Factor VIII Treatment & Management

  • Author: Robert A Schwartz, MD, MPH; Chief Editor: Emmanuel C Besa, MD   more...
 
Updated: Aug 26, 2010
 

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.[51]

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

Photograph depicting the application of a Velcro tPhotograph 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 therSelf-infusion of concentrate used for in-home therapy.

This has also improved quality of life by minimizing the time spent in hospital emergency departments, providing rapid and early therapy for acute bleeding, achieving a prompt reduction in pain due to early specific correction of the factor deficiency and joint immobilization, and allowing concomitant provision of appropriate narcotic and nonnarcotic analgesics.

Joint integrity can be preserved with the start of early prophylactic home care programs in childhood (maintain a minimum of 1-2% FVIII-C at all times by infusing replacement product at home 3 times per wk).

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.[52]

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.[53]

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.[54, 55]

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.[56] 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.[57] 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.[22]

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.[58] 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.[59, 60, 61, 62, 63] 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.[38, 64]
  • 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 below). Quality of life! A child with hemophilia at summerQuality 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 below). 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 tPhotograph 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 therSelf-infusion of concentrate used for in-home therapy.
  • 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.[65] 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.[41]
  • 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.[41]
  • 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.[66]

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.[67, 68]

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.[69]
  • 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.[70]
  • 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.[71]
  • 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.[72] 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.[68, 69, 70, 71, 73, 74, 75, 76, 77, 78, 79]

Management of inhibitors: See the Medication section.

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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.[80]

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.[81] 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.[82]
  • 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).

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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.

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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.

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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.

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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.

Acknowledgments

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.

References

  1. Brinkhous KM. A short history of hemophilia with some comments on the word "hemophilia". In: Brinkhous KM, Hemker HC, eds. Handbook of Hemophilia. New York, NY: Elsevier Science; 1975:3.

  2. Forbes CD, Aledort LM, Madhok R, eds. Hemophilia. London, England: Chapman & Hall; 1997:1-371.

  3. Owen Jr CA, Nichols WL, Walter Bowie EJ, eds. A History of Blood Coagulation. Rochester, Minn: Mayo Foundation for Medical Education and Research; 2001:117-50.

  4. 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.

  5. Reitsma PH. Genetic principles underlying disorders of procoagulant and anticoagulant proteins. In: Coleman RW, Hirsh J, Marder VJ, Clowes AW, George JN, eds. Hemostasis and Thrombosis. Basic Principles & Clinical Practice. 4th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 2001:59-87.

  6. Ozgur TT, Asal GT, Gurgey A, et al. Acquired factor VIII deficiency associated with a novel primary immunodeficiency suggestive of autosomal recessive hyper IgE syndrome. J Pediatr Hematol Oncol. May 2007;29(5):327-9. [Medline].

  7. Wion KL, Kelly D, Summerfield JA, Tuddenham EG, Lawn RM. Distribution of factor VIII mRNA and antigen in human liver and other tissues. Nature. Oct 24-30 1985;317(6039):726-9. [Medline].

  8. Tuddenham EG, Lane RS, Rotblat F, et al. Response to infusions of polyelectrolyte fractionated human factor VIII concentrate in human haemophilia A and von Willebrand's disease. Br J Haematol. Oct 1982;52(2):259-67. [Medline].

  9. Brinkhous KM, Sandberg H, Garris JB, Mattsson C, Palm M, Griggs T, et al. Purified human factor VIII procoagulant protein: comparative hemostatic response after infusions into hemophilic and von Willebrand disease dogs. Proc Natl Acad Sci U S A. Dec 1985;82(24):8752-6. [Medline]. [Full Text].

  10. Montgomery RR, Kroner PA. von Willebrand disease: a common pediatric disorder. Pediatr Ann. Sep 2001;30(9):534-40. [Medline].

  11. Vlot AJ, Mauser-Bunschoten EP, Zarkova AG, et al. The half-life of infused factor VIII is shorter in hemophiliac patients with blood group O than in those with blood group A. Thromb Haemost. Jan 2000;83(1):65-9. [Medline]. [Full Text].

  12. Rock G, Tittley P, Pipe A. Coagulation factor changes following endurance exercise. Clin J Sport Med. Apr 1997;7(2):94-9. [Medline].

  13. Wildgoose P, Nemerson Y, Hansen LL, et al. Measurement of basal levels of factor VIIa in hemophilia A and B patients. Blood. Jul 1 1992;80(1):25-8. [Medline]. [Full Text].

