII Concentrates
Recombinant
• Advate, Helixate® FS, Kogenate® FS, Recombinate, Xyntha®,
Novoeight®, Eloctate®
Plasma-Derived
• HEMOFIL M, MONARC-MTM, Monoclate-P®
Factor IX Concentrates
Recombinant
• BeneFIX®, Alprolix®
Plasma-Derived
• AlphaNine® SD, Mononine®
von Willebrand Factor Concentrates (with FVIII)
Plasma-Derived
• Alphanate®, Humate-P®, Wilate®
Bypassing Agents
• FEIBA NF, NovoSeven® RT
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Muscle Bleeding
levels will not generally be measured. In many cases
of hemarthrosis, a single dose of factor replacement is
adequate; however, if symptoms have not improved
after 1 dose, repeat doses may be added at 12-hour to
24-hour intervals until the joint normalizes.44
In addition, immobilization of the affected
joint, use of a compression bandage, and application of ice is recommended, though significant
evidence for these recommendations is lacking.14
Ice, if used, should be applied for 15 minutes every
2 to 3 hours. Analgesia is also important. Nonsteroidal anti-inflammatory drugs should be avoided
in patients with hemophilia due to concern for
adding antiplatelet effects in a patient with existing
coagulopathy. In general, acetaminophen, with or
without an opioid, is used for pain control, though
guidelines recommending this are not well researched.54 Corticosteroids are generally not recommended for pain control, and there is no evidence
that they provide significant benefit in control of
pain or prevention of arthropathy.56 Guidelines do
not recommend aspiration or arthrocentesis for
management of hemarthrosis, and there is very
little literature addressing this subject.
The second most common type of bleeding seen in
patients with hemophilia is bleeding into muscle.
Factor should be infused as soon as possible to
target predicted levels of 40% to 60%. Repeat infusions are often required every 12 to 24 hours for 2
to 3 days, along with careful monitoring (often as
an inpatient), as compartment syndrome or nerve
compression can develop, and significant rehabilitation/physical therapy may be required, which can
precipitate rebleeding.14,57
Iliopsoas Hemorrhage
One particular type of muscle bleed that merits
special mention is iliopsoas muscle hemorrhage. In
comparison to other muscle hemorrhages, iliopsoas
hemorrhage has the potential for massive blood loss
and represents a potentially life-threatening condition in patients with hemophilia. Motor limitations
can also be severe.58 In the 3 largest published series
of iliopsoas hemorrhage (all of which were retrospective chart reviews), the most common presentations involved thigh, hip, abdomen, and/or groin
pain. A flexion contracture at the hip was noted in
the vast majority of patients in all series, and paresthesia in the femoral nerve distribution was a classic
Table 4. Dosing And Duration Of Therapy For Hemophilia-Related Bleeds1,14,44,53,54
Type of Bleeding
Goal Factor
Level
Hemophilia A
(IV dose of
Factor VIII)
Hemophilia B
(IV dose of
Factor IX)
Duration of Treatment
Disposition from ED/Special Notes
Hemarthrosis
40%-60%
20-40 units/kg
40-60 units/kg
1-3 days (1 dose is usually
sufficient)
Single dose is often adequate, patient
can usually discharge home with splinting, ice, and close follow-up
Muscle hemorrhage
(except iliopsoas)
40%-60%
20-40 units/kg
40-60 units/kg
2-3 days, repeat doses with
physical therapy
Admission is occasionally required to
monitor for compartment syndrome;
physical therapy is recommended
Iliopsoas bleed
80%
50 units/kg
80-100 units/kg
7-14 days, maintain levels
> 80% for 3 days, then > 50% thereafter
Admit to hospital, strict bed rest, monitor
serial Hct, follow-up imaging with CT,
MRI, or ultrasound
Major trauma or
surgery
100%
50 units/kg
100 units/kg
14 days, maintain > 80% for
days 1-3, then > 40% for
days 4-6, and > 30% for
days 7-14
Give factor as soon as possible, prior
to imaging if any delay is anticipated;
trauma surgery consultation, admission
Intracranial hemorrhage
100%
50 units/kg
100 units/kg
14 days, maintain > 80%
for days 1-7, and > 50%
thereafter
Give factor before obtaining imaging as
soon as ICH is suspected; neurosurgery
consultation, ICU admission
Hematuria/renal
hemorrhage
50%
20-30 units/kg
50-60 units/kg
1-3 days
Admission, hydrate aggressively (3 L/m2
x 48 h), avoid antifibrinolytics, consider
urology consultation
Gastrointestinal
bleed
100%
50 units/kg
100 units/kg
7-10 days, maintain > 80%
for days 1-6, and > 30%
for days 7-10
Admit, consider antifibrinolytics, gastroenterology consultation
Deep laceration
50%
25 units/kg
50 units/kg
Up to 5-7 days, depending
on depth/location
Give factor, then suture, discharge home,
close follow-up within 24 hours
Abbreviations: CT, computed tomography; ED, emergency department; Hct, hematocrit; ICH, intracranial hemorrhage; ICU, intensive care unit; IV, intravenous; MRI, magnetic resonance imaging.
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ICH. This should occur prior to obtaining imaging, if
imaging is anticipated to delay factor administration
in any way.14
sign seen in many patients.58-60 In one of these series
of 14 iliopsoas bleeds, hip flexion contracture was
present in 13 of the 14 patients, and femoral paresthesia was present in 8 of the 14 patients.59 Bleeding
can occur spontaneously, without trauma, and delay
in seeking care is common. In a series of 46 episodes,
the duration of symptoms prior to seeking medical
attention was 3.8 days, and only 57% of the patients
reported a history of trauma.59
The initial factor treatment goal for patients with
iliopsoas bleeds is higher than that for other muscle
bleeds. The goal is a predicted postreplacement level
of 80% for at least 3 days, and then a goal of > 50%
for the remaining duration of treatment.59 Treatment
duration is typically 7 to 14 days. Expert guidelines
recommend that patients should be admitted to the
hospital and placed on strict bed rest to avoid any
significant motion at the hip, contracting the psoas
muscle and potentially exacerbating the condition.14
MRI (preferred), ultrasound, and CT scanning can
all be considered to aid in diagnosis, and can be
used for follow-up imaging as the patient recovers.14
Intracranial Hemorrhage In Neonates
Intracranial hemorrhage in patients with hemophilia represents a significant challenge, and there
is debate regarding head imaging in neonates with
known hemophilia. Some guidelines suggest screening imaging by ultrasound or CT for all newborns
with a family history of hemophilia plus an instrument-assisted delivery.64 However, as 30% of cases
of hemophilia have no family history, a high index
of suspicion for hemophilia is necessary for infants
with unusual intracranial hemorrhages in the neonatal age group.
