Hemophilia A (Factor VIII Deficiency)

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emedicine.medscape.com
Hemophilia A (Factor VIII

Deficiency)
Updated: Jul 05, 2023
Author: Douglass A Drelich, MD; Chief Editor: Srikanth Nagalla, MD, MS, FACP
Overview
Practice Essentials
Hemophilia A is an X-linked, recessive disorder caused by deficiency of functional plasma clotting factor VIII (FVIII), which may
be inherited or arise from spontaneous mutation. The development of inhibitory alloantibodies to FVIII can severely complicate
the treatment of genetic cases. Rarely, development of autoantibodies to FVIII results in acquired hemophilia A.
Signs and symptoms
Depending on the level of FVIII activity, patients with hemophilia may present with easy bruising; inadequate clotting of traumatic
or even mild injury; or, in the case of severe hemophilia, spontaneous hemorrhage.
Signs of hemorrhage include the following:
General (usuall attributed to anemia secondary to bleeding): Weakness, orthostasis, tachycardia, tachypnea
Musculoskeletal (joints): Tingling, cracking, warmth, pain, stiffness, and refusal to use joint (children)
CNS: Headache, stiff neck, vomiting, lethargy, irritability, and spinal cord syndromes
Gastrointestinal: Hematemesis, melena, frank red blood per rectum, and abdominal pain
Genitourinary: Hematuria, renal colic, and post-circumcision bleeding
Other: Epistaxis, oral mucosal hemorrhage, hemoptysis, dyspnea (hematoma leading to airway obstruction),
compartment syndrome symptoms, and contusions; excessive/prolonged bleeding with routine dental or other
procedures
See Presentation for more detail.
Diagnosis
Laboratory studies for suspected hemophilia include the following:
Complete blood cell count

Screening coagulation studies (prothrombin time [PT], activated partial thromboplastin time [aPTT])
FVIII assay (clot based or chromogenic)
FVIII inhibitor assay (Bethesda assay, Nijmegen modified Bethesda assay)
Expected laboratory values are as follows:
Hemoglobin/hematocrit: Normal (or low if associated bleeding)

Platelet count: Normal
Prothrombin time (PT): Normal
APTT: Significantly prolonged in severe hemophilia, but may be normal or minimally prolonged in mild or even moderate
hemophilia
Normal values for FVIII assays are 50-150%. Values in hemophilia A are as follows:
Mild: > 5%
Moderate: 1-5%
Severe: < 1%
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Imaging studies for acute bleeds are chosen on the basis of clinical suspicion and anatomic location of involvement, as follows:
Head computed tomography scans without contrast are used to assess for spontaneous or traumatic intracranial
hemorrhage
MRI scans of the head and spinal column are used for further assessment of spontaneous or traumatic hemorrhage
MRI is also useful in the evaluation of the cartilage, synovium, and joint space
Ultrasonography is useful in the evaluation of joints affected by acute or chronic effusions
Testing for inhibitors is indicated when bleeding is not controlled after infusion of adequate amounts of factor concentrate during
a bleeding episode. The presence of inhibitors is indicated by failure of correction of clotting times with 1:1 mix with normal
plasma. Inhibitor concentration is titrated using the Bethesda method, as follows:
Positive result: ≥ 0.6 Bethesda units (BU)

Low-titer inhibitor: ≤5 BU
High-titer inhibitor: >5 BU
See Workup for more detail.
Management
The treatment of hemophilia may involve the following:
Management of hemostasis
Management of bleeding episodes including hemostatic support and pain management
Use of factor replacement products and adjuvant medications
Gene therapy
Treatment of patients with factor inhibitors
Treatment and rehabilitation of patients with hemophilia synovitis
Disposition of treatment is as follows:
Management ideally should be provided through a comprehensive hemophilia care center

Home administration of treatment and infusions by the family or patient is customary
FVIII treatment may be given prophylactically or on demand
Hospitalization is reserved for severe or life-threatening bleeds or for patients for whom home infusion is unavailable or
impractical
For treatment of acute bleeds, target levels by hemorrhage severity are as follows:
Mild hemorrhages (eg, early hemarthrosis, epistaxis, gingival bleeding): Maintain an FVIII level of 30%
Major hemorrhages (eg, late hemarthrosis, muscle bleeds): Maintain an FVIII level of at least 50%
Life- or limb-threatening bleeding episodes (eg, major trauma or surgery, advanced or recurrent hemarthrosis, major GI
bleeding, any head trauma, signs of distal neurovascular compormise of limb or compartment syndrome): Maintain an
FVIII level of 80-100%
Ideally, therapy is individualized to specific patients. However, for general dosing, to find the number of units of factor VIII
needed to correct the factor VIII activity level, use the following formula:
Dose in FVIII IU = (weight in kg) x (desired FVIII increase) x (0.5 IU/kg per IU/dL)
FVIII regimens are as follows:
The second dose should be administered 8-12 hours after the initial dose and is usually one half the initial calculated
dose
Minor hemorrhage requires 1-3 doses of FVIII
Major hemorrhage requires many doses and continued FVIII activity monitoring with the goal of keeping the trough
activity level at least 50%
Continuous infusions of FVIII may be considered for major hemorrhage or major surgery
The following types of FVIII concentrates are available:
Plasma-based products: Purified to inactivate viruses

First-generation recombinant products: Produced in mammalian cell lines, contain animal and/or human plasma-derived
proteins in cell culture media and in final product.
Second-generation recombinant products: Produced in mammalian cell lines, contain animal and/or human plasma-
derived proteins in cell culture media but none in final product.
Third-generation recombinant products: Produced in mammalian cell lines, contain no animal and/or human plasma-
derived proteins in cell culture media or in final product.
Extended half-life recombinant FVIII products
Desmopressin vasopressin analog, or 1-deamino-8-D-arginine vasopressin (DDAVP), has the following attributes:
Depending on baseline level and goal factor level, may be considered the treatment of choice for mild and moderate
hemophilia A
Not effective in the treatment of severe hemophilia
Can be intravenously administered at a dose of 0.3 mcg/kg of body weight in the inpatient setting (Canadian labeling
recommends maximum dose of 20 mcg).
Peak effect is observed in 30-60 minutes
DDAVP leads to free water retention, which can lead to hyponatremia
A concentrated DDAVP intranasal spray is available for outpatient use
The following antifibrinolytics are used in addition to FVIII replacement for oral mucosal hemorrhage and prophylaxis:
Epsilon aminocaproic acid (Amicar)

Tranexamic acid (Cyklokapron, Lyseda)
Treatments used in patients with inhibitors of FVIII are as follows:
High doses of FVIII for low-titer inhibitors