  14. Gilbert GE, Drinkwater D. Specific membrane binding of factor VIII is mediated by O-phospho-L-serine, a moiety of phosphatidylserine. Biochemistry. Sep 21 1993;32(37):9577-85. [Medline].

  15. Bevers EM, Comfurius P, Dekkers DW, Harmsma M, Zwaal RF. Transmembrane phospholipid distribution in blood cells: control mechanisms and pathophysiological significance. Biol Chem. Aug-Sep 1998;379(8-9):973-86. [Medline].

  16. Feinstein DI. Immune coagulation disorders. In: Coleman RW, Hirsh J, Marder VJ, Clowes AW, George JN, eds. Hemostasis and Thrombosis. Basic Principles & Clinical Practice. 4th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 2001:1003-20.

  17. Roberts HR, Monroe DM III, Hoffman M. Molecular biology and biochemistry of the coagulation factors and pathways of hemostasis. In: Beutler E, Lichtman MA, Coller BS, Kipps TJ, Seligsohn U, eds. Williams Hematology. 6th ed. New York, NY: McGraw-Hill; 2001:1409-34.

  18. Wang XF, Zhao YQ, Yang RC, Wu JS, Sun J, Zhang XS, et al. The prevalence of factor VIII inhibitors and genetic aspects of inhibitor development in Chinese patients with haemophilia A. Haemophilia. Mar 12 2010;[Medline].

  19. Ma GC, Chang SP, Chen M, Kuo SJ, Chang CS, Shen MC. The spectrum of the factor 8 (F8) defects in Taiwanese patients with haemophilia A. Haemophilia. Mar 25 2008;[Medline].

  20. Abu-Amero KK, Hellani A, Al-Mahed M, Al-Sheikh I. Spectrum of factor VIII mutations in Arab patients with severe haemophilia A. Haemophilia. May 2008;14(3):484-8. [Medline].

  21. Lauer GM, Walker BD. Hepatitis C virus infection. N Engl J Med. Jul 5 2001;345(1):41-52. [Medline].

  22. Treisman GJ, Angelino AF, Hutton HE. Psychiatric issues in the management of patients with HIV infection. JAMA. Dec 12 2001;286(22):2857-64. [Medline].

  23. Favier R, Lavergne JM, Costa JM, et al. Unbalanced X-chromosome inactivation with a novel FVIII gene mutation resulting in severe hemophilia A in a female. Blood. Dec 15 2000;96(13):4373-5. [Medline]. [Full Text].

  24. Orstavik KH, Scheibel E, Ingerslev J, Schwartz M. Absence of correlation between X chromosome inactivation pattern and plasma concentration of factor VIII and factor IX in carriers of haemophilia A and B. Thromb Haemost. Mar 2000;83(3):433-7. [Medline]. [Full Text].

  25. Seligsohn U, Zivelin A, Zwang E. Combined factor V and factor VIII deficiency among non-Ashkenazi Jews. N Engl J Med. Nov 4 1982;307(19):1191-5. [Medline].

  26. Shetty S, Madkaikar M, Nair S, et al. Combined factor V and VIII deficiency in Indian population. Haemophilia. Sep 2000;6(5):504-7. [Medline].

  27. Shetty S, Madkaikar M, Nair S, et al. Combined factor V and VIII deficiency in Indian population. Haemophilia. Sep 2000;6(5):504-7. [Medline].

  28. Zhang B, Spreafico M, Zheng C, et al. Genotype-phenotype correlation in combined deficiency of factor V and factor VIII. Blood. Jun 15 2008;111(12):5592-600. [Medline].

  29. Pollmann H, Richter H, Ringkamp H, Jürgens H. When are children diagnosed as having severe haemophilia and when do they start to bleed? A 10-year single-centre PUP study. Eur J Pediatr. Dec 1999;158 Suppl 3:S166-70. [Medline].

  30. Kulkarni R, Lusher JM, Henry RC, Kallen DJ. Current practices regarding newborn intracranial haemorrhage and obstetrical care and mode of delivery of pregnant haemophilia carriers: a survey of obstetricians, neonatologists and haematologists in the United States, on behalf of the National Hemophilia Foundation's Medical and Scientific Advisory Council. Haemophilia. Nov 1999;5(6):410-5. [Medline].

  31. Kulkarni R, Lusher J. Perinatal management of newborns with haemophilia. Br J Haematol. Feb 2001;112(2):264-74. [Medline].

