Vol. V, No. IV
July/August 2002
Nadine Chehab, Pharm.D.
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A Review of Coagulation Products
Used in the Treatment of Hemophilia
Introduction
Coagulation Disorders
Congenital coagulation disorders are the result of inherited deficiencies
or defects of plasma proteins involved in blood coagulation and lead to
increased risk of bleeding secondary to the inability of the body to maintain
normal hemostasis. The most common of these disorders is von Willebrand
disease (vWD), with a prevalence in the general population of one in 1,000,
followed by hemophilias A and B, with a prevalence of approximately one
in 10,000 and one in 50,000, respectively. vWD is an autosomal hemorrhagic
disorder with variable penetration caused by a deficiency or dysfunction
of von Willebrand factor, a large adhesive glycoprotein which promotes
hemostasis by facilitating platelet adhesion at sites of vascular injury
and by stabilizing coagulation factor VIII in plasma. Other inherited
defects of coagulation factors that cause bleeding disorders (e.g., afibrinogenemia,
hypoprothrombinemia, and deficiencies of factors V, VII, X, XI, and XIII)
are generally more rare. This article will focus specifically on the management
of hemophilias A and B.
Hemophilias A and B
Hemophilia is a sex-linked hereditary coagulation disorder, carried in
females and expressed in males, resulting from a deficiency in either
factor VIII (hemophilia A) or factor IX (hemophilia B). A deficiency in
either factor VIII (FVIII) or IX (FIX) can lead to ineffective hemostasis
by inadequate thrombin generation through the intrinsic pathway of the
coagulation cascade. Hemophilias A and B are clinically indistinguishable
and can be classified according to plasma factor levels: mild (6 to 30%),
moderate (1 to 5%), and severe (< 1%). Management of hemophilia consists
of intravenous administration of coagulation factor to: 1) control bleeding
episodes, 2) provide hemostasis during surgery, 3) provide long-term prophylaxis
of bleeding, or 4) induce immune tolerance in those with alloantibodies
against a congenitally deficient factor. The treatment approach for hemophilia
is based on various considerations including the severity of the disease,
the site and severity of bleeding, the presence or absence of factor antibodies,
the patient's previous treatment history, as well as, issues relating
to product purity and cost. The goals of this article are to review the
various coagulation products that are available for the treatment of hemophilia,
as well as, the dosing strategies and potential complications of factor
replacement therapy.
Factor Replacement: Products and Indications
Factor VIII (FVIII) Products
Commercially available FVIII products, also known as antihemophilic factor
(AHF) concentrates, are used in patients with hemophilia A to manage an
acute hemorrhage or to decrease bleeding during surgery. The currently
available AHF products available in the United States are listed in Table 1.
Factor IX (FIX) Products
FIX products may be used to manage an acute hemorrhage or to decrease
the risk of bleeding associated with surgery in patients with hemophilia
B. Low-purity FIX products, also known as prothrombin complex concentrates
(PCCs), contain significant amounts of activated factors VII, X, and prothrombin,
and thus have the potential to cause disseminated intravascular coagulation
(DIC), or paradoxically, thrombosis, especially when they are administered
at frequent or prolonged intervals. Both complications are potentially
life-threatening. The use of PCCs has been largely abandoned for the high-purity
FIX products that have very little thrombogenic potential
and that undergo more rigorous virucidal methods. Recombinant FIX (BeneFix®),
which is not derived from human plasma, poses a theoretical advantage
over plasma-derived concentrates, but plasma levels of factor per unit
may be lower than for plasma-derived products. The FIX products currently
available in the United States are listed in Table 2.
Choice of FVIII or FIX Product: High or low-purity; recombinant or plasma-derived?