Major Trauma In Hemophilia
In settings of major trauma or where major emergency surgery may be indicated, immediate factor
replacement to a goal level of 100% is recommended,
with a tapering goal factor level over the days following as described in Table 4 (see page 9).14 Imaging should not delay factor administration. Further,
in any patient with hemophilia and peritoneal signs,
bleeding should be suspected regardless of whether
there is a history of preceding trauma.53
Intracranial Hemorrhage
ICH is a major source of mortality in patients with
hemophilia, with an overall mortality rate of 9% to
39%, though this is lower in the pediatric population.42 It is also a major source of long-term disability
and decreased quality of life in patients with hemophilia.61 Furthermore, ICH is quite common, with
a prevalence rate of 2% to 12% in pediatric patients
with hemophilia.41,62
The 3 most commonly associated risk factors for ICH
across multiple studies are: (1) severe hemophilia; (2)
the presence of inhibitors; and (3) a history of trauma.33,41 While trauma is a major risk factor for ICH, spontaneous ICH can occur. For example, in a series from
Brazil, a history of trauma was reported in just 21 of the
45 patients who presented with intracranial bleeding.35
The only sign consistently correlated with the
presence of ICH is a change in mental status. In a
series from the Children’s Hospital of Philadelphia
including 374 ED visits, only drowsiness and loss of
consciousness were identified as statistically significant predictors of ICH.42 However, the absence of
mental status changes does not exclude ICH. A neurologic deficit or altered mental status was only present
in 38% and 33% of cases, respectively, in the series
of patients with hemophilia with ICH from Brazil.
Furthermore, 44% of patients in that series showed no
abnormalities on physical examination.35
The prompt administration of factor is critical
in cases of potential ICH, and factor administration
within 6 hours of head trauma has been demonstrated to reduce the risk of ICH and lower mortality
rate in patients with hemophilia.63 Factor should be
administered immediately in patients with hemophilia who present with head trauma or any signs
or symptoms that raise suspicion for spontaneous
Copyright © 2015 EB Medicine. All rights reserved.
Less Common Bleeds In Patients With Hemophilia
Gastrointestinal Hemorrhage
Gastrointestinal hemorrhage is a less common site
of bleeding in patients with hemophilia, and it may
represent comorbid gastrointestinal disease. Initial
factor replacement should target factor levels of 80%
to 100% for 1 to 6 days, followed by maintenance replacement with a goal factor level of 50% for 7 to 14
days. Gastroenterology consultation is recommended to better identify the source of the hemorrhage.14
Hematuria/Renal Hemorrhage
For patients presenting with gross hematuria and
evidence of upper renal tract hemorrhage, vigorous hydration at 1.5 times the maintenance fluid
requirement for 48 hours is recommended.14 Factor
replacement to a goal of 50% for 3 to 5 days should be
provided, and urology consultation should be considered. Antifibrinolytic agents (eg, aminocaproic acid,
tranexamic acid) are contraindicated in these patients
as they can precipitate thrombi within the kidneys.14
Prophylaxis In Hemophilia
There is a significant body of literature to support
the use of regular, scheduled factor infusions as
prophylaxis to prevent long-term joint disease in patients with severe hemophilia.65,66 There is also retrospective evidence to suggest that such scheduled
prophylaxis can decrease the risk of ICH in patients
with hemophilia.33 Prophylaxis is better established
in patients with hemophilia A than in patients with
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hemophilia B, but evidence supports its use in both
groups.67 Consequently, many patients with severe
hemophilia will be receiving regular factor infusions. A typical prophylaxis schedule is infusion 3
times weekly for factor VIII and twice weekly for
factor IX, though a variety of prophylaxis schedules
exist. Note, however, that even for patients who are
nominally on prophylaxis, compliance can be a significant challenge, especially in adolescent patients,
and compliance should not be assumed.68
30 to 60 ristocetin cofactor units/kg of vWF with
maintenance dosing of 20 to 40 units/kg every 12
to 48 hours. Trough vWF:RCo and factor VIII levels
should be monitored daily and maintained at > 50
IU/dL for 3 to 5 days.
For major bleeding, a loading dose of 40 to 60
units/kg of vWF is recommended, followed by a
maintenance dose of 20 to 40 units/kg every 8 to 24
hours thereafter. Trough vWF:RCo and factor VIII
levels should be monitored daily and maintained at
> 50 IU/dL for at least 7 days. Care should be taken
to avoid excessively high factor VIII levels, which
may occur over time. See Table 5 for a quick reference on vWF dosing recommendations.
Treatment Of Bleeding From Von Willebrand
Disease
Bleeding tends to be less severe from vWD compared to hemophilia, and life-threatening bleeding in most types of vWd is uncommon. However,
familiarity with potential interventions is important.
Treatment depends on the subtype of vWD and can
include: increasing plasma concentration of vWF by
stimulation of endogenous vWF release from endothelial cells through administration of desmopressin,
replacing vWF using plasma-derived concentrates,
and/or using agents that promote hemostasis but
do not substantially alter plasma concentrations of
vWF (ie, antifibrinolytics). Treatment choice largely
depends on whether or not the patient has demonstrated a prior response to desmopressin.1
Adjunctive Therapies
Adjunctive therapies are used for specific bleeding
types in vWD. For menorrhagia, hormonal contraceptives are first-line therapy, with desmopressin and antifibrinolytics representing adjunctive
therapies.15 For mucosal bleeding in both vWD and
hemophilia, antifibrinolytic drugs (specifically aminocaproic acid and tranexamic acid) can be useful
adjuncts. These medications inhibit the conversion
of plasminogen to plasmin, which inhibits fibrinolysis, and stabilizes clots that have already formed.
They are a useful adjunct to increase vWF levels in
patients with vWD, and they are particularly helpful
in managing oral bleeding or after oral surgery, as
the oral cavity is high in fibrinolytic activity. Dosing
of aminocaproic acid is 50 to 60 mg/kg (max 5 g) intravenously or by mouth every 6 hours until bleeding is controlled, or for 5 to 7 days postoperatively.8
Dosing of tranexamic acid is 10 to 15 mg/kg oral or
intravenously every 8 to 12 hours.8,14
The major contraindication to antifibrinolytic use
is hematuria, as antifibrinolytic agents can precipitate
renovascular thrombi. A urinalysis to exclude blood is
recommended prior to initiating an antifibrinolytic.15
Desmopressin Treatment
If the patient is known to be responsive to desmopressin, desmopressin can be administered intravenously for minor bleeds at a dose of 0.3 mcg/kg
or intranasally at a dose of one 150-mcg spray for
patients weighing < 50 kg or 300 mcg (2 sprays) for
persons weighing ≥ 50 kg. Of note, desmopressin
nasal spray used to treat vWD is a higher concentration (150 mcg/spray) than that used for other indications (such as enuresis), and care should be taken
to ensure the proper concentration of solution is
administered.69 Side effects of desmopressin include
facial swelling, headache, and, most importantly,
water retention, as desmopressin mimics the effect
of antidiuretic hormone at the kidneys and causes
free-water retention. Patients should be instructed
to limit fluid intake to maintenance levels and avoid
intake of hypotonic fluids for 24 hours following
desmopressin administration. If intravenous fluids
are administered, normal saline should be used.
If multiple doses are required, serum electrolytes
should be monitored. To avoid tachyphylaxis, which
occurs as endothelial vWF stores become exhausted,
discontinue desmopressin after 2 to 3 doses.8
For patients with major bleeding or for patients
who are not responsive to desmopressin, vWF-containing concentrates are required.
