Peds0811 Bleeding Disorders

Evidence-Based Emergent
Management Of Bleeding
Disorders
Abstract
hildren with both congenital (eg, hemophilia or von Willebrand

disease) and acquired (eg, immune thrombocytopenia [ITP])
bleeding disorders frequently present to the emergency department
(ED) with a wide variety of bleeding-related problems ranging from
petechiae to intracranial hemorrhage (ICH).In many instances, such
as hemophilia or von Willebrand disease, the bleeding disorder has
been previously diagnosed because of an abnormal family history or
bleeding in infancy. However, in other instances, a patient may present with abnormal bleeding symptoms (such as a patient with ITP),
and it is the role of the emergency clinician to facilitate the diagnosis
and initiate therapy.
This Pediatric Emergency Medicine Practice article provides up-todate guidelines and an evidence-based review of the most common
bleeding disorders and management of specific bleeding emergencies in the ED.
Case Presentation
A 5-year-old girl with type 3 von Willebrand disease presents to the ED
with epistaxis after a forceful sneeze. It has not resolved after 30 minutes of
direct pressure. You recall that most patients with von Willebrand disease
have mild symptoms such as easy mucosal bleeding, but this patient is
still bleeding profusely out of both nares and is beginning to look pale with
AAP Sponsor
Martin I. Herman, MD, FAAP, FACEP
Professor of Pediatrics, UT College
of Medicine, Assistant Director of
Emergency Services, Lebonheur
Childrens Medical Center,
Memphis, TN
Medicine, University of Medicine

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

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

Ran D. Goldman, MD
PALS-NF
Associate Professor, Department
Pediatric Emergency Medicine
Jeffrey R. Avner, MD, FAAP
of
Pediatrics,
University
of
Toronto;
Attending Physician, Kapiolani
Professor of Clinical Pediatrics
Division of Pediatric Emergency
Medical Center for Women &
and Chief of Pediatric Emergency
Medicine and Clinical Pharmacology
Children; Associate Professor of
Medicine, Albert Einstein College
and Toxicology, The Hospital for Sick
Pediatrics, University of Hawaii
of Medicine, Childrens Hospital at
Children,
Toronto,
ON
John A. Burns School of Medicine,
Montefiore, Bronx, NY
Honolulu, HI; Pediatric Advanced
T. Kent Denmark, MD, FAAP, FACEP Mark A. Hostetler, MD, MPH
Life Support National Faculty
Clinical Professor of Pediatrics and
Medical Director, Medical Simulation
Representative, American Heart
Emergency Medicine, University
Center; Associate Professor of
Association, Hawaii and Pacific
of Arizona Childrens Hospital
Emergency Medicine and Pediatrics,
Island Region
Division of Emergency Medicine,
Loma Linda University Medical
Phoenix, AZ
Andy Jagoda, MD, FACEP
Center and Childrens Hospital,
Professor and Chair, Department
Loma Linda, CA
Madeline Matar Joseph,
of Emergency Medicine, Mount
MD, FAAP, FACEP
Michael J. Gerardi, MD, FAAP,
Sinai School of Medicine; Medical
Associate Professor of Emergency
FACEP
Director, Mount Sinai Hospital, New
Medicine and Pediatrics, Assistant
Clinical Assistant Professor of
York, NY
Editorial Board
August 2011
Gary R. Strange, MD, MA, FACEP

Professor and Head, Department
of Emergency Medicine, University
of Illinois, Chicago, IL
Christopher Strother, MD
Assistant Professor,Director,
Undergraduate and Emergency
Simulation, Mount Sinai School of
Medicine, New York, NY
FAAEM
Professor of Emergency Medicine
and Pediatrics; Chairman,
Adam Vella, MD, FAAP
Department of Emergency Medicine, Assistant Professor of Emergency
The University of Texas Houston
Medicine, Director Of Pediatric
Medical School, Houston, TX
Emergency Medicine, Mount Sinai
Robert Luten, MD
School of Medicine, New York, NY
Professor, Pediatrics and
Michael Witt, MD, MPH, FACEP,
Emergency Medicine, University of
FAAP
Florida, Jacksonville, FL
Medical Director, Pediatric
Ghazala Q. Sharieff, MD, FAAP,

Emergency Medicine, Elliot Hospital
FACEP, FAAEM
Manchester, NH
Associate Clinical Professor, Childrens
Hospital and Health Center/University Research Editor
of California, San Diego; Director
Lana Friedman, MD
of Pediatric Emergency Medicine,
Fellow, Pediatric Emergency
California Emergency Physicians, San
Medicine, Mount Sinai School of
Diego, CA
Medicine, New York, NY
Accreditation: EB Medicine is accredited by the ACCME to provide continuing medical education for physicians. Faculty Disclosure: Dr. Fullerton, Dr. Place, Dr. Dean, Dr. Joseph, Dr. Sharieff, Dr.
Whiteman, and their related parties report no significant financial interest or other relationship with the manufacturer(s) of any commercial product(s) discussed in this educational presentation.
Commercial Support: This issue of Pediatric Emergency Medicine Practice did not receive any commercial support.
mild tachycardia. Youre surprised by the severity of the

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

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

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

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

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

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

Ovid MEDLINE and PubMed were searched for
literature (published from 1960 to the present) on
bleeding disorders with a focus on pediatric patients. Terms used in the search included but were
not limited to: bleeding disorder, coagulation disorder,
ITP, idiopathic thrombocytopenia, immune thrombocytopenia, hemophilia, and von Willebrand disease. The
National Guideline Clearinghouse (www.guidelines.gov) and the Cochrane Database of Systematic
Reviews as well as the websites of the American
Table Of Contents
Abstract........................................................................ 1
Case Presentation.......................................................1
Critical Appraisal Of The Literature....................... 2
Epidemiology, Etiology, And Pathophysiology..... 2
Specific Bleeding Disorders...................................... 3
Coagulation Disorders.............................................. 3
Prehospital Care......................................................... 6
Emergency Department Evaluation........................ 6
Diagnostic Studies...................................................... 7
Therapy........................................................................ 9
Clinical Pathway: Emergency Department
Management Of Immune Thrombocytopenia.... 12
Management Of Hemophilia............................... 13
Management Of Hemophilia With Inhibitors.... 14
Management Of Von Willebrand Disease.......... 15
Risk Management Pitfalls In The Emergency
Treatment Of Bleeding Disorders....................... 17
Controversies/Cutting Edge.................................. 18
Cost-Effective Strategies.......................................... 18
Disposition................................................................ 19
Summary................................................................... 19
Case Conclusions..................................................... 19
References.................................................................. 20
CME Questions......................................................... 27
Pediatric Emergency Medicine Practice 2011
Epidemiology, Etiology, And

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

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

In the common pathway, factor Xa (in conjunc2
ebmedicine.net August 2011
tion with its cofactor, factor V) converts prothrombin (factor II) to thrombin. Finally, thrombin cleaves
fibrinogen into fibrin monomers that assemble into
fibrin fibers. Thrombin also facilitates the release of
von Willebrand factor from circulating von Willebrand factor/factor VIII complex, making it available for platelet activation and aggregation. (See
Figure 1.)

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

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

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

Immune thrombocytopenia is the most common
Coagulation Disorders
Hemophilia
A deficiency of any component of the coagulation
cascade, congenital or acquired, can cause a bleeding
disorder. The most common inheritable conditions
Table 1. Consensus Guidelines For Treatment Of Hemophilia And Von Willebrand Disease
Expert Panel
Subject of Guideline
Website
National Heart, Lung,

and Blood Institute, von
Willebrand Disease
Expert Panel and the
American Society of
Hematology3
The diagnosis, evaluation, and management of

von Willebrand disease
http://www.nhlbi.nih.gov/guidelines/vwd/index.htm
United Kingdom
Haemophilia Center
Doctors Organization
(UKHCDO)5
Guideline on the selection and use of therapeutic

products to treat hemophilia and other hereditary bleeding disorders
http://www.ukhcdo.org/UKHCDOguidelines.htm
United Kingdom
Haemophilia Center
Doctors Organization
(UKHCDO)8
Guidelines for management of patients with

hemophilia A and inhibitors
http://www.ukhcdo.org/UKHCDOguidelines.htm
World Federation of
Hemophilia6
Protocols for the treatment of hemophilia and von

Willebrand disease
http://www.wfh.org/2/docs/Publications/VWD_WomenBleedingDisorders/TOH-14-Protocols-Hemophilia-VWD-Revised2008.pdf
Italian Association of
Haemophilia Centres7
Evidence-based recommendations on the treatment of von Willebrand disease in Italy
Website not available
Association of Hemophilia Clinic Directors of

Canada9
Guidelines for management of patients with

hemophilia A and inhibitors
http://www.ahcdc.ca/documents/InhibitorGuide2010.pdf
August 2011 ebmedicine.net
are factor VIII deficiency (hemophilia A) and factor IX

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

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

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

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

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

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

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

Unlike many other coagulation factors, von Willebrand factor has no enzymatic activity. Von Willebrand factor is a large multimeric protein which
functions as a binding protein; it facilitates the binding of activated platelets to exposed subendothelial
collagen as well as platelet-to-platelet clumping
(through the glycoprotein Ib receptor). Von Wil-
Table 2. Platelet Disorders

Impaired Platelet Production
Platelet Destruction
Platelet Dysfunction
Infection with bone marrow suppression

(eg, HIV, parvovirus)
Leukemia
Nutritional deficiencies (eg, vitamin B12,
folate)
Medications (eg, NSAIDs, aspirin)
Congenital disorders (eg, Wiscott-Aldrich
syndrome, thrombocytopenia with absent
radius,)
Infection with bone marrow suppression
(eg HIV, parvovirus
Immune thrombocytopenia
Neonatal alloimmune thrombocytopenia
Sequestration from hypersplenism (eg, malaria)
Platelet consumption (eg, Kasabach-Meritt, disseminated intravascular coagulation, hemolyticuremic syndrome)
Medication (eg, heparin-induced thrombocytopenia, trimethroprim/sulfamethoxazole)
Platelet-vessel wall adhesion defects

(eg, Bernard-Soulier syndrome)
Platelet-platelet interaction defects
(eg, Glanzmanns thrombasthenia)
Acquired platelet dysfunction
Abbreviations: HIV, human immunodeficiency virus; NSAIDs, nonsteroidal anti-inflammatory drugs.
lebrand factor also provides a critically important

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

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

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

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

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

Acquired factor inhibitors can result in a significant bleeding diathesis.87 IgG4 autoantibodies that
bind and inactivate factor VIII have been the most
studied and occur most commonly in patients who
receive multiple factor replacement infusions (which
are subsequently recognized as foreign antigens).88,89
Inhibitors may also be seen with autoimmune and
collagen vascular disease, malignancy, and viral
infection.87 Antibody formation to other coagulation
factors may also occur in acquired von Willebrand
Acquired Coagulopathies
A variety of conditions may result in secondary
(or acquired) coagulopathies, including vitamin K
deficiency, warfarin ingestion, liver disease, disseminated intravascular coagulation (DIC), and acquired
factor inhibitors. (See Table 3.)
Hemorrhagic disease of the newborn (HDN), a
result of severe vitamin K deficiency, is seen in the
neonatal period.77 Because vitamin K is essential for
the production of functioning coagulation factors
II, VII, IX, and X, vitamin K deficiency can cause a
severe bleeding diathesis. Newborns are at particular risk of vitamin K deficiency because they have
low stores of vitamin K and receive only minimal
amounts via breast milk. Bleeding can occur from
multiple sites within 2 to 5 days of delivery, including the umbilicus, mucus membranes, circumcision,
Table 3. Differential Diagnosis Of Common

Bleeding Disorders
Figure 1. Coagulation Cascade
Platelet Problems
Inherited Coagulation Disorder*
Acquired Coagulation Disorder
Thrombocytopenia
Platelet dysfunction
Hemophilia
A (factor VIII
deficiency)
Hemophilia
B (factor IX
deficiency)
Von Willebrand
disease
Fibrinogen
deficiency
Vitamin K deficiency
Toxic ingestions
(eg, warfarin)
Liver disease
Disseminated
intravascular
coagulopathy
Acquired factor
inhibitors
* Congenital gene mutations of any factor (including factors II, VII, VIII,
IX, X, XI, XII) in the coagulation cascade may result in phenotypic
expression as a coagulation disorder
disease which is seen in patients with lymphoproliferative disorders, neoplasia (ie, Wilms tumor), and
autoimmune disorders.90,91
drug-induced thrombocytopenia in addition to

therapeutic anticoagulation. Presumably, patients
with toxic warfarin or rodenticide ingestion will
provide this information.
Current medical problems such as known
liver failure or renal insufficiency can help identify
patients at risk for bleeding diathesis. Immunodeficient patients are at risk for sepsis and DIC. Oozing
from umbilical or circumcision sites may be a clue to
severe vitamin K deficiency in neonates born outside
of the hospital. Any bite by an unidentified snake
should be considered to pose a risk of venom-mediated coagulopathy.
Identifying patients with a previously undiagnosed bleeding disorder who require further hematologic evaluation can be difficult. Children with recurrent, moderately severe epistaxis and normal labs
(ie, prothrombin time [PT]/partial thromboplastin
time [PTT]) and adolescent females presenting with
menorrhagia are potential candidates for a hematology referral and further work up. A history of heavy
or prolonged menses, easy bruising, or excessive
bleeding after dental procedures will help to guide
the emergency clinician towards subspecialty referral. Specific historical elements that are predictive of
a bleeding disorder are listed in Table 5.
Prehospital Care
Prehospital care of the patient with a bleeding disorder should focus on the management of life-threatening problems. Direct pressure should be placed on
lacerations or other sites of potential exsanguination,
and injured extremities should be immobilized. Ideally, prehospital providers will identify what therapeutic agents each individual patient might require
such as specific factor replacement products. This
information will expedite care in the ED, and many
patients are able to provide these products prior to
transport.
Emergency Department Evaluation

