Factor VIII Medication

  • Author: Robert A Schwartz, MD, MPH; Chief Editor: Emmanuel C Besa, MD   more...
 
Updated: Feb 27, 2012
 

Medication Summary

Prompt and early therapy for acute bleeding episodes, with appropriate replacement with factor concentrate to achieve adequate levels of factor VIII (FVIII), immobilization of acutely affected joints, and adequate pain relief with narcotic analgesics is essential. A variety of intermediate and high-purity factor VIII-containing products are commercially available.

Increasing blood product purity (high specific activity) and improved protection from viral contaminants result in increased costs because of the different methodologies that are used to purify factor VIII that is obtained from pooled human plasma and because of the screening procedures in place for blood donors. Careful screening of potential donors and viral testing of donated blood (eg, hepatitis B surface antigen [HBsAg]; antibody to hepatitis B core antigen [HBcAg]; antibody to hepatitis C virus; antibodies to HIV-1 and HIV-2; HIV p24 antigen; antibodies to human T–cell lymphotrophic virus [HTLV] types I and II; screening for elevated alanine aminotransferase [ALT]) have improved the safety of blood products.

Nucleic acid testing for hepatitis B virus, hepatitis C virus, and HIV have also been implemented, which further improves safety; however, risks remain for a variety of reasons, including the failure to detect infections during the window or incubation period before currently available test results can be interpreted (ie, if they are positive). Additionally, blood banks have a system to notify recipients of blood products if donors of those units subsequently develop certain viral illnesses.

Unknown agents are of continuing concern, as are emerging viruses and infections caused by agents for which blood products are not tested or for which tests are not available.

Some of the emerging pathogens previously referred to include HIV-2, HIV type O, hepatitis G, TT virus, human herpesvirus 8, SEN family of viruses (SEN D and H are transmitted parenterally and can cause hepatitis), and prions that cause Creutzfeldt-Jacob disease (CJD) and variant CJD (vCJD).[54, 86, 87] Higher risks of virally transmitted illnesses remain among patients who receive multiple units of factor VIII concentrates of lower purity.

Factor VIII concentrates are produced by the purification of factor VIII from pooled human plasma and are contaminated with fibrinogen, fibronectin, and other plasma proteins. Viral safety in plasma-derived products has been ensured through several techniques such as heating, pasteurization, solvent-detergent treatment, and monoclonal antibody purification; these procedures free replacement products from HIV and hepatitis C virus (lipid envelope).

Unfortunately, earlier methods that were less effective led to the wide prevalence of hepatitis and AIDS in persons with hemophilia who were previously treated with the less pure blood products. However, this does not solve the problem of transmission of nonlipid envelope viruses, such as hepatitis A and parvovirus B19.

Highly pure recombinant products should be used to treat previously untreated patients first, then patients still free of HIV and hepatitis, and, finally, patients who are hepatitis-positive but HIV-free. A negative impact on lymphocyte immune response has been found after the use of both intermediate-purity and recombinant products, but highly pure products clearly do not prevent progression or improve median survival time of HIV-positive patients with hemophilia.

First-generation recombinant products are produced in mammalian cell lines and have a small amount of human serum albumin added for stability. Contamination of first-generation recombinant products with TT virus due to the use of human serum albumin has been reported.[54] Second-generation recombinant products that do not use human albumin have been found to be free of the TT virus. A sucrose-formulated rFVIII (rFVIII-SF) was shown to be hemostatically effective in 22 surgical procedures in patients with severe hemophilia, thus substantiating its efficacy.[88] This product does not use human plasma albumin as a stabilizer, thereby minimizing the possible risks of human plasma albumin–transmitted infections.

In addition, concern exists about the transmission of transmissible spongiform encephalopathies and vCJD due to prions. With the newer blood products, previously unknown pathogens, including new murine viruses, may contaminate the product.

Newer emerging technologies, such as those using nucleic acid chemistry, are being used to inactivate viruses, bacteria, and parasites in an attempt to also remove prions, thus making blood and blood components safer than they are at present. These newer technologies attempt to preserve clinically useful components of blood while improving their safety. These methodologies could potentially be used to improve the safety of a wide variety of blood products.

Available replacement products to correct factor VIII deficiency are discussed below; the table offers general guidelines for therapy. One unit of factor VIII has 100% activity and is present in 1 mL of (adult male) plasma. One unit of factor VIII per kilogram of body weight raises the plasma factor VIII level by approximately 2%. Another way to estimate the initial dose is to calculate the plasma volume, which is, for example, 70 kg X 50 = 3500 total mL plasma volume.

In order to raise the factor VIII activity of the patient in this example from 0% to 100%, the 70-kg patient needs 3500 units of factor VIII to be given as a bolus. This assumption presupposes that all the infused factor VIII will be recovered, which is not the case. With recombinant products, up to 30% less factor VIII recovery is expected, emphasizing the variability in recovery, depending on the type of product used and the individual. Therefore, serial monitoring of factor VIII levels, particularly trough levels, is essential in order to confirm adequacy of dosing at all times.

With bolus dosing, administer the second dose of replacement product 8 hours after the first, followed by a regimen of every 12 hours. The level of factor VIII needed for hemostasis varies from 30-100%, depending on the nature of the bleeding. Examples of major bleeding include CNS, retroperitoneal, retropharyngeal, GI, and, sometimes, recurrent target joint bleeding, all of which may also require prolonged factor replacement for days to weeks.