Table 5. Dosing Of Von Willebrand Factor
Concentrates For Major And Minor Bleeding
And Surgery15
Von Willebrand Factor Concentrates
For minor bleeding in patients who are not responsive to desmopressin, administer a loading dose of
September 2015 • www.ebmedicine.net
Type of
Bleeding
or Surgery
Goal of
Treatment
(vWF:RCo)
Initial IV
Dose of
vWF
Duration of Treatment
Major
> 50 IU/dL for
7-14 days
40-60
units/kg
7-14 days; administer
20-40 units/kg every
8-24 hours to maintain
vWF:RCo > 50 IU/dL
Minor
> 50 IU/dL for
3-5 days
30-60
units/kg
3-5 days; administer 2040 units/kg every 1248 hours to maintain
vWF:RCo > 50 IU/dL
Abbreviations: IU, international units; IV, intravenous; vWF, von Willebrand factor; vWF:RCo, von Willebrand factor ristocetin cofactor.
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Acute Management Of Common Bleeds In Patients With Hemophilia
Patient with a known diagnosis of hemophilia presents to the ED
Priority triage: evaluate the patient within 15 minutes of arrival and
notify the patient's hematologist as soon as possible
Concern for ICH:
Patient presents with head trauma, headache, neurologic findings,
or signs of increased ICP, with severe hemophilia or inhibitors
Hemarthrosis or muscle bleed
Administer factor concentrate:
• 20-40 units/kg for hemophilia A, 40-60 units/kg for hemophilia B
(Class I)
• 270 mcg/kg rFVIIa for patient with inhibitors (FDA-approved
dose: 90 mcg/kg) (Class I)
Administer factor concentrate:
• 50 units/kg FVIII for hemophilia A, 100 units/kg FIX for hemophilia B (Class II)
• 270 mcg/kg rFVIIa for patient with inhibitors (Class II)
• Hemarthrosis: If symptoms are stable and caregivers are comfortable with home monitoring, discharge to home (Class II)
• Significant muscle bleeding: Admit for monitoring for compartment syndrome and/or nerve compression (Class II)
Obtain head CT
Positive for ICH
• Admit to the ICU
• Obtain a neurosurgical
consultation
• Maintain factor level > 80% for 7 days, then > 50% for 7 days (Class II)
Negative for ICH
• Discharge to home if
asymptomatic
• Consider admission for
observation
Abbreviations: CT, computed tomography; FDA, United States Food and Drug Administration; FIX, factor IX; FVIII, factor VIII; ICH, intracranial hemorrhage; ICP, intracranial pressure; ICU, intensive care unit; rFVIIa, recombinant factor VIIa.
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:
• One 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
• Nonrandomized or retrospective studies:
historic, cohort, or case control studies
• Less robust randomized controlled trials
• 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
This clinical pathway is intended to supplement, rather than substitute for, professional judgment and may be changed depending upon a patient’s individual
needs. Failure to comply with this pathway does not represent a breach of the standard of care.
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Emergency Department Workup For Suspected Bleeding Disorder
Patient presents with a history of
significant bleeding
Low platelets, PT/PTT abnormal
Send screening
laboratory tests:
CBC, PT, PTT,
fibrinogen
Low platelets, PT/PTT
normal
Consider and work up DIC, sepsis, or other significant
systemic derangements
Consider and work up
systemic causes of
thrombocytopenia: ITP, HUS, autoimmune disorder, bone
marrow disease, etc
PT/PTT abnormal, normal CBC
PTT only abnormal
PTT and PT abnormal
PT only abnormal
Consider:
• FVIII, FIX, FXI deficiencies, vWD
• Presence of heparin
or lupus anticoagulant
Consider:
• FV, FX, prothrombin, or fibrinogen
deficiencies
• Liver disease
• Exposure to rat
poison
• Hemorrhagic
disease of the
newborn
Consider:
• FVII deficiency
• Warfarin use
• Liver disease
• Exposure to rat
poison
• Hemorrhagic
disease of the
newborn
Consult hematology and
send:
• FVIII, FIX, FXI levels
• von Willebrand panel
(vWF:Ag, vWF:RCo,
FVIII level)
• Mixing study to
assess for lupus anticoagulant and other
inhibitors
• Verify no heparin in
sample
Consult hematology
and send:
• FV, FX, and FII
levels
• Fibrinogen level
Consult hematology
and send:
• FVII level
• Severity of the bleed should dictate disposition
• For patients with abnormal PTT (which suggests
a diagnosis of hemophilia) and severe bleeding,
admission should be strongly considered
PT/PTT normal, normal CBC
Consider:
• von Willebrand disease
• Factor XIII deficiency
• Fibrinolytic disorders (rare)
• Functional platelet disorder
• Connective tissue disorders
• Vitamin deficiencies
Consult hematology and send:
• von Willebrand panel (vWF:Ag, vWF:RCo, FVIII
level)
• Thrombin time
Consider:
• Micronutritent/vitamin levels
• Consider platelet function assay platelet aggregation studies to assess for functional platelet
disorder
Abbreviations: CBC, complete blood count; DIC, disseminated intravascular coagulopathy; FII, factor II; FIX, factor IX; FV, factor V; FVII, factor VII;
FVIII, factor VIII; FX, factor X; FXI, factor XI; HUS, hemolytic uremic syndrome; ITP, idiopathic thrombocytopenic purpura; PT, prothrombin time; PTT,
partial thromboplastin time; vWD, von Willebrand disease; vWF:Ag, von Willebrand factor antigen; vWF:RCo, von Willebrand factor ristocetin cofactor.
September 2015 • www.ebmedicine.net
13
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Special Populations
with bypassing agents should, ideally, be administered within 1 hour of bleeding onset, and homebased treatment may be appropriate for patients with
milder bleeds such as hemarthroses.78-80 Hospitalization and repeated bypassing agent administration is
recommended for severe or abnormal bleeds.38,76
There was initially significant concern that
the use of rFVIIa could lead to an increased risk of
thromboembolic events. However, a 2006 review of
185 thromboembolic events occurring in patients
given rFVIIa demonstrated that only 17 events occurred in patients with hemophilia, with the vast
majority of thrombi occurring in patients without
hemophilia who were receiving rFVIIa off-label.
