eMedicine Specialties > Hematology > Coagulation, Hemostasis, and Disorders

Factor VIII: Treatment & Medication

Author: Robert A Schwartz, MD, MPH, Professor and Head, Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, UMDNJ-New Jersey Medical School
Coauthor(s): Elzbieta Klujszo, MD, Head of Department of Dermatology, Wojewodzki Szpital Zespolony, Kielce; 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; Rajalaxmi McKenna, MD, FACP, Southwest Medical Consultants, SC, Department of Medicine, Good Samaritan Hospital, Advocate Health Systems
Contributor Information and Disclosures

Updated: Aug 13, 2009

Treatment

Medical Care

Factor VIIII (FVIII) replacement is used for acute bleeding, for perioperative prevention of bleeding during planned surgical procedures, for prophylaxis to prevent recurrent bleeding of target joints, in early institution of childhood prophylactic therapy to preserve long-term joint function, or for immune tolerance induction (ITI) regimens. Prompt and adequate therapy for bleeding is essential to avoid the long-term destructive consequences of joint bleeding. Although there are 6 wild-type factor VIII proteins, only 2 (H1 and H2) match the recombinant factor VIII products used clinically.⁵³

Home care programs have made patients self-sufficient in infusing factor replacement product (see Images 25-26 or below), with guidance and supervision from personnel at a hemophilia center or a knowledgeable physician in the local community.

All of these allow a patient to participate in more of life's activities. The specific dose and duration of factor replacement therapy is determined by the location of the bleeding, severity of the bleeding, and known actual response to previous therapy.

Intermediate- or high-purity plasma-derived products are still available for use in patients who have previously used such products. Monoclonal antibody purified plasma–derived products are usually free of some viral contaminants. In children who are starting therapy for the first time or in persons with hemophilia who are negative for HIV, recombinant products are used whenever possible because of their presumed higher viral safety.

Importantly, be aware that approximately 25% of the lots of human albumin that contain first-generation recombinant factor VIII concentrates have been found to be positive for transfusion-transmitted (TT) virus from contaminated human serum albumin. All second-generation recombinant factor VIII preparations (free from human albumin) have been negative for the virus.⁵⁴

See the table in the Medication section and related material for a general dosing guide for factor replacement therapy and for target factor VIII levels for acute bleeding. The duration of therapy depends on the site and cause of bleeding and response to therapy. Bolus dosing is still the most often used method of factor replacement, but a continuous infusion regimen generally reduces total administered doses by approximately 30%. Data on the lowest necessary dose for adequate therapy, a consideration because of the enormous cost of factor replacement products, are being obtained.⁵⁵

Monitoring actual levels of factor VIII-C is necessary to confirm the presence of adequate amounts of factor VIII in vivo to correct hemostasis when (1) a patient is first treated, (2) a new factor replacement product is being used, (2) the onset of an inhibitor is suggested, (4) active ongoing bleeding is present, or (5) persistence or inadequate correction of bleeding has been encountered with previously adequate doses.

Minor bleeding, as from cuts and abrasions, may respond to conservative measures, such as pressure and ice. Mild hematuria may subside spontaneously. Note: Do not aspirate hematomas or joints or cauterize bleeding sites unless specifically indicated, because these procedures may aggravate the bleeding.

Epistaxis and moderately severe hematuria may be adequately treated by achieving and maintaining factor VIII levels in the range of 30-50%. Use a higher dose initially, followed by a gradual lowering of the dose after the bleeding is under control, and then continue factor VIII replacement until clinical and objective evidence indicates resolution of the bleeding.

Acute joint bleeding and expanding, large hematomas require adequate factor replacement for a prolonged period until the bleed begins to resolve, as evidenced by clinical and/or objective methods. Relief of the intense pain with joint bleeding frequently requires the use of narcotic analgesics; relief of pain also accompanies cessation of bleeding after adequate factor replacement.

Life-threatening bleeding episodes are generally initially treated with factor VIII levels of approximately 100%, until the clinical situation warrants a gradual reduction in dosage. Continuous intravenous infusions avoid the low troughs and excesses of intermittent bolus dosing, maintain adequate levels at all times, and save approximately 30% of expensive factor replacement product usage.^56,57

For serious bleeding events, continue factor replacement for at least 7-10 days because of the potential risk of recurrent bleeding. A multiple-bolus drug-dosing regimen model has been developed to better estimate the loading and maintenance dose requirements to allow maintenance of a minimum trough level of factor VIII at all times.⁵⁸ In patients who may have an intracranial hemorrhage, administer a full dose of factor concentrate before the patient is sent for any diagnostic radiologic procedures in order to avoid delays in bleeding control. Surgically drain intracranial bleeding promptly, as clinically dictated, following factor replacement therapy.