Because of the disadvantages of bolus dosing (ie, peaks and troughs) and the potential for cost and product savings with continuous infusion regimens that would give better steady-state levels, more studies are turning to this dosing approach.

In a study of known patients with factor VIII (14 patients) or with factor IX (3 patients) deficiency undergoing major surgery, patients were treated first with a bolus dose of 50 U/kg and then with 100 U/kg.[89] At the end of surgery, a continuous infusion of factor VIII was started at 3 U/kg/h, but for patients needing therapy for longer than 10 days, the dose was reduced to 1.5 U/kg/h for the remainder of the postoperative period.[89]

Concentrates were reconstituted twice daily using a 50-mL syringe pump. All patients were also treated with AMCA at a dose of 40 mg/kg to reduce or prevent hemorrhage. Factor VIII-C levels were monitored every 4 hours the first day, then at least every 12 hours for the next 5 days. This method was found safe and effective and is being suggested as a first-line therapy in patients with hemophilia who are undergoing surgical procedures.[89]

Spontaneous disappearance is a feature of autoantibodies to factor VIII that presumably occurs when the antigenic stimulus subsides, as in most patients with postpartum inhibitors. The choice of blood product to treat severe bleeding episodes in patients with factor VIII inhibitors depends on their baseline titer.[68, 90, 91, 92]

Factor VIII concentrate may be used to overcome a low-titer inhibitor (< 5 BU), but failure of that method or the presence of a high-titer inhibitor is approached with the use of any one of the following products based on availability (cost) and experience: rFVIIa (NovoSeven; Novo Nordisk A/S, Bagsvaerd, Denmark), or anti-inhibitor coagulant complex (activated prothrombin-complex concentrates) (Feiba VH; Baxter Healthcare Corporation, Westlake Village, Calif).

The activated prothrombin-complex concentrates have a poorly defined mode of action, an unpredictable hemostatic response, and are derived from pooled plasma. Therefore, they have a greater risk of transmitting viral illnesses, require frequent administration, are associated with a greater failure rate, and induce an anamnestic rise in antibody titers.

The replacement products cannot be used in patients who have had an allergic response, they induce a predictable DIC, and they can be associated with arteriovenous thrombosis, including myocardial infarctions. With very high-titer inhibitors, ancillary modalities, such as plasma exchange, Sepharose A, or immunoglobulin column to adsorb the antibody, and intravenous IgG can all be used to emergently remove the antibody and reduce its titer. The long-term strategy uses immunosuppressive drugs to suppress antibody production.

ITI regimens use daily factor VIII doses, varying from a low of 25 U/kg/d to a high of 100 U/kg twice a day, until the inhibitor titer is 1 BU/d, then 150 U/kg/d until the inhibitor disappears. ITI is time and product intensive, is expensive, requires a high degree of compliance, and requires daily venous access with catheters, which may become infected, thrombose, or be associated with bleeding.

Acute bleeding during the ITI regimen requires the use of additional replacement products, as mentioned above. A steroid-resistant nephrotic syndrome can develop in ITI patients because of protein overload; this condition requires prompt withdrawal of the product to prevent repeated antigen exposure. An intriguing idea has been raised as to whether immune tolerance could be induced via breast milk.[93]

A study in 100 children (25 previously untreated patients) from Egypt who were treated with low-purity replacement products (cryoprecipitate or low-purity FVIII) showed a low (10%) prevalence of inhibitors, with 20% of these inhibitors being transient (all < 5 BU/mL).[94] These authors ascribed the lower frequency of inhibitors in these patients to the use of low-purity products. In this study, low-dose ITI with a dose of 25 units of FVIII/kg on alternate days was given to patients with inhibitor titers below 40 BU/mL, with a higher dosage of 50 U/kg on alternate days given to patients with inhibitor titers above 40 BU/mL. Low-dose ITI appeared to be effective only in those patients with titers below 40 BU/mL.

Although porcine factor VIII (Hyate:C) production was discontinued in 2004, Hyate:C was used successfully for many years to treat many patients with life-threatening bleeding due to inhibitors. It was the first product that came to the patient's rescue after the activated prothrombin-complex concentrates.

In a study that attempted to evaluate the presence of porcine endogenous retrovirus, both gag and pol porcine endogenous retrovirus mRNA were detected in 100% of Hyate:C lots tested, and approximately 77% of lots of Hyate:C were also positive for retroviral particles, but none of the plasma samples obtained from 88 recipients of Hyate:C had positive test results, showing that despite the presence of porcine endogenous retrovirus particles in the product, the risk of transmission of this virus to recipients was very low.[95]

Another study reported the absence of antibodies to porcine parvovirus in the plasma of Hyate:C recipients, although porcine parvovirus DNA was detected in 21 of 22 lots of Hyate:C tested.[96] Despite lack of evidence for transmission of this virus to humans, the manufacturers added the process of screening all porcine plasmas by polymerase chain reaction (PCR) before use in producing Hyate:C, a move designed to eliminate the possible risk of transmission of this virus to humans. Hyate:C was used at home for ITI therapy.

Recombinant factor VIIa (rFVIIa) is another useful product in the armamentarium available to treat patients with factor VIII inhibitors. This product represents another significant development in the therapy of inhibitor patients, allowing them to undergo previously impossible major surgical procedures, such as joint replacements and pseudocyst resections.