Consequently, rFVIIa is generally considered safe
for both pediatric and adult patients with hemophilia.81,82 In addition to its use in acute bleeds, there
is also some evidence to support prophylactic use of
rFVIIa in patients who have inhibitors and significant bleeding frequency.83
Patients With Hemophilia With Inhibitors
Clotting factor inhibitors develop in approximately
33% of patients with hemophilia A and 6.5% of patients
with hemophilia B.70,71 Inhibitor development represents the most significant complication of treatment in
patients with hemophilia and significantly complicates
treatment of acute bleeds. Development of inhibitors is
more likely in patients who have specific genotypes of
hemophilia, patients who are exposed to factor concentrates at a younger age, and patients who have more
exposure to early intensive therapy.72
Inhibitor activity is measured in Bethesda units
(BU). Patients with an inhibitor titer < 5 BU/mL
are considered low titer, whereas patients with an
inhibitor titer ≥ 5 BU/mL are considered high titer. In
addition, a patient is considered to have lowresponding inhibitor when the inhibitor titer remains
< 5 BU/mL despite repeated factor infusions.73
Patients with low-titer, low-responding inhibitors (<
5 BU/mL) can continue to be treated effectively with
clotting factor concentrates for acute bleeds. For such
patients, a higher dose of factor is required, and the
following formula is used to estimate the amount of
factor VIII needed as a loading dose to neutralize the
inhibitor: [body weight (kg) × 80 × (1-hematocrit) ×
antibody titer (BU/mL)] and add an additional 50
units/kg above the calculated loading dose to achieve
a measurable factor VIII activity level.73
Once a patient has an inhibitor concentration
of ≥ 5 BU/mL, as is the case for most patients with
inhibitors, factor replacement will not be effective
in treatment of bleeding episodes, and a bypassing agent is required. There are 2 bypassing agents
available for these patients: activated recombinant
factor VIIa (rFVIIa) and factor eight inhibitor bypassing activity (FEIBA).74
FEIBA contains multiple vitamin-K-dependent
clotting factors with some in active forms. Typical dosing for FEIBA is 50 to 75 units/kg for joint
bleeds and 100 units/kg for life-threatening or
limb-threatening bleeding.73 While repeat doses
can be administered every 12 hours, it is important to avoid doses > 200 units/kg/day due to
thrombotic risk.
Recombinant factor VIIa (eg, NovoSeven®,
AryoSeven®) contains activated factor VII, which
bypasses the intrinsic clotting pathway to directly
stimulate clot formation. The standard dose is 90
mcg/kg every 2 to 3 hours for 3 doses, but some
studies support a single higher dose of recombinant
factor VIIa of 270 mcg/kg.75-77 If further treatment is
required, continued doses of 90 mcg/kg every 2 to 3
hours can be administered,38 but if the 270 mcg/kg
dose is used, subsequent doses should be separated
by at least 6 hours.
As with clotting factor concentrates, treatment
Copyright © 2015 EB Medicine. All rights reserved.
FEIBA Versus Recombinant Factor VIIa For Refractory
Bleeding In Patients With Inhibitors
Large randomized trials have demonstrated that
FEIBA and rFVIIa are equally efficacious in treating bleeding in patients with hemophilia who have
high-titer inhibitors.84 However, some individual
patients may respond better to one bypassing
agent over another.14 Additionally, rFVIIa may be
a preferred choice for patients with factor IX deficiency and inhibitors, as these patients have a high
incidence of allergic reactions to exposure to factor
IX. Similarly, rFVIIa is preferred for patients with
factor VIII deficiency with inhibitors if one is limiting exposure to factor VIII while awaiting a decrease
in inhibitor titer.
The presence of inhibitors is a risk factor for
severe bleeding, and 10% to 20% of bleeding events
in patients with hemophilia with inhibitors will not
be controlled with a single bypassing agent.85 For
persistent bleeds, a strategy of initially increasing the
dose and/or frequency of bypassing product followed by switching or alternating bypassing agents is
recommended.23,32 In a series of 20 patients, sequential therapy with alternating FEIBA and rFVIIa every
6 hours was found to be effective for difficult-to-treat
bleeds and it was deemed safe, as it did not result
in thrombosis, thrombocytopenia, or disseminated
intravascular coagulation.86 Serial/alternating bypass
therapy should be reserved for life-threatening or
limb-threatening bleeds, and a pediatric hematologist
should be involved in all such cases.74
Patients With Mild Hemophilia A: Treatment
With Desmopressin
For patients with mild hemophilia A, desmopressin
can be used in lieu of factor concentrate to effectively
raise the serum concentration of factor VIII by mobiliz14
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ing intrinsic stores of vWF and factor VIII. Dosing is
the same as that for vWD, and desmopressin can be
administered intravenously (0.3 mcg/kg) or intranasally (150 mcg for patients weighing < 50 kg, 300 mcg for
patients weighing ≥ 50 kg) with excellent effect, raising
factor VIII twofold to sixfold from baseline, which is
generally adequate for most simple bleeds.87,88 As with
vWD, patients with mild hemophilia A should have a
desmopressin challenge to ensure that they are responsive to desmopressin therapy before this is used as a
first-line treatment.89 In contrast to hemophilia A, there
is virtually no evidence to support use of desmopressin
in the treatment of mild hemophilia B.90
of a specific protein factor, it is an appealing target for
gene therapy, which has shown significant promise in
early small trials, though significantly more research
is needed in this area.96,97
Disposition
Disposition depends on the type and severity of
bleeding, and recommended disposition by bleed
type is included in Table 4 (see page 9). For patients
who will be sent home, family reliability and comfort
with monitoring, and, potentially, with home factor
infusion, is critical, as is regular communication with
a hematologist. A clear point of contact with a hematologist is a critical component of safe discharge.
Patients In Resource-Limited Settings
While recombinant factor products are clearly
the preferred agents, where available, and virally
inactivated plasma-derived products are the second
choice, in settings where factor VIII or factor IX concentrates are not available and cannot be obtained,
cryoprecipitate can be used to treat hemophilia A
and fresh-frozen plasma can be used to treat hemophilia B.44,91,92 Cryoprecipitate, which contains high
levels of factor VIII and vWF, may be used initially
at a dose of 1 bag/6 kg body weight, to a maximum
of 10 units, to treat acute bleeding in patients with
hemophilia A. For patients with factor IX deficiency
in these settings, fresh-frozen plasma may be administered at a dose of 15 mL/kg as an initial dose. For
patients with severe vWD in the resource-limited
setting, cryoprecipitate can be used at the same
dosing noted for hemophilia A.1 In settings where
there is some access to factor concentrates, but such
access is limited and cost is a major constraint, emergency clinicians can refer to the World Federation of
Hemophilia guidelines for more reserved dosing of
factor for various types of bleeds.93
Summary
Hemophilia and vWD are the most common inherited bleeding disorders. The central tenet of management of bleeding in hemophilia is to administer
the appropriate factor concentrate early and at an
appropriate dose to achieve hemostasis. Factor VIII
should be administered for patients with hemophilia
A, factor IX for patients with hemophilia B, and
a bypassing agent (FEIBA or rFVIIa) for patients
with inhibitors. For vWD, bleeding is typically less
severe. If treatment is required, most patients with
type 1 vWD will respond to desmopressin, but a
demonstrated response to this therapy is necessary
before relying on it. Alternatively, a vWF concentrate
can be used. Most patients with hemarthrosis can
be managed as outpatients after initial assessment.
Patients with more-severe hemorrhages should be
admitted to the hospital for tight control of factor
levels and close monitoring for sequelae of bleeds.
Consultation with the patient’s primary hematologist can provide invaluable support in the evaluation and management of patients with established
diagnoses. For patients who do not have a known
diagnosis of a bleeding disorder and present to the
ED with atypical bleeding, PT/PTT/fibrinogen and
CBC represent the most important initial screening
laboratory tests, and the results of these studies guide
more-specific testing and management. Disposition
can then be determined in collaboration with a hematologist for inpatient admission versus discharge to
home with close hematology clinic follow-up.
