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   Vol. V, No. IV
   July/August 2002

  Nadine Chehab, Pharm.D.

 Return to
 Update Index


A Review of Coagulation Products
Used in the Treatment of Hemophilia


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