Because of its high cost, rFVIIa was used previously in patients with hemophilia in which other therapy had failed, but as experience with its use grows, more patients are being treated with rFVIIa. The starting dose varies from 30-90 mcg/kg intravenously, with careful monitoring for a decompensated DIC and repeat dosing every 2-3 hours. Based on data obtained in several trials, excellent or effective response of bleeding in inhibitor patients was usually observed within 12 hours of starting therapy.[97, 98, 99, 100, 101, 102]

Results of data obtained from experience with compassionate use showed that effective hemostasis was obtained in approximately 92% of bleeding episodes in inhibitor patients after 1-3 doses of rFVII 90 mcg/kg, suggesting the utility of the higher dose in inhibitor patients. In some instances, an even higher dose of up to 120 mcg/kg has been needed, at the physician's discretion, to stop abdominal bleeding in patients with factor VIII deficiency or with factor VIII antibodies; in these patients, the mean duration of drug dosing in patients with a deficiency was 7.2 days, and it was longer, 11.3 days, in patients with an inhibitor and abdominal bleeding. Generally, one additional dose of rFVIIa is given beyond the time when adequate hemostasis has been achieved.

An intriguing finding was that over a 6-month period of therapy, a decline to one third the original titer of factor VIII or factor IX inhibitors was noted in high-responder inhibitor patients who received rFVIIa at home for repeated bleeding. Continuous infusion of rFVIIa in high-titer inhibitor patients undergoing hip replacement has been hemostatically successful. Because factor VIIa in concert with tissue factor, phospholipids, and calcium activates factor X to generate thrombin, fibrinogen levels were monitored in a prospective, randomized, double-blind trial and found to be similar to baseline values, with very few patients showing a reduction in fibrinogen levels.

Additionally, follow-up samples obtained in patients who had received several doses of rFVIIa showed no antibody levels to rFVIIa above the cut-off value, and no new antibodies were found to baby hamster kidney cell proteins or murine IgG. Despite all this experience, the optimal dosage regimen for all clinical situations in inhibitor patients still requires further study. In addition, rFVIIa has been used in patients with factor VIII or factor IX deficiencies in the absence of inhibitors, but according to the authors of a randomized, double-blind trial, rFVIIa is not the optimal drug for use in these patients, particularly because rFVIII or rFIX is available for use in these patients.[17, 103]

Interferon alpha therapy has been used in patients with chronic active hepatitis C, but the long-term benefits of such therapy remain in question. AIDS was the primary cause of death in persons with hemophilia from the mid 1970s to the early 1990s. Therapy for persons positive for HIV consists of the use of multidrug "cocktails," including protease inhibitors, which increase the risk of bleeding. A telephone support group for the patient and family has been suggested.[104]

A reasonable dosage calculation guide for factor VIII is provided by the following formula:

FVIII dose (U) = body weight (kg) X desired FVIII increase (%) X 0.5 U/kg

In practice, administration of concentrates must be individualized based on (1) an evaluation of the extent, site, and cause of bleeding; (2) response to therapy; (3) current laboratory data; and (4) the patient's history.

Table. General Guidelines for Management With FVIII Concentrates for Intermittent Bolus Dosing (Open Table in a new window)

Type of Hemorrhage Desired



FVIII-C Activity



Dose and Duration of Therapy
Minor



Uncomplicated



hemarthroses



Superficial large



hematomas



20-30%10-15 U/kg IV q12-24h for 1-2 d
Moderate



Hematoma with dissection



Oral/mucosal hemorrhages and epistaxis*



Hematuria



25-50%15-25 U/kg IV q12-24h for 3-7 d



(shorter time for oral hemorrhages; higher dose for hematuria)



Dental extraction(s)†50-100%25-50 U/kg IV q12h for 2-5 d
Major



Pharyngeal/retropharyngeal



Retroperitoneal



GI bleeding



CNS bleeding surgery



~50-100% until bleeding is controlled; then, gradually decrease the dosage to the minimum that is required to prevent rebleeding25-50 U/kg IV q12h for 5-10 d
*Concomitant administration of EACA or AMCA (both inhibitors of fibrinolysis) can help reduce the dose of concentrate that is required to treat such bleeding. Approximately 50% of the initial dose is given as the second dose approximately 8 hours after the first; all subsequent doses are given every 12 hours.



†For dental extractions, a single preoperative dose of factor VIII of 15 U/kg and oral or intravenous Amicar at 5 g is given, followed by an Amicar maintenance dose of 1 g/h, as discussed below, for 5-7 days, with a gradual taper.



Continuous infusion of factor VIII can be used for treating patients after joint replacements or CNS bleeding, in which a continuous, steady level is desired. This can be achieved by an initial bolus dose, as discussed, followed by a maintenance infusion of 150 U/h, with monitoring of levels for adequacy.

DDAVP in a dose of 0.3 mcg/kg intravenously can be given for several doses every 12 hours to raise perioperative factor VIII levels in patients with mild hemophilia for minor procedures, such as dental extractions and even uncomplicated cholecystectomies. Previous proof of adequate response to DDAVP is ideal for elective procedures. Tachyphylaxis will develop. DDAVP may be combined with Amicar to inhibit fibrinolysis.

The duration of therapy varies depending on the site, size, and severity of the bleeding episode. In orthopedic procedures, replacement may be needed for weeks until physical therapy has been completed.

