Editors: Hillman, Robert S.; Ault, Kenneth A.; Rinder, Henry M.

Title: Hematology in Clinical Practice, 4th Edition

Copyright 2005 McGraw-Hill
> Table of Contents > Part III - Disorders of Hemostasis > Chapter 32 - Hemophilia and
Other Intrinsic Pathway Defects

Chapter 32
Hemophilia and Other Intrinsic Pathway Defects
Defects in the intrinsic pathway are associated with a significant bleeding tendency. The Xlinked recessive disorders, hemophilia A and B, are the principal examples of this type of
abnormality. A marked reduction in either factor VIII or IX is associated with spontaneous
and excessive hemorrhage, especially hemarthroses and muscle hematomas. A deficiency in
factor XI, which is encoded by a gene on chromosome 4, can result in a less severe bleeding
tendency.
THE NORMAL INTRINSIC PATHWAY
Interactions of the coagulation factors involved in the intrinsic pathway are illustrated in
Figure 32-1. The initial activation stimulus is surface contact activation of factor XII
(Hageman factor) to produce XIIa. This reaction is facilitated by the presence of highmolecular-weight kininogen (HMWK) and the conversion of prekallikrein (PK) to the active
protease, kallikrein. Although this first contact step is required in the measurement of the
partial thromboplastin time (PTT), deficiencies of factor XII, HMWK, and PK are not
associated with clinical bleeding.
Factor XIIa activates factor XI to XIa, which in turn activates factor IX (Christmas factor).
Factor IXa then catalyzes the cleavage of factor X to Xa. The reaction between factors IXa
and X is facilitated by binding, in the presence of calcium, to a phospholipid surface such as
the surface of an activated platelet. It also requires activated factor VIII as a cofactor to
achieve a maximum reaction rate. Factor IX is a single-chain, vitamin K-dependent,
glycoprotein produced in the liver. Its activation by factor XIa involves a cleavage of two
successive internal peptide bonds to form a two-chain serine protease. Factor VIII is
synthesized by the liver and reticuloendothelial tissues throughout the body. The small factor
VIII protein circulates bound to von Willebrand factor (vWF), a much larger carrier protein.
This relationship is extremely important. When the vWF level is reduced in patients with von
Willebrand disease, unbound factor VIII is more rapidly cleared from plasma, effectively
reducing the activity level. In order to participate as a cofactor in the activation of factor X,
factor VIII must first be cleaved by thrombin to form factor VIIIa.
CLINICAL FEATURES
A severe deficiency of either factor VIII or IX results in a major bleeding disorder, clinically
known as hemophilia A (VIII deficiency) or hemophilia B (IX deficiency). Even though
hemophilia is a relatively rare disorder (1 per 5000 male births for hemophilia A and 1 per
30,000 male births for hemophilia B), descriptions of hemophilia as a sex-linked familial
bleeding disorder can be traced back to biblical times. In part, this reflects the fact that the
severe hemophiliac experiences major bleeds that start soon after birth and recur at frequent
intervals during childhood. Moreover, once the hemophilia mutation appears in a family, it is
sustained through successive generations with little variation in expression. At the same time,
hemophilia can present as a new spontaneous mutation, usually in the maternal gamete, in
approximately one-third of cases.

Hemophilia A
The molecular basis of hemophilia A has now been defined. The factor VIII gene is a very
large, 186-kb gene on the X chromosome. Almost half of the patients with hemophilia A
exhibit an inversion of a major portion of the VIII gene (intron 22) with a resultant failure in
factor VIII production. The remainder show various point mutations, insertions, and deletions
that may involve as little as one base pair to the entire gene. The most severe hemophiliacs
generally have the inversion or a deletion of major portions of the X chromosome genome,
resulting in very low levels of factor VIII antigen and activity, usually less than 1% of normal
activity. Missense mutations also can be associated with severe disease. Other mutations,
including stop codon and point mutations and minor deletions, generally result in milder
disease with factor VIII levels > 1%. In some patients, a functionally abnormal protein is
produced. This can be demonstrated by showing a discrepancy between the immunologic
measurement of factor VIII antigen (protein) and the coagulation assay of factor VIII activity.
As a rule of thumb, clinical severity of hemophilia A is best correlated with the factor VIII
activity level. Severe hemophiliacs have factor VIII activity levels < 1% of normal (< 0.01
U/mL) and are usually diagnosed during childhood because of frequent, spontaneous
hemorrhages into joints, muscles, and vital organs. They require frequent treatment with
factor VIII replacement and even then are at risk of developing a progressive, deforming
arthropathy.
Even a level of detectable factor VIII activity of 1- 5% of normal is enough to reduce the
severity of the disease. These patients are at increased risk of hemorrhage with surgery or
trauma but have much less difficulty with spontaneous hemarthroses or hematomas. Patients
with factor levels 6 - 30% are only mildly affected and may go undiagnosed well into adult
life. They are at risk, however, for excessive bleeding with a major surgical procedure.
Female carriers of hemophilia A can also be at risk with surgery. Lyonization of the X
chromosome is not purely random, so that, 10% of female carriers can have factor VIII
activity levels of levels of < 30%.
An inherited combined deficiency of factors V and VIII, due in most cases to a single
mutation on the long arm of chromosome 18, is associated with a moderate bleeding defect.
The gene mutation appears to result in a defect in the transport of V and VIII from the
endoplasmic reticulum through the Golgi complex. Factor V and VIII levels are 5 - 30% of
normal.
Hemophilia B
Hemophilia B patients have a similar clinical spectrum of disease. Factor IX levels of less
than 1% are associated with severe bleeding, whereas more moderate disease is seen in
patients with levels of 1- 5%. Patients with factor IX levels of 5 - 40% generally have very
mild disease. This situation reflects the similarity in genetic transmission. Hemophilia B can
result from several genetic mutations including deletions, point mutations, and frame shift
defects involving the factor IX gene on the long arm of the X chromosome. Most patients
show an absence of factor IX activity because of a functionally abnormal protein; less
commonly there is absence of both factor IX antigen and activity. One rare mutation (F-IX
Leyden) produces a hemophilia B picture in children that resolves at puberty as factor IX
production increases.
The most characteristic clinical manifestation of the hemophilias is the bleeding into large
joints of upper and lower extremities. This condition usually begins once the affected child
reaches the toddler stage and increases in frequency as the child becomes more active. Often,
one or two joints become the principal targets of repeated hemarthroses. With time, this