Controversies And Cutting Edge
In the United States, the annual cost of care for patients with hemophilia is high, with a 2015 study estimating the mean cost of care (annually per patient)
for patients with severe hemophilia on episodic treatment to be $201,471, and $301,392 for patients on factor prophylaxis. The cost of factor concentrates represent the greatest contributor to this cost.94 For patients
on prophylactic factor infusions, frequent self-infusion, up to 4 times weekly, is often required because
of the relatively short half-life of factors VIII and IX in
circulation. Efforts are underway to synthesize factor
fusion proteins and PEGylated factor products with
longer serum half-lives, which would require much
less frequent dosing and potentially improve compliance and quality of life. Two such products are now
approved, Eloctate® (factor VIII) and Alprolix® (factor
IX).95 In addition, because hemophilia represents a
disease resulting from diminished levels or absence
September 2015 • www.ebmedicine.net
Case Conclusions
You gave the 7-year-old boy 100 units/kg of BeneFIX®
factor IX immediately to bring his factor level to 100%. A
head CT scan was subsequently obtained demonstrating
a small subdural hematoma without overlying skull fracture. He was admitted to the intensive care unit under the
neurosurgical service for serial neurological examinations
for 2 days, and he continued to receive factor IX infu15
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Risk Management Pitfalls In Hemophilia And
Von Willebrand Disease In Children
1. “I wanted to confirm on imaging that an intracranial bleed was actually present before I
infused factor.”
Factor should be administered immediately
upon suspicion of intracranial hemorrhage.
Delay in factor administration has the potential
to increase morbidity and mortality, and the risk
of factor administration is minimal. When in
doubt, infuse factor.
7. “This patient with hemophilia did not bring
his factor concentrate with him to the ED, and
we don’t stock his brand of concentrate here,
so we should wait until his factor arrives from
home to treat his hemarthrosis.”
There is no clear evidence that switching
between factor brands increases the risk of
inhibitor development. Depending on the
severity of the bleed and the anticipated delay
in acquiring the patient’s home product,
administration of another brand of product
may be appropriate. However, recombinant
products are preferred, rather than switching
from a recombinant product to a plasma-derived
product.
2. “This patient had a high-titer inhibitor, so I
gave higher doses of factor to overcome the
inhibitor to try to stop the bleeding.”
High-titer inhibitors (> 5 BU/mL) cannot be
overcome with higher doses of factor concentrates.
A bypassing agent (FEIBA or rFVIIa) is required to
treat bleeding in these patients.
8. “This patient with vWD needs emergent surgery. We can just give desmopressin preoperatively, and that should be fine.”
This may be true; however, a documented
response to desmopressin with an appropriate
increase in vWF is necessary before relying on
this therapy. If the patient has not been shown
to be responsive to desmopressin (either has not
had a test confirming desmopressin response or
has had a test which showed nonresponsiveness
to desmopressin), a factor product containing
large concentrations of vWF is indicated rather
than using desmopressin.
3. “This patient with severe hemophilia only had
minimal head trauma and has a normal examination. He can’t have a significant ICH.”
Most patients with hemophilia with ICH report
only minor trauma history, and many will have
a completely normal physical examination.
4. “This infant has no family history of hemophilia, so he can’t have hemophilia.”
Thirty percent of cases of hemophilia are new
mutations without any family history. Maintain
a high index of suspicion for hemophilia in
a male patient with significant bleeding, and
maintain a low threshold for screening PT/PTT.
9. “My patient with hemophilia is complaining
of numbness along the lateral thigh and is having trouble extending his right leg. We should
get a neurology consultation and head imaging, as this may be a stroke.”
These are typical presenting signs of an iliopsoas
hemorrhage. Treatment should be centered on
factor replacement to 80%, and imaging should
be directed at the psoas region by CT, MRI, or
ultrasound. Significant blood loss in this area is
possible, and transfusion may be required.
5. “We don’t have any factor VIII concentrates
available here. There is nothing I can do for
this patient with hemophilia A and worsening
hemarthrosis.”
In settings where factor VIII concentrate is
unavailable, cryoprecipitate (which contains
high levels of factor VIII) may be used at a dose
of 1 bag/6 kg body weight, to a max of 10 bags,
initially to treat acute bleeding.
10. “This patient has menorrhagia and easy bruising, and her mother and sister have a history of
similar symptoms. She already had a normal
von Willebrand panel test, so she can’t have
vWD.”
Many factors affect measured vWF levels,
including stress, illness, exercise, reproductive
hormone levels, and specimen storage and
transport. False negatives are common, and a
single negative test does not rule out the disease,
especially in patients with signs and symptoms
suggestive of the disease.
6. “This patient’s factor VIII level is low. He must
have hemophilia A.”
This is likely the case, but he may also have
type 2N or type 3 vWD. Distinguishing
between these diseases will help guide factor
replacement, and a von Willebrand panel should
be sent.
Copyright © 2015 EB Medicine. All rights reserved.
16
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sions of 100 units/kg for 7 days, after which he was given
factor infusions of 50 units/kg for 7 days before resuming
his normal prophylaxis regimen. He had no long-term
neurologic sequelae.
You gave the 17-year-old boy a single dose of 270
mcg/kg of rFVIIa (NovoSeven®). A compression bandage
was applied to the affected knee, and he was discharged
to home from the ED with hematology clinic follow-up
the next day. At follow-up, his swelling was starting to
improve, so no further rFVIIa was given. Within 1 week,
swelling and function had improved.
The 16-year-old patient with menorrhagia was told
that she likely had von Willebrand disease, and arrangements were made for a desmopressin challenge test in
the hematology clinic. After discussion with the patient
and her family and review for contraindications to oral
contraceptive pills, the patient was started on an oral
contraceptive pill, and her periods subsequently normalized within 2 months.
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Mannucci PM, Mancuso ME, Santagostino E. How we choose
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Lovdahl S, Henriksson KM, Baghaei F, et al. Incidence,
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7.* Yawn B, Nichols WL, Rick, ME. Diagnosis and management
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Heamophilia. 2013;19(4):602-606. (Retrospective chart review;
24 patients)
35. Antunes SV, Vicari P, Cavalheiro S, et al. Intracranial haemorrhage among a population of haemophilic patients in Brazil.
Haemophilia. 2003;9(5):573-577. (Retrospective cohort study;
401 patients, 45 with intracranial hemorrhage)
51. Mannucci PM. Treatment of haemophilia: building on
strength in the third millenium. Haemophilia. 2011;17(Suppl
3):1-24. (Review)
52. Branchford BR, Monahan PE, Di Paola J. New developments
in the treatment of pediatric hemophilia and bleeding disorders. Curr Opin Pediatr. 2013;25(1):23-30. (Review)
36. Sun GH, Aauger KA, Aliu O, et al. Posttonsillectomy hemorrhage in children with von Willebrand disease in hemophilia. JAMA Otolaryngol Head Neck Surg. 2013;139(3):245-249.