Activated prothrombin complex concentrate (aPCC)
Activated recombinant FVII (rFVIIa)
Monoclonal antibodies directed toward restoring FVIII function (eg, emicizumab)
Porcine FVIII, which has low cross-reactivity with human FVIII antibody
Desensitization
Immune tolerance induction (ITI)
See Treatment and Medication for more detail.
COVID-19
The World Federation of Hemophilia (WFH) advises that no increased susceptibility to SARS-CoV-2 infection has been found in
immunocompetent patients with bleeding disorders, and there is currently no known COVID-19 risk from blood, blood treatment
products, and plasma-derived products.[1]
In addition, the WFH notes the following:
As COVID-19 progresses, coagulation pathways are activated as part of the host inflammatory response to limit the viral
infection. Specifically, D-dimer levels are often elevated. More severe COVID-19 may lead to overt disseminated
intravascular coagulation (DIC), associated with high mortality. Close monitoring for bleeding and thrombosis is
recommended for all individuals who progress with signs or symptoms of DIC.
Anticoagulants (eg, low molecular weight heparin [LMWH]) are being recommended as part of treatment protocols for
patients with elevated D-dimers and severe infection. Use of anticoagulants should be accompanied by factor
replacement therapy.
If COVID-19 is diagnosed, prophylaxis with factor replacement therapy should be continued, with consideration of higher
trough levels (like those for major trauma) in patients hospitalized for severe infection.
The risk of COVID-19–related thrombotic complications for hemophilia patients receiving treatment with non–factor
replacement therapies, such emicizumab or other investigational agents (eg, fitusiran, anti–tissue factor pathway
inhibitor) is unknown.
Whether emicizumab may interact with COVID-19–related coagulopathy is unknown; close monitoring for thrombosis is
recommended. Prophylaxis should be continued, and in the event of missed doses, the long half-life (~30 days) of
emicizumab should be taken into consideration, since it will be present and active for a prolonged period of time.
Patients should be assessed to determine whether they need additional clotting factor replacement therapy.
Anticoagulants may be considered as per recommended treatment protocols.
In patients with FVIII inhibitors receiving emicizumab, extra precautions should be taken if they require aPCC, because of
the known drug-drug interaction between emicizumab and aPCC.
Some one-stage coagulation assays—such as aPTT, which is often used to diagnose and monitor patients in DIC—
overestimate coagulation in patients on emicizumab and thus may mask coagulopathy.
For patients who are participating in clinical studies, investigators are advised to seek guidance from the study sponsors
and medical monitors. Patients should inform health care providers they are in a clinical study; consultation with their
hematologist is recommended.
For patients participating in a clinical trial of gene therapy, in addition to caution regarding infection risk due to
immunosuppression, supplementation to higher coagulation factor levels (eg, as if treating major trauma) could be
considered in those who have had a suboptimal response to the gene therapy.
Patients with bleeding disorders of all severities and COVID-19 should be eligible for all available therapies that would be
required depending on their condition (eg, ventilation support, extracorporeal membrane oxygenation [ECMO],
hemofiltration). Having hemophilia should not exclude individuals from invasive management of COVID-19.
A case report of COVID-19 in a patient in Wuhan, China, suggests that home management with active monitoring is appropriate
for patients with hemophilia who have mild cases of COVID-19. Such patients may benefit from administration of replacement
factors at the onset of infectious illness.[2]
The WFH, in collaboration with the European Association for Haemophilia and Allied Disorders, European Haemophilia
Consortium, and US National Hemophilia Foundation, has also issued recommendations on COVID-19 vaccination for people
with bleeding disorders.[3]
Background
Hemophilia A is an inherited, X-linked, recessive disorder caused by deficiency of functional plasma clotting factor VIII (FVIII). In
a significant number of cases, the disorder results from a new mutation. Rarely this develops as an acquired auto-immune
process.
Morbidity and death are primarily the result of hemorrhage, although infectious diseases (eg, HIV infection, hepatitis) became
prominent, particularly in patients who received blood products prior to 1985.
Laboratory studies for suspected hemophilia include a complete blood cell count, coagulation studies, and an FVIII assay. In
patients with an established diagnosis of hemophilia, periodic laboratory evaluations include screening for the presence of FVIII
inhibitor and screening for transfusion-related or transmissible diseases such as hepatitis and HIV infection. Measurement of
FVIII levels is important for monitoring FVIII replacement therapy. (See Workup.)
The treatment of hemophilia may involve prophylaxis, management of bleeding episodes, immune tolerance induction for
patients with factor inhibitors, and treatment and rehabilitation of patients with hemophilia synovitis. Treatment of patients with
hemophilia ideally should be provided through a comprehensive hemophilia care center (see Treatment and Medication).[4]
Please see the following for more information:
Acquired Hemophilia
Hemophilia B
Hemophilia C
Classification
The classification of the severity of hemophilia has been based on either clinical bleeding symptoms or on plasma procoagulant
levels; the latter are the most widely used criteria. Classification according to plasma procoagulant levels is as follows:
Severe hemophilia - FVIII level less than 1% of normal (< 0.01 IU/mL)
Moderate hemophilia - FVIII level 1-5% of normal (0.01-0.05 IU/mL)
Mild hemophilia - FVIII level more than 5% but less than 40% of normal (>0.05 to < 0.40 IU/mL)
Severe disease presents in children younger than 1 year and accounts for 43-70% of hemophilia A cases. Moderate disease
presents in children aged 1-2 years and accounts for 15-26% of cases. Mild disease presents in children older than 2 years and
accounts for 15-31% of cases.
Clinical bleeding symptom criteria have been used because patients with FVIII levels of less than 1% occasionally have little or
no spontaneous bleeding and appear to have clinically moderate or mild hemophilia. Furthermore, the reverse is true for patients
with procoagulant activities of 1-5%, who may present with clinically severe disease.
Historical background
Hemophilia is one of the oldest described genetic diseases. An inherited bleeding disorder in males was recognized in Talmudic
records of the second century.
The modern history of hemophilia began in 1803 with the description of hemophilic kindred by John Otto, followed by the first
review of hemophilia by Nasse in 1820. Wright demonstrated evidence of laboratory defects in blood clotting in 1893; however,
FVIII was not identified until 1937, when Patek and Taylor isolated a clotting factor from the blood, which they called
antihemophilic factor (AHF).
A bioassay of FVIII was introduced in 1950. Although the intimate relationship between FVIII and von Willebrand factor (vWF) is
now known, it was not appreciated at the time. In 1953, decreased FVIII levels in patients with vWF deficiency was first
described. Further research by Nilson and coworkers indicated the interaction between these 2 clotting factors.
In 1952, hemophilia B was described and was named Christmas disease after the surname of the first patient who was
examined in detail. The differentiation of hemophilia B from hemophilia A followed the observation that mixing plasma from a
patient with "true hemophilia" with plasma from a patient with Christmas disease corrected the clotting time. Hemophilia A makes
up approximately 80% of hemophilia cases.
In the early 1960s, cryoprecipitate (the precipitate from fresh frozen plasma that has been thawed and centrifuged) became the
first concentrate available for the treatment of patients with hemophilia. In the 1970s, lyophilized (ie, freeze-dried) intermediate-
purity concentrates were obtained from large pools of blood donors. The introduction of concentrated lyophilized products that
are easy to store and transport dramatically improved the quality of life of patients with hemophilia and facilitated their
preparation for surgery and home care.
Unfortunately, the large size of the donor pool—as many as 20,000 donors may contribute to a single lot of plasma-derived FVIII
concentrate—heightened the risk of viral contamination of commercial FVIII concentrates. By the mid-1980s, the majority of
patients with severe hemophilia had been exposed to hepatitis A, hepatitis B, and hepatitis C viruses and human
immunodeficiency virus (HIV).
Viricidal treatment of plasma-derived FVIII concentrates has been effective in eliminating new HIV transmissions and virtually
eliminating hepatitis B and hepatitis C exposures. The introduction of recombinant FVIII concentrate, and the gradual elimination
of albumin from the production process used for these products, has virtually eliminated the risk of viral exposure.
Pathophysiology
Factor VIII production, processing, and structure
Primary sites of factor VIII (FVIII) production are thought to be the vascular endothelium in the liver and the reticuloendothelial
system. Liver transplantation corrects FVIII deficiency in persons with hemophilia.
FVIII messenger RNA has been detected in the liver, spleen, and other tissues.[5] Studies of FVIII production in transfected cell
lines have shown that following synthesis, FVIII moves to the lumen of the endoplasmic reticulum, where it is bound to several
proteins that regulate secretion, particularly immunoglobulin binding protein, from which it has to dissociate in an energy-
dependent process.
Cleavage of FVIII's signal peptide and the addition of oligosaccharides also occur in the endoplasmic reticulum. The chaperone
proteins, calnexin and calreticulin, enhance both FVIII secretion and degradation.
A part of the factor FVIII protein in the endoplasmic reticulum is degraded within the cell. The other part enters the Golgi
apparatus, where several changes occur to produce the heavy and light chains and to modify the carbohydrates. The addition of
sulfates to tyrosine residues of the heavy and light chains is necessary for full procoagulant activity, with the sulfated region
playing a role in thrombin interaction. This posttranslational sulfation of tyrosine residues impacts the procoagulant activity of
factor VIII and its interaction with von Willebrand factor (vWF).
von Willebrand factor
FVIII circulates in plasma in a noncovalently bound complex with vWF, which plays significant roles in the function, production,
stabilization, conformation, and immunogenicity of FVIII.[6] VWF has been termed FVIII-related antigen (FVIII-R); related
terminology for FVIII is FVIII-coagulant (FVIII-C).
VWF appears to promote assembly of the heavy and light chains of FVIII and more efficient secretion of FVIII from the
endoplasmic reticulum. It also directs FVIII into the Weibel-Palade bodies, which are the intracellular storage sites for vWF.
In plasma, vWF stabilizes FVIII and protects it from degradation. In the presence of normal vWF protein, the half-life of FVIII is
approximately 12 hours, whereas in the absence of vWF, the half-life of FVIII-C is reduced to 2 hours.[7, 8, 9]
The clotting cascade
The role of the coagulation system is to produce a stable fibrin clot at sites of injury. The clotting mechanism has two pathways:
intrinsic and extrinsic. See the image below.
Coagulation Cascade
The intrinsic system is initiated when factor XII is activated by contact with damaged endothelium. The activation of factor XII
can also initiate the extrinsic pathway, fibrinolysis, kinin generation, and complement activation.
In conjunction with high-molecular-weight kininogen (HMWK), factor XIIa converts prekallikrein (PK) to kallikrein and activates
factor XI. Activated factor XI, in turn, activates factor IX in a calcium-dependent reaction. Factor IXa can bind phospholipids.
Then, factor X is activated on the phospholipid surface; activation of factor X involves a complex (tenase complex) of factor IXa,
thrombin-activated FVIII, calcium ions, and phospholipid.
In the extrinsic system, the conversion of factor X to factor Xa involves tissue factor (TF), or thromboplastin; factor VII; and
calcium ions. TF is released from the damaged cells and is thought to be a lipoprotein complex that acts as a cell surface
receptor for factor VII, with its resultant activation. TF also adsorbs factor X to enhance the reaction between factor VIIa, factor
X, and calcium ions. Factor IXa and factor XII fragments can also activate factor VII.
In the common pathway, factor Xa (generated through the intrinsic or extrinsic pathways) forms a prothrombinase complex with
phospholipids, calcium ions, and thrombin-activated factor Va. The complex cleaves prothrombin into thrombin and prothrombin
fragments 1 and 2.
Thrombin converts fibrinogen into fibrin and activates FVIII, factor V, and factor XIII. Fibrinopeptides A and B, the results of the
cleavage of peptides A and B by thrombin, cause fibrin monomers to form and then polymerize into a meshwork of fibrin; the
resultant clot is stabilized by factor XIIIa and the cross-linking of adjacent fibrin strands.
Because of the complex interactions of the intrinsic and extrinsic pathways (factor IXa activates factor VII), the existence of only
one in vivo pathway with different mechanisms of activation has been suggested. See the image below.
The hemostatic pathway. APC = activated protein C (APC); AT-III = antithrombin III; FDP = fibrin degradation products; HC-II =
heparin cofactor II; HMWK = high-molecular-weight kininogen; PAI = plasminogen activator inhibitor; sc-uPA = single-chain
urokinase plasminogen activator; tc-uPA = two-chain urokinase plasminogen activator; TFPI = tissue factor pathway inhibitor;
tPA = tissue plasminogen activator
FVIII and factor IX circulate in an inactive form. When activated, these 2 factors cooperate to cleave and activate factor X, a key
enzyme that controls the conversion of fibrinogen to fibrin. Therefore, the lack of FVIII may significantly alter clot formation and,
as a consequence, result in clinical bleeding.
Genetics
The gene for FVIII (F8C) is located on the long arm of chromosome X, within the Xq28 region. The gene is unusually large,
representing 186 kb of the X chromosome. It comprises 26 exons and 25 introns. Mature FVIII contains 2332 amino acids. See
the image below.
Structural domains of human factor VIII. Adapted from: Stoilova-McPhie S, Villoutreix BO, Mertens K, Kemball-Cook G,
Holzenburg A. 3-Dimensional structure of membrane-bound coagulation factor VIII: modeling of the factor VIII heterodimer
within a 3-dimensional density map derived by electron crystallography. Blood. Feb 15 2002;99(4):1215-23; Roberts HR,
Hoffman M. Hemophilia A and B. In: Beutler E, Lichtman MA, Coller BS, et al, eds. Williams Hematology. 6th ed. NY: McGraw-
Hill; 2001:1639-57; and Roberts HR. Thoughts on the mechanism of action of FVIIa. Presented at: Second Symposium on
New Aspects of Haemophilia Treatment; 1991; Copenhagen, Denmark.
Approximately 40% of cases of severe FVIII deficiency arise from a large inversion that disrupts the FVIII gene. Deletions,
insertions, and point mutations account for the remaining 50-60% of the F8C defects that cause hemophilia A.
Low FVIII levels may arise from defects outside the FVIII gene, as in type IIN von Willebrand disease, in which the molecular
defect resides in the FVIII-binding domain of von Willebrand factor.
Hemophilia A
FVIII deficiency, dysfunctional FVIII, or FVIII inhibitors lead to the disruption of the normal intrinsic coagulation cascade, resulting
in excessive hemorrhage in response to trauma and, in severe cases, spontaneous hemorrhage. Hemorrhage sites include
joints (eg, knee, elbow); muscles; the central nervous system (CNS); and the gastrointestinal, genitourinary, pulmonary, and
cardiovascular systems. Intracranial hemorrhage occurs most commonly in patients younger than 18 years and can be fatal.
Hemorrhage into joints
The hallmark of hemophilia is hemorrhage into joints. This bleeding is painful and leads to long-term inflammation and
deterioration of the joint.
Human synovial cells synthesize high levels of tissue factor pathway inhibitor, resulting in a higher degree of factor Xa (FXa)
inhibition, which predisposes hemophilic joints to bleed. This effect may also account for the dramatic response of activated
factor VII (FVIIa) infusions in patients with acute hemarthroses and FVIII inhibitors.
Bleeding into a joint may lead to synovial inflammation, which predisposes the joint to further bleeds. A joint that has had
repeated bleeds (by one definition, at least 4 bleeds within a 6-month period) is termed a target joint. Commonly, this occurs in
knees though ankles and elbows are other commonly affected joints.
Repeated hemarthroses lead to progressive synovial hypertrophy, hemosiderin deposition, fibrosis, and damage to cartilage,
with subchondral bone-cyst formation. This results in permanent deformities, misalignment, loss of mobility, and extremities of
unequal lengths.
Inhibitors
Approximately 30% of patients with severe hemophilia A develop alloantibody inhibitors that can bind FVIII. These inhibitors are
typically immunoglobulin G (IgG), predominantly of the IgG4 subclass, that neutralize the coagulant effects of replacement
therapy. However, the inhibitors do not fix complement and do not result in the end-organ damage observed with circulating
immune complexes
Inhibitors occur at a young age (about 50% by age 10 years), principally in patients with less than 1% FVIII. Both genetic and
environmental factors determine the frequency of inhibitor development. Specific molecular abnormalities (eg, gene deletions,
stop codon mutations, frameshift mutations) are associated with a higher incidence of inhibitor development. In addition,
inhibitors are more likely to develop in black children. Missense mutations are associated with a low risk of inhibitor
development.[10]
The association of product used with the risk of inhibitor formation remains controversial. In a study of 574 patients with severe
hemophilia A, 177 of whom developed inhibitors, the risks of inhibitor development were similar with recombinant and plasma-
derived FVIII products. No association was found between the development of inhibitors and the von Willebrand factor content of
products, switching from a plasma-derived to a recombinant product, or switching among brands of FVIII products.
Unexpectedly, however, inhibitors developed more often with second-generation full-length recombinant products than with third-
generation products.[11]
A study with 303 previously untreated or minimally treated children with hemophilia demonstrated a increased risk of inhibitor
formation in patients who used recombinant products.[12] However, the European Medicines Agency (EMA) Pharmacovigilance
Risk Assessment Committee (PRAC) concluded that "there is no clear and consistent evidence of a difference in the incidence
of inhibitor development between the two classes of factor VIII medicines: those derived from plasma and those made by
recombinant DNA technology."[13]
Due to conflicting data and challenging methodological limitations, choice of initial treatment in previously untreated or minimally
treated patients should be done in a colaborative fashion between patients/caregivers and treatment teams wtih experience in
these issues.
In the United States, levels of FVIII inhibitors are most often measured by the Bethesda method. In this method, 1 Bethesda unit
(BU) equals the amount of antibody that destroys one half of the FVIII in an equal mixture of normal plasma and patient plasma
in 2 hours at 37°C. Inhibitor levels are described as low titer or high titer, depending on whether they are less than or more than
5 BU, respectively; high-titer inhibitor levels are typically far higher than 5 BU.
The Nijmegen modification uses immunodepleted FVIII–deficient plasma instead of an imidazole saline buffer to ensure pH
control to prevent non–antibody-mediated loss of FVIII-C activity during the prolonged 2-hour incubation period.[14] The
Bethesda assay tends to underestimate the titer of VIII autoantibody because of its characteristics, in contrast to a hemophilic
antibody.[15] The Oxford assay is another modification of the Bethesda inhibitor test.
Acquired hemophilia
Acquired hemophilia is the development of FVIII inhibitors (autoantibodies) in persons without a history of FVIII deficiency. This
condition can be idiopathic (occurring usually in people >50 y). It can be associated with underlying collagen vascular disease
or the peripartum period, or it may represent a drug reaction (eg, to penicillin). High titers of FVIII autoantibodies may be
associated with malignancies, particularly lymphoproliferative malignancies.[16]
Etiology
Hemophilia A is caused by an inherited or acquired genetic mutation that results in dysfunction or deficiency of factor VIII, or by
an acquired inhibitor that binds factor VIII. Of genetic cases, up to approximately one third are the result of de novo mutations
not present in the mother's X chromosome.
Inadequate factor VIII results in the insufficient generation of thrombin by the FIXa and FVIIIa complex by means of the intrinsic
pathway of the coagulation cascade. This mechanism, in combination with the effect of the tissue-factor pathway inhibitor,
creates an extraordinary tendency for impaired clotting in response to trauma and, especially in persons with severe hemophilia,
with spontaneous bleeding.
Hemophilia A is inherited in an X-linked recessive pattern. The gene for FVIII is located on the long arm of the X chromosome in
band q28. The factor VIII gene is one of the largest genes, comprising approximately 0.1% of the DNA in the X chromosome; it
is 186 kilobases (kb) long and has a 9-kb coding region that contains 26 exons. The mature protein contains 2332 amino acids
and has a molecular weight of 300 kd. It includes 3 A domains, 1 B domain, and 2 C domains.
Intron 22 of the factor VIII gene, uniquely, contains two other genes. The first gene, F8A, is transcribed in a direction opposite to
that of the factor VIII gene itself. The second gene, F8B, is transcribed in the 3' (normal) direction similar to the factor VIII gene.
Sequences called A2 and A3, homologous to the F8A sequence, are present on the X chromosome, 300 kb telomeric to the
factor VIII gene.
Homologous recombination of the factor VIII gene, with inversion and crossover involving the F8A sequence in intron 22 and the
homologous distal sequence on the X chromosome, results in a split in the factor VIII gene with the two parts aligned in opposite
directions. This causes a disruption in the normal factor VIII coding sequence, with an inability to transcribe the complete, normal
factor VIII protein, resulting in a loss of function.
The mutation in intron 22 occurs during spermatogenesis and is a common cause of severe factor VIII deficiency; it is present in
approximately 40% of patients. It is easily detected using a Southern blot analysis of the patient's DNA. These patients are more
likely to develop an inhibitor to factor VIII.
In one study, all detected inversions originated in a maternal grandparent during male meiosis (spermatogenesis), supporting
the hypothesis that an unpaired Xq, rather than a paired X chromosome, is more likely to undergo an intrachromosomal
inversion. The majority of mothers of persons with the sporadic, inversion-related severe hemophilia are carriers.[17]
The knowledge of the parental origin of the inversion mutation has important implications for genetic counseling.
Several other types of mutations have been described. Point mutations can lead to mild, moderate, or severe deficiency of factor
VIII, depending on the effect of that mutation on factor VIII gene function.
Missense mutations, such as the G-to-A single-base substitution, alter the amino acid composition of the molecule, producing a
dysfunctional molecule (FVIII antigen present with reduction in FVIII activity); these mutations are associated with mild,
moderate, or severe factor VIII reductions and are associated with the development of factor VIII inhibitors. Intracellular
accumulation of factor VIII induced by Arg 593→Cys and Asn 618→Ser missense mutations also result in reduction of cross-
reacting material in severe hemophilia A.
Gene deletions lead to factor VIII deficiency, and large gene deletions result in severe hemophilia, with no detectable factor VIII
antigen; such patients are more susceptible to inhibitor development. Insertions are apparently uncommon in the factor VIII
gene, but they usually lead to severe hemophilia A.[18] Nonsense mutations and abnormal splicing may also occur.
Other causes of this disorder remain to be identified. The Haemophilia A Mutation, Structure, Test and Resource Site
(HAMSTeRS) has a continually updated database of genetic defects related to hemophilia A.
Combined factor V and factor VIII deficiency
Combined FV and FVIII deficiency is an autosomal recessive disorder, with clinical manifestations in affected females and
males. The disorder is caused by mutations in one of two genes, lectin mannose binding protein 1 (LMAN1) or multiple
coagulation factor deficiency 2 (MCFD2), which encode proteins involved in the intracellular transport of FV and FVIII; the
coagulation factors themselves are normal.[19]
Epidemiology
Hemophilia A is the most common X-linked genetic disease and the second most common factor deficiency after von Willebrand
disease (vWD). The worldwide incidence of hemophilia A is approximately 1 case per 5000 males, with approximately one third
of affected individuals not having a family history of the disorder. The prevalence of hemophilia A varies with the reporting
country, with a range of 5.4-14.5 cases per 100,000 males. During the period 2012-2018, the number of males in the United
States with hemophilia was estimated to be about 33,000.[20]
Approximately 50-60% of patients have severe hemophilia A (FVIII < 2% of normal), associated with the severest bleeding
manifestations. Approximately 25-30% have moderate hemophilia (FVIII 2-5%) and manifest bleeding after minor trauma. Those
with mild hemophilia A (FVIII 6-30%) comprise 15-20% of all people with hemophilia; these patients develop bleeding only after
trauma or surgery.
Acquired hemophilia A, caused by the development of an autoantibody to FVIII in a person with previously normal hemostasis,
develops with a frequency of 1 case per 1 million population per year.[21] Acquired FVIII deficiency is observed in older
populations, generally those older than 60 years.
The inherited, combined deficiency of factors V and VIII is a rare but recognized cause of a bleeding disorder. The prevalence is
estimated to be 1 case per million population.[19]
Racial, sexual, and age-related differences in incidence
Hemophilia A occurs in all races and ethnic groups. In general, the demographics of hemophilia follow the racial distribution in a
given population; for example, rates of hemophilia among whites, African Americans, and Hispanics in the US are similar.
Because hemophilia is an X-linked, recessive condition, it occurs predominantly in males. Females usually are asymptomatic
carriers. However, mild hemophilia may be more common in carriers than previously recognized. In 1 study, 5 of 55 patients with
mild hemophilia (factor levels 5-50%) were girls.[22]
Females may have clinical bleeding due to hemophilia if any of the following 3 conditions is present:
Extreme lyonization (ie, inactivation of the normal FVIII allele in one of the X chromosomes)[23]
Homozygosity for the hemophilia gene (ie, father with hemophilia and mother who is a carrier, two independent
mutations, or some combination of inheritance and new mutations)
Turner syndrome (XO) associated with the affected hemophilia gene
In genetic cases, significant deficiency in FVIII may be evident in the neonatal period. It continues through the life of the affected
individual. The absence of hemorrhagic manifestations at birth does not exclude hemophilia.
Prognosis
With appropriate education and treatment, patients with hemophilia can live full and productive lives. Prophylaxis and early
treatment with FVIII concentrate that is safe from viral contamination have dramatically improved the prognosis of patients with
severe hemophilia. Nevertheless, approximately one quarter of patients with severe hemophilia aged 6-18 years have below-
normal motor skills and academic performance and have more emotional and behavioral problems than others.[24]
Factor concentrates have made home-replacement therapy possible, improving patients' quality of life. In addition, the era of
replacement therapy brought dramatic gains in life expectancy. For patients with severe hemophilia, life expectancy rose from 11
years or less before the 1960s to almost 60 years prior to HIV epidemic in the 1980s.[5, 7]
Increasing evidence associates hemophilia with low bone mineral density and increased fracture risk in both children and adults.
Physical inactivity (which may be worsened by arthropathy) and vitamin D deficiency seem to play a fundamental role.[25]
Viral infection from contaminated FVIII concentrate became a problem during the replacement era. Most patients with
hemophilia who received plasma-derived products that were not treated to eliminate potential contaminating viruses became
infected with HIV or hepatitis A, hepatitis B, or hepatitis C viruses.
The most serious of these was HIV infection. The first deaths of people with hemophilia due to AIDS were observed in the early
1980s. Rates of seroconversion were more than 75% for those with severe disease, 46% for moderate disease, and 25% for
mild disease.
In the United States, death rates of patients with hemophilia increased from 0.4 deaths per million population in 1979-1981 to
1.2 deaths per million population in 1987-1989; AIDS accounted for 55% of all hemophilia deaths. Causes of death shifted from
intracranial and other bleeding to AIDS and cirrhosis from hepatitis. AIDS remains the most common cause of death in patients
with severe hemophilia.[7] Indeed, HIV-infected individuals are more likely to die of that disease than from hemophilia.
With improved screening of donors, new methods of factor concentrate purification, and recombinant concentrates, infectious
complications now are only historically important. However, even with these methods, some viruses (eg, parvovirus B-19) cannot
be removed and may be transmitted through plasma-derived products. Other potential infectious agents include the prions that
cause Creutzfeldt-Jakob disease. With the development of animal protein–free products, the risk of contamination with these
agents may be decreased.
Intracranial hemorrhage and hemorrhages into the soft tissue around vital areas, such as the airway or internal organs, remain
the most important life-threatening complications. The lifetime risk of intracranial bleeding is 2-8% and accounts for one third of
deaths due to hemorrhage, even in the era of factor replacement. Intracranial hemorrhage is the second most common cause of
death and the most common cause of death related to hemorrhage. Of patients with severe hemophilia, 10% have intracranial
bleeding, with a mortality rate of 30%.
Chronic debilitating joint disease results from repeated hemarthrosis; synovial membrane inflammation; hypertrophy; and,
eventually, destructive arthritis. Early replacement of coagulation factors by means of infusion is essential to prevent functional
disability. Thus, prophylactic therapy administered 2-3 times weekly, starting when patients are young, is considered the
standard of care in most developed countries.
Before the widespread use of replacement therapy, patients with severe hemophilia had a shortened lifespan and diminished
quality of life that was greatly affected by hemophilic arthropathy. Home therapy for hemarthroses became possible with factor
concentrates. Prophylactic use of lyophilized concentrates that eliminate bleeding episodes help prevent joint deterioration,
especially when instituted early in life (ie, at age 1-2 y).
Overall, the mortality rate for patients with hemophilia is twice that of the healthy male population. For severe hemophilia, the
rate is 4-6 times higher. If hepatitis and cirrhosis are excluded, the overall mortality rate of patients with severe hemophilia A is
1.2 times that of the healthy male population.[7]
Patient Education
Starting in infancy, regular dental evaluation is recommended, along with instruction regarding proper oral hygiene, dental care,
and adequate fluoridation. Encourage the patient to engage in appropriate exercise. Advise the patient against participating in
contact and collision sports.
Patient and family education about early recognition of hemorrhage signs and symptoms is important for instituting or increasing
the intensity of replacement therapy. This treatment helps prevent the acute and chronic complications of the disease, which
range from those that can impair quality of life to those that are life-threatening.
Educating patients and family members about factor replacement administration at home has greatly enhanced the quality of life
of patients with severe hemophilia by allowing prompt infusion for bleeds and markedly reducing the need for emergency
department visits. Parents often can learn to infuse children as young as 2 years, and, by 8-10 years, most children with
hemophilia can learn to self-infuse.
For patient education information, see Hemophilia.
Presentation
History
For patients in whom hemophilia is suspected, inquire about the following:
History of hemorrhage disproportionate to trauma