situation can result in a chronic synovitis, destruction of cartilage and bone, and a
progressive flexion contracture. Bleeding into muscle (iliopsoas, gastrocnemius, and flexor
muscles of the arm) or soft tissues with the formation of large spreading hematomas is also
common. Damage to muscles results in further muscle atrophy and contractures. Other less
common bleeding manifestations include hematuria, intracranial hemorrhage, mucous
membrane bleeding, and prolonged bleeding following minor trauma or surgery. Milder
hemophiliacs (> 5% factor IX activity) may not be detected until surgery is performed
or the patient has a dental extraction. Usually, the procedure is completed without
evidence of unusual bleeding. However, within a few hours, the surgical wound or tooth
socket begins to ooze, wound healing is disrupted, and blood seeps into surrounding tissues.
Hematoma formation in the pharyngeal and retropharyngeal areas can threaten airway
patency and present a medical emergency.
Large subperiosteal or muscle bleeds can on occasion lead to the formation of a hemophilic
pseudotumor. These are cyst-like structures containing serosanguinous or dark brown viscous
material bound to a fibrous membrane. Over time, pseudotumors expand and impinge on
adjacent structures. Those that arise from a subperiosteal bleed, usually involving the pelvis
or femurs, can veentually erode adjacent bone to form large cystic lesions.
Acquired Factor VIII or IX Inhibitors
Hemophilia A patients are at significant risk for developing circulating inhibitors to factor
VIII, usually within the first 2030 exposures to replacement therapy. Severe mutations
(inversions, large sequence deletions, and nonsense mutations) that lead to a complete failure
of production or the release of a severely truncated factor VIII protein are associated with the
highest incidence of acquired inhibitors, 3040%. Hemophilia B patients are less likely to
develop an inhibitor to factor IX; only 35% of patients will become affected during their
lifetime.
Historically, up to 20% of all children with hemophilia A receiving fresh frozen plasma (FFP)
and cryoprecipitate developed an inhibitor by age 10 years. Unfortunately, this problem has
not been solved by the arrival of the high-purity concentrates and recombinant factor VIII.
The development of inhibitors is still a major issue. In general, factor VIII inhibitor patients
fall equally into one of two groups according to the level of inhibitor. High responders
demonstrate a marked inhibitor response after any factor infusion, reaching levels that cannot
be neutralized by high-dose replacement therapy. The response is typical of induction of an
alloantibody, and the patient is constantly at risk for an anamnestic response when reexposed
to factor antigen. In contrast, low responders develop and maintain relatively low levels of
inhibitor that are constant despite repeated exposure to factor VIII replacement.
A severe hemophilia-like syndrome can occur in genetically normal individuals secondary to
the appearance of an acquired autoantibody to either factor VIII or, very rarely, to factor IX.
These antibodies are in effect circulating anticoagulants. They bind to the factor and result in
a loss of coagulant activity. These patients are usually middle-aged or older with no personal
or family history of abnormal bleeding. They present with a sudden onset of severe,
spontaneous hemorrhage involving skin, mucous membranes, muscles, and vital organs,
rather than hemarthroses. Bleeding into the tongue and retropharynx can threaten the airway,
whereas severe muscle bleeding can be highly destructive. Even though the inhibitor is an
autoantibody against factor VIII or IX, there is only occasionally other evidence of
autoimmune disease. About 7% of patients develop their inhibitor in the postpartum period.
Viral Infections in the Hemophiliac
Viral hepatitis and HIV infection progressing to AIDS in hemophiliacs resulted from
repeated exposure to virally contaminated clotting factor concentrates. It is estimated that