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

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

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

A careful medication history may identify
medicines such as aspirin or nonsteroidal anti-inflammatory drugs that can cause significant platelet
dysfunction in predisposed individuals. Current
or recent heparin administration is known to cause
Physical Examination
The initial focus in the patient with a known or
suspected bleeding disorder is on vital signs and
circulatory status. Tachycardia, with or without
hypotension, is a sign of hypovolemia and shock in
an actively bleeding patient. The presence of altered
mental status must be determined quickly to determine whether the patient has signs of advanced
shock or unrecognized ICH. Fever may be a clue to
underlying sepsis and DIC.
Patients with various bleeding disorders will ex-
Table 4. Common Acute Complaints
Complaint
Etiology
Abdominal or flank pain
Retroperitoneal bleeding, iliopsoas hematoma
Muscle pain
Intramuscular hematoma
Premonitory symptoms: warmth,

burning, stiffness or tingling
in joint
Hemarthrosis
History of minor head trauma,

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

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

hemorrhages in the skin) may be indicative of a vasculitic disorder (eg, Henoch-Schnlein Purpura) but
may also be found with platelet problems such as
ITP.2 Large ecchymoses or prolonged bleeding from
lacerations and abrasions are more commonly noted
in patients with coagulation defects such as von
Willebrand disease or hemophilia. In ill-appearing
patients, the diagnosis of possible severe sepsis and
DIC must be aggressively pursued.
Diagnostic Studies
It is important to initiate therapy in patients with
acute symptoms and not wait for diagnostic studies.
Replacement therapy should be rapidly administered prior to sending the patient for radiographic
studies.
Laboratory Testing
Laboratory testing in the ED must focus on tests that
produce results quickly and inform the emergent
management of the patient. In the ED, this generally
means a complete blood count (CBC) with peripheral smear, PT and activated partial prothromboplastin
time (aPTT), and type and screen (when indicated).3

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

The PT and aPTT will test for gross abnormalities in the coagulation pathways. (See Table 6 on
page 8.) Isolated elevation of the aPTT is the sine
qua non of hemophilia; functional defects of the
intrinsic arm of the coagulation cascade, proximal to
the common pathway, will manifest as an elevated
aPTT in the face of a normal PT. Both factor VIII
and factor IX deficiencies should demonstrate this
pattern. Less commonly, isolated elevation of the PT
suggests an abnormality of the extrinsic pathway,
such as factor VII. Simultaneous elevation of both
tests suggests a defect in the common pathway such
as factors II and X or severe derangements in the entire coagulation cascade, such as DIC. Patients with
DIC will often have alterations in other tests such as
a platelet count of < 100,000/mm3 and the presence
of fibrin-degradation products.99
Table 5. Historical Predictors Of Potential

Bleeding Disorder3,88,89

Presence of bleeding disorder in a family member

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

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

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

Sonography may be useful when evaluating
a patient with a bleeding disorder and suspected
intraocular hemorrhage, hemarthrosis, and/or
soft-tissue hematomas.102,103 Although not specifically studied in hemophilia, ultrasonography allows
for noninvasive and rapid assessment of vitreous
hemorrhage.104,105 Ultrasonography can also be used
to identify joint effusions (eg, hip) and provides an
alternative to computed tomography (CT) scan for
the evaluation of patients with potential iliopsoas
hemorrhage, although data on this subject is limited
to case series and retrospective reviews.95,96
A CT scan is an excellent modality to assess iliopsoas hemorrhage or other retroperitoneal lesions
and may be necessary when ultrasound findings are
equivocal or unavailable.106,107 A CT scan of the abdomen/pelvis should be considered in any patient
with a bleeding disorder and lower abdominal or
hip pain.
The diagnosis of ICH in children with bleeding
disorders can be facilitated by a CT scan. However,
in the well-appearing child with a normal examination, there are no clear guidelines on when a head
CT is clinically indicated. Even among pediatric
hematologists, there is wide variation regarding the
use of head CT imaging for a well-appearing hemophiliac who has sustained a minor head injury.108
One retrospective cohort of 97 pediatric patients
with hemophilia (A and B) found that of 295 head
CT scans performed for minor head injury, 9 cases
of ICH were identified; a lack of symptoms and a
normal neurologic examination did not exclude
ICH.109 Another review of 43 patients followed over
9 years, with 73 presentations of patients suspected
to have ICH upon arrival in the ED, demonstrated
4 risk factors for ICH: severe phenotype, absence
of maintenance prophylaxis, presence of a factor
inhibitor, and altered level of consciousness at presentation.110 In particular, the authors found that the
absence of altered consciousness had a 98% negative
predictive value for ICH (67% positive predictive
value). Unfortunately, these findings have not been
confirmed in other patient groups and have not been
reproduced prospectively. In the ED, a conservative
approach should be taken: after emergent factor
replacement, a CT scan should always be performed
on patients with any neurologic examination abnormality or alteration in consciousness, with strong
consideration for imaging children with hemophilia
who present with minor head injury. The threshold
for what constitutes a severe enough minor head
injury to warrant imaging is obviously a matter of
clinical judgment.
Also, because of the susceptibility to spontaneous or traumatic ICH, a head CT should be performed on any patient with ITP, low platelets, and
headache with abnormal neurologic examination,
Radiologic Testing
While joint radiographs may demonstrate chronic
changes of hemophilic arthropathy, such as joint
space narrowing, epiphyseal overgrowth, and widened intercondylar notches, they are unnecessary in
the acute management of spontaneous hemarthrosis.
While hemarthrosis should be treated clinically,101
radiographs may help to differentiate acute fracture
from hemarthrosis or muscular hematoma in a ten-
Table 6. Interpretation Of PT And aPTT

Results
PT and aPTT
Specific Bleeding
Disorders
Coagulation Pathway
Normal PT
Normal aPTT
Von Willebrand
disease, platelet
function problem
Not a problem with

coagulation cascade
Normal PT
# aPTT
Factor deficiency
(VIII, IX, XI, or XII),
lupus anticoagulant
Intrinsic pathway
# PT
Factor VII deficiency
Extrinsic pathway
DIC, sepsis, liver

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

extrinsic pathways or
common pathway
Normal aPTT
# PT
# aPTT
Abbreviations: DIC, disseminated intravascular coagulation; PT, prothrombin time; aPTT, activated partial prothromboplastin time
and/or minor head injury. One case-control study

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

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

Historically, cryoprecipitate and FFP were the
first products used to replace coagulation factors and
treat hemophilia A and B, respectively. Beginning in
the 1970s, prothrombin complex concentrates (PCCs)
were developed to treat hemophilia B but were also
useful for replacement of other vitamin K dependent
factors (II, VII, IX, and X). A relatively high risk of
thrombosis dampened enthusiasm for its use.120
Plasma-derived, specific factor concentrates
were then developed as an effective therapy for hemophiliacs requiring factor VIII or IX replacement.
Prior to contemporary screening methods, many
patients contracted hepatitis C and HIV. However,
current virucidal techniques and donor screening
have minimized the risks of viral transmission from
human plasma-derived products.121-3
Recombinant clotting factors are now the most
commonly used products for replacement therapy
in hemophiliacs because of their efficacy and superior safety profile. Recombinant products are now
recommended as first-line therapy for patients with
hemophilia A and B requiring factor VIII or factor IX
replacement.5,6
Three generations of recombinant factor VIII
(rFVIII) have been developed with continued improvement in purity and risk of infection. The first
generation used human serum albumin for stabilization. The second-generation products were albuminfree and did not include the B-domain of the factor
VIII gene. Third generation recombinant factor
concentrates do not contain any human or animal
proteins in the manufacturing process or final preparation. Multiple prospective open-label investigations have demonstrated that recombinant products
are efficacious and do not cause more inhibitor
formation than plasma-derived factor replacement
products.12,18-24,124
Historically, PCCs were used for factor IX
replacement. Subsequently, plasma-derived factor IX concentrates were developed and found to
be much less thrombogenic than PCCs.13,25-7,125127
Over the past few decades, the purity of the
factor IX concentrates has improved greatly; high
purity and ultrapure products are now available.
However, as with factor VIII deficiency, these
have given way to recombinant factor IX (rFIX),
which is just as efficacious as plasma-derived
products and also eliminates any risk of infectious disease transmission.5,28-31
Therapy
Emergent Therapy For Congenital Bleeding
Disorders
Emergency management of hemorrhage for patients with a congenital bleeding disorder centers on
increasing the circulating levels of deficient clotting
factors. This discussion focuses on the treatments of
factor VIII and IX deficiencies and von Willebrand
disease. Many clinical trials have been performed, but
almost all of these are open-label and non-randomized. In addition, no head-to-head comparisons of the
most commonly used therapeutic agents have been
published. In a large number of studies examining
factor replacement products, the primary outcome
was the investigators (subjective) assessment of
whether the patients response was excellent/good.
Several guidelines based on evidence and expert
consensus have been published to assist with the
management of hemorrhage in patients with congenital bleeding disorders.3-7 All of these guidelines highlight that rapid correction of deficient clotting factors
is tantamount. Specific replacement products should
be used if available and are discussed in the following
section. If unavailable, cryoprecipitate (for factor VIII
deficiency) or fresh frozen plasma (FFP) (for factor IX
deficiency) may be used as a last resort. The goal of
factor replacement is generally considered to be 40%50% for minor bleeds and 80%-100% for major hemorrhages.6 For patients with severe von Willebrand
Principles Of Factor Replacement In

Hemophilia
Treatment of hemophilia revolves around using the
safest product available in the quantity necessary to
9
effectively control the bleeding condition and minimizing further morbidity. Depending on the condition, this may range from a single infusion in the ED
for mild hemarthrosis to a continuous infusion in the
intensive care unit for intracranial bleeding.
Factor replacement for hemophilia is dosed on a
unit per kilogram basis; 1 unit is considered to be the
amount of clotting activity found in 1 mL of normal
plasma. Dosing differs somewhat between factor
VIII and factor IX deficiency.
One unit/kilogram of factor VIII concentrate
will increase factor VIII activity by 2%; therefore,
to achieve 100% correction, 50 U/kg must be
administered.6
One unit/kilogram of factor IX concentrate will
only increase factor IX activity by 1%; therefore,
twice as much factor IX must be administered
for the same effect: 100 U/kg are necessary to
achieve 100% correction.6
These dosing guidelines are accurate only in the
absence of an inhibitor.
The opposite relationship exists in terms of the
timing of redosing between these 2 factors. Factor VIII has a half-life of 8 to 12 hours and needs
to be dosed twice as frequently (about every 12
hours) as factor IX, which has a longer half-life
of about 24 hours.6
hematologist can), but the presence of an undiagnosed inhibitor should be suspected when patients
fail to respond to routine therapy.
Until recently, the only option was to use large
doses of factors VIII and IX to overwhelm inhibiting antibodies. Currently, recombinant activated
factor VII (rFVIIa) (Novoseven) and activated
prothrombin complex concentrates (aPCCs) (factor eight inhibitor bypass activity [FEIBA]) are
available.136 A Cochrane Review comparing rFVIIa
concentrate with aPCCs found no difference in
effectiveness between the 2 products and no difference in safety as defined by tolerability and clotting
complications.15,137 Two studies of the economic
impact of FEIBA versus rFVIIa use found that the
cost per episode when treating acute bleeding and/
or peri-operative prophylaxis was less with the use
of FEIBA than with rFVIIa.138,139
In the United States, rFVIIa is currently approved
for the treatment of bleeding episodes in hemophiliacs (A or B) with inhibitors and patients with congenital factor VII deficiency. Several prospective openlabel multi-center trials (study sample sizes ranging
from 15 to 84 patients) have investigated the ideal
dosing of rFVIIa, and a wide range of effective bolus
doses were found; continuous and bolus interval dosing were found to be equivalent.140-143 See Table 7 for
FDA-approved dosing recommendations.144
Several investigations of rFVIIa in patients with
inhibitors in hemophilia have demonstrated that
rFVIIa is effective in the treatment of intracranial
and extracranial hemorrhage.145-7 Recombinant
activated factor VII is also effective therapy for
limb-threatening and severe abdominal bleeding in
patients with inhibitors.148-50 Off-label use of rFVIIa
includes treatment of patients with massive bleeding without a bleeding disorder.151 In addition,
case reports suggest that patients with severe von
Willebrand disease with inhibitors or refractory to
standard treatment may also benefit from the use of
rFVIIa.152-3
Factor eight inhibitor bypass activity, an
activated prothrombin complex concentrate, is an
alternate bypassing agent for patients with hemophilia and inhibitors. Unlike rFVIIa, FEIBA is a
pooled blood product and has a small risk of disease
transmission. Factor eight inhibitor bypass activity
is approved for the control of spontaneous bleeding
episodes or presurgical prophylaxis in patients with
hemophilia A and B and inhibitors.154 Recommended dosing ranges from 50 to 100 units/kg every 12
hours. Dosing should continue until signs of clinical
improvement are achieved. Several retrospective
and one open-label prospective cohort trial found
that 81% to 93% of bleeding episodes achieved
excellent/good hemostasis with FEIBA.33,34,155,156
In 2010, the FDA added a black box warning for
FEIBA emphasizing the risk of thrombotic and

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

With Factor Inhibitors
Patients with hemophilia can develop inhibitory
antibodies to factor replacement products, rendering these products ineffective and complicating the
management of acute bleeding disorders.8,9,128,129
These IgG4 antibodies bind and inactivate circulating factor. The degree of inhibition is measured in
Bethesda units, where one unit decreases factor activity by 50%. An estimated 3.6% to 17.5% of patients
with hemophilia (A or B) have inhibitors.130 A population study of 3435 hemophilia patients in France
found that for all patients with hemophilia A, 7%
had inhibitors but for patients with severe disease,
12.8% had inhibitors.130 In the same study, inhibitors
were found in 2% of all patients with hemophilia B
and 4% of patients with severe disease.130 Of note,
the presence of inhibitors in patients with hemophilia B may be associated with a risk of anaphylaxis.129
Multiple variables increase an individuals likelihood of developing inhibitors, including earlier age
at first exposure, use of prophylaxis, and frequency
of factor use.131-135 Most patients with inhibitors
should be able to provide this information (or their
10
Adjunct Therapies
thromboembolic events similar to other aPCCs as

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

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

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

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

Evidence supporting the use of factor VIII/von
Willebrand factor concentrates consists of multiple
prospective and retrospective cohort analyses, but
there have been no direct comparisons of the efficacy
of the 3 products currently available in the US.3943,161-3
Factor VIII/von Willebrand factor replacement therapy is recommended for significant bleeding events or major surgery for patient with types 2
and 3 von Willebrand disease and patients with type
1 von Willebrand disease who are unresponsive to
desmopressin.3
Table 7. Dosing Recommendations For Inhibitor Bypassing Agents