  32. Ludlam CA, Lee RJ, Prescott RJ, et al. Haemophilia care in central Scotland 1980-94. I. Demographic characteristics, hospital admissions and causes of death. Haemophilia. Sep 2000;6(5):494-503. [Medline].

  33. Evatt B, Austin H, Leon G, Ruiz-Sáez A, de Bosch N. Hemophilia treatment. Predicting the long-term risk of HIV exposure by cryoprecipitate. Haemophilia. Jul 2000;6 suppl 1:128-32. [Medline].

  34. Nichols WC, Amano K, Cacheris PM, et al. Moderation of hemophilia A phenotype by the factor V R506Q mutation. Blood. Aug 15 1996;88(4):1183-7. [Medline]. [Full Text].

  35. Roberts HR, Hoffman M. Hemophilia A and B. In: Beutler E, Lichtman MA, Coller BS, Kipps TJ, Seligsohn U, eds. Williams Hematology. 6th ed. New York, NY: McGraw-Hill; 2001:1639-57.

  36. Roelse JC, De Laaf RT, Timmermans SM, et al. Intracellular accumulation of factor VIII induced by missense mutations Arg593-->Cys and Asn618-->Ser explains cross-reacting material-reduced haemophilia A. Br J Haematol. Feb 2000;108(2):241-6. [Medline].

  37. Escuriola Ettingshausen C, Halimeh S, et al. Symptomatic onset of severe hemophilia A in childhood is dependent on the presence of prothrombotic risk factors. Thromb Haemost. Feb 2001;85(2):218-20. [Medline]. [Full Text].

  38. Ettingshausen CE, Kurnik K, Schobess R, et al. Catheter-related thrombosis in children with hemophilia A: evidence of a multifactorial disease. Blood. Feb 15 2002;99(4):1499-500. [Medline]. [Full Text].

  39. Beutler E. Discrepancies between genotype and phenotype in hematology: an important frontier. Blood. Nov 1 2001;98(9):2597-602. [Medline]. [Full Text].

  40. Clayton D, McKeigue PM. Epidemiological methods for studying genes and environmental factors in complex diseases. Lancet. Oct 20 2001;358(9290):1356-60. [Medline].

  41. Ghosh K, Shetty S, Pathare A, Mohanty D. Epsilon-aminocaproic acid inhibits the activity of factor VIII inhibitors in patients with severe haemophilia A in vivo and in vitro. Acta Haematol. 2000;103(2):67-72. [Medline].

  42. Shetty S, Ghosh K, Mohanty D. St 14 (DX S52) VNTR polymorphism in the Indian population and its application in carrier detection and prenatal diagnosis of haemophilia A families. Haematologia (Budap). 2000;30(3):203-7. [Medline].

  43. Chowdhury MR, Herrmann FH, Schroder W, et al. Factor VIII gene polymorphisms in the Asian Indian population. Haemophilia. Nov 2000;6(6):625-30. [Medline].

  44. Choi YM, Hwang D, Choe J, et al. Carrier detection and prenatal diagnosis of hemophilia A in a Korean population by PCR-based analysis of the BclI/intron 18 and St14 VNTR polymorphisms. J Hum Genet. 2000;45(4):218-23. [Medline].

  45. The Haemophilia A Mutation, Structure, Test and Resource Site (HAMSTeRS). Available at http://europium.csc.mrc.ac.uk. Accessed July 23, 2008.

  46. Keeling DM, Sukhu K, Kemball-Cook G, et al. Diagnostic importance of the two-stage factor VIII:C assay demonstrated by a case of mild haemophilia associated with His1954-->Leu substitution in the factor VIII A3 domain. Br J Haematol. Jun 1999;105(4):1123-6. [Medline].

  47. Schwaab R, Oldenburg J, Kemball-Cook G, et al. Assay discrepancy in mild haemophilia A due to a factor VIII missense mutation (Asn694Ile) in a large Danish family. Br J Haematol. Jun 2000;109(3):523-8. [Medline].

  48. Verbruggen B, Novakova I, Wessels H, et al. The Nijmegen modification of the Bethesda assay for factor VIII:C inhibitors: improved specificity and reliability. Thromb Haemost. Feb 1995;73(2):247-51. [Medline].

  49. Klinge J, Auerswald G, Budde U, et al. Detection of all anti-factor VIII antibodies in haemophilia A patients by the Bethesda assay and a more sensitive immunoprecipitation assay. Haemophilia. Jan 2001;7(1):26-32. [Medline].