80% or more of severe hemophiliacs over age 10 years were infected with HIV, hepatitis B
virus (HBV), or hepatitis C virus (HCV) during the early 1980s. With the advent of highly
purified factor VIII products, younger patients are now at far lower, even negligible, risk. The
use of second-generation recombinant products, which eliminate exposure to human or
animal source protein, also lowers the risk of both virus and nonviral pathogens, such as
Creutzfeld-Jakob disease. Coinfection with HIV and HCV promotes viral replication and
progression of the patient's liver disease. The presence of HIV increases the risk of liver
failure by 21-fold in HCV-infected hemophiliacs. There is also a higher incidence of
hepatocellular carcinoma in this group.
HIV transmission to sexual partners is a major concern. Safe sex practices are essential and, if
an HIV-positive hemophiliac chooses to have children, the couple should be counseled
regarding adoption or the use of sperm from a healthy donor. Even so, up to 15% of female
sexual partners of HIV-positive hemophiliacs will become infected. Once this occurs, there is
a significant risk of transmission to the newborn.
Factor XI Deficiency
The only other intrinsic pathway defect associated with a bleeding tendency is factor XI
deficiency (Rosenthal disease). It is inherited as an autosomal recessive trait and, therefore,
affects males and females equally. It is much rarer than either hemophilia A or B, affecting up
to 5% of Jews of Ashkenazi descent from Eastern Europe. Generally, the bleeding tendency,
if present at all, is quite mild and may only be apparent following a surgical procedure.
Hematomas and hemarthroses are very unusual, even in those patients with factor XI levels
of < 5%. Patients homozygous for the type II mutation (Glu117Stop) have very low levels of
factor XI and can develop a factor XI inhibitor when exposed to plasma therapy.
Laboratory Studies
A. PARTIAL THROMBOPLASTIN TIME AND PROTHROMBIN TIME
Severe hemophilia A or B patients have a prolonged PTT and whole blood clotting time. With
milder disease, the PTT may be only a few seconds longer than normal. Since the tissue
factor (TF)-VIIdependent (extrinsic) pathway of laboratory clotting is intact, the
prothrombin time (PT) is normal. Thus, a prolonged PTT together with a normal PT should
focus attention on an abnormality of the intrinsic pathway, that is, a deficiency of factor VIII,
IX, or XI.
B. TESTS FOR FACTOR DEFICIENCIES
As a part of the initial workup, it is also important to distinguish a factor deficiency from the
presence of an inhibitor. This process is routinely done by performing a 1:1 mix of patient
plasma and normal plasma to determine whether the prolonged PTT shortens. The mixing
study of a classic hemophilia A patient with a deficiency in factor VIII activity but no
circulating VIII inhibitor will usually show a shortening of the PTT to within 4 seconds or
less of the normal PTT control. In contrast, a patient with a factor VIII inhibitor will not
correct the PTT to that extent, if at all. It is also important to quantitate the factor VIII activity
level and, using a modification of the PTT called the Bethesda assay method, measure the
inhibitor titer (units of inhibitor/mL of plasma). One Bethesda unit is the amount of antibody
that inactivates 50% of factor VIII activity in normal plasma. Patients who develop
spontaneous factor VIII inhibitors can be a diagnostic challenge. It is essential that
nonspecific inhibitors of the PTT, heparin and lupus anticoagulants, be quickly excluded.
This can be accomplished in the laboratory by demonstrating correction of the PTT with
polybrene (heparin) and excess phospholipid (lupus anticoagulants).

Figure 32-2. The sex-linked inheritance pattern of hemophilia. Children of a female

hemophilia A or B carrier will have a 50/50 chance of inheriting the abnormal gene. All of the
involved male children will have clinical disease, whereas half of the female children will
most likely be asymptomatic carriers. As for the children of a male hemophiliac, all of the
girls will be carriers.
Full characterization of factor VIII or IX deficiency requires both an immunologic
measurement of the level of factor antigen (VIII:AG) and an assay of coagulant activity
(VIII:C). The measurement of the activity level as a percent of normal provides a guide to the
severity of the patient's illness. In the evaluation of the less severe hemophilia A patient, a
measurement of vWF antigen and activity is important to distinguish classic hemophilia from
von Willebrand disease (vWD) (see Chapter 31). Type 1 and Type 2N vWD patients
demonstrate factor VIII levels between 10 and 50% of normal. Type 2N vWD should be
considered whenever a female shows factor VIII levels below 50% or the pattern of
inheritance is unusual, or both.
C. TESTS TO DETECT CARRIERS OF HEMOPHILIA A OR B
Accurate detection of carriers of hemophilia A or B in a family is required for genetic
counseling and prenatal diagnosis. A detailed family history is essential. All of the female
children of a father with hemophilia will be obligate carriers. The same is true for the
mother of more than one hemophiliac son.These individuals do not need to be tested for
carrier status. On the other hand, as illustrated in Figure 32-2, sisters of a hemophilia patient
have a 50/50 chance of carrying the abnormal gene. Carrier status for hemophilia A may be
identified by measuring the ratio of factor VIII activity to vWF antigen; a 1:1 stoichiometry
normally exists between these. Because of the random (Lyonization) inactivation of the X
chromosome, female carriers may express from 1% to 100% factor VIII activity, whereas the
vWF antigen level is unaffected. Thus, a factor VIII/vWF ratio of less than 1 can identify >
90% of hemophilia A carriers. Identification of hemophlia B carriers is generally based on the
detection of abnormally low factor IX activity or by DNA analysis.
D. CLINICAL GENETIC TESTING
Clinical genetic testing is becoming more available. A DNA test for the intron 22 inversion,
which is found in 40 - 50% of severe factor VIII hemophiliacs, is now offered commercially.
This test should only be performed in patients who have factor VIII activities of less than 1%
or to detect carriers in families with severe hemophilia A. Alternative DNA screening
methods (eg, Southern blot, sequencing after PCR amplification) are required to detect
carriers in families with moderate or mild disease or intron 22-negative disease, in whom
point mutations or deletions are likely. In the occasional patient where a point mutation