Replacement products are made from either plasma-derived or recombinant
proteins. Plasma-derived concentrates are classified as very high, high,
or intermediate in purity. All plasma-derived products have similar hemostatic
efficacy and undergo at least one viral attenuation step during the purification
process. There is, however, a wide variability among concentrates with
respect to final product purity, as reflected by units of specific activity
(SA)/mg of protein. Product "purity" refers to the degree to
which non-factor proteins are eliminated from the final product, and is
unrelated to the degree of product contamination. Heat treatment or solvent-and-detergent
methods are utilized to produce intermediate-purity concentrates. Although
factors treated with solvents and detergents have a higher risk of potentially
being infected with non-enveloped viruses such as parvovirus and hepatitis
A, patients requiring replacement therapy can still safely receive these
products. They are associated with a lower cost than their high-purity
counterparts. Very high-purity concentrates are produced by using affinity
chromatography or monoclonal antibody techniques. They contain 2000 to
4000 units of factor activity per milligram of protein. Recombinant concentrates
are produced from hamster ovarian or renal cells by using complementary
DNA from the genes that code for the various factors. The process allows
manufacturers to produce concentrated coagulation products that can eliminate
the risk of viruses to recipients. Recombinant concentrates contain approximately
5000 units of factor activity per milligram of protein. To date, no difference
in the risk of viral transmission between monoclonal purified factors
and recombinant products has been demonstrated. Guidelines for choosing
from the various concentrates available are provided in Table 3.
Inhibitor Development and Therapy: One of the most problematic complications of hemophilia
treatment is the development of inhibitors (alloantibodies or auto-antibodies)
to FVIII or FIX. These are typically IgG antibodies that neutralize the
coagulant effects of replacement therapy. By inducing a partial or complete
refractoriness to conventional replacement therapy, the presence of these
inhibitors greatly increases the risk of life-threatening bleeds. Inhibitors
to FVIII or FIX occur in approximately 20 to 30% of severe hemophilia
A patients and 1.5 to 3% of severe hemophilia B patients. Although it
is known that both genetic and immunologic factors may have a role in
the development of inhibitors, the pathophysiology of antibody development
has not been completely elucidated. There is some evidence suggesting
that high purity concentrates produce a higher incidence of alloantibody
inhibitor formation than their low-purity counterparts.
Patients without hemophilia
may also develop auto-antibodies to FVIII or FIX, although the incidence
of these autoantibodies is not known. Inhibitors may be associated with
autoimmune disease, malignancy, or pregnancy. In 50% of spontaneous inhibitor
cases, the patient is elderly. Unlike the alloantibodies that develop
in congenital hemophilic patients, autoantibodies do not completely inactivate
FVIII activity, therefore, these patients appear to have some measurable
FVIII activity.
The presence of an inhibitor is confirmed by the Bethesda inhibitor assay, a clot-based assay
that titers the amount of neutralizing antibody present in plasma on the
basis of its ability to inhibit factor coagulant activity in vitro. This
measurement is reported in the Bethesda Unit (BU), with higher Bethesda
titers reflecting greater amounts of inhibiting antibody. FVIII and FIX
inhibitors are classified as "high titer" or "high responder"
and "low titer" or "low responder". The former is
defined by levels of > 10 BU or the development of an anamnestic response
(i.e., a rapid secondary increase in immunity) following any exposure
to the clotting factor protein antigen, while the latter usually has <
5 BU and manifests no anamnestic response. The treatment of alloantibody
inhibitors is predicated primarily on their titer. The treatment of patients
with low titer inhibitors consists of the administration of large enough
doses of human FVIII or FIX concentrates to saturate the inhibitor and
to provide adequate clotting factor activity levels. For the individual
with high-titer FVIII and FIX inhibitors, several treatment options are
available. These include FIX complex concentrates, porcine-derived AHF
concentrates, recombinant factor VIIa, and immune tolerance induction
protocols.
Factor IX Complex Concentrates ("Bypass Therapy")
The principle underlying the use of FIX concentrates in the treatment
of patients with inhibitors is that the defect in intrinsic coagulation,
not manageable with specific replacement therapy due the presence of inhibitors,
can be circumvented by activated forms of factors VII, IX, and X contained
in FIX complex concentrates. These concentrates are either those used
in the routine treatment of FIX deficiency or those purposely manufactured
to contain these activated factors in controlled amounts.
These products are effective in 48% to 64% of bleeding episodes, and are considered first-line
therapy for uncomplicated bleeding events. Their use is limited by the
potential for inducing thrombotic complications and the inability to predict
hemostatic response on the basis of laboratory testing (e.g., prothrombin
time, activated PTT, coagulation factor assays) due to the presence of
factors that artificially shorten in vitro clotting assays in a manner
that does not correlate to clinical hemostasis.