  50. Manco-Johnson MJ, Nuss R, Jacobson LJ. Heparin neutralization is essential for accurate measurement of factor VIII activity and inhibitor assays in blood samples drawn from implanted venous access devices. J Lab Clin Med. Jul 2000;136(1):74-9. [Medline].

  51. Viel KR, Ameri A, Abshire TC, et al. Inhibitors of factor VIII in black patients with hemophilia. N Engl J Med. Apr 16 2009;360(16):1618-27. [Medline].

  52. Azzi A, De Santis R, Morfini M, et al. TT virus contaminates first-generation recombinant factor VIII concentrates. Blood. Oct 15 2001;98(8):2571-3. [Medline]. [Full Text].

  53. Srivastava A, Chandy M, Sunderaj GD, et al. Low-dose intermittent factor replacement for post-operative haemostasis in haemophilia. Haemophilia. Nov 1998;4(6):799-801. [Medline].

  54. Hathaway WE, Christian MJ, Clarke SL, Hasiba U. Comparison of continuous and intermittent Factor VIII concentrate therapy in hemophilia A. Am J Hematol. Jul 1984;17(1):85-8. [Medline].

  55. Batorova A, Martinowitz U. Intermittent injections vs. continuous infusion of factor VIII in haemophilia patients undergoing major surgery. Br J Haematol. Sep 2000;110(3):715-20. [Medline].

  56. Dedík L, Durisová M, Bátorová A. Weighting function used for adjustment of multiple-bolus drug dosing. Methods Find Exp Clin Pharmacol. Sep 2000;22(7):543-9. [Medline].

  57. McKenna R, Cole ER, Doolas A. Successful surgical management of a patient with combined factor V and VIII deficiency with DDAVP + FFP. Thromb Haemost. 1987;58:1332-66.

  58. Hoots WK, Nugent DJ. Evidence for the benefits of prophylaxis in the management of hemophilia A. Thromb Haemost. Oct 2006;96(4):433-40. [Medline]. [Full Text].

  59. Schramm W. Experience with prophylaxis in Germany. Semin Hematol. Jul 1993;30(3 suppl 2):12-5. [Medline].

  60. Ljung RC. Prophylactic infusion regimens in the management of hemophilia. Thromb Haemost. Aug 1999;82(2):525-30. [Medline]. [Full Text].

  61. Miners AH, Sabin CA, Tolley KH, Lee CA. Primary prophylaxis for individuals with severe haemophilia: how many hospital visits could treatment prevent?. J Intern Med. Apr 2000;247(4):493-9. [Medline]. [Full Text].

  62. Petrini P. What factors should influence the dosage and interval of prophylactic treatment in patients with severe haemophilia A and B?. Haemophilia. Jan 2001;7(1):99-102. [Medline].

  63. van den Berg HM, Fischer K, Mauser-Bunschoten EP, et al. Long-term outcome of individualized prophylactic treatment of children with severe haemophilia. Br J Haematol. Mar 2001;112(3):561-5. [Medline].

  64. Journeycake JM, Quinn CT, Miller KL, Zajac JL, Buchanan GR. Catheter-related deep venous thrombosis in children with hemophilia. Blood. Sep 15 2001;98(6):1727-31. [Medline]. [Full Text].

  65. Meeks SL, Josephson CD. Should hemophilia treaters switch to albumin-free recombinant factor VIII concentrates. Curr Opin Hematol. Nov 2006;13(6):457-61. [Medline].

  66. McKenna R. Abnormal coagulation in the postoperative period contributing to excessive bleeding. Med Clin North Am. Sep 2001;85(5):1277-310, viii. [Medline].

  67. High KA. Gene transfer as an approach to treating hemophilia. Circ Res. Feb 2 2001;88(2):137-44. [Medline]. [Full Text].

  68. Rogers CS, Sullenger BA, George AC Jr. Gene therapy. In: Hardman JG, Limbird LE, Gilman AG, eds. Goodman and Gilman's The Pharmacologic Basis of Therapeutics. 10th ed. McGraw-Hill: New York, NY; 2001:81-112.

  69. Gallo-Penn AM, Shirley PS, Andrews JL, et al. Systemic delivery of an adenoviral vector encoding canine factor VIII results in short-term phenotypic correction, inhibitor development, and biphasic liver toxicity in hemophilia A dogs. Blood. Jan 1 2001;97(1):107-13. [Medline]. [Full Text].