cannot be identified, potential female carriers can still be identified by linkage analysis, that
is, demonstration of gene sequence differences between the subject's two X chromosomes.
The same is true for factor IX deficiency diagnosis. Direct DNA testing or linkage analysis
performed on chorionic villus biopsy material can then be used for prenatal diagnosis. This
will not, of course, identify a proband with a new mutation, which is true for up to one-third
of children born with hemophilia A or B.
THERAPY & CLINICAL COURSE
Appropriate treatment obviously depends on knowing whether the patient has hemophilia A
or B and the severity of the factor deficiency. It is also of great value to know the details of
the patient's past clinical course. This knowledge not only provides another measure of
disease severity and the response to therapy but also produces a wealth of information as to
the patient's and family's understanding of the illness and its management.

General Principles
When a hemophiliac family is identified, every attempt should be made to develop an
ongoing relationship with a regional hemophilia center, where teams of experienced nurses,
social workers, physical therapists, dentists, genetic counselors, and orthopedic surgeons
under the leadership of pediatric and adult hematologists provide a comprehensive
approach to the medical and social needs of the hemophilia patient, and family. Most
centers offer a semi annual clinic visit for the patient to meet with the comprehensive care
team and for screening for evidence of complicating viral infections such as HIV, HBV, and
HCV; for the appearance of a factor VIII or IX inhibitor; and for changes in cellular
immunity. A comprehensive center can also assist the primary care physician in the day-today management of a hemophilia patient and provide up-to-date information on available
therapeutic products.
Guidelines for Bleeding Management
The overriding principle of good management of a hemophilia bleed is rapid and effective
factor replacement. With the exception of minor lacerations, which can be controlled locally,
factor VIII or IX should be given for any episode of bleeding, regardless of location. Factor
should also be given prior to any procedure, including routine intramuscular injections, such
as a tetanus shot. The increased safety provided by purified and recombinant factor
preparations also has made long-term prophylaxis feasible. Prophylactic therapy, which in the
past was reserved for situations of anticipated bleeding, including surgery, invasive
procedures, and high-risk physical activities, is now being used to convert the phenotype of
patients with severe hemophilia to more moderate disease. Administration of recombinant
factor VIII, 20 - 40 U/kg three times weekly, or in the case of hemophilia B, 25 - 40 U/kg
twice a week will increase basal factor levels to 1% or greater, enough to prevent
spontaneous hemarthroses.
The adult hemophiliac patient is usually very sensitive to the onset of a bleed. Often there is
an aura of mild discomfort localized to the muscle or joint that becomes increasingly painful
over the next hour. This stage is followed by progressive swelling, constant severe pain, and
limitation of motion of the muscle or joint. However, the severity of the bleed can be
significantly reduced if factor treatment is begun immediately. To prevent tissue damage, any
bleed into a muscle or joint must be stopped as soon as possible. If bleeding is not stopped,
the structure of the muscle will be disrupted, resulting in severe scarring and loss of function.
Recurrent hemarthroses lead to destruction of cartilage and bone, synovial proliferation, and
with time, a loss of joint function and crippling deformity. Therefore, as soon as a bleeding
episode is suspected, the best management is self-infusion of factor. This will minimize the

extent of the bleed and will also reduce the amount of factor needed for treatment (Tables 321 and 32-2). If a hemarthrosis goes untreated for several hours or a large muscle hematoma
forms, the initial dose of factor must be increased significantly and replacement maintained
for several days or even longer, followed by extensive rehabilitation.
Table 32-1. Factor VIII replacement therapy.
Initial
Dose
(U/kg)
Maintenance (U/kg)
Hemarthrosis
10 - 20
10 - 20 q 12 h for several
days
Muscle hematoma
20 - 30
25 q 12 h for several days
Mouth bleeds
20 - 30
20 q 12 h for several days
(tongue laceration; postdental procedure)
Add antifibrinolyticsa
Major surgery/tissue damage
50
20 - 30 q 8 - 12 h or as a
(major trauma; possible intracranial bleed; potential
continuous infusion
airway obstruction; severe abdominal pain; GI
(3 - 4 U/kg/h) for 5 - 7 days
bleeding)
Dental prophylaxis
10 - 20 q 12 h for 1- 2 days
Severe hemophiliac
20
plus
Milder hemophiliac
Antifibrinolytics plus
DDAVP
a
Antifibrinolytics include either episolon caproic acid (EACA) (amicar) or tranexamic acid.
A. CENTRAL NERVOUS SYSTEM BLEEDING AFTER HEAD TRAUMA
Central nervous system bleeding following head trauma is another situation where treatment
must begin immediately. The home treatment patient should administer sufficient factor to
increase the level to 100% of normal as soon as possible after an injury to the head or face.
Hemophilia patients presenting to the emergency room with head trauma should be treated
with factor immediately, even if there are no clear signs of bleeding and certainly before
proceeding with the diagnostic workup. This strategy will prevent a fatal bleeding episode
during the time required for history, physical examination, and CT/MRI scanning.
Furthermore, no attempt should be made to perform a lumbar puncture without prior
treatment with factor. Tables 32-1 and 32-2 summarize the dosage recommendations for
replacement therapy.
B. INTERNAL BLEEDING OF THE CHEST AND ABDOMEN
Bleeding internally in the chest or abdomen can be difficult to diagnose. In the young child,
the only indication of a bleed into a large muscle group such as the iliopsoas may be vague
abdominal pain or a decrease in physical activity. To avoid severe destruction of muscle or
the development of a pseudotumor, the patient should be rapidly evaluated with diagnositic
imaging. Watchful waiting or suboptimal factor replacement is not recommended.
C. MUCOUS MEMBRANE BLEEDING
Mucous membrane bleeding can be a recurrent problem with hemophiliacs. Treatment varies
according to the site and cause. Epistaxis can be controlled by packing or cautery. However,
the clot that forms is often very friable and unstable, leading to recurrent bleeding when the
pack is removed. In this situation, factor replacement may be necessary. Any tongue or mouth
laceration in the young child must be treated immediately with appropriate factor, and