Bypassing Agent
Type Of Hemorrhage
Initial Dose
Notes
Recombinant
activated factor VII
(rFVIIa)
Mild/moderate bleed
90 mcg/kg every 2 hours
Until hemostasis achieved or response judged to be inadequate144
Severe bleed
90 mcg/kg every 2 hours
Continue dosing at 3 to 6 hour intervals after hemostasis achieved to

maintain the hemostatic plug
Joint
50 units/kg every 12 hrs
May increase to 100 units/kg/dose
Mucous membrane
May increase to 100 units/kg as needed (max 200 units/kg/day)
Soft tissue (severe)
Maximum 200 units/kg/day
Central nervous system
May increase to every 6 hours dosing interval
Factor eight inhibitor

bypass activity
(FEIBA)
11
Clinical Pathway: Emergency Department Management Of Immune

Thrombocytopenia
Immune thrombocytopenia*
Thrombocytopenia without
evidence of moderate/severe
hemorrhage
History and Physical: no hepatosplenomegaly

Laboratory tests: Complete blood count, reticulocyte count
peripheral smear, type and screen (Rh)
ED management of stable patient

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

10,000/mL and minor purpura
Strongly consider admission (Class III) for monitoring of

symptoms and side effects [at least 8 hours for Rho(D)]
Platelets > 20-30,000/mL and

asymptomatic or minor purpura
only
Choose one of the following therapies
Discharge home with close followup and observation
Thrombocytopenia with life- or

organ-threatening hemorrage
ED management of unstable
patient with immune thrombocytopenia
Platelet transfusions (Class III) 2

to 3 times usual amount
Give intravenous immunoglobulin,
methylprednisolone, or Rho(D)
concurrently (Class II-III)
Bleeding not
controlled
Intravenous
immunoglobulin
(Class II)
0.8-1g/kg IV
If Rh+,
intravenous
Rho(D) (Class
II)
50-75 mcg/
kg x 1
Prednisone
(Class II)
1-2 mg/kg/day
by mouth x 14
days or 4 mg/
kg/day by mouth
x 3 days
Emergent
splenectomy
(Class III)
Bleeding
controlled
Admit to intensive care unit
*These actions should be taken in consultation with a hematologist
Class Of Evidence Definitions

Each action in the clinical pathways section of Pediatric Emergency Medicine Practice receives a score based on the following definitions.
Class I
Always acceptable, safe
Definitely useful
Proven in both efficacy and
effectiveness
Level of Evidence:
1 or more large prospective
studies are present (with rare
exceptions)
High-quality meta-analyses
Study results consistently positive and compelling
Class II
Safe, acceptable
Probably useful
Level of Evidence:
Generally higher levels of
evidence
Non-randomized or retrospective studies: historic, cohort, or
case control studies
Less robust RCTs
Results consistently positive
Class III
May be acceptable
Possibly useful
Considered optional or alternative treatments
Level of Evidence:
Generally lower or intermediate
levels of evidence
Case series, animal studies,
consensus panels
Occasionally positive results
Indeterminate
Continuing area of research
No recommendations until
further research
Level of Evidence:
Evidence not available
Higher studies in progress
Results inconsistent, contradictory
Results not compelling
Significantly modified from: The
Emergency Cardiovascular Care
Committees of the American
Heart Association and represen-
tatives from the resuscitation

councils of ILCOR: How to Develop Evidence-Based Guidelines
for Emergency Cardiac Care:
Quality of Evidence and Classes
of Recommendations; also:
Anonymous. Guidelines for cardiopulmonary resuscitation and
emergency cardiac care. Emergency Cardiac Care Committee
and Subcommittees, American
Heart Association. Part IX. Ensuring effectiveness of communitywide emergency cardiac care.
JAMA. 1992;268(16):2289-2295.
This clinical pathway is intended to supplement, rather than substitute for, professional judgment and may be changed depending upon a patients individual
needs. Failure to comply with this pathway does not represent a breach of the standard of care.
Copyright 2010 EB Medicine. 1-800-249-5770. No part of this publication may be reproduced in any format without written consent of EB Medicine.
12
Clinical Pathway: Emergency Department Management Of Hemophilia
Hemophilia*
No inhibitors
Known inhibitors
Suspected hemorrhage:
CNS, abdominal/GI tract,
compartment syndrome,
ocular trauma or unstable vital signs?
See Clinical Pathway on

page 14.
YES
NO
ED management of
unstable patient
ED management of
stable patient
Minor bleeding: renal, oral, nasal, intramuscular

(except iliopsoas), or lacerations
Suspected
Hemarthrosis
Factor replacement to
100% physiological
level before imaging
100% physiological
level**
50% physiological level
Hemophilia A
Hemophilia B
Hemophilia A
Hemophilia B
rFVIII (Class II) 50 IU/kg
rFIX or high purity FIX

(Class II) 100-150 IU/
kg***
rFVIII (Class II) 25 IU/kg
rFIX or high purity FIX

(Class II) 50-75 IU/
kg***
Bleeding controlled?
Diagnostic imaging and consider admission to intensive

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

Replace factor to
100%

Desmopressin
(Class II) if pretested

Amicar (Class III)

Admission if bleeding uncontrolled
Abbreviations: CNS, central nervous system; GI, gastrointestinal.
13
YES
Discharge with close

follow-up with hematologist.
Clinical Pathway: Emergency Department Management

Of Hemophilia With Inhibitors
Hemophilia with inhibitors
Mild bleeding**
Inhibitor level < 5 BU/

mL***
Low responder***
High dose rFVIII (Class

III) or FEIBA (Class III)
or rFVIIa (Class III)
Severe life- or limb-threatening bleeding
Inhibitor level > 5 BU/

mL***
Inhibitor level < 5 BU/

mL***
Inhibitor level > 5 BU/

mL***
Unconfirmed but suspected inhibitors
High responder***
FEIBA (Class II) or

rFVIIa (Class III)
High dose rFVIII (Class

III) or FEIBA (Class III)
or rFVIIa (Class III)
FEIBA (Class III) or rFVIIa (Class III) or plasmapheresis and rFVIII (Class III)
Bleeding well controlled?
YES
NO
Discharge home with

close follow-up with
hematologist
Admit for further management
Consider admission to intensive care unit.
*These actions should be taken in consultation with a hematologist. Consider inhibitors in patients
who do not respond as expected to traditional factor replacement.
**For patients with mild Hemophilia A and mild bleeding. DDAVP may be a useful first-line therapy.
***Low responders are patients with inhibitor levels < 5 BU/ml and do not develop an amnestic
response following exposure to FVIII.
Abbreviation: BU, bethesda unit.
14
Clinical Pathway: Emergency Department Management

Of Von Willebrand Disease
Von Willebrand disease*
History and physical and

initial stabilization
Type 2B, 2N, or 3 von

Willebrand disease?
NO
YES
Cryoprecipitate
(Class III)****
Only if concentrate
not available
FVIII concentrate rich in

von Willebrand factor**
(Class II)
Major life- or organthreatening bleeding?
YES
NO
Major life- or organthreatening bleeding?
NO
YES
Admit to intensive care

unit.
Bleeding controlled?
NO
Desmopressin (Class II)

Intravenous: 0.3 mcg/kg

Intranasal (Stimate*):

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

2 sprays: age >
5 years, weight >
50 kg
YES
Adjunct therapies***
Amicar (Class III)
Topical thrombin
(Class III)
Bleeding well
controlled
Bleeding not controlled
Admission
Consider: FVIII with von
Willebrand factor infusion
Discharge home with close follow-up

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

**Use home supply if possible; use entire vial. Examples of FVIII concentrate with von Willebrand factor are Humate P, Koate DVA, Alphanate SD, and Wilate. See package inserts for product specific dosing.
***Adjunct therapies may be administered at same time as replacement products or desmopressin.
****Amount of von Willebrand factor and FVIII in cryoprecipitate is variable (at least 80 IU/bag of FVIII). Dosing is based on FVIII component.
15
subsequent water intake is not carefully monitored

(particularly in younger children).170,171

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

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

In addition, topical thrombin or fibrin glue is
often used concomitantly for local control.6 The evidence supporting their use is also based primarily
on case series.178-180
cally significant bleeding, such as ICH, is low with

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

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

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

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

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

It is believed that IVIG works by flooding Fc receptors on macrophages in the reticuloendothelial system, eliminating their ability to secure and destroy
opsonized platelets. Intravenous immunoglobulin is
Table 8. Adjunct Agents

Route of Administration
Initial Dose
Infusion Time
Peak Effect
Intravenous desmopressin
0.3 mcg/kg
30 min
30-60 minutes
Intranasal Stimate (150 mcg/spray)
1 spray if weight < 50 kg

2 sprays if weight > 50 kg
N/A
90-120 minutes
Oral Amicar (epsilon-aminocaproic

acid)
100 to 200 mg/kg (max 10 g/dose or 30 g/day)
N/A
45-99 minutes
16
equivalent or slightly superior to glucocorticoids at

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

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

Rho(D) immune globulin (WinRho SDF) acts by
coating Rh-positive red blood cells, which then provide
competitive interference of reticuloendothelial Fc
receptors, inhibiting platelet sequestration. (There is a
predictable 1 to 2 g/dL decline in hemoglobin levels over the subsequent 2 weeks). Therefore, Rho(D)
is only useful in Rh-positive patients who have not
undergone splenectomy.192 Recommended dose of intravenous Rho(D) is 50 to 75 mcg/kg for a single dose.2
Platelet Transfusions
Rarely, patients with ITP may require intervention
to immediately address active hemorrhage. Previously mentioned therapies merely halt ongoing
destruction and rely on the bone marrow to replace
and increase platelet levels. With clinically significant bleeding (eg, ICH), functional platelets must be
Risk Management Pitfalls In The Emergency

Treatment Of Bleeding Disorders
1. Management without the hematologist. Initiating treatment and workup without consulting
the hematologist results in errors and wasted
resources.
2. Waiting for the hematologist before doing
anything. Even though involvement of the hematologist is critical for these uncommon conditions, waiting for the consultant before initiating
therapy simply allows the condition to progress.
3. Confirming intracranial bleeding before initiating therapy. Treat first; image second.
4. Guessing which factor to give. (The family
may say I think it is B.) Make sure that you
are clear what the patients condition is before
initiating therapy
5. Basing treatment solely on physical examination. If a hemophiliac has discomfort in a joint,
it must be treated before progression to visible
findings.
6. Excessive ED management. Rho(D) and transfusions are best left for inpatient management
unless clinical condition warrants emergent
therapy.
7. Desmopressin is for pretested patients only,
8.
9.
10.
11.
12.
17
not the condition itself. Some patients are nonresponders, and therapy should be based on
these results.
Empirically starting steroid therapy for ITP.
Just because you can does not mean that you
should.
Failure to recognize vitamin K deficiency as a
cause of bleeding in the neonate.
With anticoagulant ingestions, treat the patient, not the number.
Disregarding the possibility of a bleeding condition with a normal PT/PTT. Von Willebrand
disease is the most common congenital bleeding
condition and will typically present with normal
screening labs.
Obtaining spurious lab values secondary to
testing error. Patients who have heparinized
indwelling central lines will have elevated PT/
PTT values if the sample blood is drawn from
the line. The laboratory must be instructed to
conduct the test with heparin neutralization. In
addition, coagulation test values may be falsely
elevated if insufficient blood volume is placed in
the sample tubes.
Controversies/Cutting Edge
provided immediately, with doses as high as 2 to 3

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

for use in patients with hemophilia. Because of its
utility as a general hemostatic agent, many physicians are using rFVIIa for off-label purposes, including treatment of hemorrhage associated with
acquired coagulopathies associated with hepatic
failure, DIC, and surgery as well as bleeding associated with prematurity, malignancies, and trauma.210-216 The increasing use of rFVIIa for off-label
purposes was demonstrated by a 2010 multicenter
cohort investigation of 4942 patients that determined
that 74% of patients given rFVIIa were being treated
for off-label indications.210 In the pediatric literature, multiple retrospective analyses and case series
demonstrate that rFVIIa given for massive bleeding
in non-hemophiliac children decreases the need for
blood product administration but is associated with
a significant risk of thrombotic events.211-216
Emergent Splenectomy
Splenectomy is a therapy of last resort for ITP and is
rarely performed emergently.2 Multiple case reports
have demonstrated successful treatment of refractory hemorrhage with emergency splenectomy,
but no controlled trials have been conducted.204-209
Although an effective method of increasing platelet
counts, splenectomy has many potentially serious
complications, including hemorrhage, infection,
thrombosis, prolonged hospitalizations and death.209
Cost-Effective Strategies
1. Routine labs, such as factor levels or a PT/
PTT, in patients with a known coagulopathy
are generally unnecessary. Most patients with
congenital bleeding disorders who present to the
ED are already diagnosed. Laboratory evaluation simply documents what is already known
and consumes unnecessary time and resources.
Unless requested by the hematologist, laboratory studies prior to providing factor concentrate
is generally unnecessary.
2. Factor II levels and a bleeding time are not appropriate testing in the ED. There are a plethora
of tests that can be ordered in patients with a
suspected but undiagnosed bleeding condition.
Beyond the basic screening tests listed above,
targeted testing is best left to the hematologist.
Tests for suspected bleeding conditions, even
one as common as von Willebrand disease, can
be difficult to interpret and are best left to the
specialist. Simply ordering tests to be helpful
and get things started do not improve the timeliness, accuracy, or efficiency of the evaluation.
3. Diagnostic radiographs provide no significant
clinical information in hemophiliacs without
a history of trauma. Spontaneous hemarthroses
are exceedingly common in patients with severe
hemophilia (most hemophiliacs) and x-rays
merely document chronic changes and acute
effusions, neither of which aid in the clinical
management.
4. Ordering a type and cross where a type and

screen should be sufficient. It is common to
reflexively order a type and cross when patients
present with a bleeding condition. It is much
more expensive than a type and screen and frequently unnecessary. Avoid ordering a type and
cross unless transfusion is a likely intervention.
5. Use the patients own medications when
possible. Most patients have a supply of their
condition-specific factor and will bring it to the
ED. Using this factor will reduce errors and
will minimize the theoretical risk of increasing
inhibitors with changes in brands of factor.
6. Consider outpatient observation for patients
with low but not dangerous platelet levels
in ITP. Bleeding risk is threshold related. All
patients with ITP do not need admission, only
those at significant risk of life-threatening complications in need of immediate therapy. These
patients will require prompt (1-3 day) follow-up
with a hematologist.
7. Attempt to use adjunct therapy where appropriate before moving on to factor concentrate.
Patients with minor bleeding (oral lesions,
epistaxis) and mild hemophilia A or von Willebrand disease may benefit from adjuncts such
as Amicar or desmopressin without the need
for expensive factor concentrate.
18
Disposition
asymptomatic or have only minor purpura can be

safely discharged and may not require any treatment
other than repeated laboratory monitoring.11
Hemophilia And Von Willebrand Disease