(Retrospective chart review; 508 patients)
53. Nguyen DD, Takenaka K. Evaluation and management of
hereditary hemophilia in the emergency department. J Emerg
Nurs. 2009;35(5):437-441. (Review)
37. Kavakli K, Yesilipek A, Antmen B, et al. The value of early
treatment in patients with haemophilia and inhibitors. Haemophilia. 2010;16(3):487-494. (Retrospective cohort study; 129
bleeding episodes)
54. Alexander M, Barnes C, Barnett P. Prospective audit of
patients with haemophilia: Bleeding episodes and management. J Pediatr and Child Health. 2012;48(2):177-179. (Prospective cohort study; 66 children)
38. Sørensen B, Dargaud Y, Kenet G, et al. On-demand treatment
of bleeds in haemophilia patients with inhibitors; strate-
Copyright © 2015 EB Medicine. All rights reserved.
18
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55. Petrini P. Treatment strategies in children with hemophilia.
Pediatr Drugs. 2002;4(7):427-437. (Review)
patient with a factor VIII inhibitor. Blood. 2009;113(1):11-17.
(Review)
56. Kisker CT, Burke C. Double-blind studies on the use of steroids in the treatment of acute hemarthrosis in patients with
hemophilia N Engl J Med. 1970;282(12):639-642. (Review)
74. Collins PW, Chalmers E, UK Hemophilia Centre Doctors, et
al. Diagnosis and treatment of factor VIII and IX inhibitors
in congenital haemophilia: (4th edition). UK Haemophilia
Centre Doctors Organization. Br J Haematol. 2013;160(2):153170. (Practice guidelines)
57. Rodriguez-Merchan E. Acute compartment syndrome in
haemophilia. Blood Coagul Fibrinolysis. 2013;24(7):677-682.
(Systematic review; 34 patients)
75. Pan-Petesch B, Laguna P, Mital A, et al. Single-dose (270 ug/
kg) recombinant activated factor VII for the treatment and
prevention of bleeds in haemophilia A patients with inhbitors: experience from seven European haemophila centers.
Haemophilia. 2009;15(3):760-765. (Retrospective study and
expert recommendation; 8 patients)
58. Ashrani AA, Osip J, Christie B, et al. Iliopsoas haemorrhage
in patients with bleeding disorders--experience from one
centre. Haemophilia. 2003;9(6):721-726. (Retrospective review;
297 patients)
59. Balkan C, Kavakli K, Karapinar D. Iliopsoas haemorrhage in
patients with haemophilia: results from one centre. Haemophilia. 2005;11(5):463-467. (Chart review; 146 patients)
76. Santagostino E, Mancuso ME, Rocino A, et al. A prospective
randomized trial of high and standard dosages of recombinant factor VIIa for treatment of hemarthroses in hemophiliacs with inhibitors. J Thromb Haemost. 2006;4(2):367-371.
(Randomized trial; 20 patients)
60. Fernandez-Palazzi F, Hernandez SR, De Bosch NB, et
al. Hematomas within the iliopsoas muscles in hemophilic patients: the Latin American experience. Clin Orthop.
1996;328:19-24. (Retrospective cohort study)
77. Laguna P, Mital A. Single higher dose of recombinant activated factor VII in the treatment of hemorrhages in patients
with hemophilia complicated by inhibitors. Adv Clin Exp
Med. 2012;21(4):519-524. (Prospective trial; 7 patients)
61. Revel-Vilk S, Golomb MR, Achonu C, et al. Effect of intracranial bleeds on the health and quality of life of boys with
hemophilia. J Pediatr. 2004;144(4):490-495. (Case-control
study; 172 patients, 18 with intracranial hemorrhage)
78. Parameswaran R, Shapiro AD, HTRS Registry Investigators, et al. Dose effect and efficacy of rFVIIa in the treatment
of haemophilia patients with inhbitors: analysis from the
Hemophilia and Thrombosis Research Society Registry.
Haemophilia. 2005;11(2):100-106. (Retrospective chart review;
38 patients, 555 bleeding episodes)
62. Klinge J, Auberger K, Auerswald G, et al. Prevalence and
outcome of intracranial haemorrhage in haemophiliacs
- a survey of the paediatric group of the German Society of Thrombosis and Haemostasis (GTH). Eur J Pediatr.
1999;158(Suppl 3):S162-S165. (Retrospectve cohort study;
744 patients, 30 intracranial hemorrhages)
79. Young G, Shapiro AD, Walsh CE, et al. Patient/caregiverreported recombinant factor VIIa(rFVIIa) dosing: home
treatment of acute bleeds in the Dosing Observational Study
in Hemophilia (DOSE). Haemophilia. 2012;18(3):392-399.
(Prospective observational study; 158 bleeding episodes)
63. Andes WA, Wulff K, Smith WB. Head trauma in hemophilia.
A prospective study. Arch Intern Med. 1984;144(10):1981-1983.
(Prospective study; 140 patients)
64. Malec LM, Sidonio RF Jr, Smith KJ, et al. Three costutility analyses of screening for intracranial hemorrhage
in neonates with hemophilia. J Pediatr Hematol Oncol.
2014;36(6):474-479. (Cost-utility analysis)
80. Holme PA, Glomstein A, Grønhaug S, et al. Home treatment with bypassing products in inhitor patients: a 7.5 year
experience. Haemophilia. 2009;15(3):727-732. (Prospective
observational study; 10 patients)
65. Iorio A, Marchesini E, Marcucci M, et al. Clotting factor
concentrates given to prevent bleeding and bleeding related
complications in people with hemophilia A. Cochrane Database Syst Rev. 2011;9:CD003429. (Systematic review)
81. O’Connell KA, Wood JJ, Wise RP, et al. Thromboembolic
adverse events after use of recombinant human coagulation
factor VIIa. JAMA. 2006;295(2):293-298. (Database review;
431 adverse event reports)
66. Manco-Johnson MJ, Abshire TC, Shaprio AD, et al. Prophylaxis versus episodic treatment to prevent joint disease in
boys with severe hemophilia. N Engl J Med. 2007;357(6):535544. (Randomized controlled trial; 65 patients)
82. Neufeld EJ, Saxena K, Kessler CM, et al. Dosing, efficacy, and
safety of recombinant factor VIIa (rFVIIa) in pediatric versus
adult patients: the experience of the Hemostasis and Thrombosis Research Society (HTRS) Registry (2004-2008). Pediatr
Blood Cancer. 2013;60:1178-1183. (Retrospective database
review; 284 children with 1712 episodes, 146 adults with
329 episodes)
67. Nagel K, Walker I, Decker K, et al. Comparing bleed frequency and factor concentrate use between haemophilia A and B
patients. Haemophilia. 2011;17(6):872-874. (Data analysis; 78
patients)
83. Konkle BA, Ebbeson LS, Erhardtsen E, et al. Randomized,
prospective clinical trial of recombinant factor VIIa for secondary prophylaxis in hemophilia patients with inhibitors. J
Thromb Haemost. 2007;5(9):1904-1913. (Randomized prospective trial; 38 patients)
68. Pasi KJ. Haemophila and adolescence. Haemophilia.
2011;17(Suppl. 3):1-24. (Review)
69. Khair K, Baker K, Mathias M, et al. Intranasal desmopressin
(Octim): a safe and efficacious treatment option for children
with bleeding disorders. Haemophilia. 2007;13(5):548-551.