therapy will need to be continued over several days to avoid rebleeding. Uncontrolled
bleeding into the soft tissues of the mouth can result in airway obstruction if blood tracks into
the retropharyngeal area.
Table 32-2. Factor IX replacement therapy.
Initial Dose (U/kg)
Maintenance (U/kg)
Hemarthrosis
20
Repeat if needed
At onset/minor bleed
3060
20 q 24 h for several days
Fully developed
Muscle hematoma
20 q 24 h
Minor bleed
2030
30 q 24 h for 57 days
Severe bleed
3050
Major surgery/tissue damage
60100
4060 q 24 h for 57 days
Intracranial bleed
80100
6080 q 24 h for 57 days
Dental prophylaxis
1020
20 q 12 h for 12 days
D. BLEEDING AFTER A DENTAL EXTRACTION
Bleeding following a dental extraction can be prevented with prophylactic therapy, or in the
less severe hemophiliac, by pretreatment with DDAVP, an antifibrinolytic agent such as
tranexamic acid or epsilon aminocaproic acid (EACA). The latter work by stabilizing the clot
that normally forms immediately following extraction. If the original clot can be maintained
long enough to permit normal healing, high-dose factor therapy is usually unnecessary. This
strategy also can be effective for very minor surgical procedures. However, most hemophilia
patients undergoing even minor surgery should be prepared with appropriate factor therapy.
E. HEMATURIA AND GASTROINTESTINAL BLEEDING
Hematuria, either microscopic or macroscopic, occurs in nearly all moderate and severe
hemophilia patients. The course is usually self-limited and the bleeding source rarely
identified. However, gross or persistent hematuria should provoke evaluation for a renal
papillary hematoma or underlying urinary tract infection. Hematuria is best managed with
bedrest, increased fluid intake and a short course of prednisone (1 mg/kg per day for 3 days).
Factor therapy for several days may be needed in patients with gross or persistent
genitourinary bleeding. Gastrointestinal (GI) bleeding is much less common. If it occurs, the
patient should be fully evaluated for GI disease. The assumption that the bleed is the result of
stress gastritis should be avoided. Bleeding from hemorrhoids or proctitis can usually
be controlled with local measure, unless severe or protracted. Factor therapy to achieve factor
levels > 50% is indicated any time a laceration requires suturing.
F. MAJOR SURGERY IN HEMOPHILIA A PATIENTS
Whenever major surgery is necessary in a patient with hemophilia A, the factor VIII level
must be brought to near normal (100%) for the procedure. In addition, repeat doses should be
given postoperatively every 812 hours or the patient should receive a continuous infusion
dose of 34 U/kg per hour, to avoid any significant period of low factor VIII levels. Peak
and trough factor VIII levels should be measured to confirm the appropriate dosing level and
dosing interval. Therapy must be continued for up to 2 weeks to avoid postoperative bleeding
that disrupts wound healing. Longer periods of therapy may be required in patients who
undergo bone or joint surgery or who have a pseudotumor excised. In this situation, 46
weeks of replacement therapy may be needed.