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

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

In consultation with the hematologist, patients
with hemophilia or von Willebrand disease who
have well-controlled, non-life threatening hemorrhage usually can be discharged with plans for close
follow-up. Conditions that are often managed on an
outpatient basis include epistaxis, bleeding from the
oral mucosa, small intramuscular hematomas, and
hemarthroses. Some of these patients may require
repeat factor administration on an outpatient basis.
Summary
Children with bleeding disorders frequently present to the ED with a wide variety of complaints
ranging from minor to life threatening. Much of the
morbidity and mortality associated with bleeding
disorders can be prevented by early and aggressive
recognition and intervention. Critical interventions
should be initiated based on the history alone, prior
to the advent of physical examination abnormalities and prior to obtaining diagnostic studies. With
knowledge of the basic evidenced-based principles
of emergency management outlined in this article,
the emergency clinician will be able to successfully
identify and intervene in the emergent presentations
of bleeding disorders.
Case Conclusions
You do a quick literature search of von Willebrand disease
and realize that this patient has a severe type of von Willebrand disease that has no circulating von Willebrand
factor and almost no FVIII. Therefore, her epistaxis will
not likely respond to desmopressin (the most commonly
used therapy in von Willebrand disease). In consultation
with a hematologist, you administer a Humate-P infusion along with the adjunct therapy of oral Amicar. You
pack the nose with gauze and have the mother hold direct
pressure on the area. Approximately 30 minutes later,
all bleeding has stopped. A CBC demonstrates that your
patient now has mild anemia, but her tachycardia resolves
with a normal saline bolus.

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

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

Finally, you can focus on the 4-year-old with ITP
Immune Thrombocytopenia
Hospital admission is generally reserved for patients
at risk of clinically significant bleeding.11 All patients with severe, life-threatening bleeding must be
admitted to an intensive care setting. Patients with
platelet counts of < 20,000/mm3 and mucous membrane bleeding or patients with platelet counts of
less than < 10,000/mm3 and minor purpura require
medical therapy with IVIG, Rho(D), or steroids and
are usually admitted for parental medication administration and monitoring.
Discharged patients should have reliable families who have received teaching regarding signs and
symptoms of bleeding and a physician available to
give advice at all times. They must be instructed regarding the avoidance of non-steroidal anti-inflammatory drugs, and the children may not participate
in contact sports or high impact activities. In general,
patients with platelet counts > 30,000/mm3 who are
19
receiving Rho(D). You realize this patient is most likely

experiencing intravascular hemolysis from the Rho(D)
that is being administered. You recognize that this is a
potentially severe complication of Rho(D) administration
and stop the infusion immediately. Prior to the Rho(D)
administration, you had sent a type and screen to the lab,
but you now send a type and cross because transfusions of
packed red blood cells may be necessary if hemolysis continues. You emergently notify the hematologist and administer a normal saline bolus. The patient is transferred
to the pediatric intensive care unit for close monitoring of
clinical status, hemolytic anemia, and renal function.
10.
11.
12.
References
13.
Evidence-based medicine requires a critical appraisal of the literature based upon study methodology and number of subjects. Not all references are
equally robust. The findings of a large, prospective,
randomized, and blinded trial should carry more
weight than a case report.

To help the reader judge the strength of each
reference, pertinent information about the study,
such as the type of study and the number of patients
in the study, will be included in bold type following
the reference, where available.
1.
2.
3.
4.
5.
6.
7.
8.
9.
14.
15.
16.
Rodeghiero F, Stasi R, Gernsheimer T, et al. Standardization of terminology, definitions and outcome criteria in
immune thrombocytopenic purpura of adults and children,
report from an international working group. Blood. 2009 Mar
113(11):2386-2393. (Expert consensus guidelines)
Provan D, Stasi R, Newland AC, et al. International consensus report on the investigation and management of primary
immune thrombocytopenia. Blood. 2010 Jan 115(2):168-186.
(Expert consensus guidelines)
Nichols WL, Hultin MB, James AH, et al. The diagnosis,
evaluation and management of von Willebrand Disease. U.S.
Department of Health and Human services National Institutes of Health, National Heart Lungs and Blood Institute.
Dec 2001. (Expert consensus guidelines)
American Society of Hematology. 2008 Clinical Practice
Guideline on the Evaluation and Management of von Willebrand Disease. National Heart, Lungs, and Blood Institute,
NIH Pub. No. 08-5832. Dec 2007. (Expert consensus guidelines)
Keeling D, Tait C, Makris M. Guideline on the selection and
use of therapeutic products to treat haemophilia and other
hereditary bleeding disorders. Haemophilia. 2008;14:671-684.
Hemophilia of Georgia, World Federation of Hemophilia.
Protocols for the treatment of hemophilia and von Willebrand disease. April 2008, No. 14. (Expert consensus
guidelines)
Evidence-based recommendations on the treatment of von
Willebrand disease in Italy. Mannucci PM, Franchini M,
Castaman G, Federici AB et al. Blood Transfus. 2009;7:117-126.
Charles R, Hay M, Brown S, et al. The diagnosis and management of factor VIII and IX inhibitors: a guideline from the
United Kingdom Haemophilia Centre Doctors Organisation.
British J of Haematol. 2006;133: 591-605. (Expert consensus
guidelines)
Rubinger M, Rivard GE, Teitel J, et al. Inhibitor SubCommittee of the Association of Hemophilia Clinic Directors
17.
18.
19.
20.
21.
22.
20
of Canada. Suggestions for the management of factor VIII

inhibitors. Haemophilia. 2000; 6(Suppl.1):52-59. (Expert consensus guidelines)
Provan D, Stasi R, Newland AC, et al. International consensus report on the investigation and management of primary
immune thrombocytopenia. Blood. 2010 Jan 14;115(2):168-186.
George JN, Woolf SH, Raskob GE, et al. Idiopathic thrombocytopenic purpura: a practice guideline developed by
explicit methods for the American Society of Hematology.
Blood. 1996 Jul;88(1):3-40. (Expert consensus guidelines)
Di Paola J, Smith MP, Klamroth R, et al. ReFacto and Advate:
a single-dose, randomized two-period crossover pharmacokinetics study in subjects with haemophilia A. Haemophilia.
2007 Mar;13(2):124-130. (Unblinded, prospective, randomized, cross-over; 18 patients)
Poon AC, Aledort LM, Anderle K, et al. Comparison of the
recovery and half-life of a high-purity factor IX concentrate
with those of a factor IX complex concentrate. Factor IX
Study Group. Transfusion. 1995 Apr;35(4):319-323. (Unblinded, prospective, cross-over; 29 patients)
Astermark J, Donfield S, DiMichele DM, et al. A randomized
comparison of bypassing agents in hemophilia complicated by an inhibitor: the FEIBA Novo Seven Comparitive
(FENOC) Study. Blood. Jan 2007;109(2):546-551. (Prospective,
randomized, cross-over, double-blind; 42 patients)
Arkin S, Cooper HA, Hutter JJ, et al. Activated recombinant
human coagulation factor VII therapy for intracranial hemorrhage in patients with hemophilia A or B with inhibitors.
Results of the novoseven emergency-use program. Haemostasis. 1998 Mar-Apr;28(2):93-98. (Prospective, open-label,
randomized, crossover; 96 bleeding episodes in 48 patients)
Sjamsoedin LJ, Jeijnen L, Mauser-Bunschoten EP, et al. The
effect of activated prothrombin-complex concentrate (FEIBA)
on joint and muscle bleeding patients with hemophilia A and
antibodies to factor VIII. A double-blind clinical trial. NEngl J
Med. 1981 Sep 24;305(13):717-721. (Prospective, randomized,
double-blind; 150 bleeding episodes)
Rodeghiero F, Castaman G, Mannucci PM. Prospective multicenter study on subcutaneous concentrated desmopressin
for home treatment of patients with von Willebrand disease
and mild or moderate hemophilia A. Thromb Haemost. 1996
Nob;76(5):692-696. (Prospective, randomized, unblinded,
cross-over; 14 patients)
Bray GL, Gomperts ED, Courter S, et al. A multicenter study
of recombinant factor VIII (Recombinate): safety, efficacy and
inhibitor risk in previously untreated patients with Hemophilia A. (Prospective, open-label; 79 patients)
Seremetis S, Lusher JM, Abildgaards CF, et al. Human recombinant DNA-derived antihaemophilic factor (factor VIII)
in the treatment of haemophilia A: conclusions of a 5-year
study of home therapy. The KOGENATE Study Group.
Haemophilia. 1999 Jan;5(1):9-16. (Prospective, open-label; 58
patients)
Abshire TC, Brackmann HH, Scharrer I, et al. Sucrose formulated recombinant human antihemophilic factor VIII is
safe and efficacious for treatment of hemophilia A in home
therapy International Kogenate-FS Study Group. Thromb
Haemost. 2000 Jun;83(6):811-816. (Prospective, open-label; 71
patients)
Negrier C, Shapiro A, Berntorp E, et al. Surgical evaluation
of a recombinant factor VIII prepared using a plasma/albumin-free method: efficacy and safety of Advate in previously
untreated patients. Thromb Haemost. 2008 Aug;100(2):217-233.
(Prospective, open-label; 58 patients)
Den Uijl I, Mauser-Bunschoten EP, Roosendaal G, et al.
Efficacy assessment of a new clotting factor concentrate in
haemophilia A patients, including prophylactic treatment.
Haemophilia. 2009 Nov;15(6):1215-1218. (Retrospective, pairwise comparison using registry data; 82 patients)
23. Berntorp E. Second generation, B-domain deleted recombinant factor VIII. Thromb Haemost 1997 Jul;78(1):256-260.
(Review of several clinical trials)
24. Blanchette VS, Shapiro AD, LIesner RJ, et al. Plasma and
albumin-free recombinant factor VIII: pharmacokinetics,
efficacy and safety in previously treated pediatric patients.
J Thromb Haemost. 2008 Aug;6(8):1319-1326. (Prospective,
open-label, cohort study; 53 patients)
25. Kim, HC, McMillan CW, White GC, et al. Purified factor IX
using monoclonal immunoaffinity technique: clinical trials
in hemophilia B and comparison to prothrombin complex
concentrates. Blood. 1992 Feb 1;79(3):568-575. (Prospective,
open-label, cohort study; 10 patients)
26. White GC 2nd. Safety and recovery of mononine in multipledose, high-dose regimens. Acta Haematol. 1995;94 Suppl
1:53-57. (Report of 2 studies: Prospective, open-label cohort
of 10 patients and Prospective, open-label cohort of 72
patients)
27. Lissitchkov T, Matysiak M, Zawilska K, et al. An open
clinical study assessing the efficacy and safety of Factor IX
Grifols, a high-purity factor IX concentrate , in patient with
severe haemophilia B. Haemophilia. 2010 Mar;16(2):240-246.
(Prospective, open-label cohort study; 25 patients)
28. Shapiro AD, Di Paola J, Cohen A, et al. The safety and efficacy of recombinant human blood coagulation factor IX
in previously untreated patients with severe or moderately
severe hemophilia B. Blood. 2005 Jan 15;105(2):518-525. (Prospective, open-label cohort study; 67 patients)
29. Roth DA, Kessler CM, Pasi KJ, et al. Human recombinant factor IX: safety and efficacy studies in hemophilia B
patients previously treated with plasma-derived factor IX
concentrates. Blood. 2001 Dec 15;98(13):3600-3606. (Prospective, open-label cohort study; 1796 bleeding episodes, 56
patients)
30. White G, Shapiro A, Ragni M, et al. Clinical evaluation of
recombinant factor IX. Semin Hematol. 1998 Apr;35(2 Suppl
2):33-38. (Prospective, open-label cohort study; 1070 bleeding episodes, 56 patients)
31. Lambert T, Recht M, Valentino LA, et al. Refomulated
BeneFIX: efficacy and safety in previously treated patients
with moderately severe to severe haemophilia B. Haemophilia. 2007 May;13(3):233-243. (Prospective, double-blind,
randomized, crossover; 34 patients)
32. Monahan PE, Liesner R, Sullivan ST, et al. Safety and efficacy
of investigator-prescribed BeneFIX prophylaxis in children
less than 6 years of age with severe haemophilia B. Haemophilia. 2010 May;16(3):460-468. (Prospective, open-label,
cohort; 25 patients)
33. DiMichele D, Negrier C. A retrospective postlicensure survey
of FEIBA efficacy and safety. Hemophilia. 2006 Jul;12(4):352362. (Retrospective, post-licensure survey; 63 patients)
34. Negrier C, Goudemand J, Sultan Y, et al. Multicenter
restrospective study on the utilization of FEIBA in France
in patients with factor VIII and factor IX inhibitors. French
FEIBA Study Group. Factor Eight Bypassing Activity. Thromb
Haemost. 1997 Jun;77(6):1113-1119. (Retrospective; 433 bleeding episodes, 60 patients)
35. Rangarajan S, Yee TT, Wilde J. Experience of four UK comprehensive care centres using FEIBA for surgeries in patients
with inhibitors. Haemophilia. 2010 Jul 20 [epub ahead of
print]. (Retrospective, 12 patients)
36. Rodeghiero F, Castaman G, Mannucci PM. Prospective multicenter study on subcutaneous concentrated desmopressin
for home treatment of atients with von Willebrand disease
and mild or moderate hemophilia A. Thromb Haemost. 1996
Nob;76(5):692-696. (Prospective, open-label, cohort; 219
bleeding episodes, 169 patients)
37. Leissinger C, Becton D, Cornell C Jr, et al. High-dose DDAVP
nasal spray (Stimate) for the prevention and treatment
of bleeding in patients with mild haemophilia A, mild or
38.
39.
40.
41.
42.
43.
44.
45.
46.
47.
48.
49.
50.
21
moderate type 1 von Willebrand disease, and symptomatic