Patients with combined factor V and factor VIII deficiency require combined replacement with factor VIII concentrates and FFP for factor V, which also supplies a small amount of factor VIII. The use of 1-deamino-8-D-arginine vasopressin (DDAVP) to raise factor VIII levels (without concomitant FVIII concentrate) in combination with FFP as a source of factor V was successful in the perioperative management of an older Italian man who was undergoing surgical repair of massive bilateral inguinal hernias.⁵⁹ However, pooled solvent-detergent–treated plasma (PLAS⁺ SD; VI Technologies, Inc (Vitex), Watertown, Mass / American Red Cross, Washington, DC) is safer than standard FFP, because lipid-enveloped viruses are removed. See the Medication section for further details of PLAS⁺ SD.

Collaboration with an infectious diseases consultant is a major need in caring for patients with HIV/AIDS or hepatitis. The serious psychiatric issues present in the management of patients infected with HIV may require the assistance of a psychiatrist.²¹

Simple immediate ancillary measures of ice, pressure, elastic bandage (ACE) wrap, immobilization of the affected joint, and avoidance of NSAIDs must not be forgotten.

The benefits of prophylaxis in the management of hemophilia A should be emphasized.⁶⁰ There are clear advantages of prophylaxis for patients with hemophilia A compared with on-demand treatment, including a reduction in the number of bleeding episodes, improved joint function, and greater patient well-being. Sadly, there is a heavier economic burden with increased factor use.

• Prophylactic factor replacement
  • Secondary prophylaxis thus far has been undertaken mainly in patients with target joint–related recurrent bleeding in a biweekly or triweekly intravenous dose of factor VIII (25-40 U/kg) to maintain trough factor VIII-C levels in the range of 3-5%. There are data which clearly show that in order to preserve joint function, primary prophylaxis must be started early in childhood, after the child experiences the first few episodes of bleeding into a joint.
  • This approach may appear to be an expensive proposition, but it has been shown to be good for the patient's joints and quality of life, and, over the long term, early primary prophylaxis reduces costs by reducing the number of in-hospital days and outpatient and day care visits when compared with on-demand therapy.^{61,62,63,64,65} Moreover, on-demand and secondary prophylaxis do not prevent hemophilic arthropathy, whereas early primary prophylaxis better preserves normal joint structure and function and a normal quality of life, while presumably delaying or even reducing the need for early joint replacement.
  • As early as 1994, the Medical Advisory and Safety Committee recognized the long-term physical and psychosocial benefits of early prophylaxis in allowing the hemophiliac patient to lead a normal lifestyle, and it endorsed the principle of prophylactic therapy as the optimal approach to hemophilic care. However, venous access problems do arise, especially in children, and indwelling lines invariably lead to recurrent infections and thrombotic complications. Subclavian, brachiocephalic, jugular, and superior venocaval thrombi have been objectively documented in hemophilic children with long-term (>1 y) central venous catheters for access. Approximately 50% of patients with central venous catheters for longer than 1 year have deep vein thrombosis.^37,66
  • An intriguing, relatively new concept is the development of an oral peptide, peptidomimetic, or other compound that may activate the coagulation mechanism, with an ability to control the extent of activation. This is the reverse side of the coin of controlled anticoagulant use in the treatment of thrombotic diseases.
• Home therapy
  • In the last few decades of the 20th century, home therapy revolutionized the type of care provided to individuals with hemophilia. New factor replacement products resulted in improved patient outcomes, which considerably improved the quality of patients' lives.
  • The typical picture of earlier times of a wheelchair-bound, disabled adult with hemophilia has been replaced by that of an ambulating patient with a lesser degree of joint damage. However, the fact remains that many affected individuals require joint replacements at a younger age than persons without hemophilia but with osteoarthritis.
  • Patients with hemophilia and their families have become self-sufficient with the application of sterile home infusion techniques, with prompt replacement of the missing factor at the earliest evidence of pain and/or possible bleeding, rather than having to spend hours waiting for care in crowded emergency departments. Distant travel and summer camp experiences have also become feasible (see Image 24 or below).
    