G. TREATMENT OF HEMOPHILIA B
Recommended dosage schedules for the treatment of hemophilia B are summarized in Table
32-2. Guidelines for managing hemophilia B patients do not differ significantly from those
for hemophilia A patients. Recombinant/purified product or factor IX-prothrombin complex
concentrate (FIX-PCC) is used to treat mild bleeding episodes or as prophylaxis with minor
procedures. However, a note of caution is needed when using FIX-PCC preparations, which
can contain activated clotting factors, at higher doses. When given in amounts sufficient to
increase factor IX levels to 50% or greater, there is an increased risk of thromboembolic
complications, especially in patients undergoing orthopedic procedures. Therefore, it is
essential to use only recombinant IX in treating patients undergoing major orthopedic surgery
and those with severe traumatic injuries or liver disease.
Acquired Inhibitors
Management of the hemophilia A patient with an inhibitor will vary according to whether the
patient is a high or low responder. The factor VIII inhibitor should always be titered. Using a
modification of the PTT called the Bethesda assay, it is possible to measure units of inhibitor
per milliliter of plasma. Low responders have titers < 510 Bethesda U/mL and do not
show anamnestic responses to factor VIII concentrates, whereas the high responders can have
titers of several thousand Bethesda units and dramatic anamnestic responses to therapy.
Patients in the low-responder category can usually be managed with factor VIII concentrates.
Larger initial and maintenance doses of factor VIII are required and frequent assays of factor
VIII levels are essential to guide therapy. When the titer of the factor VIII inhibitor exceeds
10 U/mL (high responder category), treatment with factor VIII concentrates alone is not
feasible. Faced with this dilemma, it is best to try to manage the patient conservatively
without replacement therapy for minor bleeding episodes. Major, life-threatening bleeds can
be treated with bypass products such as activated prothrombin complex concentrate
(Autoplex T, FEIBA), or recombinant factor VIIa (NovoSeven). These therapies have
associated risks that must be taken into account. Treatment with activated PCCs runs the risk
of initiating DIC or widespread thromboembolism.
Recombinant factor VIIa may well be the treatment of choice for acquired inhibitors.
Although hemophiliacs can generate Xa via factor VIIa binding to TF-expressing monocytes
and smooth muscle cells, they are unable to generate Xa and the subsequent thrombin burst
on the platelet surface in the absence of factor VIII or IX. Recombinant factor VIIa in high
concentrations appears to essentially replace the VIIIa/IXa Xase complex requirement by
binding to the platelet surface independent of TF and increasing both Xa generation and the
thrombin burst. Although the thrombin formed via VIIa is not as strong as that seen with
factor VIII therapy, it does reduce bleeding and does not carry an increased risk of
thromboembolism. A parallel approach to inhibitor management is to induce immune
tolerance using large daily doses of factor VIII given for up to a year or more. Although this
is extremely expensive, it is actually more cost effective over the long run for the 6080%
of children with inhibitors who successfully develop tolerance.
Severe hemophilia B patients are also at risk for developing a factor IX inhibitor, but the
incidence is far less than in hemophilia A. They need to be evaluated in the same manner as
the factor VIII inhibitor patients. A modified Bethesda assay is similarly used to quantitate
the inhibitor level. Usually, factor IX inhibitor patients can be managed acutely using the
bypass products noted above. Attempts to induce immune tolerance in hemophilia B patients
have been problematic, because many of these patients can experience anaphylactic reactions
with the subsequent administration of FIX-PCC or develop nephrotic syndrome. Therefore,
they should be treated with recombinant VIIa.
Patients who develop an autoantibody to factor VIII or IX without a past history of
hemophilia can present with life-threatening hemorrhage and exhibit very high inhibitor

levels in excess of several thousand Bethesda units. Treatment with recombinant factor VIIa
or an activated prothrombin concentrate is required; factor VIII or IX alone will not be
effective. Immunosuppressive therapy is also needed to suppress autoantibody production.
Most patients will respond to prednisone (5080 mg/day) or, in the case of higher titer
inhibitors, in combination with oral cyclophosphamide (100200 mg/day). Anecdotal
reports have shown successful control of spontaneous inhibitors with anti-CD20 (rituximab),
2-chlorodeoxyadenosine, and intravenous immuniglobulin therapy. Spontaneous
improvement with a decrease in the antibody level and a recovery of factor occurs in the
majority of women with postpartum factor VIII inhibitors.
THERAPEUTIC PREPARATIONS
Major progress is being made in developing safe, effective products for treating hemophilia A
and B, especially in the development of third-generation recombinant products. It is
important, therefore, to be aware of the various products available and to check on whether a
new agent has been released. Hemophilia patients and their families follow the development
and availability of new products very closely and will want to be treated with the safest
product regardless of cost.
Hemophilia A
Products available for treating hemophilia A include DDAVP, antifibrinolytics (tranexamic
acid and EACA), fresh frozen plasma (FFP), cryoprecipitate, purified/ recombinant factor
VIII, and recombinant VIIa. For patients with a high titer spontaneous inhibitor, recombinant
VIIa is preferred.
A. DDAVP
DDAVP is an arginine vasopressin analogue that rapidly releases von Willebrand factor
(vWF) from endothelial cells. Since vWF is the carrier protein for factor VIII, DDAVP can
increase the circulating level of factor VIII by twofold to tenfold in the milder hemophiliac.
Severe hemophiliacs will not respond, so DDAVP's effectiveness must be defined for each
patient by measuring the factor VIII level 3060 minutes after administration (peak effect).
If the factor VIII level increases significantly, DDAVP can be used to manage minor bleeding
episodes or for preparing the patient for minor surgery or dental work, especially if used in
conjunction with antifibrinolytics.
An intravenous dose of 0.3 g/kg (up to 20 g) of DDAVP infused slowly over 2030
minutes is the same as recommended for the treatment of Type 1 vWD. Alternatively,
DDAVP can be given as an intranasal spray (Stimate) in doses of 150 g (one metered
dose) for individuals less than 50 kg in weight or 300 g (2 doses) for heavier patients.
Peak effect is observed 6090 minutes after administration. DDAVP treatments can then be
repeated at 12- to 24-hour intervals, although there is a significant risk of tachyphylaxis after
the first few doses. Side effects include flushing, headache, tachycardia, nausea, and
abdominal cramping. In patients who are receiving hyponatremic intravenous fluids, there is
a risk of water intoxication secondary to the antidiuretic effect of repeated injections.
B. ANTIFIBRINOLYTICS
Antifibrinolytic agents can be helpful in controlling milder bleeding episodes, especially
those associated with dental procedures. In effect, these agents enhance hemostasis by
stabilizing the clot and discouraging rebleeding. The adult dose for epsilon aminocaproic
acid, EACA (Amicar), is 5 g every 6 hours orally or the same dose by slow intravenous
infusion, whereas the dose in children is 100200 mg/kg initially, followed by 50100
mg/kg every 6 hours. The other available antifibrinolytic, tranexamic acid, is given in doses