History of spontaneous hemorrhage
Bleeding disorders in the family
Concomitant illness (especially those associated with acquired hemophilia, such as chronic inflammatory disorders,
autoimmune diseases, hematologic malignancies, and allergic drug reactions)
Recent pregnancy
For individuals with documented hemophilia, ascertain the type of deficiency (eg, factor VIII [FVIII], FIX, von Willebrand), degree
of factor deficiency, known presence of inhibitors, and HIV/hepatitis status. For patients with mild-to-moderate disease,
determine responsiveness to desmopressin acetate (DDAVP).[8]
Signs and symptoms of hemorrhage include the following:
General - Weakness and orthostasis (related to anemia/hypovolemia secondary to bleeding)
Musculoskeletal (joints) - Tingling, cracking, warmth, pain, stiffness, refusal to use the joint (young children)
Central nervous system (CNS) - Headache, stiff neck, vomiting, lethargy, irritability, spinal cord syndromes
Gastrointestinal (GI) - Hematemesis, melena, frank red blood per rectum, abdominal pain
Genitourinary - Hematuria, renal colic, post-circumcision bleeding
Other - Epistaxis, oral mucosal hemorrhage, hemoptysis, dyspnea (hematoma leading to airway obstruction),
compartment syndrome symptoms, contusions, excessive bleeding with routine dental or other procedures
Evidence of infectious disease includes the following:
HIV/AIDS-related symptoms
Hepatitis-related symptoms
Newborn boys with severe hemophilia may present with prolonged bleeding at circumcision. Easy bruising may occur at the start
of ambulation or primary dentition. Older patients may have a history of hemarthroses and prolonged bleeding with surgical
procedures, trauma, and dental extraction, and may have spontaneous bleeding in soft tissues.
A traumatic challenge relatively late in life may have to occur before mild or moderate hemophilia is diagnosed. Factors that
elevate FVIII levels (eg, age, ABO blood type, stress, exercise) may mask mild hemophilia.
Weight-bearing joints and other joints are principal sites of bleeding in patients with hemophilia. The muscles most commonly
affected are the flexor groups of the arms and gastrocnemius of the legs. Iliopsoas bleeding is dangerous because of the large
volume of blood loss and because compression of the femoral nerve may occur.
In the genitourinary tract, gross hematuria may occur in as many as 90% of patients. In the GI tract, bleeding may complicate
common GI disorders. Bleeding in the CNS is the leading cause of hemorrhagic death in patients with hemophilia.
Acquired hemophilia
Acquired hemophilia due to an autoantibody in previously hemostatically normal individuals tends to affect elderly persons who
have comorbid conditions, but may also develop post partum. Persons with acquired hemophilia may experience extensive,
often life threatening, bleeding before the condition is recognized.
In contrast to persons with severe inherited hemophilia A, in whom joint bleeding is common, patients with acquired hemophilia
present with large intramuscular, retroperitoneal, limb, subcutaneous, genitourinary, GI, or excessive postoperative or
postpartum bleeding. Bleeding into an extremity can result in findings that are easily confused with deep vein thrombosis.
Massive upper extremity bleeding can be precipitated by a simple venipuncture. Bleeding can develop at any site.
Postpartum acquired hemophilia usually comes to attention 2 to 5 months after delivery, when bleeding symptoms supervene.
Rarely, the inhibitor may develop during pregnancy.
Physical Examination
Systemic signs of hemorrhage include the following:
Tachycardia
Tachypnea
Hypotension
Orthostasis
Organ system–specific signs and symptoms of hemorrhage include the following:
Musculoskeletal (joints) - Tenderness, pain with movement, decreased range of motion, effusion, and warmth
Central nervous system (CNS) - Abnormal neurologic exam findings, altered mental status, and meningismus
Gastrointestinal (GI) - Can be painless; hepatic/splenic tenderness, and peritoneal signs
Genitourinary - Bladder spasm/distension/pain and costovertebral angle pain
Other - Hematoma leading to location-specific signs (eg, airway obstruction, compartment syndrome)
Signs of infectious disease include the following:
HIV/AIDS-related signs
Hepatitis-related signs
Approximately 30-50% of patients with severe hemophilia present with manifestations of neonatal bleeding (eg, after
circumcision). Approximately 1-2% of neonates have intracranial hemorrhage. Other neonates may present with severe
hematoma and prolonged bleeding from the cord or umbilical area.
After the immediate neonatal period, bleeding is uncommon in infants until they become toddlers, when trauma-related soft-
tissue hemorrhage occurs. Young children may also have oral bleeding when their teeth are erupting. Bleeding from gum and
tongue lacerations is often troublesome because the oozing of blood may continue for a long time despite local measures.
As children grow and become more physically active, hemarthroses and hematomas occur. Chronic arthropathy is a late
complication of recurrent hemarthrosis in a target joint. Traumatic intracranial hemorrhage is a serious life-threatening
complication that requires urgent diagnosis and intervention.
Petechiae usually do not occur in patients with hemophilia. The reason is that petechiae are manifestations of capillary blood
leakage, which is typically the result of vasculitis or abnormalities in the number or function of platelets.
Hemophilia is classified according to clinical severity as mild, moderate, or severe (see Table 1, below). Patients with severe
disease usually have less than 1% factor VIII (FVIII) activity and experience spontaneous hemarthrosis and soft-tissue bleeding
in the absence of apparent precipitating trauma. Patients with moderate disease have 1-5% FVIII activity and bleed with minimal
trauma. Patients with mild hemophilia have more than 5% factor activity and bleed only after significant trauma or surgery.
Table 1. Hemophilia Severity, Factor Activity, and Hemorrhage Type (Open Table in a new window)
Classification Factor Activity, % Cause of Hemorrhage
Mild >5-40 Major trauma or surgery
Moderate 1-5 Mild-to-moderate trauma
Severe <1 Spontaneous
Direct the examination to identify signs related to spontaneous bleeding, or bleeding with minimal challenge, in the joints,
muscles, and other soft tissues. Observe the patient's posture. Examine the weight-bearing joints, especially the knees and
ankles, and, in general, the large joints for deformities or ankylosis. Look for jaundice and other signs of liver failure (eg,
cirrhosis), and for signs of opportunistic infections in patients who are HIV positive.
Pseudotumors are produced by a slow expansion of repeated hemorrhages in bone or soft tissues. They can be restricted by
the fascial planes of a muscle, cause resorption of neighboring bone by pressure-induced ischemia, or develop under the
periosteum, leading to erosion of the bony cortex. They develop slowly over months to years and often are asymptomatic,
unless pressure on the nerves or vascular compromise occurs.
Pseudotumors contain a brownish material and can become infected. The buttock, pelvis, and thighs are common locations for a
pseudotumor (see the images below).
Transected pseudocyst (following disarticulation of the left lower extremity due to vascular compromise, nerve damage, loss of
bone, and nonfunctional limb). This photo shows black-brown old blood, residual muscle, and bone.
Dissection of a pseudocyst.
Transected pseudocyst with chocolate brown-black old blood.
Photograph of a patient who presented with a slowly expanding abdominal and flank mass, as well as increasing pain, inability
to eat, weight loss, and weakness of his lower extremity.
Plain radiograph of the pelvis showing a large lytic area.
Intravenous pyelogram showing extreme displacement of the left kidney and ureter by a pseudocyst.
Photograph depicting extensive spontaneous abdominal wall hematoma and thigh hemorrhage in an older, previously
unaffected man with an acquired factor VIII inhibitor.
DDx
Diagnostic Considerations
Problems to be considered include vitamin K deficiency and other factor deficiencies. Other congenital bleeding disorders must
be excluded. These may include the following:
von Willebrand disease (autosomal dominant transmission)

Platelet disorders (eg, Glanzmann thrombasthenia)
Deficiency of other coagulation factors (ie, factor II, V, VII, X, or XI; or fibrinogen)
Clinical differentiation of severe hemophilia A from severe hemophilia B is almost impossible, but specific factor assays can help
with the distinction. Conditions that can increase factor VIII levels (eg, age, ABO blood type, stress, exercise) can obscure the
diagnosis of hemophilia A.
Acquired Hemophilia
Hemophilia B
Hemophilia C
Combined factor V and factor VIII deficiency