Porcine-derived AHF Concentrate [AHF(P)]
Alloantibody inhibitors manifest varying degrees of species specificity,
typically cross-reacting with porcine plasma-derived FVIII with less avidity
than with human factor VIII. Thus, AHF(P) can be used for therapy for
high titer inhibitors in which human FVIII produces no discernable increase
of activity. Assays for cross-reactivity to human factor VIII should be
performed prior to use to rule out high anti-porcine factor titer, which
will negate the effect of AHF(P). Levels of human AHF inhibitors of >50
BU or porcine FVIII inhibitors of >15 BU predict a poor response to
AHF(P). Typically, FVIII activity response to AHF(P) improves with repeated
dosing, suggesting in-vitro saturation of the circulating inhibitor by
the AHF(P). Unlike FIX complex concentrates, AHF(P) permits measurement
of FVIII activity in vitro to predict the clinical response in vivo. This
treatment is efficacious in about 80% of patients, and is considered as
a first-line agent for elective surgery, unless contraindicated by inhibitor
cross-reactivity against porcine FVIII. However, its limited availability,
high price, and ability to produce anamnestic responses in 35% of patients
limits the utility of porcine FVIII. Currently, the only available AHF(P)
in the United States is Hyate-C® (Speywood) and costs approximately
$6,405 per dose (based on the dose required to achieve an AHF level 100%
of normal for a 70-kg patient).
Recombinant Factor VIIa (rFVIIa)
rFVIIa (NovoSeven®) is an additional option for treating
hemorrhages in patients with FVIII and FIX inhibitors. It is a vitamin-K
dependant glycoprotein consisting of 406 amino acid residues and is structurally
similar to human plasma-derived factor VIIa (FVIIa). This product received
FDA-approval in 1999, and has been reported to be clinically effective
and safe in hemophiliacs with inhibitors, as well as, in acquired hemophiliacs.
rFVIIa induces hemostasis by activating the intrinsic pathway of the coagulation
cascade which is normally initiated by the formation of a complex between
exposed tissue factor (TF) and FVIIa available in the circulating blood.
The administration of exogenous rFVIIa induces thrombin generation both
by ensuring that all TF sites at the site of injury are saturated with
FVIIa and by generating thrombin on the activated platelet surface. Overall,
rFVIIa has some potential advantages over FIX complex concentrates, such
as higher viral safety and the absence of the severe anaphylactic reactions
that may occur in patients treated with FIX complex concentrates.
In addition, the risk
of thromboembolic side effects is theoretically reduced because rFVIIa
promotes coagulant activity only after forming a complex with TF. This
product has provided adequate hemostasis in very high-titer inhibitor
patients who otherwise would not be candidates for surgical procedures
due to previous failures with other bypassing agents. Disadvantages of
rFVIIa are its high cost and the need for repeated administration due
a short half-life (3 to 4 hours). However, repeated administration may
be avoided by administering rFVIIa as a continuous infusion.
Immune Tolerance Induction Protocols
Immune tolerance protocols refer to daily administration of factor concentrates
until the alloantibody inhibitors disappear. The goal of treatment is
to suppress the production of FVIII inhibitors by building tolerance in
patients through repeated exposure to the antigen. It may be advantageous
in the treatment of inhibitors because it can lead to permanent neutralization
of the antibody, and thus, permit future treatment with the usual factors.
Immune tolerance protocols tend to be completely successful in up to 68%
of patients and partially successful in another 8%. Complete elimination
is defined as a final inhibitor titer of < 0.6 BU, > 60% of predicted
recovery of the infused factor within 30 minutes of administration, and
a normal half-life of infused FVIII or FIX. The best predictor of success
is a 50% reduction in the titer within 6 months and total disappearance
of the inhibitor within 12 to 18 months. The probability of success is
greatest for those receiving high-dose protocols (>100 U/kg/d), those
whose protocol was initiated early in the course of inhibitor development,
and those with the lowest initial titers. Immune tolerance protocols are
expensive, and are reserved for patients who require a major surgical
procedure and are highly compliant.
Dosing and Monitoring:
Dosing regimens for factor replacement therapy are based on: 1) the volume
of the clotting factor's distribution within the intravascular or extravascular
compartments, which affects in vivo factor recovery in plasma following
an infusion, 2) the factor's half-life in plasma, and 3) the minimal hemostatic
factor level required to control the particular type and extent of hemorrhage.
Clotting factor is dosed in "units" of activity, with 1 unit
of factor representing the amount present in 1 mL of normal plasma. In
vivo recovery is the ratio of the observed peak factor concentration to
the predicted peak factor concentration and can vary depending on the
patient's plasma volume and dose of factor. Treatment of hemophilia should
be done by or in consult with a hematologist. The following equations
are only guidelines.