Products available for FVIII replacement therapy in patients with hemophilia A

  • Intermediate-purity products: Plasma-derived (FVIII-specific activity of 1-10 U/mg)
    • Humate-P (CSL Behring) – Heat-treated
    • Profilate (not available in the US) – Solvent-detergent–treated
  • High-purity products: Plasma-derived (FVIII-specific activity of 50-100 U/mg)
    • Alphanate (Grifols Biologicals Inc, Los Angeles, Calif) – Solvent-detergent–treated
    • Koate HP (Baxter) – Solvent-detergent–treated
  • Ultra–high-purity products: Monoclonal-antibody–purified (FVIII-specific activity of >3000 U/mg)
    • Hemophil M or Hemofil M (Baxter) – Solvent-detergent–treated
    • Monoclate P (CSL Behring) – Pasteurized
  • Ultra–high-purity products: Recombinant (FVIII-specific activity of >3000 U/mg)
    • Bioclate (Baxter) – Heat-treated, solvent-detergent–treated
    • Helixate (CSL Behring) – Heat-treated
    • Kogenate (Bayer Health Care, Tarrytown, NY) – Heat-treated, baby hamster kidney cells
    • Recombinate (Baxter) – Heat-treated, solvent-detergent–treated, Chinese hamster ovary cells
    • ReFacto (Wyeth Pharmaceuticals Inc, Philadelphia, Penn) – Chinese hamster ovary cells, B domain deleted

Products available to treat FVIII inhibitors

  • Human FVIII concentrates – Loading dose of 10,000 U followed by 1000 U/h depending on the factor VIII levels achieved and maintained
  • Feiba VH – Dose of 25-100 U/kg at least every 12 hours, usually more often; not to exceed 200 U/kg/d
  • Autoplex-T – No longer available. The dose was 25-100 U/kg at least every 12 hours
  • Porcine FVIII - (Hyate:C is no longer available.) The dosage is based on inhibitor titer and absence of in vitro cross-reactivity to the patient's inhibitor; initial dose is 50-100 U/kg, repeated at 8- to 12-hours intervals
  • rFVIIa – Initial dose of 30 mcg/kg, up to 90 mcg/kg intravenously, repeated every 2-3 hours

Advantages and disadvantages of products used to treat patients with FVIII inhibitors

Human factor VIII concentrates may be in very limited supply. The needs of a single inhibitor patient may exhaust all factor replacement products available at several hospitals in a city because of the large doses needed, even in low-titer inhibitor patients.

Porcine factor VIII is expensive. It is effective when insignificant or no cross-reactivity occurs between porcine factor VIII and the patient's inhibitor, with a cross-reactivity titer of below 10 BU (cross-reactivity in approximately 15%; only 2% had total cross-reactivity). Good venous access is required.

rFVIIa is the most expensive of the replacement products discussed. Monitoring for DIC is optimal. Drawbacks include possible thrombotic complications, the need for good venous access, and the frequency of the intravenous doses needed. rFVIIa is effective and has markedly increased viral safety when compared with human plasma–derived products; no viral illnesses are thought to be transmitted by this product. Hemostasis is usually localized to the site of injury, with no anamnestic rise in antibody titer. It has proven safety even with home therapy.

Activated prothrombin-complex concentrates have a poorly defined mode of action, an unpredictable hemostatic response, are derived from pooled plasma (thereby posing a high risk of transmission of virally induced illnesses), and require good access and frequent administration. They have a greater failure rate, induce an anamnestic rise in antibody titer, and cannot be used at home.

ITI regimens can be associated with a nephrotic syndrome, which would require discontinuation of the product.

Use of PLAS+ SD as a source of FV

Patients with a combined deficiency of factor V and factor VIII require FFP as a source of factor V, because available factor concentrates do not supply factor V. Patients who receive multiple units of FFP have a higher risk of transfusion-transmitted viral illnesses. The use of solvent (tri{n-butyl phosphate} [TNBP]) and detergent (Triton X-100; Rohm & Haas Co, Philadelphia, Penn) to treat pooled human plasma (PLAS+ SD) results in significant inactivation of lipid-enveloped viruses (eg, HIV, hepatitis B and C). The greater degree of viral safety ensured by this treatment has led to the exclusive use of PLAS+ SD instead of FFP in some countries (Norway and Belgium).

In addition, PLAS+ SD delivers consistent and reproducible levels of coagulation factors, in contrast to the extreme variability in levels after use of FFP. Moreover, unlike in FFP, PLAS+ SD has no leukocytes, most of the physiologic inhibitors are in the normal range, coagulation zymogens are not activated, levels of other plasma proteins and immunoglobulins are normal, all lots have anti–hepatitis A virus antibody levels of ≥0.8 IU/mL (providing passive administration of antibody, which may neutralize hepatitis A virus), the largest von Willebrand multimers are absent, and efficacy in a variety of bleeding disorders has been proven.

Assays of several lots of PLAS+ SD showed that factor V activity was at 1.06 ± 0.02 IU/mL without any loss of factor V activity after solvent-detergent treatment. Importantly, factor V activity was fully preserved after 18 months of storage at –18°C. A mean factor V recovery of 169 ± 71% was obtained in 7 patients who had received PLAS+ SD in serial plasma exchanges, with an approximately 33% rise in factor V levels post exchange. Five patients with congenital factor V deficiency and active bleeding were successfully treated with this product. Following an infusion dose of 15 mL/kg, the average rise in factor V is 0.13 U/mL and the average recovery is 72% in deficient patients, with a linear increase at doses of 15-20 mL/kg.