In rare cases a true hemophilic factor VIII deficiency may be associated with hereditary factor V deficiency. Treatment of
bleeding episodes in these patients requires use of fresh-frozen plasma (FFP) to replace factor V, and replacement of factor VIII
by FFP and desmopressin or FVIII concentrates.[19]
Combined deficiency of factor VIII and factor V has been traced to mutations in the lectin mannose binding protein 1 (LMAN1) or
multiple coagulation factor deficiency 2 (MCFD2) genes, which encode proteins involved in the intracellular transport of FV and
FVIII.[19] A similarly reduced level of factor V and factor VIII clotting activities in plasma, and finding other members in the same
family with combined factor V and factor VIII deficiency, are all clues to the disorder.
Most difficult to detect on the basis of the history alone is the presence or absence of consanguinity (a feature of recessive
disorders requiring 2 doses of the gene for clinical manifestations). In families with known mutations, allele-specific hybridization
studies show the difference between homozygotes and heterozygotes.
Acquired multiple-factor coagulopathies due to liver disease, diffuse intravascular coagulation (DIC), warfarin excess, or
coagulopathy of dysproteinemias should also be considered.
Differential Diagnoses
Acquired Hemophilia
Ehlers-Danlos Syndrome
Factor XI Deficiency
Glanzmann Thrombasthenia
Hemophilia C
Hemophilia, Type B
Physical Child Abuse
Platelet Disorders
von Willebrand Disease
Workup
Workup
Approach Considerations
Laboratory studies for suspected hemophilia include a complete blood cell count, coagulation studies, and a factor VIII (FVIII)
assay. Never delay indicated coagulation correction pending diagnostic testing.
On the hemoglobin/hematocrit assay, expect normal or low values. Expect a normal platelet count. On coagulation studies, the
prothrombin time (which assesses the extrinsic coagulation pathway) and thrombin time are normal.
Usually, the activated partial thromboplastin time (aPTT) is prolonged; however, a normal aPTT does not exclude mild or even
moderate hemophilia because of the relative insensitivity of the test. The aPTT is significantly prolonged in severe hemophilia.
For FVIII assays, levels are compared with a normal pooled-plasma standard, which is designated as having 100% activity or
the equivalent of FVIII U/mL. Normal values are 50-150%. Values in hemophilia are as follows:
Mild: > 5%
Moderate: 1-5%
Severe: < 1%
Aging, pregnancy, oral contraceptive use, and estrogen replacement therapy are associated with increased FVIII levels.
Because FVIII is a large molecule that does not cross the placenta, the diagnosis can be made at birth with quantitative assay of
cord blood.
Three main FVII assay methods are in use: one-stage and two-stage clotting assays and a two-stage chromogenic method. In
approximately one-third of patients with mild hemophilia, FVIII levels on the automated one-stage FVIII assay are significantly
higher than—typically, more than double—those of the two-stage coagulation assay.[26, 27]
Those discrepancies, which result from differences in the underlying FVIII mutations in these patients, can result in missed
diagnoses or mismanagement due to underestimation of bleeding risk.[26, 28] Given the possibility of discrepant hemophilia A,
as this condition is termed, use of the chromogenic FVIII assay combined with FVIII gene mutation analysis has been
recommended for diagnosis of mild hemophilia A.[26]
Differentiation of hemophilia A from von Willebrand disease is possible by observing normal or elevated levels of von Willebrand
factor antigen and ristocetin cofactor activity. A caveat to this is the rare patient with type 2N von Willebrand disease in which
the VW antigen and activity levels are normal but binding to FVIII is impaired resulting in short circulating half-life of Factor VIII
and low levels. While type 2N VWD is very rare, it is relevant to exclude this diagnosis as those patients may require therapy
wtih combined VWF/FVIII product rather than isolated FVIII concentrate. Bleeding time is prolonged in patients with von
Willebrand disease but conflicting reports of presence of elevation patients with hemophilia as well of lack of standardization and
familiarity with proper performance of this assay limits the utility of the bleeding time as a diagnostic strategy.
In patients with an established diagnosis of hemophilia, periodic laboratory evaluations include screening for the presence of
FVIII inhibitor and screening for transfusion-related or transmissible diseases such as hepatitis and HIV infection. Screening for
infection may be less important in patients who receive only recombinant FVIII concentrate.
Imaging studies for acute bleeds
Early and aggressive imaging is indicated, even with low suspicion for hemorrhage, after coagulation therapy is initiated.
Imaging choices are guided by clinical suspicion and the anatomic location of involvement.
Head CT scans without contrast are used to assess for spontaneous or traumatic intracranial hemorrhage. Perform magnetic
resonance imaging (MRI) on the head and spinal column for further assessment of spontaneous or traumatic hemorrhage. MRI
is also useful in the evaluation of the cartilage, synovium, and joint space.
Ultrasonography is useful in the evaluation of joints affected by acute or chronic effusions. This technique is not helpful for
evaluating the bone or cartilage. Special studies such as angiography and nucleotide bleeding scan may be clinically indicated.
Testing for Inhibitors

Laboratory confirmation of a FVIII inhibitor is clinically important when a bleeding episode is not controlled despite infusion of
adequate amounts of factor concentrate. For the assay, the aPTT measurement is repeated after incubating the patient's plasma
with normal plasma at 37°C for 1-2 hours. If the prolonged aPTT is not corrected, the inhibitor concentration is titrated using the
Bethesda method. Ideally, the Nijmegen modification of the Bethesda inhibitor assay should be used to detect an inhibitor if the
mixing test result is positive.[14]
By convention, more than 0.6 Bethesda units (BU) is considered a positive result for an inhibitor. Less than 5 BU is considered a
low titer of inhibitor, and more than that is a high titer. The distinction is clinically significant, as patients with low-titer inhibitors
may respond to higher doses of FVIII concentrate while those with high-titer inhibitors require treatment with agents that bypass
FVIII and consideration for induction of immune tolerance.
Caution is warranted when obtaining blood samples for coagulation assays from heparinized central lines because of the effect
of heparin contamination on all coagulation test results. The excess heparin causes false-positive results and/or higher inhibitor
titer values than are actually present in the patient, because heparin is also an inhibitor of coagulation.
One study found significant heparin contamination in 45% of all specimens obtained through implanted venous access devices.
These researchers suggested that all blood samples obtained from such devices, which are usually flushed with heparin, should
be treated with heparinase before performing an inhibitor assay.[29]
Carrier Testing and Fetal Testing

Screening for carrier status can be performed by measuring the ratio of FVIII coagulant activity to the concentration of von
Willebrand factor (vWF) antigen. A ratio that is less than 0.7 suggests carrier status.
The International Society on Thrombosis and Haemostasis has proposed nomenclature for the diagnosis and management of
hemophilia carriers.[30] For hemophilia A, the nomenclature uses FVIII levels and clinical characteristics to distinguish the
following categories for women/girls:
Mild hemophila A: FVIII > 0.05 and < 0.40 IU/mL

Moderate hemophilia A: FVIII 0.01-0.05 IU/mL
Severe hemophilia A: FVIII < 0.01 IU/ml, respectively
Symptomatic carriage: FVIII ≥0.40 IU/mL with a bleeding phenotype
Asymptomatic carriage: FVIII ≥0.40 IU/mL without a bleeding phenotype
Direct genetic testing for known gene mutation is a more accurate screening technique. Linkage analysis by restriction fragment
length polymorphism (RFLP) in multiple family members can be used. Direct mutation analysis is available in several
laboratories for unknown FVIII mutations. Inversion of the FVIII gene can be detected by Southern blot.
For prenatal testing, carriers whose mutation has been identified can have chorionic villus sampling at approximately 10-12
weeks' gestation or amniocentesis at 16-20 weeks' gestation to obtain fetal cells for DNA analysis or for linkage studies. If DNA
analysis cannot be performed, then fetal blood obtained by fetoscopy at approximately 20 weeks' gestation can be assayed for
factor VIII level.
All of those procedures carry a risk ranging from a low of 0.5% for maternal-fetal complications to a high of 1-6% for fetal death
from fetoscopy. These procedures should be undertaken only after patients receive intense genetic and obstetric counseling.
Genetic counseling before the woman becomes pregnant is ideal and may help couples make informed decisions before
conception.
Noninvasive prenatal diagnosis using quantitative digital polymerase chain reaction testing of free fetal DNA in the maternal
circulation has been reported. However, this technique remains a research tool.[31]
If the fetus is a female, the couple may elect to carry the pregnancy to term because carriers rarely have bleeding problems. If
the fetus is a severely affected male, the couple must make a decision about continuing the pregnancy to term. With
pregnancies that will be carried to term, prenatal diagnosis allows for planning of delivery so as to minimize the risk of
intracranial hemorrhage (eg, avoidance of vacuum devices).[31]
Radiography
Radiography for joint assessment is of limited value in acute hemarthrosis. Evidence of chronic degenerative joint disease may
be visible on radiographs in patients who have been untreated or inadequately treated or in those with recurrent joint
hemorrhages. In these patients, radiographs may show synovial hypertrophy, hemosiderin deposition, fibrosis, and damage to
cartilage that progresses with subchondral bone cyst formation.
Hemophilic arthropathy evolves through 5 stages, starting as an intra-articular and periarticular edema due to acute hemorrhage
and progressing to advanced erosion of the cartilage with loss of the joint space, joint fusion, and fibrosis of the joint capsules.[9]
See the image below. For discussion of the 5-stage Arnold-Hilgartner classification of hemophilic arthropathy, see Imaging in
Musculoskeletal Complications of Hemophilia.
Photograph of a hemophilic knee at surgery, with synovial proliferation caused by repeated bleeding; synovectomy was
required.
Treatment
Approach Considerations
The treatment of hemophilia may involve prophylaxis, management of bleeding episodes, treatment of factor VIII (FVIII)
inhibitors, and treatment and rehabilitation of hemophilia synovitis. Use of factor replacement products and other medications,
including pain medications, is typically required.
Treatment of patients with hemophilia ideally should be provided through a comprehensive hemophilia care center. These
centers, which are found in many US cities, follow a multidisciplinary approach, with specialists in hematology, orthopedics,
dentistry, and surgery; nurses; physiotherapists; social workers; and related allied health professionals. Patients treated at
comprehensive care clinics have been shown to have better access to care, less morbidity, and better overall outcome.
Ambulatory replacement therapy for bleeding episodes is essential for preventing chronic arthropathy and deformities. Home
treatment and infusion by the family or patient is possible in most cases. Prompt and appropriate treatment of hemorrhage is
important to prevent long-term complications and disability.
Dose calculations are directed toward achieving an FVIII activity level of 30-40% for most mild hemorrhages, of at least 50% for
severe bleeds (eg, from trauma) or prophylaxis of major dental surgery or major surgery, and 80-100% in life-threatening
hemorrhage. Hospitalization is reserved for severe or life-threatening bleeds, such as large-soft tissue bleeds; retroperitoneal
hemorrhage or other internal bleeding; and hemorrhage related to head injury, surgery, or dental work.
Patients can be treated with prophylaxis or with intermittent, on-demand therapy for bleeding events. Prophylaxis has been
shown in many studies to prevent or at least reduce the progression of damage to target sites, such as joints.[32, 33] According
to a review of 6 randomized controlled trials, preventive therapy started early in childhood, as compared with on-demand
treatment, can reduce total bleeds and bleeding into joints, resulting in decreased overall joint deterioration and improved quality
of life.[34]
In most developed countries with access to recombinant product, prophylaxis is primary (ie, therapy is started in patients as
young as 1 y and continues into adolescence). A cost-benefit analysis indicates that this approach reduces overall factor use
and significantly reduces morbidity.[35] In situations in which this is not feasible, secondary prophylaxis (ie, therapy after a target
joint has developed, to prevent worsening of the joint) is instituted for a defined period.
For prophylaxis, dosing is designed to maintain trough levels of 2% or higher. This usually requires the administration of FVIII 3
times per week. Individualized therapy (ie, tailored prophylaxis) has been also used with success; the best approach has yet to
be determined.
The treatment of patients with inhibitors of FVIII is difficult. Bleeding episodes in patients with low-titer inhibitors (ie,
concentrations below 5 Bethesda units [BU]) occasionally can be overcome with high doses of factor VIII.[36] Options in other
cases include a variety of agents that bypass FVIII, such as activated FVII and emicizumab; desensitization; and immune
tolerance induction.
In patients who develop synovitis from joint bleeds, injection of radioisotopes into the joint to ablate the synovium
(radiosynovectomy) can be used to decrease bleeding, slow progression of cartilage and bone damage, and prevent
arthropathy. Unresponsive cases may require arthroscopic synovectomy or arthroplasty.[37]
Increasing evidence associates hemophilia with low bone mineral density; consequently, careful assessment and management
of fracture risk are recommended. Regular exercise, fall prevention strategies, and optimization of calcium and vitamin D intake
are recommended, along with prophylactic factor replacement therapy in severe hemophilia.[25]
Acquired Hemophilia
Hemophilia B
Hemophilia C
Prehospital Care
Rapid transport to definitive care is the mainstay of prehospital care. Prehospital care providers should do the following:
Apply aggressive hemostatic techniques

Assist patients capable of self-administered factor therapy
Gather focused historical data if the patient is unable to communicate
Emergency Department Care

Before treating a patient with hemophilia, obtain the following information:
The type and severity of factor deficiency

The nature of the hemorrhage or the planned procedure
The patient's previous treatments with blood products
Whether inhibitors are present and if so, their probable titer
Any previous history of desmopressin acetate (DDAVP) use (mild hemophilia A only), with the degree of response and
clinical outcome.
Use aggressive hemostatic techniques. Correct coagulopathy immediately. Include a diagnostic workup for hemorrhage, but
never delay indicated coagulation correction pending diagnostic testing. If possible, draw blood for the coagulation studies (see
Workup), including 2 blue-top tubes to be spun and frozen for factor and inhibitor assays.
Minor bleeding, as from cuts and abrasions, may respond to conservative measures, such as pressure and ice. Mild hematuria
may subside spontaneously. Do not aspirate hematomas or joints or cauterize bleeding sites unless specifically indicated,
because these procedures may aggravate the bleeding.
Epistaxis and moderately severe hematuria may be adequately treated by achieving and maintaining FVIII levels in the range of
30-50%. Use a higher dose initially, followed by a gradual lowering of the dose after the bleeding is under control, and then
continue FVIII replacement until clinical and objective evidence indicates resolution of the bleeding.
Acute joint bleeding and expanding, large hematomas require adequate factor replacement for a prolonged period until the bleed
begins to resolve, as evidenced by clinical and/or objective methods. Relief of the intense pain with joint bleeds frequently
requires the use of narcotic analgesics; relief of pain also accompanies cessation of bleeding after adequate factor replacement.
Life-threatening bleeding episodes are generally initially treated with FVIII levels of approximately 100%, until the clinical
situation warrants a gradual reduction in dosage. Continuous intravenous infusions avoid the low troughs and excesses of
intermittent bolus dosing, maintain adequate levels at all times, and reduce usage of expensive factor replacement product by
approximately 30%.
If admission is indicated, disposition (intensive care unit vs floor) should be based on severity of hemorrhage and potential for
morbidity and death. Choose the attending service based on the etiology and site of hemorrhage. Hematology/ blood
bank/pathology consultation is mandatory.
Patients whose condition and bleeding are stabilized should be transferred to a comprehensive hemophilia care center for
further treatment and monitoring. These centers offer a multidisciplinary approach by specialists experienced in hemophilia.
Further outpatient care for patients with minor hemorrhage (not life threatening) consists of continued hemostatic measures (eg,
brief joint immobilization, bandaging). Hematologist or primary care physician follow-up care is indicated. The patient should
continue factor replacement and monitoring.
If a patient has HIV seroconversion, arrange appropriate outpatient care at a specialty infectious disease clinic. These patients
require monitoring of their CD4 count, observation for adverse effects of anti-HIV treatment, and monitoring for and treatment of
possible opportunistic infections.
Factor VIII Concentrates