carriers of haemophilia A. Haemophilia. 2001 May;7(3):258266. (Prospective, open-label cohort; 278 patients)
Mannucci PM, Bettega D, Cattaneo M. Patterns of development of tachyphylaxis in patients with haemophilia and von
Willebrand disease after repeated doses of desmopressin
(DDAVP). Br J Haematol. 1992 Sep;82(1):87-93. (Prospective,
Federici AB, Castaman G, Franchini M, et al. Clinical use
of Haemate P in inherited von Willebrands disease: a
cohort study on 100 Italian patients. Haematologica. 2007
Jul;92(7):944-951. (Retrospective, cohort; 100 patients)
Lillicrap D, Poon MC, Walker I, et al. Efficacy and safety of
the factor VIII/von Willebrand factor concentrate, haemateP/humate-P: ristocetin cofactor unit dosing in patients with
von Willebrand disease. Thromb Haemost. 2002 Feb;87(2):224230. (Retrospective; 97 patients)
Lethagen S, Kyrle PA, Castaman G, et al. Von Willebrand
factor/factor VIII concentrate (Haemate P) dosing based on
pharmacokinetics: a prospective multicenter trial in elective
surgery. J Thromb Haemost. 2007 Jul;5(7):1420-1430. (Prospective, open-label cohort; 28 patients)
Rivard GE, Aledort L, Alphanate Surgical Investigators.
Efficacy of factor VIII/von Willebrand factor concentrate
Alphanate in preventing excessive bleeding during surgery
in subjects with von Willebrand disease. Haemophilia. 2008
Mar;14(2):271-275. (Retrospective; 39 patients)
Berntorp E, Windyga J, European Wilate Study Group. Treatment and prevention of acute bleedings in von Willebrand
diseaseefficacy and safety of Wilate, a new generation von
Willebrand factor/factor VIII concentrate. Haemophilia. 2009
Jan;15(1):122-130. (Prospective, open-label, cohort; 1095
bleeding episodes, 44 patients)
Blanchette VS, Luke B, Andrew M, et al. A prospective,
randomized trial of high-dose intravenous immune globulin
G therapy, oral prednisone therapy, and no therapy in childhood acute immune thrombocytopenic purpura. J Pediatr.
1993 Dec;123(6):989-995. (Prospective, randomized, openlabel controlled trial; 53 patients)
Bellucci S, Charpak Y, Chastang C, et al. Low doses versus
conventional doses of corticoids in immune thrombocytopenic purpura (ITP): results of a randomized clinical trial in
160 children, 223 adults. Blood. 1988 Apr;71(4):1165-1169.
(Prospective, randomized controlled trial; 383 patients)
Imbach P, Wagner HP, Berchtold W, et al. Intravenous immunoglobulin versus oral corticosteroids in acute immune
thrombocytopenic purpura in childhood. Lancet. 1985 Aug
31;2(8453):464-468. (Prospective, randomized, open-label,
controlled trial; 108 patients)
Ozsoylu S, Sayli TR, Ozturk G. Oral megadose methylprednisolone versus intravenous immunoglobulin for acute
childhood idiopathic thrombocytopenic purpura. Pediatr
Hematol Oncol. 1993 Oct-Dec;10(4):317-321. (Prospective,
randomized, open-label, controlled trial; 20 patients)
Albayrak D, Islek I, Kalayci AG, et al. Acute immune
thrombocytopenic purpura: a comparative study of
very high oral doses of methylprednisolone and intravenously administered immune globulin. J Pediatr. 1994
dec;125(6pt1):1004-1007. (Prospective, randomized, openlabel, controlled trial; 57 patients)
Blanchette V, Imbach P, Andrew M, et al. Randomised trial of
intravenous immunoglobulin G, intravenous anti-D and oral
prednisone in childhood acute immune thrombocytopenic
purpura. Lancet. 1994 Sep 10;344(8924)703-707. (Prospective,
randomized, open-label, controlled trial; 146 patients)
Buchanan GR, Holtkamp CA. Prednisone therapy for children with newly diagnosed idiopathic thrombocytopenic
purpura. A randomized clinical trial. Am J Pediatr Oncol 2984
Winter;6(4):355-361. (Prospective, randomized, blinded,
controlled trial; 27 patients)
51. Tarantino MD, Young G, Bertolone SJ, et al. Single dose of

anti-D immune globulin at 75 microg/kg is as effective as
intravenous immune globulin at rapidly raising the platelet
count in newly diagnosed immune thrombocytopenic purpura in children. J Pediatr. 2006 Apr;148(4):489-494. (Prospective, randomized controlled trial; 105 patients)
52. El Alfy MS, Mokhtar GM, El-Laboudy MA, et al. Randomized trial of anti-D immunoglobulin versus low-dose
intravenous immunoglobulin in the treatment of childhood
chronic idiopathic thrombocytopenic purpura. Acta Haematol. 2006;115(1-2):46-52. (Prospective, randomized, openlabel, controlled trial; 34 patients)
53. Neunert CE, Bechanan GR, Imbach P, et al. Severe hemorrhage in children with newly diagnosed immune thrombocytopenic purpura. Blood 2008 Nov 15;112(10):4003-4008.
(Prospective cohort; 863 patients)
54. Yong M, Schoonen WM, Li L, et al. Epidemiology of paediatric immune thrombocytopenia in the General Practice
Research Database. Br J Haematol 2010 June;149(6): 855-864.
(Population-based study; 1145 patients, 257 children)
55. Psaila B, Petrovic A, Page L, et al. Intracranial hemorrhage
(ICH) in children with immune thrombocytopenia (ITP):
study of 40 cases. Blood 2009 Nov 26;114(23):4777-4783. (Retrospective; 120 patients)
56. Terrell DR, Beebe LA, Vesely SK, et al. The incidence of
immune thrombocytopenic purpura in children and adults:
a critical review of published reports. Am J Hematol 2010
Mar;85(30):174-180 (Systematic review)
57. Walker RW, Walker R. Idiopathic thrombocytopenia, initial
illness and long term follow up. Arch Dis Child 1984;59:316322. (Retrospective cohort; 181 patients)
58. Robb LG ,Tiedeman K. Idiopathic thrombocytopenic
purpura: predictors of chronic disease. Arc Dis Child 1990
May;65(5):502-506. (Retrospective cohort; 289 patients)
59. Den Ottolander GJ, Gratama JW, deKoning J, et al. Longterm follow-up study of 168 patients with immune thrombocytopenia. Implications for therapy. Scand J Haematol 1984
Jan;32(1):101-110. (Retrospective cohort; 168 patients)
60. Glanz J, France E, Xu S, et al. A Population-Based, Multisite Cohort study of the predictors of chronic idiopathic
thrombocytopenic purpura in children. Pediatrics 2008
Mar;3(121):e505-513. (Retrospective cohort; 259 patients)
61. Mannucci PM, Tuddenham EGD. The HemophiliasFrom
Royal Genes to Gene Therapy N Engl J Med 2001 Jun 344(23):
1773-1779. (Review)
62. Franchini M, Favoloro EJ, Mild Hemophilia A. J Thromb
Haemost 2010 Mar; 8(3):421-432. (Review)
63. Darby SC, Wan SW, Spooner RJ, et al. Mortality rates, life
expectancy and causes of death in people with hemophilia
A or B in the United Kingdom who were not infected with
HIV. Blood 2007 Aug;110(3): 815-826. (Retrospective; 6018
patients)
64. Klinge J, Auberger K, Auerswald G, et al. Prevalence and
outcome of intracranial haemorrhage in haemophiliacsa
survey of the paediatric group of the German Society of
Thrombosis and Haemostasis (GTH). Eur J Pediatr 1999
Dec;158 Supple 3:S162-165. (Survey; 744 patients)
65. Martinowitz U, Varon D, Jonas P, et al. Circumcision in
hemophilia: the use of fibrin glue for local hemostasis. J Urol
1992 Sep;148(3):855-857. (Case series; 10 patients)
66. Kulkarni R, Soucie JM, Lusher J, et al. Sites of initial bleeding
episodes, mode of delivery and age of diagnosis in babies
with haemophilia diagnosed before the age of 2 years: a
report from the Centers for Disease Control and Preventions
(CDC) universal data collection (UDC) project. Haemophilia
2009 Nov 15(6):1281-1290. (Prospective cohort; 580 patients)
67. Pollmann H, Richter H, Ringkamp H, et al. When are children diagnosed as having severe haemophilia and when do
they start to bleed? A 10-year single-centre PUP study. Eur J
Pediatr 1999 Dec;158 Supple 3:S166-170. (Prospective cohort;
37 patients)
68. Morgan LM, Kissoon N, deVebber BL. Experience with the
hemophiliac child in a pediatric emergency department. J of
Emerg Med 1993; 11:519-524. (Retrospective, 36 patients)
69. Stieltjes N, Calvez SN, Demiuel V, et al. Intracranial haemorrhages in French haemophilia patients (1991-2001): clinical
presentation, management and prognosis factors for death.
Haemophilia 2005 Sep;11(5):452-458. (Retrospective, historical
70. Rodeghiero F, Cataman G, Dini E. Epidemiological investigation of the prevalence of von Willebrands disease. Blood 1987
Feb;69(2):605-609. (Population-based, cross-sectional study;
1218 subjects)
71. Werner EJ, Broxson EH, Tucker EL. Prevalence of Von Willebrand disease in children: a multiethnic study. J Pediat 1993
Dec;123(6):893-898. (Cross-sectional study; 600 children)
72. Woods AI, Meschengieser SS, Blanco AN, et al. Clinical
features and laboratory patterns in a cohort of consecutive
Argentinian patients with von Willebrands disease. Haematologica 2001; 86:420-427. (Prospective; 2339 subjects)
73. Ravni MV, Bontempo FA, Hassett AC. Von Willebrand disease and bleeding in women. Haemophilia 1999 Sep; 5(5):313317. (Retrospective cohort)
74. Ziv O, Ragni MV. Bleeding manifestations in males with von
Willebrand disease. Haemophilia 2004 Mar; 10(2) 162-168.
(Retrospective chart review; 42 patients)
75. Sadler JE, Budde U, Eikenboom JC, et al. Update on the
pathophysiology and classification of von Willebrand disease: a report of the Subcommittee on von Willebrand Factor.
J Thromb Haemost 2006 Oct;4(10):2103-2114. (Expert opinion)
76. Metjian AD, Wang C, Sood SL, et al. Bleeding symptoms and
laboratory correlation in patients with severe von Willebrand
disease. Haemophilia 2009 Jul; 15(4):918-925. (Retrospective
77. American Academy of Pediatrics, Committee on Fetus and
Newborn. Policy Statement: controversies concerning vitamin K and the newborn. Pediatrics Jul 2003; 112(1):191-192.
(Expert opinion)
78. Sutor AH, von Kries R, Cornelissen EA, et al. Vitamin K
deficiency bleeding (VKDB) in infancy. Thromb Haemost
1999;81:456-461. (Expert opinion)
79. American Academy of Pediatrics, Committee on Nutrition.
Vitamin K compounds and the water-soluble analogues:
use in therapy and prophylaxis in pediatrics. Pediatrics
1961;28:501-507. (Expert opinion)
80. Bronstein AC, Spyker DA, Cantilena LR, et al. 2008 annual report of the American Association of Poison Control
Centers National Poison Data System (NPDS): 26th annual
report. Clin Toxicol (Phila). 2009;47: 911-1084 (Population
based, database report)
81. Mullins ME, Brands CL, Daya MR. Unintentional pediatric
superwarfarin exposures: do we really need a prothrombin
time? Pediatrics 2000 Feb; 105(2): 402-404. (Retrospective; 542
children)
82. Spero JA, Lewis JH, Hasiba U. Disseminated intravascular
coagulation. Findings in 346 patients. Thromb Haemost 1980
Feb 29;43(1):28-33. (Retrospective; 346 patients)
83. Siegal T, Seligsohn U, Aghai E, et al. Clinical and laboratory
aspects of disseminated intravascular coagulation (DIC): a
study of 118 cases. Thromb Haemost. 1978 Feb 28;39(1):122134. (Retrospective; 118 patients)
84. Rodriguez V, Lee A, Witman PM, et al. Kasabach-Meritt Phenomenon. Case series and retrospective review of the Mayo
Clinic experience. J Pediatr Hematol Oncol. Jul 2009;31(7):522526. (Case series and retrospective review; 9 patients)
85. Masci PP, Rowe EA, Whitaker AN, et al. Fibrinolysis as a
feature of disseminated intravascular coagulation (DIC) after
Pseudonaja textilis textilis envenomation. Thromb Res 1990
Sep 1;59(5):859-870. (Case series; 4 patients)
86. Lifshitz M, Kapelushnik J, Ben-Harosh M, et al. Disseminat-
22
ed intravascular coagulation after cerastes vipera envenomation in a 3-year-old child: a case report. Toxicon. 2000
Nov;38(11):1593-1598. (Case report; 1 patient)
87. Collins PW, Hirsch S, Baglin TP, et al. Acquired hemophilia
A in the United Kingdom: a 2-year national surveillance
study by the United Kingdom Haemophilia Centre Doctors
Organization. Blood. 2007 Mar;109(5):1870-1877. (Prospective, observational, cohort; 172 patients)
88. Andersen BR, Terry WD. Gamma G4-glubulin antibody
causing inhibition of clotting factor VIII. Nature. 1968
Jan;217:174-175. (Review of case reports)
89. Spiegel PC, Jacquemin M, Saint-Remy JR, et al. Structure of
a factor VIII C2 domain-immunoglobulin G4k Fab complex:
indetification of an inhibitor antibody epitope on the surface
of factor VIII. Blood. 2001 Jul;98(1):13-20. (Scienctific paper,
molecular analysis)
90. Federici AB, Rand JH, Bucciarelli P, et al. Acquired von
Willebrand syndrome: data from an international registry.
Thromb Haemost. 2000 Aug;84(2):345-349. (Retrospective
survey, convenience sample; 211 patients)
91. Scott JP, Montgomery RR, Tubergen DG, et al. Acquired
von Willebrands Disease in association with Wilms tumor:
regression following treatment. Blood. 1981 Oct;58(4):665-669.
(Case report; 1 patient)
92. Sramek A, Eikenboom JC, Briet E, et al. Usefulness of patient
interview in bleeding disorders. Arch Intern Med. 1995 Jul
10;155(13):1409-1415. (Cross-sectional, case-control; 697
subjects)
93. Biss TT, Blanchette VS, Clark DS, et al. Quantitation of bleeding symptoms in children with von Willebrand disease: use
of a standardized pediatric bleeding questionnaire. J Thromb
Haemost. 2010 May;9(5): 950-956. (Cross-sectional, casecontrol; 129 children)
94. Hoots WK. Emergency care issues in hemophilia. Treatment
of Hemophilia. World Federation of Hemophilia 2007 Nov;43.
(Expert opinion)
95. Graif M, Martinovitz U, Strauss S, et al. Sonographic localization of hematomas in hemophilic patients with positive
liopsoas sign. AJR Am J Roentgenol. 1987 Jan;148(1):121-123.
96. Balkan C, Kavakli K, Karapinar D. Iliopsoas haemorrhage in
patients with haemophilia: results from one centre. Haemophilia. 2005 Sep;11(5):463-467. (Retrospective cohort; 146
patients)
97. Mant MJ, Doery JC, Gauldie J, et al. Pseudothrombocytopenia due to platelet aggregation and degraunulation in blood
collected in EDTA. Scand J Haematol. 1975 Oct;15(3):161-170.
(Case series; 3 patients)
98. Bizzaro N. EDTA-dependent pseudothrombocytopenia: a
clinical and epidemiological study of 112 cases, with 10-year
follow-up. Am J Hematol. 1995 Oct;50(2):103-109. (Prospective cohort, 112 patients)
99. Levi M, ten Cate H. Disseminated intravascular coagulation.
NEMJ. 1999 Aug 341(8):586-92. (Review article)
100. Haward, CPM. Diagnosis and Management of Mild Bleeding
Disorders. Hematology 2005. American Society of Hematology. (Review article)
101. Pergantou H, Matsinos G, Papadopoulos A, et al. Comparitive study of validity of clinical, X-ray and magnetic
resonance imaging scores in evaluation and management
of haemophilic arthropathy in children. Haemophilia. 2006
May;12(3):241-247. (Prospective comparison; 165 joints, 40
children)
102. Zukotynski K, Jarrin J, Babyn PS, et al. Sonography for assessment of haemophilic arthropathy in children; a systematic protocol. Haemophilia. 2007 May 13(3):293-304. (Review
and expert opinion)
103. Beyer R, Ingerslev J, Sorensen B. Current practice in the
management of muscle haematomas in patients with severe
haemophilia. Haemophilia. 2010 May 21. [Epub ahead of
print]. (Cross-sectional survey; 22 hematology consultants)