All PLAS+ SD units should be ABO-compatible with each patient's red blood cells.[105] One of its few disadvantages is a minor allergic reaction; however, this reaction is observed with all blood products and it responds to antihistamines. Another adverse effect of PLAS+ SD may be volume overload in cardiovascularly compromised patients. Rarely, citrate toxicity, hypothermia, or other metabolic problems arise if large volumes are used, and patients may develop noncardiogenic pulmonary edema. Antibody-induced positive direct antiglobulin test (DAT) results and hemolysis may also occur rarely. This product should not be given to patients with known IgA deficiency. (For further details see the drug tables below, under the specific drugs.)

Antifibrinolytic agents

Antifibrinolytic agents are used as ancillary agents to control and reduce bleeding.

The recognition of the importance of the lysine-binding sites in various interactions in the fibrinolytic pathway led to the synthesis of lysine analogues such as EACA (6-aminohexanoic acid, Amicar) and trans-p -amiomethyl-cyclohexane carboxylic acid (AMCA, Cyklokapron). These synthetic lysine analogues induce a conformational change in plasminogen when they bind to its lysine-binding site. In the absence of EACA, plasminogen has the shape of a prolate ellipsoid; after EACA binds to plasminogen, it elongates into a long structure in which the interaction between the parts of plasminogen as they existed are lost.

In vivo, the lysine analogues probably prevent plasminogen activation and, in large doses, also bind plasmin, thereby preventing it from binding to its substrate, fibrin. When one looks at binding sites on plasminogen for EACA, the tightest binding is to kringle 1, followed by kringles 4 and 5. The interaction with kringle 2 is weak, and kringle 3 does not interact at all. A model of the structure of kringle 4 shows that the shallow trough formed by the hydrophobic amino acids is surrounded by positively and negatively charged amino acids at an ideal distance to interact with EACA.[106, 107, 108]

EACA is the most widely used antifibrinolytic drug in the United States. The minimal dose needed to inhibit either normal or excessive fibrinolysis is unknown. EACA is absorbed well orally, and 50% is excreted in the urine in 24 hours. Generally, an initial loading dose is followed by a maintenance dose to adequately inhibit fibrinolysis until excessive bleeding is controlled. The maintenance dose is then gradually tapered until it can be stopped. Rarely, myopathy and muscle necrosis may develop. Lower doses of EACA are adequate when bleeding involves the urinary tract because drug concentrations are 75- to 100-fold higher in urine than in plasma.

AMCA is also excreted rapidly in the urine, with more than 90% excreted in 24 hours. However, its antifibrinolytic effect lasts longer than that of EACA; AMCA inhibits fibrinolysis at lower plasma concentrations, although its serum half-life is similar to that of EACA. Therefore, AMCA can be given less frequently and at lower doses.

The doses of both EACA and AMCA must be reduced in patients with renal failure. See the package insert of each replacement product for the full details.

Aprotinin (Trasylol; Bayer), an antifibrinolytic drug obtained from bovine lung, is a nonhuman protein inhibitor of several serine proteases, including plasmin. It was approved by the US Food and Drug Administration (FDA) to reduce operative blood loss in patients undergoing open heart surgery. Aprotinin has also reduced blood loss and transfusion requirements in patients undergoing orthotopic liver transplantation or in patients undergoing elective resection of a solitary liver metastasis originating from a colon cancer. Aprotinin is the most expensive of the drugs discussed below, and it is now only available via a limited-access protocol.

Fergusson et al reported an increased risk for death compared with tranexamic acid or aminocaproic acid in high-risk cardiac surgery.[109] For more information, see the article from Medscape.

Blacks appear to have unique haplotypes and are twice as likely as white patients to produce inhibitors against factor VIII proteins given as replacement therapy.[53]

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Antihemophilic Agents

Class Summary

Antihemophilic agents are used for factor VIII (FVIII) replacement therapy in patients with hemophilia A (classic hemophilia). Advantages and disadvantages of several blood products available to treat patients with factor VIII inhibitors are discussed above (see the Medication section). For all the products listed below, the physician is encouraged to read the FDA-approved package inserts for further details. Appropriate monitoring is needed to manage active bleeding and to monitor and manage any allergic reactions that may develop during infusion of foreign proteins.

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Factor VIII, human plasma derived (Humate-P, Alphanate, Koate-DVI, Hemofil)

 

Protein found in normal plasma necessary for clot formation. Can temporarily correct coagulation defect of patients with hemophilia A, in which there is deficiency of FVIII-C. Specific activity and calculated vs actual recoveries vary with each product and patient. Actual dose depends on patient's weight, severity of hemorrhage, severity of deficiency, actual recovery, presence of inhibitors, and desired level of FVIII. Control of bleeding and the FVIII level achieved in the patient are the most important determinants of dosage and duration of therapy. When inhibitors are present, dosage requirements are extremely variable and determined by clinical response and FVIII activity achieved in vivo. The need for larger amounts of antihemophilic factor than previously needed to achieve adequate hemostasis in a person known to have hemophilia may be the first clue to the presence of an inhibitor.

Pooled plasma, solvent-detergent treated (PLAS+ SD)

 

Pooled plasma is treated using a procedure developed by the American Red Cross and Vitex Technologies (see details under Medical Care). Solvent-detergent (SD) treatment of pooled human plasma disrupts and kills lipid-enveloped viruses (eg, HIV, hepatitis B and C). SD treatment is followed by ultrafiltration and sterile filtration; however, these treatments do not remove all viruses from plasma, nor is the method capable of totally eliminating viral infectivity from plasma-derived products. However, such treatments improve safety compared with standard FFP. Efficacy and safety have been proven in the treatment of several coagulopathies.