(Prospective noncontrolled single-arm medication trial; 20
children)
84. Astermark J, Donfield, SM, Di Michele DM, et al. A randomized comparison of bypassing agents in hemophilia complicated by an inhibitor: the FEIBA NovoSeven Comparative
(FENOC) Study. Blood. 2007;109(2):546-551. (Randomized
trial; 96 bleeding episodes in 48 patients)
70. Di Michele D. Inhibitor treatment in haemophilias A and
B: inhibitor diagnosis. Haemophilia. 2006;12(Suppl 6):37-42.
(Review)
85. Gringeri A, Fischer K, Karafoulidou A, et al. Sequential
combined bypassing therapy is safe and effective in the treatment of unresponsive bleeding in adults and children with
haemophilia and inhibitors. Haemophilia. 2011;17(4):630-635.
(Retrospective database review; 11 patients)
71. Oren H, Yaprak I, Irken G. Factor VIII inhibitors in patients
with hemophilia A. Acta Haematologica. 1999;102(1):42-46.
(Retrospectve chart review; 58 patients)
72. Hay CR, Palmer B, Chalmers E, et al. Incidence of factor
VIII inhibitors throughout life in severe hemophilia A in the
United Kingdom. Blood. 2011;117(23):6367-6370. (Database
review; 2528 patients)
86. Schneiderman J, Nugent DJ, Young G. Sequential therapy
with activated prothrombin complex concentrate and recombinant factor VIIa in patients with severe haemophilia and
inhibitors. Haemophilia. 2004;10(4):347-351. (Retrospective
73. Kempton CL, White GC. How we treat a hemophilia A
September 2015 • www.ebmedicine.net
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1. Which of the following statements about vWD
is TRUE?
a. Most cases of vWD show X-linked inheritance.
b. Von Willebrand disease always represents a quantitative deficiency in vWF.
c. Up to 1% of the United States population meets laboratory criteria for diagnosis of
vWD, but far fewer than this have symptomatic disease.
d. Most patients with vWD have bleeding episodes similar to those seen in severe hemophilia.
chart review; 20 patients)
87. 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 Willedbrand disease. J Pediatr. 2002;140(5):595-599.
(Open-label single-dose trial; 25 patients)
88. Santagostino E. Managing mild haemophila A. Haemophilia.
2011;17(Suppl. 3):21-24. (Review)
89. Revel-Vilk S, Blanchette VS, Sparling C, et al. DDAVP challenge tests in boys with mild/moderate haemophilia A. Br J
Haematol. 2001;117(4):947-951. (Retrospective chart review;
62 patients)
90. Ehl S, Severin T, Sutor AH. DDAVP (desmopressin; 1-deamino-cys-8-D-arginine-vasopressin) treatment in children with
hemophilia B. Br J Haematol. 2000;111(4):1260-1262. (Prospective trial; 4 patients.)
2. Which of the following statements about hemophilia is TRUE?
a. Hemophilia A is the most common inherited bleeding disorder in the United States.
b. De novo mutations resulting in hemophilia are extremely rare (< 1%). In the vast majority of cases, a family history of hemophilia can be elicited.
c. Hemophilia causes isolated prolongation of the measured PT.
d. Patients classified as having severe hemophilia have < 1% of normal clotting factor level activity.
91. Chuansumrit A. Treatment of haemophilia in the developing
countries. Haemophilia. 2003;9(4):387-390. (Review)
92. De Kleijn P, Odent T, Berntorp E, et al. Differences between
developed and developing countries in paediatric care in
haemophilia. Haemophilia. 2012;18 Suppl 4:94-100. (Review)
93. Treatment Guidelines Working Group. Guidelines for the
management of hemophilia. Montreal, Quebec: World Federation of Hemophilia. 2005. (Consensus guidelines)
94. Zhou ZY, Koerper MA, Johnson KA, et al. Burden of illness:
direct and indirect costs among persons with hemophilia A
in the United States. J Med Econ. 2015;18(6):457-465. (Multicenter retrospective review and data analysis; 222 patients)
95. Powell JS, Pasi KJ, Ragni MV, et al. Phase 3 study of recombinant factor IX Fc fusion protein in hemophilia B. N Engl J
Med. 2013;369(24):2313-2323. (Phase 3 nonrandomized openlabel study; 123 patients)
3. A 3-year-old boy with no known history or
family history of a bleeding disorder presents
with a large left ankle hemarthrosis after mild
trauma. What are the initial considerations
when evaluating this patient?
a. This patient cannot have hemophilia given the absence of a history of this disease.
b. This patient cannot have hemophilia, as he is already aged 3 years and has had no prior bleeding episodes.
c. Screening CBC, PT/PTT/fibrinogen should be sent to evaluate for a bleeding disorder.
d. Factors VIII, IX, XI, and XII levels along with a vWD panel and thrombin time should be sent on first screening in the ED.
96. Sharma A, Easow Mathew M, Sriganesh V, et al. Gene
therapy for haemophilia. Cochrane Database Syst Rev.
2014;11:CD010822. (Systematic review)
97. Nathwani AC, Tuddenham EG, Rangarajan S, et al. Adenovirus-associated virus vector-mediated gene transfer in hemophilia B. N Engl J Med. 2011;365(25):2357-2365. (Prospective
cohort study; 6 participants)
CME Questions
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Copyright © 2015 EB Medicine. All rights reserved.
4. A 7-year-old boy with severe hemophilia A
without inhibitors presents to the ED with a
clinical examination that is consistent with a
right knee hemarthrosis. What is the appropriate management of this patient?
a. A single dose of factor VIII concentrate at 20 to 40 units/kg with repeat doses at 12-hour to 24-hour intervals until symptoms have resolved.
b. Pain control with ibuprofen and opioids.
c. Perform a CT or MRI of the knee to confirm the diagnosis.
d. Aspirate the knee joint to confirm the diagnosis.
20
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5. A 16-year-old boy with hemophilia A who is
on 3-times-weekly prophylaxis presents to
the ED with thigh and hip pain and a flexion
contracture at the right hip that started while
he was sitting in class at school today. He has
paresthesias in the femoral nerve distribution
on the affected side. Which of the following
should be considered in this case?
a. Imaging by CT or MRI is not helpful in confirming the diagnosis or following for subsequent resolution.
b. Major, life-threatening bleeding may result from this type of bleed and hemoglobin/ hematocrit levels should be checked and serially followed, if decreased.
c. The patient should be encouraged to ambulate immediately to improve range of motion in the affected muscle.
d. Factor replacement should be dosed at the same level as for hemarthrosis.