Various FVIII concentrates are available to treat hemophilia A. Fresh frozen plasma and cryoprecipitate are no longer used in
hemophilia because of the lack of safe viral elimination and concerns regarding volume overload.
Various purification techniques are used in plasma-based FVIII concentrates to reduce or eliminate the risk of viral transmission,
including heat treatment, cryoprecipitation, and chemical precipitation. These techniques inactivate viruses such as hepatitis B
virus, hepatitis C virus, and HIV. However, the transmission of nonenveloped viruses (eg, parvovirus and hepatitis A virus) and
poorly characterized agents (eg, prions) is still a potential problem.
Many recombinant FVIII concentrates are currently available. The advantage of such products is the elimination of viral
contamination. Third-generation products with no exposure to animal proteins further decrease this risk. The effectiveness of
these products appears comparable to that of plasma-derived concentrates. Concerns regarding higher incidences of inhibitor
development remains a complex problem and selection of products, particularly wtih previously untreated or minimially treated
patients, should ideally be done in conjunction with a provider with experience in hemophilia following a discussion of risks and
benefits with patient/caregiver.
With wider availability of improved products (ie, better stability, purity), use of continuous infusion for administration has
incrementally increased. Continuous infusion of antihemophilic factors prevents the peaks and valleys in factor concentrations
that occur with intermittent infusion; this benefit is particularly important when treatment is required for prolonged periods.
Besides improved hemostasis, continuous infusion decreases the amount of factor used, which can result in significant savings.
The indications for this approach include the following:
Intracranial hemorrhage
Vascular compromise
Iliopsoas bleeding
Preparation for surgery
In most minor-to-moderate bleeding episodes, intermittent boluses are adequate. Intermittent boluses can also be used
prophylactically, especially in the treatment of recurrent bleeding in target joints.
Doses of FVIII concentrate are calculated according to the severity and location of bleeding. Guidelines for dosing are provided
in Table 2 below. As a rule, FVIII 1 U/kg increases FVIII plasma levels by 2%. The half life of infused factor is usually 8-12 hours.
Incremental recovery (i.e. the amount increase of factor activity per unit per kg) and half life vary from patient to patient and
ideally should be individualized based on that patient's experience.
Target levels by hemorrhage severity are as follows:
Mild hemorrhages (ie, early hemarthrosis, epistaxis, gingival bleeding): Maintain an FVIII level of 30%
Major hemorrhages (ie, hemarthrosis or muscle bleeds with pain and swelling, prophylaxis after head trauma with
negative findings on examination): Maintain an FVIII level of 50%
Life-threatening bleeding episodes (ie, major trauma or surgery, advanced or recurrent hemarthrosis): Maintain an FVIII
level of 80-90% until stabilization; after stabilization, maintain levels above 40-50% for a minimum of 7-10 days
Table 2. General Guidelines for Factor Replacement for the Treatment of Bleeding in Hemophilia (Open Table in a new window)
FVIII
Factor level
Indication or Site of Bleeding Dose, Comment
Desired, %
IU/kg
Severe epistaxis; mouth, lip, tongue, or

20-50 10-25 Consider aminocaproic acid (Amicar), 1-2 d
dental work
Joint (hip or groin) 40 20 Repeat transfusion in 24-48 h
No therapy if site small and not enlarging

Soft tissue or muscle 20-40 10-20
(transfuse if enlarging)
Muscle (calf and forearm) 30-40 15-20 None
Muscle deep (thigh, hip, iliopsoas) 40-60 20-30 Transfuse, repeat at 24 h, then as needed
Neck or throat 50-80 25-40 None
Hematuria 40 20 Transfuse to 40% then rest and hydration
Laceration 40 20 Transfuse until wound healed
GI or retroperitoneal bleeding 60-80 30-40 None
Head trauma (no evidence of CNS

50 25 None
bleeding)
Head trauma (probable or definite CNS Maintain peak and trough factor levels at
bleeding, eg, headache, vomiting, 100 50 100% and 50% for 14 d if CNS bleeding
neurologic signs) documented†
Trauma with bleeding, surgery 80-100 50 10-14 d
Variations in responses related to patient or product parameters make determinations of factor levels important. These
determinations are performed immediately after infusions and thereafter to ensure an adequate response and maintenance
levels. Obtain factor level assays daily before each infusion to establish a stable pattern of replacement regarding the dose and
frequency of administration.
Desmopressin
Desmopressin vasopressin analog, or 1-deamino-8-D-arginine vasopressin (DDAVP), is considered the treatment of choice for
mild and moderate hemophilia A. It is not effective in the treatment of severe hemophilia. DDAVP stimulates a transient increase
in plasma FVIII levels. Other possible mechanisms of action are noted.
DDAVP may result in sufficient hemostasis to stop a bleeding episode or to prepare patients for dental and minor surgical
procedures. A test dose should be performed before prophylactic use. It can be intravenously administered at a dose of 0.3
mcg/kg of body weight in the inpatient setting. Its peak effect is observed in 30-60 minutes.
If the test dose produces an appropriate rise in the FVIII level, at least 1 week should elapse before performance of any
procedures. This allows time for replenishment of endogenous stores of FVIII, so that an adequate DDAVP-induced rise in FVIII
is obtained for the procedure.
A concentrated DDAVP intranasal spray (1.5 mg/mL) is available for outpatient use. Its effectiveness is similar to that of the
intravenous preparation, although its peak effect is observed later, at 60-90 minutes after administration.
Hyponatremia due to water retention is a potentially serious adverse effect. Patients should be advised to limit water intake for
approximately 12-18 hours after the administration of DDAVP, until the antidiuretic effect passes, and should avoid three
consecutive daily doses. Due to risk of hyponatremia, any use of IV fluids should be reviewed carefully and sodium levels may
need to be monitored. In addition, patients should be alerted to the distinct drop in urine output they will experience after
DDAVP administration, and the subsequent increase when the antidiuretic effect of DDAVP wanes.
Tachyphylaxis may occur even after first dose, but the drug can be effective again after several days. A minor adverse effect of
DDAVP is facial flushing.
Management of Bleeding Episodes by Site

Musculoskeletal bleeding
The most common sites of clinically significant bleeding are joint spaces. Weight-bearing joints in the lower extremities are often
target areas for recurrent bleeding. Joint hemorrhage is associated with pain and limitation in the range of motion, which is
followed by progressive swelling in the involved joint. Many patients report a prodrome of warmth or tingling of the joint prior to
symptoms of frank hemorrhage.
Immobilization of the affected limb and the application of ice packs are helpful in diminishing swelling and pain. Early infusion
upon the recognition of initial symptoms of a joint bleed may often eliminate the need for a second infusion by preventing the
inflammatory reaction in the joint. Prompt and adequate replacement therapy is the key to preventing long-term complications.
Cases in which treatment begins late or causes no response may require repeated infusions for 2-3 days.
Do not aspirate hemarthroses unless they are severe and involve significant pain and synovial tension. Some hemarthroses may
pose particular problems because they interfere with the blood supply. Arthrocentesis is indicated if septic arthritis is suspected.
Hip joint hemorrhages can be complicated by aseptic necrosis of the femoral head. Administer adequate replacement therapy
for at least 3 days.
Deep intramuscular hematomas are difficult to detect and may result in serious muscular contractions. Appropriate and timely
replacement therapy is important to prevent such disabilities.
Iliopsoas muscle bleeding may be difficult to differentiate from hemarthrosis of the hip joint. Physical examination usually reveals
normal hip rotation but significant limitation of extension. Ultrasonography in the involved region may reveal a hematoma in the
iliopsoas muscle. This condition requires adequate replacement therapy for 10-14 days and a physical therapy regimen that
strengthens the supporting musculature.
Closed-compartment hemorrhages pose a significant risk of damaging the neurovascular bundle. These can occur in any area
where fascial planes restrict the expanding hematoma and can cause neurovascular compression and compromise. They
cause swelling, pain, tingling, numbness, and loss of distal arterial pulses. Infusion must be aimed at maintaining a normal level
of FVIII. Other interventions include elevation of the affected part to enhance venous return and, rarely, surgical decompression.
Oral bleeding
Oral bleeding from the frenulum and bleeding after tooth extractions are not uncommon. Bleeding is aggravated by the
increased fibrinolytic activity of saliva. If not treated appropriately, dental bleeding can persist and expand to sublingual,
pharyngeal, facial, or dissecting neck hematomas or other serious bleeding.
Combine adequate replacement therapy with an antifibrinolytic agent (epsilon-aminocaproic acid [EACA] or tranexamic acid
[TA]) to neutralize the fibrinolytic activity in the oral cavity. Topical agents such as fibrin sealant, bovine thrombin, and human
recombinant thrombin can also be used.[38]
Hematoma in the pharynx or epiglottic regions frequently results in partial or complete airway obstruction; therefore, it should be
treated with aggressive infusion therapy. Such bleeding may be precipitated by local infection or surgery.
Dental extractions or mucosal procedures can be handled with a single preprocedure dose of FVIII, to achieve a peak level of
approximately 30%, along with a single 20 mg/kg dose of EACA.[39] Routine practice is to continue antifibrinolytic therapy in an
outpatient setting for several days after the dental extraction.
Gastrointestinal bleeding
GI bleeds are much less common in persons with hemophilia than in those with von Willebrand disease and, therefore, require
an evaluation for an underlying cause. Manage GI hemorrhage with repeated or continuous infusions to maintain nearly normal
circulating levels of FVIII.
Intracranial bleeding
Intracranial hemorrhage is often trauma induced; spontaneous intracranial hemorrhages are rare. If CNS hemorrhage is
suspected, immediately begin an infusion prior to radiologic confirmation. Maintain the factor level in the normal range for 7-10
days until a permanent clot is established.
All head injuries must be managed with close observation and investigated by imaging such as CT scanning or MRI. If the
patient is not hospitalized, instruct the patient and his or her family regarding the neurologic signs and symptoms of CNS
bleeding so that the patient can know when to return for reinfusion.
Treatment of Patients with Inhibitors
Inhibitors are antibodies that neutralize factor VIII (FVIII) and can render replacement therapy ineffective. They are found more
commonly in patients with moderate to severe hemophilia (up to 30% of those with severe disease) who have received
significant amounts of replacement therapy. Inhibitors develop in relatively young children, usually within their first 50 exposures
to FVIII.
Rarely, inhibitors can develop in individuals without genetic hemophilia (eg, elderly persons, pregnant women). These
occasionally are responsive to immunosuppressive therapy (eg, prednisone).
The treatment of patients with inhibitors of FVIII is difficult. Assuming no anamnestic response, low-titer inhibitors (ie,
concentrations below 5 Bethesda units [BU]) occasionally can be overcome with high doses of factor VIII.[36] There is no
established treatment for bleeding episodes in patients with high-titer inhibitors.
Other approaches to treating patients with FVIII inhibitors include the following:
Porcine FVIII, which has low cross-reactivity with human FVIII antibody
Activated prothrombin complex concentrate (aPCC)
Activated recombinant FVII (rFVIIa)
Desensitization
Immune tolerance induction (ITI)
Monoclonal antibodies that bridge FIXa and FX (eg, emicizumab)
Emicizumab
Emicizumab is a first-in-class bispecific monoclonal antibody that performs the function of activated FVIII, bridging activated FIX
and FX to restore the coagulation cascade, but is unaffected by FVIII inhibitors. In November 2017, following a priority review,
the FDA approved emicizumab for routine prophylaxis of bleeding episodes in adult and pediatric patients (including
newborns) with hemophilia A who have FVIII inhibitors. Approval was based on the HAVEN 1 and 2 clinical trials. In 2018, the
FDA extended approval for use of emicizumab to patients without FVIII inhibitors, based on the HAVEN 3 trial results.[40]
The HAVEN 1 trial included 109 adult and adolescent males aged 12 years or older who had hemophilia A with inhibitors.
Patients taking emicizumab experienced about 2.9 treated bleeding episodes per year, compared with about 23.3 treated
bleeding episodes per year for patients who did not receive prophylactic treatment, representing an 87% reduction in the rate of
treated bleeding episodes (P < 0.001). Emicizumab-treated patients also reported an improvement in hemophilia-related
symptoms (painful swellings and joint pain) and physical functioning (pain with movement and difficulty walking).[41]
Interim results from the single-arm HAVEN 2 study in children aged younger than 12 years with hemophilia A with inhibitors who
received emicizumab prophylaxis are consistent with the positive results from the HAVEN 1 study. After a median observation
time of 12 weeks, only 1 of the 19 study patients receiving emicizumab reported a treated bleed.[42]
Three patients in the HAVEN 1 trial who experienced breakthrough bleeding despite emicizumab prophylaxis and were treated
with aPCC developed thrombotic microangiopathy (TMA). Episodes of TMA occurred only in patients who received, on average,
cumulative doses of aPCC of more than 100 U/kg daily for 24 hours or more. This complication appears to represent a unique
interaction between emicizumab and aPCC, as no cases of TMA had previously been reported in patients receiving aPCC alone.
Strategies for treating breakthrough bleeding in patients receiving emicizumab may include the use of recombinant FVIIa, FVIII
in patients with a low inhibitor titer, and lower doses of aPCC.[43]
Recombinant activated factor VII
Recombinant activated FVII (rFVIIa) has become the first choice of bypassing agents.[44] Recombinant FVIIa is a vitamin K–
dependent glycoprotein that is structurally similar to human plasma–derived FVIIa.[45] It is manufactured by using DNA
biotechnology.
Intravenous recombinant FVIIa has been studied for the treatment of bleeding episodes and for providing hemostasis during
surgery in patients with a particular bleeding diathesis.[44] Recombinant FVIIa is also effective and well tolerated in patients with
acquired hemophilia and in those with Glanzmann thrombasthenia.
To date, recombinant activated FVIIa has proved to be relatively free of the risk of antigenicity, thrombogenicity, and viral
transmission. However, the cost of this product and its short half-life have precluded its use as prophylaxis in patients with
inhibitors for FVIII; furthermore, when it has been used for this indication, select patients have had severe complications related
to bleeding.
In pediatric patients, off-label treatment with recombinant FVIIa significantly reduced blood product administration, with 82% of
patients subjectively classified as responders. Clinical context and pH values before administration were independently
associated with response and 28-day mortality. Thromboembolic adverse events were reported in 5.4% of patients.[46]
Desensitization
Desensitization in nonemergency situations also may be feasible. This approach comprises large doses of FVIII along with
steroids or intravenous immunoglobulin (IVIG) and cyclophosphamide. Success rates of 50-80% have been reported. In life-
threatening bleeding, methods to quickly remove the inhibiting antibody have been tried. Examples include vigorous
plasmapheresis in conjunction with immunosuppression and infusion of FVIII with or without antifibrinolytic therapy.
Immune tolerance induction
In ITI, tolerance to FVIII is induced by means of regular exposure to FVIII over several months to years.[36, 47] The overall
likelihood of success with ITI is 70% ± 10%.
Factors associated with successful outcome of ITI include the following[48] :
Historical inhibitor titers < 200 BU and immediate pre-ITI titers < 10 BU
Younger age at ITI initiation
An interval of < 5 years between inhibitor diagnosis and ITI start
ITI interruption < 2 weeks in duration
First described by Backmann in 1977, ITI has been used with variations in the dosing schedule for FVIII and with or without
immunosuppressive therapy (eg, cyclophosphamide, prednisone). Most of the recent protocols that use FVIII alone have
avoided use of immunosuppression because of the toxicity risk. This technique is well established in persons with congenital
hemophila with allo-antibodies but does not have a role in persons wtih acquired hemophilia A with auto-antibodies.
Rituximab, a chimeric human-mouse monoclonal antibody against CD20 that rapidly and specifically depletes B cells, has been
used with success in ITI.[49, 50] A 4-week course of weekly rituximab, with or without prednisone and/or cyclophosphamide, has
shown durable and complete responses in several small trials in patients with autoimmune hemophilia and inhibitor titers of 5 to
more than 200 BU.[51] Rituximab appears to be more effective in treating inhibitors in acquired hemophilia than in hereditary
hemophilia.[52, 53]
The choice of FVIII dosing regimen for ITI has ranged from 50 IU/kg 3 times weekly to 300 IU/kg/d. An international study in
patients with severe hemophilia and high-titer inhibitors found no significant difference between low-dose and high-dose ITI in
terms of the percentage of subjects achieving tolerance (70%) or in the time taken to achieve tolerance. However, the study was
stopped early because of safety considerations involving bleeding (significantly more common early on in the low-dose arm) and
lack of statistical power.[48]
Prophylactic Treatment
Most of the care for children with severe hemophilia now takes place at home, in the community, and at school, allowing these
children to participate in normal activities that are otherwise impossible. This approach resulted from the development of
prophylactic regimens of factor concentrate infusions that are administered at home, usually by a parent.
The main goal of prophylactic treatment is to prevent bleeding symptoms and organ damage, in particular to joints. Hemophilia
arthropathy that results from recurrent or target joint bleeding can be prevented by this method.
Prophylaxis is not universally accepted, with only about half the children with hemophilia A receiving this treatment modality in
the United States. Reasons cited for the lack of acceptance include need for venous access, factor availability, repeated
venipunctures, and cost, among others. Research questions that remain unanswered include when to initiate and stop infusions,
dosing, and dose schedule.
In 2013, the US Food and Drug Administration (FDA) expanded the indication for anti-inhibitor coagulant complex (Feiba NF) to
include routine prophylaxis in patients with hemophilia A or B who have developed inhibitors. Approval was based on data from a
pivotal phase III study in which a prophylactic regimen resulted in a 72% reduction in median annual bleed rate compared with
on-demand treatment.[54] An earlier study showed a 62% reduction in all bleeding episodes with prophylaxis versus an on-
demand regimen.[55]
In 2014 the FDA approved a long-acting recombinant FVIII–Fc fusion protein (rFVIIIFc) product (Eloctate) for control of bleeding
episodes, management of perioperative bleeding, and routine prophylaxis in patients with hemophilia A. For routine prophylaxis,
rVFIIIFC is infused every 4 days, whereas other available recombinant FVIII products are administered every 2-3 days.[56, 57]
The rFVIIIFc product was developed by fusing rFVIII to the Fc portion of IgG1, which allows a naturally occurring pathway to
prolong the product's duration of action. FDA approval was based on a study in 164 patients with hemophilia A in which the
median rate of bleeding episodes with prophylactic use of rFVIIIFc was 1.6 per year, compared with 33.6 per year in patients
receiving on-demand treatment.[56, 57] In an open-label extension study of rFVIIIFc in 211 patients, with included up to 5 years
of follow-up, no inhibitors were observed, annualized bleed rates remained low in patients on individualized prophylaxis, and
most patients maintained extended-dosing intervals (median of 3.5 days).[58]
Other rFVIII products are also approved by the FDA for routine prophylaxis (eg, NovoEight, Kogenate, Nuwiq, Adynovate,
Kovaltry, Afstyla, Jivi). Adynovate and Jivi are pegylated rFVIII products that allow less frequent administration. For prophylaxis,
Jivi is administered every 5 days and Adynovate is administered 2 times per week.
In the phase III PROPEL trial, which studied pharmacokinetic-guided prophylaxis with Adynovate, targeting FVIII trough levels of
1-3% or 8-12% both proved effective.[59] Patients with higher trough levels were more likely to be completely free of bleeds: in
the second 6 months of the trial, rates with 1-3% vs 8-12% trough levels were as follows:
Zero total bleeds: 42% vs 62% ( P = 0.055)