104. Bedi DG, Gombos DS, Ng CS, et al. Sonography of the eye.
AJR. 2006 Oct 187:1061-1072. (Review)
105. Rabinowitz R, Yagev R, Shoham A, et al. Comparison
between clinical and ultrasound findings in patients with
vitreous hemorrhage. Eye. 2004;18:253-256. (Retrospective
chart review; 106 eyes, 96 patients)
106. Nino-Murcia M, Wechsler RJ, Brennan RE. Computed
tomography of the iliopsoas muscle. Skeletal Radiol.
1983;10(2):107-12. (Case series; 13 patients)
107. Perri G, Camerini E, Busoni F. Usefulness of CT in the evaluation of hematoma of the iliopsoas muscle in hemophiliacs.
Radiol Med. 1986 Jan-Feb;72(1-2):3-6. (Case series; 4 patients)
108. Witmer CM, Manno CS, Butler RB, et al. The clinical
management of hemophilia and head trauma: a survey of
current clinical practice among pediatric hematology/oncology physicians. Pediatr Blood Cancer. 2009 Sep;53(3):406-410.
(Cross-sectional survey; 252 hematologists)
109. Witmer CM, Raffini LJ, Manno CS. Utility of computed
tomography of the head following head trauma in boys with
haemophilia Haemophilia. 2007 Sep;13(5):560-566. (Retrospective cohort; 97 patients)
110. Traivaree C, Blanchette V, Armstrong D, et al. Intracranial
bleeding in haemophilia beyond the neonatal periodthe
role of CT imaging in suspected intracranial bleeding. Haemophilia. 2007 Sep;13(5):552-559. (Retrospective cohort; 43
patients)
111. Kuhne T, Buchanan GR, Zimmerman S, et al. A prospective
comparative study of 2540 infants and children with newly
diagnosed idiopathic thrombocytopenic purpura (ITP) from
the Intercontinental Childhood ITP Study Group. J Pediatr
2003 Nov;143(5):605-608. (Prospective cohort; 2540 patients)
112. Elalfy M, Elbarbary N, Khaddah N, et al. Intracranial hemorrhage in acute and chronic childhood immune thrombocytopenic purpura over a ten-year period: an Egyptian multicenter study. Acta Haematol. 2010;123(1):59-63. (Retrospective
113. Choudhary DR, Naithani R, Mahapatra M, et al. Intracranial
hemorrhage in childhood immune thrombocytopenic purpura. Pediatr Blood Cancer. 2009 Apr;52(4):529-531. (Retrospective cohort; 750 patients)
114. Panicker JN, Pavithran K, Thomas M. Management of
subdural hematoma in immune thrombocytopenic purpura:
report of seven patients and a literature review. Clin Neurol
Neurosurg. 2009 Feb;111(2):189-192. (Review and case series;
7 patients)
115. Balkan C. Kavakli K, Karapinar D. Spinal epidural haematoma in a patient with haemophilia B. Haemophilia. 2006
Jul;12(4):437-440. (Case report; 1 patient)
116. Rois PV. Lopez MR, de Vergara BC, et al. Spinal epidural
hematoma in hemophilic children: controversies in management. Childs Nerv Syst. 2009 Aug;25(8):987-991. (Case Report;
1 patient)
117. Kiehna EN, Waldron PE, Jane JA. Conservative management
of an acute spontaneous heolocord epidural hemorrhage in
a hemophiliac infant. J Neurosurg Pediatr. 2010 Jul;6(1):43-48.
(Case Report; 1 patient and review)
118. Hamre MR, Haller JS. Intraspinal hematomas in hemophilia.
Am J Pediatr Hematol Oncol. 1992 May;14(2):166-169. (Case
Report; 1 patient)
119. Yu W, Lin Q, Guermazi A, et al. Comparison of radiography,
CT and MR imaging in detection of arthropathies in patients
with haemophilia. Haemophilia. 2009 Sep;15(5):1090-1096.
(Prospective; 14 patients)
120. White GC, Roberts HR, Kingdon HS, et al. Prothrombin complex concentrates: potentially thrombogenic materials and
clues to the mechanism of thrombosis in vivo. Blood. 1977
Feb;49(2):159-170. (Scientific paper, molecular biology)
121. Ludlam CA, Powderly WG, Bozzette S, et al. Clinical
perspectives of emerging pathogens in bleeding didorders.
23
Lancet. 2006 Jan 21;367(9506):252-261. (Review)

122. Smid WM, Van der Merr J, Halie MR. Efficacy and safety
of a monoclonal purified factor VIII concentrate: 5-year
follow-up in previously treated HIV-negative haemophiliacs.
Haemostasis. 1995 Sep-Oct;25(5):229-236. (Prospective cohort,
historical controls; 22 patients)
123. Lusher JM, Salzman PM. Viral safety and inhibitor development associated with factor VIIIC ultra-purified from plasma
in hemophiliacs previously unexposed to factor VIIIC
concentrates. The Monoclate Study Group. Semin Hematol.
1990 Apr;27(2 Suppl 2):1-7. (Prospective cohort, open-label;
38 patients)
124. Gouw SC, van der Bom JG, Auerswald G, et al. Recombinant
versus plasma-derived factor VIII products and the development of inhibitors in previously untreated patients with
severe hemophilia A: the CANAL cohort study. Blood. 2007
Jun; 109(11):4693-4697. (Retrospective cohort; 316 patients)
125. Thomas DP, Hampton KK, Dasani H, et al. A cross-over
pharmacokinetic and thrombogenicity study of a prothrombin complex concentrate and a purified factor IX concentrate.
Br J Haematoli. 1994 Aug;87(4):782-788. (Prospective crossover; 19 patients)
126. Mannucci PM, Bauer KA, Gringeri A, et al. No activation
of the common pathway of the coagulation cascade after a
highly purified factor IX concentrate. Br J Haematol. 1991
Dec;79(4):606-11.Limentani SA, Gowell KP, Deitcher SR.
High-purity factor IX concentrates for treatment of hemophilia B: relative purity and thromogenic potential. Acta
Haematol. 1995;94 Suppl 1:12-7. (Prospective comparison,
non-randomized; 24 patients)
127. Limentani SA, Gowell KP, Deitcher SR. High-purity factor IX
concentrates for treatment of hemophilia B: relative purity
and thromogenic potential. Acta Haematol. 1995;94 Suppl
1:12-7. (Laboratory in vitro comparison)
128. Gouw SC, van der Bom JG, Marijke van den Berg H.
Treatment-related risk factors of inhibitor development
in previously untreated patients with hemophilia A: the
CANAL cohort study. Blood. 2007 Jun 1;109(11):4648-4654.
(Retrospective cohort; 366 patients)
129. Warrier I, Lewenstein BM, Koerper MA, et al. Factor IX
inhibitors and anaphylaxis in hemophilia B. J Pediatr Hematol
Oncol. 1997 Jan-Feb;19(1):23-7. (Retrospective cohort; 18
patients)
130. Sultan Y. Prevalence of inhibitors in a population of 3435
hemophilia patients in France. French Hemophilia Sutdy
Group. Thromb Haemost. 1992 Jun 1;67(6):600-602. (Population-based data, cross-sectional study)
131. Villar MM, Himenez Yuste V, Quintana M, et al. Prophylactic
treatment effects on inhibitor risk: experience in one centre.
Haemophilia. 2005 Mar;11(2):79-83. (Retrospective cohort, 50
patients)
132. Sharathkumar A, Lillicrap D, Blanchette VS, et al. Intensive
exposure to factor VIII is a risk factor for inhibitor development in mild hemophilia A. Thromb Haemost. 1:1228-1236.
(Retrospective cohort; 54 patients, and review)
133. Van der Born JG, Mauser-Bunschoten EP, Fischer K, et al.
Age at first treatment and immune tolerance to factor VIII in
severe hemophilia. Thromb Haemost. 2003 Mar;89(3):475-479.
134. Lorenzo JL, Lopez A, Altisent C, et al. Incidence of factor VIII
inhibitors in severe haemophilia: the importance of patient
age. Br J Haematol. 2001; 113:600-603. (Retrospective cohort;
62 patients)
135. Santagostino E, Mancuso ME, Rocino A, et al. Environmental risk factors for inhibitor development in children with
haemophilia A: a case-control study. Br J Haematol. 2005;
130:422-427. (Retrospective, ase-control; 108 patients)
136. Astermark J, Rocino A, Von Depka M, et al. Haemophilia.
2007 Jan;13(1):38-45. (Questionnaire regarding variation in
practice)
137. Matino IA, Damico R, Makris M. Recombinant Factor VIIa

concentrate versus plasma derived concentrates for the treatment of acute bleeding episodes in people with haemophilia
and inhibitors. Cochrane Database of Systematic Reviews. 2010
Issue 11. (Systematic review)
138. Steen Carlsson K, Astermark J, Donfield S, et al. Cost and
outcome: comparisons of two alternative bypassing agents
for persons with haemophilia A complicated by an inhibitor. Thromb Haemost. 2008 Jun;99(6):1060-1067. (Prospective,
cross-over; 48 patients)
139. Bonnet PO, Yoon BS, Wong WY, et al. Cost minimization
analysis to compare activated prothrombin complex concentrate (APCC) and recombinant factor VIIa for haemophilia
patients with inhibitors undergoing major orthopaedic
surgeries. Haemophilia 2009 Sep;15(5):1083-1089. (Cost-minimization model)
140. Pruthi RK, Mathew P, Valentino LA, et al. Haemostatic
efficacy and safety of bolus and continuous infusion of
recombinant factor VIIa are comparable in haemophilia
patients with inhibitors undergoing major surgery. Results
from an open-label, randomized, multicenter trial. Thromb
Haemost. 2007 Oct;98(4):726-732. (Prospective, randomized,
open-label; 24 patients)
141. 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 Feb;4(2):367-371.
(Prospective, randomized, open-label, cross-over; 22
patients)
142. Macik BG, Lindley Cm, Lusher J, et al. Safety and initial
clinical efficacy of three dose levels of recombinant activated
factor VII (rFVIIA): results of a phase I study. Blood Coagul
Fibrinolysis. 1993 Aug;4(4):521-527. (Prospective, open-label
cohort, 15 patients)
143. Lusher JM, Roberts HR, Davignon G, et al. A randomized,
double-blind comparison of two dosage levels of recombinant factor VIIa in the treatment of joint, muscle and
mucocutaneous haemorrhages in persons with haemophilia
A and B, with and without inhibitors. rFVIIa Study Group.
Haemophilia.1998 Nov;4(6)790-798. (Prospective, randomized, double-blind; 84 patients)
144. FDA Summary Basis for Approval. Reference Number
96-0597. Drug Licensed Name: Coagulation Factor VIIa (Recombinant) (rFVIIa). Manufacturer: Novo Nordisk Pharmaceuticals Inc. Trade name: Novo Seven. (Summary basis for
approval by the FDA)
145. Arkin S, Cooper HA, Hutter JJ, et al. Activated recombinant
human coagulation factor VII therapy for intracranial hemorrhage in patients with hemophilia A or B with inhibitors.
Results of the novoseven emergency-use program. Haemostasis. 1998 Mar-Apr;28(2):93-98. (Prospective, open-label,
emergency use, cohort; 12 patients)
146. Nakar C, Cooper Dl, DiMichele D. Recombinant activated
factor VII safety and efficacy in the treatment of cranial
haemorrhage in patients with congenital haemophilia with
inhbitors: an analysis of the Hemophilia and Thrombosis
Research Society Registry (2004-2008). Haemophilia. 2010 Jul
1;16(4):625-631. (Retrospective; 29 patients)
147. Rice KM, Savidge GF. NovoSeven (reocmbinant factor VIIa)
in central nervous system bleeds. Haemostasis. 1996;26 Suppl
1:131-134. (Review of two prior investigations)
148. Arkin S, Blei F, Fetten J, et al. Human coagulation factor
FVIIa (recombinant) in the management of limb-threatening
bleeds unresponsive to alternative therapies: results from
the NovoSeven emergency-use programme in patients with
severe haemophilia or with acquired inhibitors. Blood Coagul
Fibrinolysis. 2000 Apr;11(3):255-259. (Prospective, open-label;
17 patients)
149. Liebman HA, Chediak J, Fink KI, et al. Activated recombinant human coagulation factor VII (rFVIIA) therapy for
24
abdominal bleeding in patients with inhibitory antibodies to