    

    Quality of life! A child with hemophilia at summer camp.

    [ CLOSE WINDOW ]

    

    Quality of life! A child with hemophilia at summer camp.

  • The availability of lyophilized replacement product, the equipment and teaching needed for intravenous self-infusion, and the security to infuse the replacement product have helped release patients from the necessity of remaining in the vicinity of a hospital for emergent care (see Images 25-26). This aspect is also extremely important from the psychologic standpoint of allowing parents and other family members to become actively involved in the care of their loved one.
    

    

    Photograph depicting the application of a Velcro tourniquet, followed by self-infusion of concentrate used for in-home therapy (see Image 26).

    [ CLOSE WINDOW ]

    

    Photograph depicting the application of a Velcro tourniquet, followed by self-infusion of concentrate used for in-home therapy (see Image 26).

    
    

    

    Self-infusion of concentrate used for in-home therapy (same patient as in Image 25).

    [ CLOSE WINDOW ]

    

    Self-infusion of concentrate used for in-home therapy (same patient as in Image 25).

  • The subsequent increase in replacement product usage has led to an increasing risk of exposure to virally transmitted illnesses and led to the AIDS and hepatitis epidemics. Patient who are negative for HIV and the hepatitis C virus and those who have not undergone treatment as yet are now being treated exclusively with the more expensive recombinant products.
  • With the availability of concentrates of factor VIII and developments in the field of joint replacement, previously disabled patients can ambulate and become self-sufficient in their daily lives. There are advantages and disadvantages in using the albumin-free recombinant factor VIII concentrates in the treatment of hemophilia A.⁶⁷ The third-generation recombinant factor VIII product Advate (antihemophilic factor [Recombinant], plasma/albumin-free method; Baxter Healthcare Corporation, Westlake Village, Calif) is safe and effective in treating bleeding associated with hemophilia A. However, controversy remains with regard to a higher risk of inhibitor development with recombinant products, and the higher cost may play a role in product choice. Each patient and family should be educated about the advantages and disadvantages of all factor VIII concentrates, and they should be allowed to make an informed decision about which replacement product to use.
• Other therapeutic measures
  • DDAVP, or desmopressin acetate (Stimate; ZLB Behring LLC, King of Prussia, Penn), is an arginine vasopressin analogue, which, when given intravenously in a dose of 0.3 mcg/kg over 15-20 minutes, causes a transient 2- to 4-fold rise in factor VIII and von Willebrand factor levels by inducing release of factor VIII and von Willebrand factor from storage sites. The doses are usually repeated 8-12 hours later, but an approximate 30% lower response may be expected after the second dose.
  • Repeated administration of DDAVP results in a markedly reduced response (tachyphylaxis). Factor XI levels also rise in response to this drug. The rise in factor VIII level is accompanied by an increase in fibrinolytic activity due to the simultaneous release of tissue plasminogen activator (tPA).
  • DDAVP can also be given by intranasal spray (150 mcg in each nostril), but the time to maximal rise in factor VIII levels is delayed (unlike the response to an intravenous dose); therefore, extra time is required for a response. This approach may be inadequate under some clinical circumstances.
  • DDAVP is a good drug to use in patients with mild hemophilia (whose condition has had proven response to the drug) to prevent bleeding associated with minor procedures or surgeries that are expected to be associated with very little bleeding.
  • Patients must be tested and proven to have a good treatment response to DDAVP before the use of DDAVP in a patient who has been scheduled for surgery. If an appropriate rise in factor VIII level is obtained in response to the test dose of DDAVP, then at least 1 week should elapse between the date of the test dose of DDAVP and the surgery. This allows time for replenishment of endogenous stores of factor VIII-C before surgery, so that an adequate DDAVP-induced rise in factor VIII is again obtained perioperatively.
  • Patients with severe hemophilia are not proper candidates for DDAVP therapy, because they do not have intravascular stores of factor VIII available for release.
  • Hyponatremia due to water retention is a potentially serious adverse effect; a patient's oral or intravenous intake of fluids must be curtailed for approximately 12-18 hours after the administration of DDAVP, until the antidiuretic effect passes. Importantly, alert the patient to this effect, so that the patient will be aware of the distinct drop in urine volume following DDAVP administration, with an increase in urinary output when the antidiuretic effect of DDAVP wanes. (There have been instances in which this author's patients who had been educated about the antidiuretic effect pointed out the lack of antidiuretic effect and the lack of the flushing that accompanies DDAVP administration, thus alerting the physician to the possible lack of DDAVP in the bag provided by the pharmacy.)
• Antifibrinolytic agents
  • Preservation of the hemostatic plug formed in the presence of adequate levels of factor VIII at the time of surgical trauma (as with dental procedures or with mucosal bleeding) can be achieved by inhibiting fibrinolysis with epsilon-aminocaproic acid, also called EACA (Amicar; Xanodyne Pharmaceuticals, Inc, Newport, Ky), or tranexamic acid (trans-p-aminomethyl-cyclohexane carboxylic acid [AMCA]) (Cyklokapron, Pharmacia & Upjohn, New York, NY) given orally or, if needed, intravenously.
  • The first dose of EACA (5 g PO/IV slowly) is administered before the surgical procedure, along with a dose of factor VIII sufficient to raise the level, followed by a maintenance dose of EACA (1 g/h) postoperatively for several hours until it is clinically appropriate to start tapering the dose over the next several days.