Zero spontaneous bleeds: 60% vs 76% ( P = 0.101)
Zero spontaneous joint bleeds: 65% vs 85% ( P = 0.026)
FVIII consumption varied widely in each treatment group, with overlapping ranges, emphasizing the need for personalized
treatment. However, most patients in the 1-3% arm were able to achieve their target FVIII trough with approximately twice-
weekly dosing, whereas most of those in the 8-12% arm needed to infuse every other day, or even daily.[59]
Emicizumab
The bispecific monoclonal antibody emicizumab is approved for prophylaxis in adults and children (including newborns) who
have hemophilia A with or without FVIII inhibitors (see Treatment of Patients with Inhibitors). The HAVEN 3 trial demonstrated
that emicizumab prophylaxis is also effective in patients without inhibitors.[40]
In this phase III trial, 152 patients 12 years of age or older who had been receiving episodic treatment with FVIII were
randomized to emicizumab prophylaxis once weekly or every 2 weeks, or no prophylaxis. The annualized bleeding rate was 1.5
in patients receiving weekly dosing and 1.3 with biweekly dosing, versus 38.2 events in patients receiving no prophylaxis. More
than half of the study patients who received prophylaxis had no treated bleeding events. Those patients who had previously
received FVIII prophylaxis had significantly lower bleeding rates with emicizumab prophylaxis.[40]
Assessing adherence to prophylaxis
The Validated Hemophilia Regimen Treatment Adherence Scale–Prophylaxis (VERITAS-Pro) prophylaxis is a patient/parent
questionnaire that uses 6 subscales (time, dose, plan, remember, skip, communicate), each containing 4 items, to assess
patient adherence to prophylactic hemophilia treatment. In a study of 67 patients with hemophilia, including 53 with severe FVIII
deficiency, Duncan et al found a strong correlation between VERITAS-Pro scores and adherence assessments (eg, infusion log
entries).[60]
Pain Management
Pain management can be challenging in patients with severe hemophilia. Acute bleeding in joints and soft tissues can be
extremely painful. This requires immediate analgesic relief.
Hemophilic chronic arthropathy is painful. Narcotic agents have been used, but their benefit for long-term therapy is limited by
side effects, the development of tolerance, and the risk of addiction.
Nonsteroidal anti-inflammatory drugs can be effective in managing acute and chronic arthritic pain but significant caution must
be used in dose and frequency due to concerns for increased risk of bleeding. Although they pose a risk of gastrointestinal
bleeding, their effects on platelet function are reversible. Avoid aspirin because of its irreversible effect on platelet function. Other
analgesics may include acetaminophen in combination with small amounts of codeine or synthetic codeine analogs.
Complications
HIV-associated immune thrombocytic purpura is an exceedingly serious complication in patients with hemophilia because it may
result in lethal intracranial bleeding. Correct platelet counts to greater than 50,000/mL. Steroids are of limited effectiveness, and
intravenous immunoglobulin or anti-Rh(D) generally induces only transient remissions. Anti-HIV medications and splenectomies
may result in long-term improvement of thrombocytopenia.
Allergic reactions are occasionally reported with the use of factor concentrates and these can be severe. Premedication or
adjustment of the rate of infusion may resolve the problem. It is quite possible that residucal cell line proteins (from mouse or
hamster cell lines) may contribute to this and change of product to different source cell line can be considered.
Deterrence/Prevention
Do not circumcise boys born to mothers who are known or thought to be carriers of hemophilia unless disease in the infant has
been excluded with appropriate laboratory testing. Perform blood assays of FVIII with cord blood. When a cord blood sample is
not available, obtain a sample from a superficial limb vein; avoid femoral and jugular sites.
Routine immunizations that require injection (eg, diphtheria, tetanus toxoids, and pertussis [DPT] or measles-mumps-rubella
[MMR] vaccines) may be given by means of a deep subcutaneous (rather than deep intramuscular) injection with a fine-gauge
needle. Administer the hepatitis B vaccine (now routinely administered to all children) soon after birth to all infants with
hemophilia. Administer the hepatitis A vaccine to those individuals with hemophilia and no hepatitis A virus antibody in their
serum.
In severe hemophilia, consider prophylactic or scheduled factor VIII. Prophylactic replacement of FVIII is used to maintain a
measurable level at all times, with the goal of avoiding hemarthrosis and the vicious cycle of repetitive bleeding and
inflammation that results in destructive arthritis.[61] This goal is achieved by administering factor 2-3 times a week. The National
Hemophilia Foundation has recommended the administration of primary prophylaxis, beginning at the age of 1-2 years.
Carrier testing is valuable for women who are related to obligate carrier females or males with hemophilia. Carrier testing may
prevent births of individuals with major hemophilia. This testing can be offered to women interested in childbearing who have a
family history of hemophilia. Prenatal diagnosis is important even if termination of the pregnancy is not desired because plans
for delivery and neonatal management can be made.
Preimplantation genetic diagnosis has been used as a possible alternative to prenatal diagnosis in combination with in vitro
fertilization to help patients avoid having children with hemophilia or other serious inherited diseases.[62, 63, 64] The genetic
diagnosis is made by using single cells obtained during biopsy from embryos before implantation. For this, fluorescence in situ
hybridization is used. This technique circumvents pregnancy termination. However, it is expensive and has limited success
rates, with a 22% chance for a live birth.[31]
Activity
Generally, individuals with severe hemophilia should avoid high-impact contact sports and other activities with a significant risk
of trauma. However, mounting evidence suggests that appropriate physical activity improves overall conditioning, reduces injury
rate and severity, and improves psychosocial functioning. Kumar et al reported that aerobic exercise on a stationary cycle
resulted in significant improvement in hemostatic indices in post-adolescent patients with mild to moderate hemophilia A.[65]
Patients with severe hemophilia can bleed from any anatomic site after negligible or minor trauma, or they may even bleed
spontaneously. Any physical activity may trigger bleeding in soft tissues. Prophylactic factor replacement early in life may help
prevent bleeding during activity, as well as helping to prevent chronic arthritic and muscular damage and deformity.
Gene Therapy
With the cloning of FVIII and advances in molecular technologies, the possibility of a cure for hemophilia A with gene therapy
was conceived.[66] Although the development of gene therapy for hemophilia A faced several complications, including the large
size of the FVIII gene, preclinical studies in mice and dogs with hemophilia resulted in long-term correction of the bleeding
disorders and, in some cases, a permanent cure.[67] Possible approaches to gene therapy for hemophilia A include the
following[68] :
Ex vivo gene therapy, in which cells to be transplanted are genetically modified to secrete factor VIII and then are
reimplanted into the recipient
In vivo gene therapy, in which a vector (typically a virus altered to include FVIII DNA) is directly injected into the
patient[69]
Nonautologous gene therapy, in which cells modified to secrete FVIII are packaged in immunoprotected devices and
implanted into recipients
The FDA approved the first gene therapy for hemophilia A, valoctocogene roxaparvovec (Roctavian), in June 2023. It is a one-
time, single-dose IV adeno-associated virus vector-based gene therapy indicated for severe hemophilia A (congenital FVIII
deficiency with FVIII activity < 1 IU/dL) in adults without pre-existing antibodies to adeno-associated virus serotype 5 (AAV5)
detected by an FDA-approved test.
Approval was based on the phase 3, open-label, single-group GENEr8-1 trial (n=134). Among the 132 HIV–negative
participants, the mean FVIII activity level at weeks 49 through 52 increased by 41.9 IU/dL (P < 0.001; median change, 22.9
IU/dL). After week 4 following infusion, the 112 participants enrolled from a prospective noninterventional study decreased their
annualized rates of FVIII concentrate use by 98.6%, and their rates of treated bleeds decreased by 83.8% (P < 0.001 for both
comparisons).[70]
The usefulness of AAV-based gene therapy such as valoctocogene roxaparvovec is limited by the fact that approximately one
third of patients with hemophilia A have antibodies to AAV5. Ex vivo gene therapy offers a potential alternative in such cases.[71]
Gao et al reported that this approach can result in stable, long-term engraftment of FVIII-producing cells. These researchers
transduced endothelial colony-forming cells (ECFCs) and placenta-derived mesenchymal stromal cells (PMSCs) with a lentiviral
vector that expressed FVIII, and administered the cells by intramuscular injection. Use of ECFCs and PMSCs together produced
better results than either cell type separately, and engraftment rates were higher in neonatal mice than in adult mice.[72]
transplantation of endothelial colony-forming cells (ECFCs) and placenta-derived mesenchymal stromal cells
(PMSCs)Implantation of liver-derived stem cells that have been expanded in vitro is under consideration, as these could
theoretically induce a steady-state production of quantities of factor sufficient to prevent spontaneous bleeding.
Consultations
Management should be provided in coordination with a comprehensive hemophilia care center. Specific consultations may be
indicated with a hematologist, blood bank, pathologist, or others as indicated by hemorrhagic complications. Early hematology
consultation for management of inhibitors is essential. Annual dental evaluation is recommended.
A genetic counselor may be consulted. Genetic testing for hemophilia A is available and must be offered to potential carriers.
Prenatal testing is performed by using amniocentesis or chorionic villus biopsy.
Before elective surgery is planned, a hematologist should be consulted to arrange adequate coverage with antihemophilic
factors and to arrange close follow-up to ensure that factor levels are sufficient during the operation and in the recovery and
healing period.
Consult an orthopedic surgeon in cases of permanent joint deformities resulting from recurrent hemarthrosis, as may occur in
relatively neglected cases or, occasionally, in cases of repetitive bleeding in a single joint despite intensive prophylactic
replacement of factor and physiotherapy. Open surgical or arthroscopic synovectomy may decrease bleeding and pain in the
affected joint.
Radiosynovectomy
In patients who develop synovitis from joint bleeds, intra-articular injection of radioisotopes to ablate the synovium
(radiosynovectomy) can be used to decrease bleeding, slow progression of cartilage and bone damage, and prevent
arthropathy. Yttrium-90 and rhenium-186 have proved equally effective for radiosynovectomy.[73] A review by Rodriguez-
Merchan et al concluded that radiosynovectomy is effective, safe, and well tolerated.[73]
The review by Rodriguez-Merchan included 500 synovectomies in 443 joints of 345 patients with chronic hemophilic synovitis.
One to three injections were administered, with a 6-month interval between injections. On average, the number of hemarthroses
decreased by 64.1%, articular pain decreased by 69.4%, the degree of synovitis decreased by 31.3%, and the World Federation
of Haemophilia score improved by 19%. Only four complications (0.9%) occurred. In 28 joints (6.3%), arthroscopic synovectomy
or total knee replacement was eventually required.[37]
Guidelines
Guidelines Summary
Guidelines on the management of acute joint bleeds and chronic synovitis in hemophilia were issued by the United Kingdom
Haemophilia Centre Doctors' Organisation in 2017.[74] Recommendations on hemostatic management of patients with
hemophilia A without inhibitors were as follows:
All patients with severe hemophilia A and other patients at risk of joint bleeding should be offered home treatment.
The initial treatment of early and moderate bleeds should aim for a peak factor VIII (FVIII) of 50 to 60 IU dL −1. This is
equivalent to 25 to 30 IU kg −1 for severe hemophilia A for standard and extended half-life products.
Early bleeds often do not require a second infusion, and moderate bleeds often respond to a single infusion but may
require up to 2 infusions.
Children may require more frequent or higher doses, as they have a shorter factor half-life than adults.
For joint-immobilizing bleeds, higher initial doses are recommended, which aim to raise the peak FVIII level to 60 to 80 IU
dL −1. Doses should be administered every 24 hr until complete resolution of pain. For severe bleeds, more frequent
administration may be required in the initial 48 hr with standard FVIII.
Recommendations for hemostatic management of patients with inhibitors to FVIII were as follows:
Inhibitor patients should be encouraged to be on a home treatment program, and bleeds should be treated as early as
possible.
Activated prothrombin complex (aPCC) 50–100 μg kg −1 or recombinant factor VIIa (rFVIIa) 270 μg kg −1 as a single
dose (or 90 μg kg −1 2–3 hourly) are equally acceptable treatments for joint or soft tissue bleeds with repeated doses as
necessary. The frequency of infusion and duration of treatment should be determined by the clinical response.
The total daily dose of aPCC should not exceed 200 IU kg −1.
Tranexamic acid can be considered as adjunctive therapy to aPCC and rFVIIa.
Sequential alternating treatment of aPCC and rFVIIa can be considered for the management of limb/life-threatening
bleeds.
Medication
Medication Summary
Factor VIII (FVIII) is the treatment of choice for acute or potential hemorrhage. Recombinant FVIII concentrate is generally the
preferred source of factor VIII. Prophylactic administration of FVIII is often recommended for patients with severe disease. The
FVIII activity level should be corrected to 100% of normal for potentially serious hemorrhage (eg, central nervous system,
trauma related, gastrointestinal [GI], genitourinary, epistaxis) and to 30-50% of normal for minor hemorrhage (eg, hemarthrosis,
oral mucosal, muscular).
One unit of FVIII is the amount of FVIII in 1 mL of plasma (1 U/mL or 1%). The volume of distribution of FVIII is that of plasma,
approximately 50 mL/kg. The difference between the desired FVIII activity level and the patient's native FVIII activity level can be
calculated by simple subtraction and expressed as a fraction (eg, 100% - 5% = 95% or 0.95).
To determine the number of units of FVIII needed to correct the FVIII activity level, use the following formula:
Units FVIII = (weight in kg)(50 mL plasma/kg)(1 U FVIII/mL plasma)(desired FVIII level minus the native FVIII level)
As an example, an 80-kg individual diagnosed with hemophilia with known 1% FVIII activity level presents to the emergency
department with a severe upper GI bleed. The correct dose of FVIII to administer in this case would be calculated as follows:
Units FVIII = (80 kg)(50 mL/kg)(1 U FVIII/mL)(0.99) = 3960
The next dose should be administered 12 hours after the initial dose and is one half the initial calculated dose. Minor
hemorrhage requires 1-3 doses of FVIII. Major hemorrhage requires many doses and continued monitoring of FVIII activity with
the goal of keeping the trough activity level at no lower than 50%. Continuous infusions of FVIII may be considered for major
hemorrhage. It is important to recall that response to factor replacement and half-life of product varies substantially across the
population and that therapy should ideally be individualized for that patient. Peak and trough values drawn after a treatment and
just prior to next treatment can be very helpful in individualizing therapy.
The specific factor product that patients use is often part of their individualized treatment plan. Patients, or parents of young
children, will usually be well educated on their dosing/products. This information also can be found on institutional treatment
center/blood bank databases.
Other medicinal adjuncts to factor VIII (eg, desmopressin acetate [DDAVP], antifibrinolytics) often are useful in achieving
hemostasis and can lessen the need for FVIII infusion. Antifibrinolytic agents, such as aminocaproic acid and tranexamic acid,
are especially useful for oral mucosal bleeds but are contraindicated as initial therapies for hemophilia-related hematuria
originating from the upper urinary tract because they can cause obstructive uropathy or anuria.
Coagulation Factors
Class Summary
FVIII concentrates replace deficient FVIII in patients with hemophilia A, with the goal of achieving a normal hematologic
response to hemorrhage or preventing hemorrhage. Recombinant products should be used initially and subsequently in all
newly diagnosed cases of hemophilia that require factor replacement. Agents that bypass FVIII activity in the clotting cascade
(eg, activated FVII) are used in patients with FVIII inhibitors.
Antihemophilic factor recombinant (Advate, Adynovate, Afstyla, Eloctate,