Human AHF Concentrates
Dosing of AHF concentrates is based on the assumption that AHF is primarily
distributed into the intravascular space (i.e., plasma volume is used
to estimate the volume of distribution of AHF). Patients should receive
both a loading and maintenance dose to achieve and maintain hemostatic
serum AHF levels. The following equation can be used to determine the
loading dose needed to achieve target serum level:
Dose (units) =
[(AHFdesired - AHFbaseline) x total body weight
(kg)]/2
Where AHFdesired is
the desired AHF concentration as a percentage of normal (e.g., 100%) and
AHFbaseline is the patient's baseline serum AHF level (e.g.,
0%). The equation assumes that 1 unit of factor VIII raises the serum
AHF level by 2% (2 U/dL). Assuming an average half-life
of 12 hours, an initial maintenance dose equal to 50% of the initial dose
should be administered every 12 hours to ensure that the patients maintain
the minimum hemostatic level throughout the dosage interval. The recommended
minimum hemostatic levels and AHF desired for each type of hemorrhage
are described in Table 4.
Porcine-derived AHF Concentrate [AHF(P)]
AHF(P) is dosed based on levels of human or porcine AHF inhibitors. Patients
with human AHF inhibitor levels of <5 BU should receive 20 to 50 units
of AHF(P) per kg for an acute hemorrhage. The recommended dose for 5 to
50 BU is 50 to 100 units/kg. Patients with inhibitor levels of > 50
BU are not likely to respond to AHF(P) and should receive other treatments.
Other approaches to dosing AHF(P) are predicated on the basis of AHF inhibitor
levels and plasma volumes.
Factor IX Concentrates
The in vivo recovery measured for factor IX should be lower than the recovery
of AHF because factor IX appears to be distributed into both the intravascular
and extravascular spaces. The increase in serum factor IX levels after
a dose ranges from 0.67 to 1.28 U/dL for each unit of factor IX administered
per kg of body weight. Most clinicians assume a mean in vivo recovery
equal to 1% (or 1 U/dL) for each unit of factor IX administered per kilogram
of body weight. The half-life of FIX ranges from 11 to 27 hours. To achieve
and maintain hemostatic serum levels, patients should receive a loading
dose followed by maintenance dose. The following equation can be used
to determine the loading dose of factor IX concentrates needed to manage
an acute hemorrhage:
Dose (units) =
(FIXdesired - FIXbaseline) x total body weight (kg)
Where FIXdesired
is the desired FIX concentration as a percentage of normal (e.g., 100%)
and FIXbaseline is the patient's baseline serum
FIX level (e.g., 0%). Assuming an average half-life of 24 hours, an initial
maintenance dose equal to 50% of the initial dose should be administered
every 24 hours to ensure that patients maintain the minimum hemostatic
level throughout the dosage interval. The recommended minimum hemostatic
levels and AHF desired for each type of hemorrhage are shown in Table 4. The long half-life probably precludes the need for a continuous
intravenous infusion, but patients requiring prolonged treatment for life-
threatening bleeding or surgery may benefit from a continuous intravenous
infusion.
Recombinant Factor VIIa (rFVIIa)
The recommended dose of rFVIIa for hemophilia A or B patients with inhibitors
is 90 mcg/kg given every 2 hours until hemostasis is achieved, or until
the treatment has been judged to be inadequate. Some authors recommend
administering rFVIIa according to the severity of the hemorrhage, whereas
the manufacturer recommends one dose for all hemorrhages. Basing doses
on severity of the hemorrhage stems from several compassionate use trials
in which patients with inhibitors and hemophilia were successfully treated
with doses ranging from 35 to 120 mcg/kg. In these trials, a majority
of patients showed an excellent or effective response to rFVIIa for surgical
prophylaxis and management for moderate to severe hemorrhages. Preliminary
evidence suggests that hemostasis occurs when FVII concentrations reaches
8 units/mL. Continuous infusion is also an alternative option for rFVIIa.
The feasibility of using rFVIIa in this way has been demonstrated, but
formal pharmacokinetic studies are lacking. Dosing recommendations should
become better defined as clinical experience with rFVIIa accumulates.