Per the package insert (from American Red Cross), the half-life of coagulation factors in recipients of this product is similar to reference range values at the time they were measured. SD-treated plasma, if available, can be used in patients with combined FV and FVIII deficiencies as a source of FV because no concentrate is available to treat FV deficiency.

As with any bleeding disorder, serial measurement of the specific coagulation factor in question is essential to ensure consistent hemostatic adequacy of the levels of the deficient factors. On average, 1 U of SD plasma raises factor levels by approximately 2-3%, whereas 4-6 U raises factor levels by approximately 8-18% in a 70-kg person. These numbers do not specifically apply to FV and are provided only as a general guide.

PLAS+ SD contains not less than 0.7 U/mL of FV, and serial monitoring of FV levels is necessary. PLAS+ SD should be stored at -18°C or colder and thawed at 30-37°C in a water bath with very gentle shaking; once thawed, keep at room temperature and use as soon as possible, preferably within 24 h. Thawed material should not be stored in the cold.

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Antihemophilic Factor recombinant

 

Recombinant FVIII containing human serum albumin. Can temporarily correct the coagulation defect of patients with classic hemophilia (hemophilia A) who have a deficiency of the plasma clotting factor FVIII. Provides a means of temporarily replacing the missing clotting factor to correct or prevent bleeding episodes or to provide perioperative hemostasis.

The dose depends on patient's weight, disease severity, and duration of hemorrhage; the severity of the baseline deficiency; the presence of inhibitors; and the target FVIII level to be maintained. A positive clinical effect with cessation or prevention of bleeding in the patient is the most important determinant of the dose and duration of therapy.

When inhibitors develop or are present, the dosage requirements are extremely variable and should be determined by clinical response (larger amounts of antihemophilic FVIII may be necessary to achieve the desired results). Cannot be used to correct the deficiency in persons with von Willebrand disease.

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Antihemophilic Factor recombinant (ReFacto)

 

Recombinant FVIII with albumin-free final formulation. Intended for promoting hemostasis by replacing FVIII activity. Used for the treatment and prevention of hemorrhagic episodes in patients with hemophilia A (congenital FVIII deficiency or classic hemophilia). ReFacto does not contain vWF.

Antihemophilic factor, porcine

 

Can temporarily correct the coagulation defect of patients with FVIII inhibitors. The dose depends on the patient's weight, the severity of the hemorrhage, the inhibitor's titers, and the response of the bleeding to the therapy.

The clinical effect is the most important determinant of the therapy. When inhibitors are present, the dosage requirements may vary considerably, even in the same patient. Increasing doses of porcine FVIII may sometimes be necessary.

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Factor VIIa, recombinant (Novo Seven)

 

FVIIa activates hemostasis by combining with tissue factor and is able to achieve hemostasis by generating thrombin by directly activating FX and bypassing the need for FVIII or FIX, thus being useful even in patients with inhibitors to FVIII or FIX.

The dose depends on the inhibitor titer, patient's weight, severity of hemorrhage, and response to the therapy; see extensive discussions above. The clinical effect is most important determinant of therapy. When treating bleeding in patients with inhibitors, the dosage requirements may be extremely variable and should be guided by the clinical response.

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Anti-inhibitor coagulant complex (Feiba VH Immuno)

 

Use in patients with FVIII inhibitors. Can temporarily correct the coagulation defect of patients with inhibitors to FVIII; generally used in patients with inhibitor titers of ≥ 5 BU/mL. The dose depends on the patient's weight, severity of hemorrhage, titer of inhibitor, and in vivo effect. The clinical effect on bleeding is the most important determinant of the dose and frequency of therapy. When inhibitors are present, the dosage requirements are extremely variable and determined by the clinical response.

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Antifibrinolytics

Class Summary

Antifibrinolytic agents are used together with single dose of factor replacement and given before minor surgical procedures (eg, dental extractions, sinus surgery) so that they can be administered in an outpatient setting with the use of a single dose of product. Concern about the possible causal relationship of these drugs with acute thrombotic events remains, although a causal relationship with thrombotic complications has been questioned, because the underlying disease state and genetic risk factors usually determine the site and extent of thrombosis. See the general discussion on these agents, preceding the discussion of specific drugs.

When antifibrinolytics are used in patients with upper urinary tract bleeding together with factor replacement therapy, the formation of a firm, unlysable clot in the urinary tract may result in acute urinary obstruction within a few hours.

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Aminocaproic acid (Amicar, EACA)

 

Hemostatic agent that diminishes bleeding by inhibiting the fibrinolysis of the hemostatic plug. Can be used PO/IV.

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Tranexamic acid (Cyklokapron)

 

Fibrinolytic inhibitor used with FIX replacement to reduce the need for hospitalization and more than one dose of FIX concentrate in patients with hemophilia B who require dental or sinus procedures. Can be used similarly in patients with hemophilia A. Also used to inhibit fibrinolysis in other conditions.

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Aprotinin injection (Trasylol)

 

5/14/08: Only available via limited-access protocol.

Broad-spectrum protease inhibitor, which modulates the systemic inflammatory response associated with bypass surgery and results in the attenuation of the inflammatory response and thrombin generation and fibrinolytic response.