Helixate FS, Jivi, Kogenate FS, Kovaltry, NovoEight, Nuwiq, Obizur,
Recombinate, Xyntha)
These are synthetic products and are the most commonly used form of treatment when the administration of clotting protein
factor VIII is indicated. In hemophilia A patients, it temporarily restores hemostasis
Factor VIII, human plasma derived (Monoclate-P, Hemofil M, Koate DVI)

These are pooled plasma products (high purity) with factor VIII, which is necessary for stable clot formation and for maintenance
of hemostasis.
Anti-inhibitor coagulant complex (Feiba NF, Feiba VH Immuno)

This agent is a freeze-dried sterile human plasma fraction with FVIII inhibitor bypassing activity. It contains factors II, IX, and X,
mainly nonactivated; and FVII, mainly in the activated form. It may shorten the activated partial thromboplastin time of plasma
containing factor VIII inhibitors.
Anti-inhibitor coagulant complex is indicated for prevention and control of spontaneous hemorrhage or bleeding during surgical
interventions in hemophilia patients who have autoantibodies or alloantibodies to coagulation factors. It is also indicated for
routine prophylaxis to prevent or reduce the frequency of bleeding episodes in patients with hemophilia A or B who have
developed inhibitors.
Factor VIIa, recombinant (NovoSeven RT, Sevenfact)

Recombinant activated factor (FVIIa) is indicated for the treatment of bleeding episodes in patients with hemophilia A and
inhibitors. When complexed with tissue factor, this agent can activate the conversion of coagulation factor X to factor Xa as well
as coagulation factor IX to IXa. Factor Xa, in complex with other factors, then converts prothrombin to thrombin, which leads to
the formation of a hemostatic plug by converting fibrinogen to fibrin and thereby inducing local hemostasis. This process may
also occur on the surface of activated platelets.
Antihemophilic factor/von Willebrand factor complex (Alphanate, Humate P,

Wilate)
Antihemophilic Factor (FVIII) and von Willebrand Factor (VWF) are constituents of normal plasma, which are required for
clotting. Temporarily increases the plasma level of FVIII, thus minimizing the hazard of hemorrhage in patients with hemophilia
A; FVIII is an essential cofactor in activation of Factor X leading to formation of thrombin and fibrin. Indicated for control and
prevention of bleeding episodes for hemophilia A in adults and children (brand dependent). These concentrates have different
ratios of the the amount of Factor VIII and VWF in the product and the prescriber should familiarize themselves with these
differences to optomized dosing.
Monoclonal Antibodies
Class Summary
Monoclonal antibodies are used to bind to one specific substance in the body (eg, molecules, antigens). This binding is very
versatile and can mimic, block, or cause changes to enact precise mechanisms (eg, bridging molecules, replacing or activating
enzymes or cofactors, immune system stimulation).
Emicizumab (Hemlibra, emicizumab-kxwh)

Emicizumab is a first-in-class bispecific monoclonal antibody that bridges activated FIX and FX to restore the function of
activated FVIII. It is indicated for routine prophylaxis to prevent or reduce the frequency of bleeding episodes in adult and
pediatric patients (including newborns) with hemophilia A with or without factor VIII inhibitors.
Rituximab (Rituxan)
Rituximab is a monoclonal antibody directed against the CD20 antigen on B-lymphocytes. It is recommended as second-line
therapy in immune tolerance induction regimens for patients with FVIII inhibitors, especially those with high inhibitor titers. This
agent binds to, and mediates destruction of, B-cells, thereby decreasing production of FVIII inhibitors and autoimmunization.
Vasopressin-Related
Class Summary
Desmopressin transiently increases the FVIII plasma level in patients with mild hemophilia A.
Desmopressin (DDAVP, Stimate)

Desmopressin causes a transient increase (up to 4-fold) in FVIII plasma levels of patients with mild hemophilia A. It also
produces a dose-dependent increase in plasminogen activator. It is useful for minor hemorrhage episodes only. It may be useful
in patients with FVIII inhibitors.
Desmopressin Increases the cellular permeability of the collecting ducts, resulting in renal reabsorption of water. This can result
in hyponatremia which can be severe, particularly with repeat dosing. Tachyphylaxis may occur even after first dose, but drug
can be effective again after several days.
Antifibrinolytic Agents
Class Summary
These agents are used in addition to factor VIII replacement for oral mucosal hemorrhage and prophylaxis, as the oral mucosa
is rich in native fibrinolytic activity. Their use is contraindicated as initial therapies for hemophilia-related hematuria originating
from the upper urinary tract because they can cause obstructive uropathy or anuria. They should not be used in combination
with prothrombin complex concentrate (PCC).
Epsilon aminocaproic acid (Amicar)

This lysine inhibits fibrinolysis by blocking the binding of plasminogen to fibrin and inhibiting plasminogen and conversion to
plasmin, resulting in the inhibition of fibrinolysis. The principal drawbacks of this agent are that thrombi formed during treatment
are not lysed, and its effectiveness is uncertain. It has been used to prevent recurrence of subarachnoid hemorrhage.
This agent is widely distributed. Its half-life is 1-2 hours. Peak effect occurs within 2 hours. Hepatic metabolism is minimal.
Tranexamic acid (Cyklokapron, Lysteda)

This agent is an alternative to aminocaproic acid. It inhibits fibrinolysis by displacing plasminogen from fibrin. It also inhibits the
proteolytic activity of plasmin.
Clotting Factors, Gene Therapies
Class Summary
These therapies are designed to introduce a functional copy of a transgene encoding the human coagulation factor VIII.
Valoctocogene roxaparvovec (Roctavian)

Valoctocogene roxaparvovec is an adeno-associated virus serotype 5 (AAV5) based gene therapy vector, designed to introduce
a functional copy of a transgene encoding the B-domain deleted SQ form of human coagulation factor VIII (hFVIII-SQ). The
expressed hFVIII-SQ replaces the missing coagulation factor VIII needed for effective hemostasis. It is indicated for severe
hemophilia A (congenital factor VIII deficiency with factor VIII activity <1 IU/dL) in adults without pre-existing antibodies to adeno-
associated virus serotype 5 detected by an FDA-approved test.
Questions & Answers