  70. Bristol JA, Shirley P, Idamakanti N, Kaleko M, Connelly S. In vivo dose threshold effect of adenovirus-mediated factor VIII gene therapy in hemophiliac mice. Mol Ther. Sep 2000;2(3):223-32. [Medline]. [Full Text].

  71. Chao H, Mao L, Bruce AT, Walsh CE. Sustained expression of human factor VIII in mice using a parvovirus-based vector. Blood. Mar 1 2000;95(5):1594-9. [Medline]. [Full Text].

  72. Rosenberg JB, Greengard JS, Montgomery RR. Genetic induction of a releasable pool of factor VIII in human endothelial cells. Arterioscler Thromb Vasc Biol. Dec 2000;20(12):2689-95. [Medline]. [Full Text].

  73. Lipshutz GS, Sarkar R, Flebbe-Rehwaldt L, Kazazian H, Gaensler KM. Short-term correction of factor VIII deficiency in a murine model of hemophilia A after delivery of adenovirus murine factor VIII in utero. Proc Natl Acad Sci U S A. Nov 9 1999;96(23):13324-9. [Medline]. [Full Text].

  74. Hedner U, Ginsburg D, Lusher JM, High KA. Congenital Hemorrhagic Disorders: New Insights into the Pathophysiology and Treatment of Hemophilia. Hematology Am Soc Hematol Educ Program. 2000;241-65. [Medline]. [Full Text].

  75. Hortelano G, Chang PL. Gene therapy for hemophilia. Artif Cells Blood Substit Immobil Biotechnol. Jan 2000;28(1):1-24. [Medline].

  76. Sarkar R, Gao GP, Chirmule N, Tazelaar J, Kazazian HH Jr. Partial correction of murine hemophilia A with neo-antigenic murine factor VIII. Hum Gene Ther. Apr 10 2000;11(6):881-94. [Medline].

  77. Coukos G, Rubin SC. Gene therapy for ovarian cancer. Oncology (Williston Park). Sep 2001;15(9):1197-204, 1207; discussion 1207-8. [Medline].

  78. Gura T. Hemophilia. After a setback, gene therapy progresses...gingerly. Science. Mar 2 2001;291(5509):1692-7. [Medline].

  79. Dunbar C. Lentiviruses get specific. Blood. Jan 15 2002;99(2):397. [Full Text].

  80. Aznar JA, Magallón M, Querol F, Gorina E, Tusell JM. The orthopaedic status of severe haemophiliacs in Spain. Haemophilia. May 2000;6(3):170-6. [Medline].

  81. Zanon E, Martinelli F, Bacci C, Zerbinati P, Girolami A. Proposal of a standard approach to dental extraction in haemophilia patients. A case-control study with good results. Haemophilia. Sep 2000;6(5):533-6. [Medline].

  82. Dickneite G, Metzner H, Nicolay U. Prevention of suture hole bleeding using fibrin sealant: benefits of factor XIII. J Surg Res. Oct 2000;93(2):201-5. [Medline].

  83. MediView Express. Recombinant therapy enhances safety and quality of life for hemophilia patients. Presented at: 53rd Annual Meeting of the National Hemophilia Foundation; November 16, 2001; Nashville, Tenn.

  84. Rigas B, Hasan I, Rehman R, et al. Effect on treatment outcome of coinfection with SEN viruses in patients with hepatitis C. Lancet. Dec 8 2001;358(9297):1961-2. [Medline].

  85. Scharrer I, Brackmann HH, Sultan Y, et al. Efficacy of a sucrose-formulated recombinant factor VIII used for 22 surgical procedures in patients with severe haemophilia A. Haemophilia. Nov 2000;6(6):614-8. [Medline].

  86. Tagariello G, Davoli PG, Gajo GB, et al. Safety and efficacy of high-purity concentrates in haemophiliac patients undergoing surgery by continuous infusion. Haemophilia. Nov 1999;5(6):426-30. [Medline].

  87. Hay CR, Baglin TP, Collins PW, Hill FG, Keeling DM. The diagnosis and management of factor VIII and IX inhibitors: a guideline from the UK Haemophilia Centre Doctors' Organization (UKHCDO). Br J Haematol. Oct 2000;111(1):78-90. [Medline].

  88. Lusher JM. Inhibitor antibodies to factor VIII and factor IX: management. Semin Thromb Hemost. 2000;26(2):179-88. [Medline].

  89. Penner JA. Haemophilic patients with inhibitors to factor VIII or IX: variables affecting treatment response. Haemophilia. Jan 2001;7(1):103-8. [Medline].