of 1.5 g orally (oral prparation not available in the United States) or 1 g intravenously every 8
hours to adults and 10 mg/kg intravenously to children.
C. FRESH FROZEN PLASMA
FFP contains the same factor VIII and IX concentrations as normal plasma, that is, 1 unit of
VIII or IX activity per milliliter of plasma. Therefore, the normal FFP unit contains
200300 units of factors VIII and IX. When transfused, each unit of FFP can be expected to
increase a patient's factor VIII level by only 510%. Since very large volumes of FFP
would be needed to achieve factor levels better than 50% of normal, FFP has a very limited
use in an emergency situations where other factor products are not readily available.
D. CRYOPRECIPITATE
Another product that can be used in a directed-donor program of for the emergent treatment
of bleeding when purified VIII concentrates are unavailable, is cryoprecipitate.
Cryoprecipitate is prepared from FFP and contains high levels of factor VIII, vWF, and
fibrinogen. One cryoprecipitate unit prepared from a single unit of donated blood will
contain from 80150 units of factor VIII in a small volume (30-fold concentrated compared
with FFP). In a 75-kg patient who needs an initial treatment dose of 20 U/kg (total dose 1500
units), infusion of 1015 cryoprecipitate units should provide an adequate
treatment dose. A postinfusion measurement of factor VIII will help confirm the success of
the treatment.
Complications of FFP and cryoprecipitate therapy include allergic reactions,
immunosuppression, and transmission of viral infections. Allergic reactions include urticaria,
bronchospasm, and anaphylaxis. Before the development of purified and recombinant
products, most severe hemophiliacs became infected with hepatitis A, B, or C. Prior to the
introduction of HIV testing in 1985, most patients were also exposed to HIV. The
combination of HCV and HIV can result in severe hepatitis that is poorly responsive to
interferon therapy. Up to 20% of HBV-infected hemophiliacs are chronic antigen carriers.
E. PURIFIED FACTOR VIII
Purified factor VIII concentrates are easy to store and prepare for infusion, and are, therefore,
preferred by most patients. Dosing is straightforward because each product is assayed for the
concentration of factor VIII activity. Several purification processes are used to decrease the
risk of viral transmission, including pasteurization, dry heat treatment, solvent-detergent
treatment, and immunoaffinity purification using mouse monoclonal antibodies (Table 32-3).
Manufacturers test product for HIV, HCV, HBV, and, in some cases, HAV and B19
parvovirus using PCR amplification assays. To date, no assay for spongiform encephalopathy
pathogen or Creutzfeld-Jakob disease is available. Current products that have been tested for
purity include the very high purity (immunoaffinity purified) productsHemophil M,
Monarc-M, and Monoclate P, and the intermediate/high-purity productsAlphanate, Koate
DVI, and Humate-P. The latter group also contain high-molecular-weight multimers of vWF,
making them more effective for the treatment of Types 2 and 3 vWD patients. Affinitypurified VIII is capable of initiating an allergic reaction secondary to small amounts of mouse
protein in the final product.

Table 32-3. Factor VIII concentrates.

Brand Name
Preparation Method to Inactivate Viruses
Factor VIII: Ultrapure recombinant
Recombinate
Pasteurization of albumin stabilizer
Kogenate FS
Solvent detergent
Helixate FS
Solvent detergent
Refacto
None
Factor VIII: High purity from human plasma
Monoclate P
Pasteurization
Hemofil M
Solvent detergent
Monarc M
Solvent detergent
Factor VIII: Intermediate/high purity from plasma
Alphanate
Solvent-detergent, dry heat
Koate DVI
Solvent-detergent, dry heat
Humate-P
Pasteurization
F. RECOMBINANT FACTOR VIII
Recombinant factor VIII is commercially produced using mammalian cells transfected with
factor VIII complementary DNA. It appears to be biologically identical to human factor VIII
and has proved both safe and effective in clinical trials. Compared with cryoprecipitate or
purified concentrates, recombinate products (Recombinate and Kogenate) are equally
efficacious, although considerably more expensive. Despite the costs, recombinant factor VIII
is recommended for mild hemophiliacs who are HIV negative and have only the occasional
need for factor therapy. Severe adult hemophiliacs can be given either recombinant or, to
reduce the cost, purified product, recognizing that the latter may still carry a risk of
transmitting an as yet unrecognized infectious agent. First-generation recombinate products
may be contaminated with small amounts of human or animal source protein, thereby posing,
at least, a theoretical risk of transmitting a nonviral pathogen such as the prions responsible
for spongiform encephalopathy (Creutzfeld-Jakob disease). Second-generation concentrates
are manufactured without protein exposure.
An understanding of the pharmacokinetics of a factor VIII infusion is important. Dosage
recommendations in Table 32-1 are general guidelines that need to be modified according to
the character of the bleed and the patient's measured response. Replacement of factor VIII to
achieve a 100% plasma factor level will require an initial infusion of 5060 U/kg
(35004000 units in a 70-kg patient). Since the half-life of factor VIII is approximately 12
hours in adults, repeated infusions of 2530 U/kg every 12 hours will be needed to keep the
plasma factor VIII level above 50%. When lower doses (2030 U/kg) are used, mean
postinfusion plasma levels will fall between 30% and 50% (for each unit per kilogram
infused the plasma VIII level will rise ~2%). In children the half-life of factor VIII may be as
short as 6 hours, necessitating more frequent infusions and laboratory assays to confirm
efficacy.
Up to 30% of patients with severe hemophilia A exposed to factor VIII concentrate or
recombinant product will eventually develop inhibitor antibodies, some within 1012 days
of first exposure. Approximately a third or more are low-responders (< 5 Bethesda units), and
some of these will disappear spontaneously. In the management of patients with high-titer
inhibitors, it is possible to reduce inhibitor levels by inducing immune tolerance. This
strategy involves desensitizing the patient's immune system to factor VIII by administering
large, frequent doses of factor VIII product (100 U/kg twice a day) over a prolonged period.
Lower-dose regimens (2550 U/kg) given daily or every other day, have also been
successful. Immunosuppressive agents also have been used as adjuncts to high-dose therapy.