Overview
What is hemophilia A?
What are the signs and symptoms of hemophilia A?
Which lab studies are performed in the evaluation of suspected hemophilia A?
Which lab values suggest hemophilia A?
What values for factor VIII (FVIII) assays indicate hemophilia A?
What is the role of imaging studies in the diagnosis of hemophilia A?
What is the role of inhibitors testing in the diagnosis of hemophilia A?
What is included in the treatment of hemophilia A?
Where is treatment for hemophilia A administered?
What are the treatment options for acute bleeds in hemophilia A?
How is the number of units of factor VIII needed to correct the factor VIII activity level in hemophilia A determined?
What are the possible regimens for factor VIII (FVIII) dosing in hemophilia A?
What types of factor VIII (FVIII) are available for the treatment of hemophilia A?
What are the attributes of desmopressin vasopressin analog for the treatment of hemophilia A?
What is the role of antifibrinolytics in the treatment of hemophilia A?
Which treatments are used for hemophilia A in patients with inhibitors of factor VIII (FVIII)?
What are the World Federation of Hemophilia (WFH) recommendations for the management of COVID-19 in patients with
hemophilia A?
What is hemophilia A?
What causes morbidity and death in patients with hemophilia A?
Which lab studies are performed in the evaluation of suspected hemophilia A?
What are the treatment options for hemophilia A?
How is the severity of hemophilia A classified?
What is the historical background of hemophilia A?
What is the pathophysiology of factor VIII (FVIII) in hemophilia A?
What is the role of the von Willebrand factor (vWF) in the pathophysiology of hemophilia A?
What is the role of the coagulation system in the pathogenesis of hemophilia A?
What is the role of genetics in the pathophysiology of hemophilia A?
What is the role of factor VIII (FVIII) in the pathophysiology of hemophilia A?
What causes hemorrhage into joints in the pathophysiology of hemophilia A?
What is the role of alloantibody inhibitors in the pathogenesis of hemophilia A?
What causes inhibitor formation in patients with hemophilia A?
What are the methods used to measure levels of factor VIII (FVIII) inhibitors in hemophilia A?
What is the pathophysiology of acquired hemophilia A?
What causes hemophilia A?
What is the role of factor VIII (FVIII) in the etiology of hemophilia A?
What is the role of genetics in the etiology of hemophilia A?
Which genetic mutations have a role in the etiology of hemophilia A?
What is the role of gene deletions in the etiology of hemophilia A?
What is the role of combined factor V (FV) and factor VIII (FVIII) in the etiology of hemophilia A?
What is the prevalence of hemophilia A?
What are the racial predilections of hemophilia A?
How does the presentation of hemophilia A differ in females?
In which age group is hemophilia A typically identified?
What is the prognosis of hemophilia A?
How have factor concentrates improved the prognosis of hemophilia A?
Which factors increase the risk of fractures in patients with hemophilia A?
How do viral infections affect the prognosis of hemophilia A?
What are the death rates of hemophilia A in the US?
Which infectious agents may be transmitted in factor concentrates to patients with hemophilia A?
What are possible life-threatening complications of hemophilia A?
What causes chronic debilitating joint disease in patients with hemophilia A?
What is the mortality rate for hemophilia A?
What is included in patient education for hemophilia A?
Presentation
What should be the focus of the history for suspected hemophilia A?
What are the signs and symptoms of hemorrhage in hemophilia A?
What is the evidence of infectious disease in hemophilia A?
Which clinical history is characteristic of severe hemophilia A?
Which clinical history is characteristic of mild or moderate hemophilia A?
What are the principal bleeding sites in patients with hemophilia A?
Which clinical history is characteristic of hemophilia A in the genitourinary tract?
Which clinical history is characteristic of acquired hemophilia A?
What are the systemic signs of hemorrhage in hemophilia A?
What are the physical findings characteristic of hemophilia A?
What are the signs of infectious disease in hemophilia A?
What is the manifestation of severe hemophilia A?
What are physical findings characteristic of hemophilia A after the immediate neonatal period of?
What are the physical findings characteristic of hemophilia A in growing children?
What is the manifestation of petechiae in hemophilia A?
How is hemophilia A classified?
What are pseudotumors in hemophilia A?
DDX
Which conditions should be included in the differential diagnosis of hemophilia A?
How is hemophilia A differentiated from hemophilia B?
What are the differential diagnoses for Hemophilia A (Factor VIII Deficiency)?
Workup
What is the role of lab studies in the workup of hemophilia A?
What is the role of imaging studies in the workup of hemophilia A?
How is the presence of factor VIII (FVIII) inhibitor confirmed in hemophilia A?
What tests are performed for hemophilia A carrier and fetal screening?
What is included in the prenatal testing of hemophilia A carriers?
What is the role of radiography in the workup of hemophilia A?
Treatment
What are the treatment options for hemophilia A?
How are dose calculations determined in the treatment of hemophilia A?
What is the role of prophylaxis in the management of hemophilia A?
What are the treatment options for hemophilia A and inhibitors of factor VIII (FVIII)?
How is synovitis due to hemophilia A joint bleeding treated?
How can fractures be prevented in hemophilia A?
What is included in prehospital care for hemophilia A?
What should be obtained before emergency department (ED) treatment is initiated for hemophilia A?
What is included in initial emergency department (ED) care for hemophilia A?
How is minor bleeding managed in hemophilia A?
How is epistaxis or moderately severe hematuria treated in hemophilia A?
How is acute joint bleeding and expanding hematuria treated in hemophilia A?
How are life-threatening bleeding episodes initially treated in patients with hemophilia A?
What are indications for admission to an intensive care unit for treatment of hemophilia A?
When should patients with hemophilia A be transferred for treatment to a hemophilia care center?
What is included in outpatient care for hemophilia A patients with minor hemorrhage?
What is included in outpatient care of hemophilia A patients with HIV seroconversion?
Which factor VIII (FVIII) concentrates are used for the treatment of hemophilia A?
What is the indication for continuous infusion of factor VIII (FVIII) concentrates in the treatment of hemophilia A?
What is the proper dosing of factor VIII (FVIII) concentrate for the treatment of hemophilia A?
What is the role of desmopressin vasopressin analog in the treatment of hemophilia A?
How is desmopressin vasopressin analog administered for the treatment of hemophilia A?
What are adverse effects of desmopressin vasopressin analog for hemophilia A?
What are the most common sites of clinically significant bleeding in hemophilia A?
How are musculoskeletal bleeding episodes managed in patients with hemophilia A?
How are oral bleeding episodes managed in patients with hemophilia A?
How are GI bleeding episodes managed in patients with hemophilia A?
How are intracranial bleeding episodes managed in patients with hemophilia A?
What is the primary treatment for hemophilia A with factor VIII (FVIII) inhibitors?
What are alternative treatment options for hemophilia A with factor VIII (FVIII) inhibitors?
What is the role of emicizumab in the treatment of hemophilia A?
What is the role of recombinant activated factor VIII (FVIII) the treatment of hemophilia A?
What is the role of desensitization in the treatment of hemophilia A?
Which factors are associated with successful outcome of immune tolerance induction (ITI) in the treatment of hemophilia A?
How is immune tolerance induction (ITI) administered in the treatment of hemophilia A?
What is the role of rituximab in the treatment of hemophilia A?
What are the dosing regimen used for immune tolerance induction (ITI) in the treatment of hemophilia A?
What is the role of emicizumab in hemophilia A prophylaxis?
What are the benefits of prophylactic treatment for hemophilia A?
What is the main goal of prophylactic treatment of hemophilia A?
What is the prevalence of prophylactic treatment of hemophilia A?
What is the role of recombinant FVIII products in the treatment of hemophilia A?
How is adherence to prophylaxis for hemophilia A assessed?
How is pain managed in patients with hemophilia A?
What are potential complications of hemophilia A?
How should routine vaccinations be administered to children with hemophilia A?
How is repetitive bleeding and inflammation prevented in severe hemophilia A?
What is the role of carrier testing in the prevention of hemophilia A?
What is the role of preimplantation genetic diagnosis in the prevention of hemophilia A?
Which activity restrictions are indicated for patients with hemophilia A?
What is the role of gene therapy in the treatment of hemophilia A?
What is the efficacy of gene therapy for hemophilia A?
Which specialist consultations may be beneficial in the treatment of hemophilia A?
What is the role of radiosynovectomy in the treatment of hemophilia A?
Guidelines
What are the UK treatment guidelines for acute joint bleeds and chronic synovitis in hemophilia A?
Medications
Which medications are used in the treatment of hemophilia A?
What is the calculation for number of units of factor VIII (FVIII) needed to correct factor VIII (FVIII) activity level for hemophilia A?
Where should the factor products used in the treatment of a specific patient with hemophilia A be recorded?
Which medical adjuncts to factor VIII (FVIII) are used in the treatment of hemophilia A?
Which medications in the drug class Antifibrinolytic Agents are used in the treatment of Hemophilia A (Factor VIII Deficiency)?
Which medications in the drug class Vasopressin-Related are used in the treatment of Hemophilia A (Factor VIII Deficiency)?
Which medications in the drug class Monoclonal Antibodies are used in the treatment of Hemophilia A (Factor VIII Deficiency)?
Which medications in the drug class Coagulation Factors are used in the treatment of Hemophilia A (Factor VIII Deficiency)?
Contributor Information and Disclosures
Author
Douglass A Drelich, MD Director, Cardeza Foundation, Hemostasis and Thrombosis Center, Associate Director, Cardeza
Special Coagulation Laboratory, Thomas Jefferson University Hospital; Assistant Professor of Medicine, Sidney Kimmel Medical
College of Thomas Jefferson University
Douglass A Drelich, MD is a member of the following medical societies: American Medical Association, American Society of
Clinical Oncology, American Society of Hematology
Disclosure: Nothing to disclose.
Chief Editor
Srikanth Nagalla, MD, MS, FACP Chief of Benign Hematology, Miami Cancer Institute, Baptist Health South Florida; Clinical
Professor of Medicine, Florida International University, Herbert Wertheim College of Medicine
Srikanth Nagalla, MD, MS, FACP is a member of the following medical societies: American Society of Hematology, Association
of Specialty Professors
Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Alexion; Alnylam; Kedrion;
Sanofi; Dova; Apellis; Pharmacosmos<br/>Serve(d) as a speaker or a member of a speakers bureau for: Sobi; Sanofi; Rigel.
Additional Contributors
Emmanuel C Besa, MD Professor Emeritus, Department of Medicine, Division of Hematologic Malignancies and Hematopoietic
Stem Cell Transplantation, Kimmel Cancer Center, Jefferson Medical College of Thomas Jefferson University
Emmanuel C Besa, MD is a member of the following medical societies: American Association for Cancer Education, American
Society of Clinical Oncology, American College of Clinical Pharmacology, American Federation for Medical Research, American
Society of Hematology, New York Academy of Sciences
Mary A Furlong, MD Associate Professor and Program/Residency Director, Department of Pathology, Georgetown University
School of Medicine
Mary A Furlong, MD is a member of the following medical societies: United States and Canadian Academy of Pathology
Gary D Crouch, MD Associate Professor, Program Director of Pediatric Hematology-Oncology Fellowship, Department of
Pediatrics, Uniformed Services University of the Health Sciences
Gary D Crouch, MD is a member of the following medical societies: American Academy of Pediatrics, American Society of
Hematology
Robert A Zaiden, MD Adjunct Associate Professor, Division of Cancer Medicine, Baptist MD Anderson Cancer Center
Robert A Zaiden, MD is a member of the following medical societies: American College of Physicians, American Society of
Clinical Oncology
Acknowledgements
Dimitrios P Agaliotis, MD, PhD, FACP Consulting Staff, Department of Medicine, Baptist Health System
Dimitrios P Agaliotis, MD, PhD, FACP is a member of the following medical societies: American College of Physicians, American
Medical Association, American Society of Hematology, and Florida Medical Association
Jeffrey L Arnold, MD, FACEP Chairman, Department of Emergency Medicine, Santa Clara Valley Medical Center
Jeffrey L Arnold, MD, FACEP is a member of the following medical societies: American Academy of Emergency Medicine and
American College of Physicians
Emmanuel C Besa, MD Professor, Department of Medicine, Division of Hematologic Malignancies and Hematopoietic Stem Cell
Transplantation, Kimmel Cancer Center, Jefferson Medical College of Thomas Jefferson University
Emmanuel C Besa, MD is a member of the following medical societies: American Association for Cancer Education, American
College of Clinical Pharmacology, American Federation for Medical Research, American Society of Clinical Oncology, American
Society of Hematology, and New York Academy of Sciences
Max J Coppes, MD, PhD, MBA President, BC Cancer Agency, Vancouver
Max J Coppes, MD, PhD, MBA, is a member of the following medical societies: Alberta Medical Association, American College
of Healthcare Executives, American Society of Pediatric Hematology/Oncology, and Society for Pediatric Research
Disclosure: Astellas Pharma US Inc Honoraria Chair Endpoint Review Committee
Brendan R Furlong, MD Clinical Chief, Department of Emergency Medicine, Georgetown University Hospital
Brendan R Furlong, MD is a member of the following medical societies: American College of Emergency Physicians and Society
for Academic Emergency Medicine
Pere Gascon, MD, PhD Professor and Director, Division of Medical Oncology, Institute of Hematology and Medical Oncology,
IDIBAPS, University of Barcelona Faculty of Medicine, Spain
Pere Gascon, MD, PhD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians,
New York Academy of Medicine, New York Academy of Sciences, and Sigma Xi
William G Gossman, MD Associate Clinical Professor of Emergency Medicine, Creighton University School of Medicine;
Consulting Staff, Department of Emergency Medicine, Creighton University Medical Center
William G Gossman, MD is a member of the following medical societies: American Academy of Emergency Medicine
Lawrence F Jardine, MD, FRCPC Associate Professor, Department of Pediatrics, Schulich School of Medicine and Dentistry,
University of Western Ontario; Head, Section of Pediatric Hematology and Oncology, Children's Hospital of Western Ontario;
Associate Scientist, Child Health Research Institute
Lawrence F Jardine, MD, FRCPC is a member of the following medical societies: American Society of Hematology, American
Society of Pediatric Hematology/Oncology, Canadian Medical Protective Association, Children's Oncology Group, College of
Physicians and Surgeons of Ontario, Hemophilia and Thrombosis Research Society, Ontario Medical Association, and Royal
College of Physicians and Surgeons of Canada
Disclosure: Baxter Honoraria Consulting; Bayer Honoraria Consulting; Novartis Honoraria Speaking and teaching
Elzbieta Klujszo, MD Head of Department of Dermatology, Wojewodzki Szpital Zespolony, Kielce
Adonis Lorenzana, MD Consulting Staff, Department of Pediatric Oncology, St John Hospital and Medical Center
Adonis Lorenzana, MD is a member of the following medical societies: American Academy of Pediatrics and American Society of
Pediatric Hematology/Oncology
Rajalaxmi McKenna, MD, FACP Southwest Medical Consultants, SC, Department of Medicine, Good Samaritan Hospital,
Advocate Health Systems
Rajalaxmi McKenna, MD, FACP is a member of the following medical societies: American Society of Clinical Oncology, American
Society of Hematology, and International Society on Thrombosis and Haemostasis
Saduman Ozturk, PA-C Physician Assistant, Bone Marrow Transplant Center, Florida Hospital Cancer Institute
Ronald A Sacher, MB, BCh, MD, FRCPC Professor, Internal Medicine and Pathology, Director, Hoxworth Blood Center,
University of Cincinnati Academic Health Center
Ronald A Sacher, MB, BCh, MD, FRCPC is a member of the following medical societies: American Association for the
Advancement of Science, American Association of Blood Banks, American Clinical and Climatological Association, American
Society for Clinical Pathology, American Society of Hematology, College of American Pathologists, International Society of Blood
Transfusion, International Society on Thrombosis and Haemostasis, and Royal College of Physicians and Surgeons of Canada
Disclosure: Glaxo Smith Kline Honoraria Speaking and teaching
Hadi Sawaf, MD Director, Pediatric Hematology Oncology, Van Elslander Cancer Center; Clinical Assistant Professor, Wayne
State University School of Medicine
Hadi Sawaf, MD is a member of the following medical societies: American Academy of Pediatrics, American Society of Clinical
Oncology, and American Society of Hematology
Rebecca J Schmidt, DO, FACP, FASN Professor of Medicine, Section Chief, Department of Medicine, Section of Nephrology,
West Virginia University School of Medicine
Rebecca J Schmidt, DO, FACP, FASN is a member of the following medical societies: American College of Physicians, American
Medical Association, American Society of Nephrology, International Society of Nephrology, National Kidney Foundation, Renal
Physicians Association, and West Virginia State Medical Association
Disclosure: Renal Ventures Ownership interest Other
Robert A Schwartz, MD, MPH Professor and Head, Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive
Medicine and Community Health, Rutgers New Jersey Medical School
Robert A Schwartz, MD, MPH is a member of the following medical societies: Alpha Omega Alpha, American Academy of
Dermatology, American College of Physicians, New York Academy of Medicine, and Sigma Xi
Karen Seiter, MD Professor, Department of Internal Medicine, Division of Oncology/Hematology, New York Medical College
Karen Seiter, MD is a member of the following medical societies: American Association for Cancer Research, American College
of Physicians, and American Society of Hematology
Disclosure: Novartis Honoraria Speaking and teaching; Novartis Consulting fee Speaking and teaching; Ariad Honoraria
Speaking and teaching; Celgene Honoraria Speaking and teaching
Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy;
Editor-in-Chief, Medscape Drug Reference
Disclosure: Medscape Salary Employment
Acknowledgments
The authors gratefully acknowledge the provision of several photographs used in this article by a dedicated colleague from
Chicago, Margaret Telfer, MD. The authors would also like to acknowledge Professor K.N. Subramanian (Department of
Molecular Genetics, University of Illinois Medical Center) for general discussions relating to some aspects of the gene structure
and mutation of the FVIII gene.
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Hemophilia A (Factor VIII Deficiency)

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Hemophilia A (Factor VIII Deficiency)

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6/21/24, 5:50 PM emedicine.medscape.

Hemophilia A (Factor VIII

Signs and symptoms

Signs of hemorrhage include the following:

See Presentation for more detail.

Laboratory studies for suspected hemophilia include the following:

Complete blood cell count

Expected laboratory values are as follows:

Hemoglobin/hematocrit: Normal (or low if associated bleeding)

Positive result: ≥ 0.6 Bethesda units (BU)

See Workup for more detail.

The treatment of hemophilia may involve the following:

Disposition of treatment is as follows:

Management ideally should be provided through a comprehensive hemophilia care center

FVIII regimens are as follows:

The following types of FVIII concentrates are available:

Plasma-based products: Purified to inactivate viruses

Epsilon aminocaproic acid (Amicar)

Treatments used in patients with inhibitors of FVIII are as follows:

High doses of FVIII for low-titer inhibitors

See Treatment and Medication for more detail.

In addition, the WFH notes the following:

Please see the following for more information:

von Willebrand factor

The clotting cascade

Hemorrhage into joints

Combined factor V and factor VIII deficiency

Racial, sexual, and age-related differences in incidence

Turner syndrome (XO) associated with the affected hemophilia gene

For patient education information, see Hemophilia.

History of hemorrhage disproportionate to trauma

Signs and symptoms of hemorrhage include the following:

General - Weakness and orthostasis (related to anemia/hypovolemia secondary to bleeding)

Genitourinary - Hematuria, renal colic, post-circumcision bleeding

Evidence of infectious disease includes the following:

Organ system–specific signs and symptoms of hemorrhage include the following:

Signs of infectious disease include the following:

Classification Factor Activity, % Cause of Hemorrhage

Mild >5-40 Major trauma or surgery

Moderate 1-5 Mild-to-moderate trauma

Severe <1 Spontaneous

Transected pseudocyst with chocolate brown-black old blood.

Plain radiograph of the pelvis showing a large lytic area.

von Willebrand disease (autosomal dominant transmission)

Please see the following for more information:

Combined factor V and factor VIII deficiency

Physical Child Abuse

von Willebrand Disease

Imaging studies for acute bleeds

Testing for Inhibitors

Carrier Testing and Fetal Testing

Mild hemophila A: FVIII > 0.05 and < 0.40 IU/mL

Please see the following for more information:

Apply aggressive hemostatic techniques

Emergency Department Care

The type and severity of factor deficiency

Factor VIII Concentrates

Target levels by hemorrhage severity are as follows:

Severe epistaxis; mouth, lip, tongue, or

Joint (hip or groin) 40 20 Repeat transfusion in 24-48 h

No therapy if site small and not enlarging

Muscle (calf and forearm) 30-40 15-20 None

Neck or throat 50-80 25-40 None

Hematuria 40 20 Transfuse to 40% then rest and hydration