In platelets, reduces glycoprotein loss, whereas in granulocytes, prevents the expression of proinflammatory adhesive glycoproteins. Thus, not a pure inhibitor of fibrinolysis. Is a nonhuman protein obtained from bovine lung, with a potential for sensitization and allergic reactions, especially with repeated administration. Reactions range from rashes to anaphylaxis and death. Risk of sensitization with repeated exposure is 5%. Premedication with 50 mg diphenhydramine and 300 mg cimetidine IV with 650 mg acetaminophen PO is given 30 min before a small test dose, followed by a 30-min infusion of the regular dose to avoid hypotension.

Injectable drug that has been successfully used to reduce bleeding in patients undergoing cardiopulmonary bypass, which is its FDA-approved indication. Two different dosage regimens (A & B) have been shown to reduce bleeding in patients undergoing repeat CABG surgery who participated in a randomized clinical trial. Comparisons were made against placebo and another arm in which the drug was only given into the priming fluid. Interestingly, 1100 patients >65 y had outcomes no different than those seen in younger adults.

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Contributor Information and Disclosures
Author

Robert A Schwartz, MD, MPH  Professor and Head, Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, University of Medicine and Dentistry of New Jersey-New Jersey Medical School

Robert A Schwartz, MD, MPH is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American College of Physicians, and Sigma Xi

Disclosure: Nothing to disclose.

Coauthor(s)

Elzbieta Klujszo, MD  Head of Department of Dermatology, Wojewodzki Szpital Zespolony, Kielce

Disclosure: Nothing to disclose.

Pere Gascon, MD, PhD  Professor and Director, Division of Medical Oncology, Institute of Hematology and Medical Oncology, IDIBAPS, University of Barcelona Faculty of Medicine, Spain

Pere Gascon, MD, PhD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, New York Academy of Medicine, New York Academy of Sciences, and Sigma Xi

Disclosure: Nothing to disclose.

Rajalaxmi McKenna, MD, FACP  Southwest Medical Consultants, SC, Department of Medicine, Good Samaritan Hospital, Advocate Health Systems

Rajalaxmi McKenna, MD, FACP is a member of the following medical societies: American Society of Clinical Oncology, American Society of Hematology, and International Society on Thrombosis and Haemostasis

Disclosure: Nothing to disclose.

Specialty Editor Board

Charles S Greenberg, MD  Director of Thrombosis and Transglutaminase Research Laboratory, Professor, Departments of Pathology and Medicine, Division of Hematology/Oncology, Duke University Medical Center

Charles S Greenberg, MD is a member of the following medical societies: American Society of Hematology and International Society on Thrombosis and Haemostasis

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD  Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Ronald A Sacher, MB, BCh, MD, FRCPC  Professor, Internal Medicine and Pathology, Director, Hoxworth Blood Center, University of Cincinnati Academic Health Center

Ronald A Sacher, MB, BCh, MD, FRCPC is a member of the following medical societies: American Association for the Advancement of Science, American Association of Blood Banks, American Clinical and Climatological Association, American Society for Clinical Pathology, American Society of Hematology, College of American Pathologists, International Society of Blood Transfusion, International Society on Thrombosis and Haemostasis, and Royal College of Physicians and Surgeons of Canada

Disclosure: Glaxo Smith Kline Honoraria Speaking and teaching; Talecris Honoraria Board membership

Rebecca J Schmidt, DO, FACP, FASN  Professor of Medicine, Section Chief, Department of Medicine, Section of Nephrology, West Virginia University School of Medicine

Rebecca J Schmidt, DO, FACP, FASN is a member of the following medical societies: American College of Physicians, American Medical Association, American Society of Nephrology, International Society of Nephrology, National Kidney Foundation, Renal Physicians Association, and West Virginia State Medical Association

Disclosure: Renal Ventures Ownership interest Other

Chief Editor

Emmanuel C Besa, MD  Professor, Department of Medicine, Division of Hematologic Malignancies, Kimmel Cancer Center, Jefferson Medical College of Thomas Jefferson University

Emmanuel C Besa, MD is a member of the following medical societies: American Association for Cancer Education, American College of Clinical Pharmacology, American Federation for Medical Research, American Society of Clinical Oncology, American Society of Hematology, and New York Academy of Sciences

Disclosure: Nothing to disclose.

Additional Contributors

The author gratefully acknowledges the provision of several photographs used in this article and in Factor IX by a dedicated colleague from Chicago, Margaret Telfer, MD. The author would also like to acknowledge Professor K.N. Subramanian (Department of Molecular Genetics, University of Illinois Medical Center) for general discussions relating to some aspects of the gene structure and mutation of the FVIII gene.