  • An intriguing in vitro observation is the finding that EACA in a final concentration of 1.25-5 mg/mL (concentrations achievable with a large loading dose) inhibits factor VIII inhibitor activity without affecting other immunologic reactions.⁴⁰
  • In vivo confirmation of this phenomenon was obtained in plasma from 2 patients with inhibitors who received EACA in a dose of 100 mg/kg over 10 minutes; the lysine-binding sites did not appear to mediate this effect.⁴⁰
  • AMCA is given in a dose of 1.5 g intravenously every 6-8 hours and then tapered, as needed.
  • These drugs can also be used as a mouthwash for oral bleeding, and they have been used to stop local intracavitary oozing.
  • Antifibrinolytic agents are contraindicated in patients with hematuria because of the risk of developing a firm, occluding clot in the ureters when given simultaneously with factor replacement. These drugs are not useful in the management of joint bleeding.
  • In the past few years, the use of NSAIDs by individuals with hemophilia has increased in an effort to ease the pain of chronic, disabling, and frequently crippling joint disease. Although these agents allow improved joint function, because of the impact of NSAIDs on primary hemostasis, their use comes at a price of increased bleeding episodes and an increased incidence of GI and other bleeding, all requiring more use of concentrate. Cyclooxygenase (COX)-2 inhibitors have been tried with caution, but these drugs are likely to increase the bleeding risk. Alternatives to NSAIDs, such as acetaminophen and codeine-type analgesics, are much less effective because they lack an anti-inflammatory effect; additionally, some of these drugs are addictive.
• Fibrin glue
  • This product is very useful for controlling bleeding at surgical sites. Fibrin glue consists of a mixture of fibrinogen, thrombin, and factor XIII to cross-link freshly formed fibrin. Cryoprecipitate has also been used as a source of fibrinogen and factor XIII, with bovine thrombin used to start the clotting process. Some preparations also incorporate antifibrinolytic agents to inhibit clot lysis.
  • Fibrin glue has been particularly useful in orthopedic and pseudotumor-related surgical procedures and to achieve adequate hemostasis at operative sites in patients with an inhibitor to factor VIII.
  • Bovine thrombin present in fibrin glue can elicit an antibody, as it has in other postoperative states.⁶⁸
• Gene therapy: Several ideal characteristics have been proposed for a DNA delivery system, including the fact it (1) is produced in concentrated form, (2) is targeted to specific cell types, (3) results in long-term gene expression with stable levels for years, (4) is nontoxic, and (5) is nonimmunogenic.^69,70 Several studies have been undertaken in humans using different approaches to introduce the factor VIII gene into a patient so that higher factor VIII levels can be maintained in persons with severe hemophilia; maintenance of basal levels of 3-10% significantly ameliorate bleeding in patients with severe hemophilia. The most successful and least toxic method of introducing the gene remains to be determined. Some of the problems with gene therapy are as follows:
  • Despite a high level of short-term expression of factor VIII in a canine model of hemophilia A by the use of an attenuated adenoviral vector, liver toxicity, thrombocytopenia, and the development of an anticanine factor VIII antibody occurred as a result of the immunologic response to the vector.⁷¹
  • Another issue is a question of the appropriate in vivo vector dose, with evidence for a threshold dose requirement. Short-term correction of factor VIII levels due to high gene expression in the neonatal period following injection of an adenoviral murine vector in utero has also been accomplished.⁷² An adenoviral vector encoding a human B-domain–deleted factor VIII complementary DNA corrected bleeding in hemophilic mice and dogs, suggesting that this is another viable approach. Successful production of significant amounts of factor VIII by a parvovirus-based vector in immunocompetent mice in the absence of significant hepatotoxicity suggests a promising new vector for use in gene therapy.⁷³
  • An interesting approach consists of transducing human umbilical vein endothelial cells with a retroviral construct to create a store of factor VIII-C and von Willebrand factor in the Weibel-Palade bodies, which can then be released in a functional state. Thus, the vascular endothelium could also be an appropriate target of gene therapy.⁷⁴ Transgenic mice with expression of factor VIII in the epidermis support the possibility of cutaneous gene therapy for a systemic bleeding disorder.
  • The development of antibodies to replaced proteins is another major disadvantage of human gene therapy. In a gene knockout mice model of hemophilia A, the immune system was shown to be capable of recognizing a species-specific transgene protein as a neoantigen and produced cytotoxic T cells despite a temporary rise in factor VIII levels. An approach to preventing this problem was suggested by the success of the injection of murine CTLA4-immunoglobulin to block T-cell function, which completely blocked the primary response to factor VIII in hemophilic mice.
  • Several possible approaches to gene therapy include: ex vivo gene therapy, in which cells to be transplanted are modified to secrete factor VIII or factor IX and then are reimplanted into the recipient; in vivo gene therapy, in which the vector is directly injected into the patient; and nonautologous gene therapy, in which cells modified to secrete the missing factor are packaged in immunoprotected devices and implanted into recipients. Several trials using different vectors were under way until the death of a patient treated for a metabolic disorder led to a halt in clinical trials, with reevaluation of the type of vector, dose, route, and toxicity of the different approaches to gene therapy.^{70,71,72,73,75,76,77,78,79,80,81}
• Management of inhibitors: See the Medication section.