factor VIII. Am J Hematol. 2000 Mar;63(3):109-113. (Prospective, open-label, cohort; 8 patients)
150. Lusher, JM. Acute hemarthroses: the benefits of early versus
late treatment with recombinant activated factor Vii. Blood
Coagul Fibrinolysis. 2000 Apr;11 Supl:S45-9. (Retrospective;
223 hemarthroses)
151. Hay CR, Negrier C, Ludlam CA. The treatment of bleeding
in acquired haemophilia with recombinant factor VIIa: a
multicentre study. Thromb Haemost. 1997 Dec;78(6):1463-1467.
(Prospective cohort, 28 patients)
152. Ciaverella N, Schiavoni M, Valenzano E, et al. Use of
recombinant factor VIIa (NovoSeven) in the treatment of
two patients with type III von Willebrands disease and an
inhibitor against von Willebrand factor. Haemostasis 1996;26
Suppl 1:150-154. (Case series; 2 patients)
153. Friederich PW, Wever PC, Briet E, et al. successful treatment
with recombinant factor VIIa of therapy-resistant severe
bleeding in a patient with acquired von Willebrand disease.
Am J Hematol. 2001 Apr;66(4):292-4. (Case report; 1 patient)
154. FEIBA NF (Anti-inhibitor Coagulant Complex), Package
insert. Baxter Healthcare Corporation. (Package insert)
155. Hilgartner, Knatterus GL, and the FEIBA Study Group. The
use of Factor Eight Inhibitor By-Passsing Activity (FEIBA
Immuno) product for treatment of bleeding episodes in
hemophiliacs with inhibitors. Blood. 1983 Jan; 61(1):35-40.
(Prospective, open-label cohort; 46 patients)
156. Smejkal SP, Brabec P, Matyskova M, et al. FEIBA in treatment
of acute bleeding episodes in patients with haemophilia A
and factor VIII inhibitors: a retrospective survey in regional
haemophilia centre. Haemophilia. 2009 May;15(3):743-751.
(Retrospective cohort; 6 patients, 61 bleeding episodes)
157. FDA Letter to healthcare Professionals. Important Drug
Warning: Risk of thrombotic and thromboembolic events following infusion of FEIBA VH or FEIBA NF, particularly following the administration of high doses and/or in patients
with thrombotic risk factors. July 2010. www.fda.gov. (Black
box warning)
158. CSL Behring. Antihemophilic Factor/von Willebrand Factor
Complex (Human), Dried, pasteurized. Humate-P?. U.S.
Package Insert. (Package insert)
159. FDA News Release P07-11. FDA approves New Product to
Treat Von Willebrand Disease. February 2, 2007. (FDA approval letter)
160. Wilate, von Willebrand Factor/Coagulation Factor VIII complex. Package insert. Octapharma. (Package insert)
161. Mannucci PM, Chediak J, Hanna W, et al. Treatment of von
Willebrand disease with a high-purity factor VIII/von Willebrand factor concentrate: a prospective multi-center study.
Blood. 2002 Jan 15;99(2):450-456. (Prospective, 81 patients)
162. Franchini M, Rossetti G, Tagliaferri A, et al. Efficacy and
safety of factor VIII/von Willebrands factor concentrate
(Haemate-P) in preventing bleeding during surgery or
invasive procedures in patients with von-Willebrand disease.
Haematologica. 2003 Nov;88(11):1279-1283. (Prospective
163. Thompson AR, Gill JC, Ewenstein BM, et al. Successful treatment for patients with von Willebrand disease undergoing
urgent surgery using factor VIII/VWF concentrate (HumateP). Haemophilia. 2004 Jan;10(1):42-51. (Prospective, openlabel, non-randomized; 39 patients)
164. Mannucci PM, Ruggieri ZM, Pareti FL, et al. 1-Deamino-8d-arginine vasopressin: a new pharmacological approach
to the management of haemophilia and von Willebrands
diseases. Lancet. 1977 Apr 23;1(8017):869-872. (Prospective;
10 patients)
165. Mannucci PM. Desmopressin (DDAVP) in the Treatment
of Bleeding Disorders: The First 20 Years. Blood. 1997 Oct
1;90(7):2515-2521. (Review)
166. De la Fuente B, Kasper CK, Rickles FR, et al. Response of
patients with mild and moderate hemophilia A and von Willebrands disease to treatment with desmopressin. Ann Intern
Med. 1985 Jul;103(1):6-14. (Prospective; 68 patients)
167. Revel-Vilk S, Blanchette VS, Sparling C, et al. DDAVP challenge tests in boys with mild/moderate haemophilia A. Br J
Haematol. 2002 Jun;117(4):947-951. (Retrospective cohort)
168. Gill JC, Ottum M, Schwartz B. Evaluation of high concentration intranasal and intravenous desmopressin in pediatric
patients with mild hemophilia A or mild-to-moderate type
1 von Willebrand disease. J Pediatr. 2002 May;140(5):595599. (Prospective with comparison to historical cohort; 25
patients)
169. Rodeghiero F, Castaman G, DiBona E, et al. Consistency of
responses to repeated DDAVP infusions in patients with
von Willebrands disease and hemophilia A. Blood. 1989 Nov
1;74(6):1997-2000. (Prospective; 32 patients)
170. Dunn AL, Powers JR, Ribeiro MJ, et al. Adverse events during use of intranasal desmopressin acetate for haemophilia
A and von Willebrand disease: a case report and review of
40 patients. Haemophilia. 2000 Jan;6(1):11-14. (Case report; 1
patient and Retrospective; 40 patients)
171. DDAVP desmopressin acetate solution. Package insert.
Sanofi-Aventis U.S. LLC. (Package insert)
172. Amicar? (Aminocaproic acid). Package insert. Xanodyne
pharmaceuticals, Inc. Rev 09/08 Code 909A00. (Package
insert)
173. Gill JC: Diagnosis and treatment of von Willebrand disease.
Hematol Oncol Clin North Am 2004;18(6):1277-99. (Review)
174. Djulbegovic B, Hannan MM, Bergman GE. Concomitant
treatment with factor IX concentrates and antifibrinolytics in
hemophilia B. Acta Haematol. 1995(94) Suppl 1:43-7. (Retrospective; 19 patients)
175. Djulbegovic B, Marasa M, Pesto A, et al. Safety and efficacy
of purified factor IX concentrate and antifibrinolytic agents
for dental extractions in hemophilia B. Am J Hematol. 2996
Feb;51(2):168-170. (Prospective; 8 patients)
176. Ghosh K, Shetty S, Pathare A, et al. Epsilon-aminocaproic
acid inhibits the activity of factor VIII inhibitors in patients
with severe haemophilia A in vivo an in vitro. Acta Haematol.
2000;103(2):67-72. (Prospective, 6 patients)
177. Ghosh K, Shetty S, Jijina F, et al. Role of episilon amino
caproic acid in the management of haemophilic patients with
inhibitors. Haemophilia. 2004 Jan;10(1):58-62. (Prospective; 10
patients)
178. Rakocz M, Mazar A, Varon D, et al. Dental extractions in
patients with bleeding disorders. The use of fibrin glue. Oral
Surg Oral Med Oral Pathol. 1003 Mar;75(3):280-282. (Prospective; 80 patients)
179. Federici AB, Sacco R, Stabile F, et al. Optimising local
therapy during oral surgery in patients with von Willebrand
disease: effective results from a retrospective analysis of 63
cases. Haemophilia. 2000 Mar;6(2):71-77. (Retrospective, 63
patients)
180. Yilmaz D, Akin M, Ay Y, et al. A single centre experience in
circumcision of haemophilia patients: Izmir protocol. Haemophilia. 2010 Nov ;16(6):888-91. (Retrospective; 50 patients)
181. Blanchette VS, Luke B, Andrew M, et al. A prospective,
randomized rial of high-dose intravenous immune globulin
G therapy, oral prednisone therapy, and no therapy in childhood acute immune thrombocytopenic purpura. J Pediatr.
1993 Dec;123(6):989-995. (Prospective, randomized, openlabel, clinical trial; 53 patients)
182. Bellucci S, Charpak Y, Chastang C, et al. Low doses versus
conventional doses of corticoids in immune thrombocytopenic purpura (ITP): results of a randomized clinical trial
in 160 children, 223 adults. Blood. 1988 Apr;71(4):1165-1169.
(Prospective, randomized, open-label clinical trial; 383
patients)
183. Imbach P, Wagner HP, Berchtold W, et al. Intravenous immunoglobulin versus oral corticosteroids in acute immune
25
thrombocytopenic purpura in childhood. Lancet. 1985 Aug

31;2(8453):464-468. (Prospective, randomized, open-label
clinical trial; 108 patients)
184. Ozsoylu S, Sayli TR, Ozturk G. Oral megadose methylprednisolone versus intravenous immunoglobulin for acute
childhood idiopathic thrombocytopenic purpura. Pediatr
Hematol Oncol. 1993 Oct-Dec;10(4):317-321. (Prospective,
randomized, open-label clinical trial; 20 patients)
185. Albayrak D, Islek I, Kalayci AG, et al. Acute immune
thrombocytopenic purpura: a comparitive study of very
high oral doses of methylprednisolone and intravenously administered immune globulin. J Pediatr. 1994
dec;125(6pt1):1004-1007. (Prospective, randomized, openlabel clinical trial 57 patients)
186. Blanchette V, Imbach P, Andrew M, et al. Randomised trial of
intravenous immunoglobulin G, intravenous anti-D and oral
prednisone in childhood acute immune thrombocytopenic
purpura. Lancet. 1994 Sep 10;344(8924)703-707. (Prospective,
randomized, open-label clinical trial; 146 patients)
187. Buchanan GR, Holtkamp CA. Prednisone therapy for children with newly diagnosed idiopathic thrombocytopenic
purpura. A randomized clinical trial. Am J Pediatr Oncol 2984
Winter;6(4):355-361. (Prospective, randomized, placebocontrolled clinical trial; 27 patients)
188. De Mattia D, Del Principe D, Del Vecchio GC, et al. Acute
childhood idiopathic thrombocytopenic purpura: AIEOP
consensus guidelines for diagnosis and treatment. Haematologica. 2000;85:420-424. (Expert opinion and consensus
guidelines)
189. Beck CE, Nathan PC, Parkin PC, et al. Corticosteroids versus
intravenous immune globulin for the treatment of acute
immune thrombocytopenic purpura in children: a systematic
review and meta-analysis of randomized controlled trials. J
Pediatr. 2005 Oct;147(4):521-527. (Systematic review)
190. Bussel JB, Goldman A, Imbach P, et al. Treatment of acute
idiopathic thrombocytopenia of childhood with intravenous
infusions of gammaglobulin. J Pediatr. 1985 Jun;106(6):886890. (Prospective; 29 patients)
191. Imbach P, Barandun S, dApuzzo V, et al. High-dose intravenous gammaglobulin for idiopathic thrombocytopenic
purpura in childhood. Lancet. 1981 Jun 6;1(8232):1228-31.
(Prospective; 7 patients)
192. Scaradavou A, Woo B, Woloski BM, et al. Intravenous anti-D
treatment of immune thrombocytopenic purpura: experience
in 272 patients. Blood. 1997 Apr 15;89(8);2689-2700. (Prospective; 261 patients)
193. Tarantino MD, Madden RM, Fennewald DL, et al. Treatment
of childhood acute immune thrombocytopenic purpura
with anti-D immune globulin or pooled immune globulin. J
Pediatr. 1999 Jan;134(1):21-26. (Retrospective; 33 patients)
194. Tarantino MD, Young G, Bertolone SJ, et al. Single dose of
anti-D immune globulin at 75 microg/kg is as effective as
intravenous immune globulin at rapidly raising the platelet
count in newly diagnosed immune thrombocytopenic purpura in children. J Pediatr. 2006 Apr;148(4):489-494. (Prospective, randomized clinical trial; 105 patients)
195. Kane I, Ragucci D, Shatat IF, et al. Comparison of intravenous immune globulin and high dose anti-D immune
globulin as initial therapy for childhood immune thrombocytopenic purpura. Br J Haematol. 2010 Apr;149(1):79-83.
(Retrospective; 53 patients)
196. El Alfy MS, Mokhtar GM, El-Laboudy MA, et al. Randomized trial of anti-D immunoglobulin versus low-dose
intravenous immunoglobulin in the treatment of childhood
chronic idiopathic thrombocytopenic purpura. Acta Haematol. 2006;115(1-2):46-52. (Prospective, randomized clinical
trial; 34 patients)
197. Gaines AR. Acute onset hemoglobinemia and/or hemoglobinuria and sequelae following Rh(o)(D) immune globulin
intravenous administration in immune thrombocytopenic
purpura patients. Blood. 2000 Apr 15;95(8):2523-2529. (Retrospective case series; 15 patients)
198. Rubinstein PG, Chen YH. Delayed hemolysis after intravenous ant-D immune globulin infusion in a patient with
idiopathic thrombocytopenic purpura. Am J Hematol. 2008
Aug;83(8):684-685. (Case report)
199. Gaines AR. Disseminated intravascular coagulation associated with acute hemoglobinemia or hemoglobinuria following Rho(D) immune globulin intravenous administration for
immune thrombocytopenic purpura. Blood. 2005;106:15321537. (Retrospective case series; 6 patients)
200. FDA U.S. Food and Drug Administration. Safety warning:
WinRho SDF (Rho(D) Immune Globulin Intravenous (Human): Risk of Intravascular Hemolysis. 3/10/10. (Safety
warning)
201. Carr JM, Kruskall MS, Kaye JA, et al. Efficacy of platelet
transfusions in immune thrombocytopenia. Am J Med. 1986
Junl80(6):1051-1054. (Retrospective, 11 patients)
202. Salama A, Kiesewetter H, Kalus U, et al. Massive platelet
transfusion is a rapidly effective emergency treatment in
patients with refractory autoimmune thrombocytopenia.
Thromb Haemost. 2008 Nov;100(5):762-765. (Prospective, 10
patients)
203. Spahr JE, Rodgers GM. Treatment of immune-mediated
thrombocytopenia purpura with concurrent intravenous
immunoglobulin and platelet transfusion: a retrospective
review of 40 patients. Am J Hematol. 2008 Feb;83(2):122-125.
204. Zerella JT, Martin LW, Lampkin BC. Emergency splenectomy
for idiopathic thrombocytopeni purpura in children. J Pediatr
Surg. 1978 Jun;13(3):243-246. (Retrospective; 30 patients)
205. Jacobs P, Wood L. Emergency surgery and refractory immune thrombocytopenic purpura. A case report. S Afr Med J.
1986 Mar 1;69(5):321-322. (Case report; 1 patient)
206. Wanachiwanawin W, Piankijagum A, Sindhvananda K, et al.
Emergency splenectomy in adult idiopathic thrombocytopenic purpura. A report of seven cases. Arch Intern Med. 1989
Jan;148(1):217-219. (Case series; 7 patients)
207. Gural A, Gillis S, Gafanovich A, et al. Massive intracranial
bleeding requiring emergency splenectomy in a patient with
CMV-associated thrombocytopenia. Haemostasis. 1998 SepOct;28(5):250-255. (Case report; 1 patient)
208. Pastore Y, Wacker P, Ozsahin H, et al. Emergency splenectomy in the management of intracranial hemorrhage in childhood immune thrombocytopenic purpura. J Pediatr Hematol
Oncol. 1999 Jul-Aug;21(4):306-307. (Case report; 1 patient)
209. Kojouri K, Vesely SK, Terrell DR, et al. Splenectomy for adult
patients with idiopathic thrombocytopenic purpura: a systematic review to assess long-term platelet count responses,
prediction of response, and surgical complications. Blood.
2004 Nov 1;104(9):2623-2634. (Retrospective; 135 patients)
210. Witmer CM, Huang YS, Lynch K, et al. Offlabel recombinant factor VIIa use and thrombosis in children: A Multi-center Cohort Study. J Pediatr. 2010 Dec 9. [epub ahead of print]
(Retrospective cohort; 3764 patients)
211. Hong I, Stachnik J. Unlabeled uses of factor VIIa (recombinant) in pediatric patients. Am J Health Syst Pharm. 2010 Nov
15;67(22):1909-1919. (Review)
212. Alten JA, Benner K, Green K, et al. Pediatric off-label use of
recombinant factor VIIa. Pediatrics. 2009 Mar;123(3): 10661072. (Retrospective case series; 135 patients)
213. Chuansumrit A, Teeraratkul S, Wanichkul S, et al. Recombinant-activated factor VII for control and prevention of
hemorrhage in nonhemophilic pediatric patients. Blood
Coagul Fibrinolysis. 2010 Jun;21(4):354-362. (Retrospective;
103 patients)
214. Young G, Wicklund B, Neff P, et al. Off-label use of rFVIIa
in children with excessive bleeding: a consecutive study of
153 off-label uses in 139 children. Pediatr Blood Cancer. 2009
Aug;53(2):179-183. (Retrospective)
26
3. According to this article, severe vitamin K deficiency may lead to which of the following:
a. Hemorrhagic disease of the newborn
b. Bone loss
c. Vision loss
d. Low birth weight
215. Yilmaz D, Karapinar B, Balkan C, et al. Single-center experience: use of recombinant factor VIIa for acute life-threatening bleeding in children without congenital hemorrhagic
disorder. Pediatr Hematol Oncol. 2008 Jun;25(4):301-311.
216. Hsia CC, Chin-Yee IH, McAlister VC. Use of recombinant
activated factor VII in patients without hemophilia: a
meta-analysis of randomized controlled trials. Ann Surg.
2008;248(1):61-68. (Systematic review)
4. Emergency clinicians should always use the