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Obituary in the March 22, 1796, Salem Gazette (Massachusetts) for a 19-year-old man who bled to death after suffering a foot injury. Also detailed are the deaths of 5 brothers by various minor injuries.
The hemostatic pathway: role of factor VIII.
Structural domains of human factor VIII. Adapted from: Stoilova-McPhie S, Villoutreix BO, Mertens K, Kemball-Cook G, Holzenburg A. 3-Dimensional structure of membrane-bound coagulation factor VIII: modeling of the factor VIII heterodimer within a 3-dimensional density map derived by electron crystallography. Blood. Feb 15 2002;99(4):1215-23; Roberts HR, Hoffman M. Hemophilia A and B. In: Beutler E, Lichtman MA, Coller BS, et al, eds. Williams Hematology. 6th ed. NY: McGraw-Hill; 2001:1639-57; and Roberts HR. Thoughts on the mechanism of action of FVIIa. Presented at: Second Symposium on New Aspects of Haemophilia Treatment; 1991; Copenhagen, Denmark.
Cell surface–directed hemostasis (adapted from: Hoffman M, Monroe DM 3rd. A cell-based model of hemostasis. Thromb Haemost. Jun 2001;85(6):958-65. Initially, a small amount of thrombin is generated on the surface of the tissue factor–bearing cell. Following amplification, the second burst generates a larger amount of thrombin, leading to fibrin (clot) formation.
Possible genetic outcomes in individuals carrying the hemophilic gene.
Photograph of a teenage boy with bleeding into his right thigh as well as both knees and ankles.
Photograph of the right knee in an older man with a chronically fused, extended knee following open drainage of knee bleeding that occurred many years previously.
Photograph depicting severe bilateral hemophilic arthropathy and muscle wasting. The 3 punctures made into the left knee joint were performed in an attempt to aspirate recent aggravated bleeding.
Radiograph depicting advanced hemophilic arthropathy of the knee joint. These images show chronic severe arthritis, fusion, loss of cartilage, and joint space deformities.
Radiograph depicting advanced hemophilic arthropathy of the elbow. This image shows chronic severe arthritis, fusion, loss of cartilage, and joint space deformities.
Photograph of a hemophilic knee at surgery, with synovial proliferation caused by repeated bleeding; synovectomy was required.
Large amount of vascular synovium removed at surgery.
Microscopic appearance of synovial proliferation and high vascularity. If stained with iron, diffuse deposits would be demonstrated; iron-laden macrophages are present.
Large pseudocyst involving the left proximal femur.
Transected pseudocyst (following disarticulation of the left lower extremity due to vascular compromise, nerve damage, loss of bone, and nonfunctional limb). This photo shows black-brown old blood, residual muscle, and bone.
Dissection of a pseudocyst.
Transected pseudocyst with chocolate brown-black old blood.
Photograph of a patient who presented with a slowly expanding abdominal and flank mass, as well as increasing pain, inability to eat, weight loss, and weakness of his lower extremity.
Plain radiograph of the pelvis showing a large lytic area.
Intravenous pyelogram showing extreme displacement of the left kidney and ureter by a pseudocyst.
Photograph depicting extensive spontaneous abdominal wall hematoma and thigh hemorrhage in an older, previously unaffected man with an acquired factor VIII inhibitor.
Magnetic resonance image of an extensive spontaneous abdominal wall hematoma and thigh hemorrhage in an older, previously unaffected man with an acquired factor VIII inhibitor.
Image depicting the 28q region of the X chromosome. Adapted from: Kazazian HH Jr, Tuddenham EGD, Antonarakis SE. Hemophilia A and parahemophilia: deficiencies of coagulation factors VIII and V. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Bases of Inherited Disease. 7th ed. New York, NY: McGraw-Hill; 1995:3241-67; Reitsma PH. Genetic principles underlying disorders of procoagulant and anticoagulant proteins. In: Coleman RW, Hirsh J, Marder VJ, et al, eds. Hemostasis and Thrombosis: Basic Principles & Clinical Practice. 4th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 2001:59-87; Roberts HR, Monroe DM III, Hoffman M. Molecular biology and biochemistry of the coagulation factors and pathways of hemostasis. In: Beutler E, Beutler E, Lichtman MA, et al, eds. Williams Hematology. 6th ed. New York: McGraw-Hill, 2001:1409-34; and Roberts HR, Hoffman M. Hemophilia A and B. In: Beutler E, Lichtman MA, et al, eds. Williams Hematology. 6th ed. New York: McGraw-Hill, 2001:1639-57.
Quality of life! A child with hemophilia at summer camp.
Photograph depicting the application of a Velcro tourniquet, followed by self-infusion of concentrate used for in-home therapy.
Self-infusion of concentrate used for in-home therapy.
Table. General Guidelines for Management With FVIII Concentrates for Intermittent Bolus Dosing
Type of Hemorrhage Desired



FVIII-C Activity



Dose and Duration of Therapy
Minor



Uncomplicated



hemarthroses



Superficial large



hematomas



20-30%10-15 U/kg IV q12-24h for 1-2 d
Moderate



Hematoma with dissection



Oral/mucosal hemorrhages and epistaxis*



Hematuria



25-50%15-25 U/kg IV q12-24h for 3-7 d



(shorter time for oral hemorrhages; higher dose for hematuria)



Dental extraction(s)†50-100%25-50 U/kg IV q12h for 2-5 d
Major



Pharyngeal/retropharyngeal



Retroperitoneal



GI bleeding



CNS bleeding surgery



~50-100% until bleeding is controlled; then, gradually decrease the dosage to the minimum that is required to prevent rebleeding25-50 U/kg IV q12h for 5-10 d
*Concomitant administration of EACA or AMCA (both inhibitors of fibrinolysis) can help reduce the dose of concentrate that is required to treat such bleeding. Approximately 50% of the initial dose is given as the second dose approximately 8 hours after the first; all subsequent doses are given every 12 hours.



†For dental extractions, a single preoperative dose of factor VIII of 15 U/kg and oral or intravenous Amicar at 5 g is given, followed by an Amicar maintenance dose of 1 g/h, as discussed below, for 5-7 days, with a gradual taper.



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