Surgical Care

• Preoperative evaluation of the aPTT, along with a mixing test that includes prolonged incubation of a patient's plasma with normal pooled plasma to exclude an inhibitor, is very important. Most individuals with hemophilia are routinely tested when examined by a physician with expertise in this area. The patient must receive the proper dose of factor VIII (FVIII) before and serially after surgery to achieve and maintain an adequate level of factor VIII-C to permit maintenance of good hemostasis. Following bone and joint surgery, prolonged replacement for several weeks is necessary not only to allow healing at the surgical site, but also to prevent bleeding during the necessary intensive postoperative physical therapy, which allows for maximum joint mobility to develop.⁸²
• Procedures such as endoscopies, although considered routine for unaffected people, require preprocedural factor product replacement in persons with hemophilia so that they do not bleed either during or following a needed biopsy. Postbiopsy replacement with factor VIII must continue until the biopsy site has healed.
• Dental extractions or mucosal procedures can be handled with a single preprocedure dose of factor VIII, along with Amicar. A standard approach to dental extractions has been proposed based on a case-control study, which proved the validity of the tested approach.⁸³ In this study, patients received a single 20 mg/kg dose of AMCA, along with a single infusion of factor VIII, to achieve a peak level of approximately 30% before the dental extraction. No significant differences in bleeding rates occurred when compared with controls, with a cost reduction due to outpatient management. Routine practice is to continue therapy with antifibrinolytics in an outpatient setting for several days after the dental extraction, with a gradual tapering of the dosage over 5-7 days.
• The use of ancillary measures, such as fibrin glue and antifibrinolytics (see Medical Care), is very valuable in surgical procedures in which excessive bleeding is anticipated or encountered.
  • Fibrin glue consists of a mixture of fibrinogen, thrombin, and factor XIII used to cross-link the freshly formed fibrin clot. Cryoprecipitate has also been used as a source of fibrinogen and factor XIII, with the use of bovine thrombin to clot fibrinogen. Some preparations also incorporate antifibrinolytic drugs to inhibit premature lysis of the fibrin clot.
  • Fibrin glue has been particularly useful in orthopedic surgery and with surgical procedures in patients with inhibitors. Bovine thrombin may elicit antibodies. Bleeding from suture holes is a complication of a variety of invasive vascular procedures (eg, surgery, radiography, coronary angiography).
  • In an experimental porcine vascular graft model, fibrin sealant containing factor XIII effectively reduced blood loss as well as reduced the time to achieve adequate hemostasis when compared with fibrin alone or with thrombin-coated gelatin sponges.⁸⁴
  • Perioperative avoidance of NSAIDs and other known platelet-inhibiting drugs, including herbal remedies, is essential to minimize the bleeding risk. Ice packs and pressure are always useful whenever feasible.
• Orthotopic liver transplantation for hepatic failure corrects factor VIII levels in patients with hemophilia. Interestingly, factor VIII-C levels in persons with mild hemophilia rise to normal levels as their chronic liver disease advances (author's observations).
• When treating patients with combined factor V and factor VIII deficiency, a factor V level of approximately 25% is sufficient for major surgery. Maintain factor VIII levels as for patients with hemophilia A. FFP in a loading dose of approximately 20 U/kg preoperatively or emergently for a bleeding episode, followed by FFP in a dose of 5-10 U/kg every 12 hours to maintain a minimal hemostatic level of factor V, may be required. PLAS⁺ SD is safer than FFP and may be substituted for FFP whenever it is available (see the Medication section). Use antifibrinolytics and other ancillary measures as discussed in the management of patients with hemophilia A (see Medical Care).