hospitals supply of a therapeutic agent instead
of one the patient brought from home.
a. True
b. False
CME Questions
Take This Test Online!
5. Patients with bleeding disorders may present

with which of the following complaints:
a. Abdominal or flank pain
b. Muscle pain
c. Headache without trauma
d. All of the above
Current subscribers receive CME credit absolutely

free by completing the following test. Monthly online testing is now available for current and archived
issues. Visit http://www.ebmedicine.net/CME
Take This Test Online!
today to receive your free CME credits. Each issue
includes 4 AMA PRA Category 1 CreditsTM, 4 ACEP
Category I credits, 4 AAP Prescribed credits, and 4
AOA category 2A or 2B credits.
6. Which of the following statements are true

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

are now considered second-line therapies by

many hematologists.
d. Both A and C
1. According to this article, the 2 main categories

of platelet disorders are:
a. Quantitative thrombocytopenia and

functional platelet dysfunction
b. Inherited and acquired
c. Immune and active
d. Emergent and chronic
7. All patients with a bleeding disorder and clinically significant or uncontrolled hemorrhage
require admission.
a. True
b. False
2. According to this article, the most common

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

deficiency (hemophilia B)
b. Fibrinogen and prothrombin deficiency
c. FVII deficiency and FXIII deficiency
d. FX deficiency and FXI deficiency
27
Coming Soon In Pediatric Emergency

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

Date of Original Release: August 1, 2011. Date of most recent review: July 10, 2010.
Termination date: August 1, 2014.
Accreditation: EB Medicine is accredited by the ACCME to provide continuing medical
education for physicians.
Credit Designation: EB Medicine designates this enduring material for a maximum of 4
AMA PRA Category 1 CreditsTM. Physicians should claim only credit commensurate with
the extent of their participation in the activity.
ACEP Accreditation: Pediatric Emergency Medicine Practice is also approved by the
American College of Emergency Physicians for 48 hours of ACEP Category I credit per
annual subscription.
AAP Accreditation: This continuing medical education activity has been reviewed by the
American Academy of Pediatrics and is acceptable for a maximum of 48 AAP credits per
year. These credits can be applied toward the AAP CME/CPD Award available to Fellows
and Candidate Fellows of the American Academy of Pediatrics.
AOA Accreditation: Pediatric Emergency Medicine Practice is eligible for up to 48 American
Osteopathic Association Category 2A or 2B credit hours per year.
Needs Assessment: The need for this educational activity was determined by a survey
of medical staff, including the editorial board of this publication; review of morbidity and
mortality data from the CDC, AHA, NCHS, and ACEP; and evaluation of prior activities for
emergency physicians.
Target Audience: This enduring material is designed for emergency medicine physicians,
physician assistants, nurse practitioners, and residents.
Goals: Upon reading Pediatric Emergency Medicine Practice, you should be able to: (1)
demonstrate medical decision-making based on the strongest clinical evidence; (2) costeffectively diagnose and treat the most critical ED presentations; and (3) describe the
most common medicolegal pitfalls for each topic covered.
Objectives: Upon completion of this article, you should be able to: (1) communicate
intelligently with the hematology consultant about patients with hematological conditions
in the ED; (2) manage common bleeding complications in patients with hemophilia; (3)
be familiar with various factor concentrate products and their use; (4) identify and begin
the appropriate evaluation for suspected, previously undiagnosed bleeding conditions,
including immune thrombocytopenic purpura; and (5) recognize less common conditions
associated with coagulopathy.
Discussion of Investigational Information: As part of the newsletter, faculty may be
presenting investigational information about pharmaceutical products that is outside Food
and Drug Administration approved labeling. Information presented as part of this activity is
intended solely as continuing medical education and is not intended to promote off-label
use of any pharmaceutical product.
Faculty Disclosure: It is the policy of EB Medicine to ensure objectivity, balance,
independence, transparency, and scientific rigor in all CME-sponsored educational
activities. All faculty participating in the planning or implementation of a sponsored activity
are expected to disclose to the audience any relevant financial relationships and to assist
in resolving any conflict of interest that may arise from the relationship. Presenters must
also make a meaningful disclosure to the audience of their discussions of unlabeled
or unapproved drugs or devices. In compliance with all ACCME Essentials, Standards,
and Guidelines, all faculty for this CME activity were asked to complete a full disclosure
statement. The information received is as follows: Dr. Fullerton, Dr. Place, Dr. Dean, Dr.
Joseph, Dr. Sharieff, Dr. Whiteman, and their related parties report no significant financial
interest or other relationship with the manufacturer(s) of any commercial product(s)
discussed in this educational presentation.
Hardware/Software Requirements: You will need a Macintosh or PC with internet
capabilities to access the website. Adobe Reader is required to download archived
articles.
Additional Policies: For additional policies, including our statement of conflict of interest,
source of funding, statement of informed consent, and statement of human and animal
rights, visit http://www.ebmedicine.net/policies.
Method of Participation:
Print Subscription Semester Program: Paid subscribers who read all CME articles during
each Pediatric Emergency Medicine Practice six-month testing period, complete the posttest and the CME Evaluation Form distributed with the June and December issues, and
return it according to the published instructions are eligible for up to 4 hours of CME credit
for each issue. You must complete both the post-test and CME Evaluation Form to receive
credit. Results will be kept confidential.
Online Single-Issue Program: Current, paid subscribers who read this Pediatric
Emergency Medicine Practice CME article and complete the online post-test and CME
Evaluation Form at ebmedicine.net/CME are eligible for up to 4 hours of Category 1 credit
toward the AMA Physicians Recognition Award (PRA). You must complete both the posttest and CME Evaluation Form to receive credit. Results will be kept confidential.
CEO: Robert Williford; President & Publisher: Stephanie Ivy; Director of Member Services: Liz Alvarez
Managing Editor & CME Director: Jennifer Pai; Managing Editor: Dorothy Whisenhunt; Marketing & Customer Service Coordinator: Robin Williford
Direct all questions to:
EB Medicine
1-800-249-5770
Outside the U.S.: 1-678-366-7933
Fax: 1-770-500-1316
5550 Triangle Parkway, Suite 150
Norcross, GA 30092
E-mail: ebm@ebmedicine.net
Website: EBMedicine.net
To write a letter to the editor, email: JagodaMD@ebmedicine.net
Subscription Information:
1 year (12 issues) including evidence-based print issues;
48 AMA PRA Category 1 CreditsTM, 48 ACEP Category 1 Credits, 48 AAP
Prescribed credits, and 48 AOA Category 2A or 2B credit; and full online access
to searchable archives and additional free CME: $299
(Call 1-800-249-5770 or go to www.ebmedicine.net/subscribe to order)
Single issues with CME may be purchased at
www.ebmedicine.net/PEMPissues
Pediatric Emergency Medicine Practice (ISSN Print: 1549-9650, ISSN Online: 1549-9669) is published monthly (12 times per year) by EB Medicine. 5550 Triangle Parkway, Suite 150, Norcross, GA
30092. Opinions expressed are not necessarily those of this publication. Mention of products or services does not constitute endorsement. This publication is intended as a general guide and is intended
to supplement, rather than substitute, professional judgment. It covers a highly technical and complex subject and should not be used for making specific medical decisions. The materials contained herein
are not intended to establish policy, procedure, or standard of care. Pediatric Emergency Medicine Practice is a trademark of EB Medicine. Copyright 2010 EB Medicine All rights reserved. No part of this
publication may be reproduced in any format without written consent of EB Medicine. This publication is intended for the use of the individual subscriber only, and may not be copied in whole or in part or
redistributed in any way without the publishers prior written permission including reproduction for educational purposes or for internal distribution within a hospital, library, group practice, or other entity.
28

Peds0811 Bleeding Disorders

Uploaded by

Document Information

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Peds0811 Bleeding Disorders

Uploaded by

Copyright:

Available Formats

Evidence-Based Emergent

hildren with both congenital (eg, hemophilia or von Willebrand

Medicine, University of Medicine

Chair for Pediatrics - Emergency

Alson S. Inaba, MD, FAAP,

Gary R. Strange, MD, MA, FACEP

Ghazala Q. Sharieff, MD, FAAP,

mild tachycardia. Youre surprised by the severity of the

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

Critical Appraisal Of The Literature

Epidemiology, Etiology, And

ebmedicine.net August 2011

cause of isolated thrombocytopenia. While ITP is

Specific Bleeding Disorders

National Heart, Lung,

The diagnosis, evaluation, and management of

Guideline on the selection and use of therapeutic

Guidelines for management of patients with

Protocols for the treatment of hemophilia and von

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

Website not available

Association of Hemophilia Clinic Directors of

Guidelines for management of patients with

August 2011 ebmedicine.net

Pediatric Emergency Medicine Practice 2011

are factor VIII deficiency (hemophilia A) and factor IX

Intramuscular hematomas can be incredibly

Von Willebrand Disease

Table 2. Platelet Disorders

Infection with bone marrow suppression

Platelet-vessel wall adhesion defects

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

Pediatric Emergency Medicine Practice 2011

ebmedicine.net August 2011

lebrand factor also provides a critically important

lungs, and intracranially. Intracranial hemorrhage

Table 3. Differential Diagnosis Of Common

Inherited Coagulation Disorder*

Acquired Coagulation Disorder

August 2011 ebmedicine.net

Pediatric Emergency Medicine Practice 2011

drug-induced thrombocytopenia in addition to

Emergency Department Evaluation

Table 4. Common Acute Complaints

Abdominal or flank pain

Retroperitoneal bleeding, iliopsoas hematoma

Premonitory symptoms: warmth,

History of minor head trauma,

Headache without trauma

Anterior or posterior nosebleed

Bleeding from mouth

Bleeding from oral mucosa

Eye pain, visual changes

Back pain, weakness

ebmedicine.net August 2011

well-appearing patients, purpura (small palpable

Table 5. Historical Predictors Of Potential

Presence of bleeding disorder in a family member

August 2011 ebmedicine.net

Pediatric Emergency Medicine Practice 2011

der or swollen limb.

Table 6. Interpretation Of PT And aPTT

Not a problem with

Factor VII deficiency