8. A 9-year-old girl weighing 28 kg with a history
of frequent nosebleeds underwent evaluation by a hematologist. She was found to have
laboratory tests consistent with type I vWD,
and was also found to be responsive to desmopressin. She is now complaining of worsening
epistaxis. Which of the following is a reasonable therapeutic recommendation?
a. Administer an intravenous vWF concentrate at an initial dose of 40 to 60 units/kg.
b. Administer intranasal desmopressin at a dose of 150 mcg. She should be told to drink plenty of water in order to stay well hydrated.
c. Administer intranasal desmopressin at a dose of 300 mcg and restrict fluid intake in the 24 hours following treatment.
d. Administer intranasal desmopressin at a dose of 150 mcg and restrict fluid intake to maintenance levels for 24 hours following treatment.
6. A 13-year-old boy with hemophilia B without
inhibitors presents to the ED after being struck
in the head by a baseball at high speed. He
was not wearing a helmet at the time of the
incident. He is on prophylaxis twice a week,
and he received his last dose of factor 3 days
ago. He is presently awake and alert. The first
step in initial management in the ED for this
patient is:
a. Immediate administration of factor IX concentrate at a dose of 50 units/kg
b. CT scan of the head as soon as available, followed by factor administration if an intracranial hemorrhage is evident on CT
c. Immediate administration of factor IX concentrate at a dose of 100 units/kg
d. Administration of rFVIIa at a dose of 270 mcg/kg
9. A 17-year-old girl with type 2 vWD that is not
responsive to desmopressin presents to the ED
with appendicitis. She requires open appendectomy. What is the appropriate preoperative
management of this patient?
a. Administer 300 mcg of desmopressin via the intranasal route.
b. Administer 0.3 mcg/kg of desmopressin via the intravenous route.
c. Administer vWF-containing concentrate 40 to 60 ristocetin cofactor units/kg via the intravenous route.
d. Administer factor IX 40 to 60 units/kg via the intravenous route.
10. A 15-year-old boy with hemophilia A and a
high-titer inhibitor presents to the ED with a
large intramuscular bleed into his left calf. Appropriate management of this patient includes:
a. Administration of factor VIII concentrate at a dose of 20 to 40 units/kg, followed by hospital admission for monitoring and repeat administrations, as needed
b. Administration of factor VIII concentrate at
a dose of 100 units/kg, followed by discharge to home with hematology clinic follow-up within 1 week
c. Administration of either FEIBA 50 to 75 units/kg or rFVIIa (90 mcg/kg every 2-3 hours for 3 doses, or a single dose of 270 mcg/kg), followed by hospital admission for monitoring and repeat administrations as needed
d. Administration of either intravenous FEIBA 50 to 75 units/kg or rFVIIa 270 mcg/kg followed by discharge to home with hematology follow-up within 1 week
7. Which of the following is a contraindication to
adjunctive use of antifibrinolytics in patients
with bleeding disorders?
a. Bleeding localized to a mucosal site (eg, dental bleeding)
b. An underlying diagnosis of type 1 vWD with heavy menses that is not responsive to oral contraceptive pills
c. The presence of hematuria
d. An underlying diagnosis of mild hemophilia
September 2015 • www.ebmedicine.net
21
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Upcoming Issues In
Pediatric Emergency Medicine Practice
Acute Management Of Inhaled
Foreign Bodies In Pediatric Patients
In The Emergency Department
Use Of Diagnostic Ultrasound In The
Emergency Department To Assess
Conditions In Pediatric Patients
While much is known about the management of
inhaled foreign bodies, it remains a significant risk to
young children, affecting thousands every year. There
is a substantial amount of literature on the topic in
otolaryngology and surgery; however, there is limited
emergency medicine literature addressing inhaled
foreign bodies. This review discusses the etiology,
pathophysiology, diagnosis, and management of inhaled
foreign bodies. For the purposes of this review, inhaled
foreign bodies will refer to foreign bodies (both organic
and inorganic) located in the posterior nasopharynx,
larynx, trachea, and bronchi. The focus will be on risk
factors and clinical clues to the diagnosis, as well as
emergent management of inhaled foreign bodies.
Performing a diagnostic ultrasound at the point of care in
the emergency department can answer focused clinical
questions in a rapid manner. Over the last 20 years, the use of
ultrasound in the emergency department has become a core
requirement in emergency medicine residencies and some
pediatric emergency medicine fellowships. In the pediatric
setting, the growth has been slower, but there is increasing
demand for these studies, given the absence of ionizing
radiation with ultrasound. This review focuses on the current
evidence for the most common indications for diagnostic
ultrasound. Evidence in the pediatric setting is presented,
or extrapolated from adult literature where pediatric
evidence is scarce. The limitations of diagnostic ultrasound
in the emergency department as well as current trends,
controversies, and future directions are discussed.
Time- And Cost-Effective Strategies
• Chest radiography is the first line of investigation
in the management of a suspected inhaled foreign
body. Normal chest radiography does not exclude
the diagnosis of an inhaled foreign body, and thus,
additional investigations are sometimes necessary.
• Rigid bronchoscopy is considered the standard of
care in most centers when evaluating a child with
possible foreign body inhalation. This procedure
allows for better visualization of the airways,
removal of the foreign body with a variety of
instruments, and better control of bleeding after
removal. Flexible bronchoscopy is routinely used
to evaluate a child with recurrent pneumonia or
chronic cough, but recently has been shown to
be effective and safer than rigid bronchoscopy for
excluding the presence of a foreign body in patients
with low suspicion of foreign body inhalation.
• The American Academy of Pediatrics recommends
that anticipatory guidance be provided to parents
when their child is 6 months of age. At this age,
children begin to develop the fine motor skills
needed to pick up small objects. It is important to
advise parents not to offer small food items, such
as peanuts, until the child is old enough to chew
properly. It is also important to advise parents to
discourage their child from eating while running,
laughing, or playing, and to encourage their child to
sit upright.
Copyright © 2015 EB Medicine. All rights reserved.
Risk Management Pitfalls In The Use Of Ultrasound For
Diagnostic Purposes In The Emergency Department
1. “While caring for a child with possible intussusception,
I couldn’t obtain a good view of the abdomen on
ultrasound, so I figured it was not intussusception, and I
discharged the patient.”
Emergency ultrasound is meant to answer yes or no
questions. If your examination is technically inadequate
or you are unsure that you adequately answered your
clinical question based on your images, then ask for a
radiology-performed ultrasound or another available
imaging study.
2.
3.
22
“In a pediatric patient with cardiac arrest, there was
no evidence of cardiac activity on ultrasound, so I
recommended that we should discontinue resuscitation
efforts.”
While there are data on adults that ultrasound can be
used as a prognostic indicator in cardiac arrest, there
are insufficient data in children for it be used alone to
prognosticate outcomes in pediatric cardiac arrest.
“The patient had a pericardial effusion and was
tachycardic. However, I saw no signs of cardiac
tamponade on ultrasound, so I did not consult cardiology
or cardiac surgery.”
Cardiac tamponade is a clinical diagnosis. If the patient
has a pericardial effusion and is unstable, then cardiac
tamponade should be considered despite the lack of
ultrasound findings of tamponade.
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Physician CME Information
Date of Original Release: September 1, 2015. Date of most recent review: August 15,
2015. Termination date: September 1, 2018.
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