Consultations

Hematologists, orthopedists, physical therapists, dentists, social workers, psychologists, infectious disease specialists, gastroenterologists/hepatologists, geneticists, and appropriately equipped special laboratories all play important roles in providing optimal care for patients and their families.
 
The efforts of the National Hemophilia Foundation and its regional chapters must be recognized in helping with educating patients and their families, facilitating home care programs and summer camps, improving financial support for health care through legislation, assisting service providers, and fostering dialogue among affected individuals to exchange discussions about problems and ideas for new solutions.

Diet

A healthy, nutritional, normal diet is encouraged in patients with hemophilia. Avoidance of unproven health remedies is necessary because several of these agents have been shown to potentiate bleeding. Caution is warranted when taking any natural supplement.

Activity

Activity restrictions depend on the condition of the joints; appropriate physical activity and physical therapy must be encouraged to maintain and preserve muscle function. Studies have shown that compared with age-matched controls, children with hemophilia have poorer muscle mass and function.

Medication

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).^54,85,86 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.⁸⁷ 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.⁸⁸ 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.⁸⁸

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.⁸⁸

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.^68,89,90,91

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.⁹²

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).⁹³ 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.⁹⁴

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.⁹⁵ 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.^{96,97,98,99,100,101}

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.^17,46

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.¹⁰²

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 new window

*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.¹⁰³ 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.^104,105,106

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.¹⁰⁷ 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  

Antihemophilic Agents

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.

Antihemophilic factor, human (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.

Antihemophilic factor VIII (Recombinate)

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.

Antihemophilic factor (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.

Recombinant factor VIIa (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.

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.

Antifibrinolytics

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.

Aminocaproic acid (Amicar, EACA)

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

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.

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.

• Search for CME/CE on This Topic »

• Hemophilia A and B (Pediatrics: General Medicine)
• Hemophilia, Type A (Emergency Medicine)
• Hemophilia, Acquired (Hematology)
• Hemophilia, Overview (Hematology)

• Hemophilia Treatment
• Hemophilia Causes
• Hemophilia Symptoms
• Blood and Lymphatic System Center
• Hemophilia Overview
• Blood in Urine Overview
• Kidneys and Urinary System Center

• Many Factors Tied to Inhibitor Formation in Hemophilia
• FDA Committee Assesses vCJD Risk in US Plasma Products
• Bleeding Disorders May Cause Menorrhagia and Postpartum Hemorrhage

• Differential Effects of Th1, Monocyte/Macrophage and Th2 Cytokine Mixtures on Early Gene Expression for Molecules Associated With Metabolism, Signaling and Regulation in Central Nervous System Mixed Glial Cell Cultures
• Prognostic Significance of Mast Cell Number and Microvascular Density for the Survival of Patients With Primary Colorectal Cancer
• Pelvic Surgery in A Child With Hemophilia C: A Rare Disease, A Real Challenge, A Simple Solution