Intermittent versus Continuous Infusion
If a patient requires prolonged treatment, a continuous IV infusion rather
than intermittent IV bolus administration may be used to manage an acute
hemorrhage. Intermittent bolus infusions of factor concentrates have been
used successfully for many years. However, pharmacokinetics may vary between
product and patients, and the wide fluctuations in factor levels during
therapy can make management difficult at times. Continuous infusion protocols
have been developed, which reduce factor utilization, facilitate laboratory
monitoring of factor levels (i.e., since lab values reflect a steady state
rather than a peak or a trough), and may decrease the overall cost of
therapy. Using a continuous IV infusion may avoid potentially dangerous
trough concentrations and can sustain therapeutic serum levels and allow
the use of lower dosages to maintain minimum hemostatic serum levels.
Lower total doses are required for patients receiving continuous infusions
because the hemostatic level can be achieved and maintained throughout
the infusion period. Patients receiving multiple intermittent IV bolus
doses require high peak serum AHF levels to ensure that they maintain
the minimum hemostatic serum levels until the end of the dosage interval.
This approach has been associated with excellent hemostasis and safety
and has been used with factor VIII, factor IX, porcine factor VIII, rFVIIa,
and activated prothrombin complex concentrates for therapy in patients
with inhibitors. Some studies note a 30% to 75% decrease in the use of
concentrate with continuous infusions administered in the surgical setting,
and also report a progressive decrease in the plasma clearance of coagulation
factors. A typical continuous infusion protocol begins with a bolus designed
to achieve 100% of normal levels followed by an infusion of 2 U/kg/hr.
The results of FVIII or IX levels obtained thereafter are used to guide
changes in the infusion regimen. Typically, if the measured factor level
is low, the infusion rate can be increased or a small bolus given to bring
the levels up to the desired value. Although the loss of product potency
with time and an increased risk of infection are potential disadvantages
of continuous infusion protocols, it appears that most high-purity concentrates
maintain more than 80% of initial activity after 3 to 7 days without evidence
of infectious complications.
Complications of Factor Replacement Therapy
Blood-borne pathogens
Plasma-derived concentrates used to treat hemophilia carry a low risk
of transmitting blood-borne infectious agents, as pooled plasma used in
manufacturing coagulation concentrates are now screened for HBV, HCV,
and HIV. However, patients treated with coagulation products may still
acquire hepatitis viruses, HIV or other viruses due to the lack of 100%
sensitivity of these assays and the inability to identify infected donors
who do not yet have an antibody response.
Non-infectious complications
Aside from infectious complications, clotting factor concentrates produce
few clinically significant adverse reactions. Transfusion-associated anaphylaxis
is rarely observed. However, there are recent reports of anaphylaxis to
FIX concentrates in individuals with severe hemophilia B in close association
with the development of FIX inhibitors. Any plasma-derived or recombinant
FIX concentrate is capable of producing such a complication and treatment
of bleeding events with rFVIIa is the only effective alternative. Transfusion
reactions (e.g., chills, fever, and rashes) have also been reported with
porcine FVIII. Treatment or prophylaxis with hydrocortisone, antihistamines,
and acetaminophen can alleviate these reactions. Porcine FVIII has also
been associated with thrombocytopenia, which may be caused by vWF-induced
platelet aggregation. If the platelet count declines to less than 20,000/uL,
porcine FVIII should be discontinued to reduce the risk of bleeding.
Thrombotic complications
Thrombotic complications have been reported with the use of low-purity
FIX complex concentrates when they are infused repeatedly in large amounts,
but not with FVIII concentrates. DIC, deep vein thrombosis (DVT), pulmonary
embolism (PE), and fatal or life-threatening acute myocardial infarction
(MI) have been reported. The high-purity plasma-derived recombinant FIX
preparations have virtually eliminated this thrombogenicity.
Summary: There are various coagulation products available for the treatment of bleeding
in hemophilia A and B, including plasma-derived and recombinant products.
The choice of product for the treatment of bleeding depends on the presence
or absence of factor antibodies, the patient's previous treatment history,
as well as, product purity and cost. The dosing regimens for factor replacement
therapy are primarily based on the various pharmacokinetic parameters
of the particular factor, the minimal hemostatic factor level required
to control the particular type, and the severity of hemorrhage being treated.
Although factor products are typically administered as intermittent bolus
infusions, continuous infusion protocols have been developed, and have
been associated with a reduction in factor utilization, laboratory monitoring
of factor levels, and cost of therapy.
The article's author and CCF Department of Pharmacy Drug Information Center would like to thank Dr. Steven Deicher for his input and review of the article.
References available upon request
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