Lower-titer inhibitors generally respond within 6 months, while higher-titer antibodies may
take 1240 months to respond, if at all. Newer recombinant prreparations have not resulted
in a reduction in the incidence of inhibitor formation.
Table 32-4. Factor IX concentrates.
Preparation Method to Inactivate Viruses

Brand Name
Factor IX: recombinant
Benefix
Membrane filtration
Factor IX: purified concentration
AlphaNine SD
Solvent-detergent, nanofiltered
Mononine
Affinity purified, ultrafiltration
Factor IX: complex concentrates (factors IX, II, and X)
Proplex T
Dry heat
Profilnine SD
Solvent-detergent
Bebulin VH
Vapor heated
Factor IX: activated complex (factors IX, II, X, and activated VII)
Autoplex T
Dry heat
FEIBA VH
Vapor heated
P.378

G. PROTHROMBIN COMPLEX CONCENTRATE

Prothrombin complex concentrate (PCC) can be used to treat life-threatening bleeding in
severe hemophiliacs with high-titer inhibitors. Dosing (Autoplex or FEIBA) is on the order of
5075 U/kg every 812 hours. Because of the risk of thromboembolic complications,
PCC is relatively contraindicated in postoperative or septic patients and those with other risk
factors for thromboembolic disease. As a practical matter, most inhibitor patients are now
treated with recombinant VIIa.
H. RECOMBINANT FACTOR VIIA
At high concentrations, factor VIIa facilitates the conversion of factor X to Xa and the
generation of thrombin on the platelet surface, even when factors VIII or IX or both are
absent or a high-titer inhibitor is present. Recombinant VIIa (NovoSeven) is currently
recommended for the treatment of patients with factor VIII or IX inhibitors at a dose of
90120 mg/kg intravenously every 23 hours until hemostasis is achieved. Continuous
infusions of factor VIIa also have been used to manage patients undergoing surgery.
Laboratory monitoring will demonstrate a shortening of the activated PTT, but this does not
appear to correlate with the clinical control of hemostasis. Recombinant VIIa therapy is
successful in controlling bleeding in > 80% of inhibitor patients. The risk of serious side
effects, including widespread thrombosis or DIC, appears to be very low, although the
experience to date is still limited. Factor VII-deficient patients can be managed with a lower
dose, 2030 mg/kg, with redosing according to prothrombin time results.
Hemophilia B
Several products are also available for treating hemophilia B patients. Purified factor IX
preparations are preferable and include AlphaNine and Mononine and the recombinant
product Benefix. Benefix and Mononine have no detectable factor II or X activity, whereas
AlphaNine has minimal activity of both factor II and X. Factor IX-prothrombin complex
concentrates (FIX-PCC) including Proplex T, Profinine, and Bebulin VH, are also available
for treatment (see Table 32-4).

Like factor VIII replacement, purified factor IX concentrates or recombinant IX is used over
several days to treat bleeding in hemophilia B. Dosing recommendations are approximately
double those for factor VIII concentrates (see Table 32-2). Because of absorption to collagen
sites in the vasculature, recovery of factor IX is about half that of factor VIII. Therefore, in
order to achieve a 100% plasma level in a severe hemophiliac, a dose of 100 U/kg (7000
units in a 70-kg patient) needs to be administered. At the same time, factor IX has a half-life
of 18 - 24 hours, so repeated infusions at 50% of the original dose every 12 - 24 hours are
sufficient to keep the factor IX plasma level above 50%. Like factor VIII recommendations,
doses of 30 - 50 U/kg will generally give mean IX levels of 20 - 40%, which is adequate for
less-severe bleeds. As for factor VIII inhibitors, factor VIIa is the therapy of choice for factor
IX inhibitor patients.
Gene Therapy
Hemophilia is the ideal disease for gene therapy. Techniques are now under development to
introduce the factor VIII gene into various tissue cells using adeno-associated viral vectors.
Stable expression of even a small number of gene-transfected cells appears to convey a
significant benefit. An increase in the factor VIII or IX level of only a few percent appears to
reduce the clinical severity of the disease.
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