  90. Yee TT, Lee CA. Oral immune tolerance induction to factor VIII via breast milk, a possibility?. Haemophilia. Sep 2000;6(5):591. [Medline].

  91. El Alfy MS, Tantawy AA, Ahmed MH, Abdin IA. Frequency of inhibitor development in severe haemophilia A children treated with cryoprecipitate and low-dose immune tolerance induction. Haemophilia. Nov 2000;6(6):635-8. [Medline].

  92. Heneine W, Switzer WM, Soucie JM, et al. Evidence of porcine endogenous retroviruses in porcine factor VIII and evaluation of transmission to recipients with hemophilia. J Infect Dis. Feb 15 2001;183(4):648-52. [Medline]. [Full Text].

  93. Soucie JM, Erdman DD, Evatt BL, et al. Investigation of porcine parvovirus among persons with hemophilia receiving Hyate:C porcine factor VIII concentrate. Transfusion. Jun 2000;40(6):708-11. [Medline].

  94. Tagariello G, De Biasi E, Gajo GB, et al. Recombinant FVIIa (NovoSeven) continuous infusion and total hip replacement in patients with haemophilia and high titre of inhibitors to FVIII: experience of two cases. Haemophilia. Sep 2000;6(5):581-3. [Medline].

  95. Negrier C, Hay CR. The treatment of bleeding in hemophilic patients with inhibitors with recombinant factor VIIa. Semin Thromb Hemost. 2000;26(4):407-12. [Medline].

  96. Liebman HA, Chediak J, Fink KI, et al. Activated recombinant human coagulation factor VII (rFVIIa) therapy for abdominal bleeding in patients with inhibitory antibodies to factor VIII. Am J Hematol. Mar 2000;63(3):109-13. [Medline]. [Full Text].

  97. Hough RE, Hampton KK, Preston FE, et al. Recombinant VIIa concentrate in the management of bleeding following prothrombin complex concentrate-related myocardial infarction in patients with haemophilia and inhibitors. Br J Haematol. Dec 2000;111(3):974-9. [Medline].

  98. Ingerslev J. Efficacy and safety of recombinant factor VIIa in the prophylaxis of bleeding in various surgical procedures in hemophilic patients with factor VIII and factor IX inhibitors. Semin Thromb Hemost. 2000;26(4):425-32. [Medline].

  99. Lusher JM, Roberts HR, Davignon G, et al. A randomized, double-blind comparison of two dosage levels of recombinant factor VIIa in the treatment of joint, muscle and mucocutaneous haemorrhages in persons with haemophilia A and B, with and without inhibitors. rFVIIa Study Group. Haemophilia. Nov 1998;4(6):790-8. [Medline].

  100. Roberts HR. Thoughts on the mechanism of action of FVIIa. Presented at: Second Symposium on New Aspects of Haemophilia Treatment; 1991; Copenhagen, Denmark.

  101. Stewart MJ, Hart G, Mann K, Jackson S, Langille L, Reidy M. Telephone support group intervention for persons with hemophilia and HIV/AIDS and family caregivers. Int J Nurs Stud. Apr 2001;38(2):209-25. [Medline].

  102. Pooled plasma, solvent detergent treated, PLAS+SD [package insert]. Watertown, Mass: VI Technologies, Inc (Vitex) / Washington, DC, American Red Cross; September 1999.

  103. Bachmann F. The fibrinolytic system and thrombolytic agents. In: Bachmann F, ed. Fibrinolytics and Antifibrinolytics. New York, NY: Springer-Verlag; 2001:3-15.

  104. Bachmann F. The plasminogen-plasmin enzyme system. Haemostasis and Thrombosis. In: Colman RW, Hirsh J, Marder VJ, Clowes AW, George JN, eds. Hemostasis and Thrombosis: Basic Principles and Clinical Practice. 4th ed. Philadelphia, Pa: Lippincott, Williams & Wilkins; 2001:275-320.

  105. Bachmann F. Disorders of fibrinolysis and use of antifibrinolytic agents. In: Beutler E, Lichtman MA, Coller BS, Kipps TJ, Seligsohn U, edsTJ,. Williams Hematology. 6th ed. New York, NY: McGraw-Hill; 2001:1829-40.

  106. [Best Evidence] Fergusson DA, Hébert PC, Mazer CD, et al. A comparison of aprotinin and lysine analogues in high-risk cardiac surgery. N Engl J Med. May 29 2008;358(22):2319-31. [Medline].

  107. Di Bisceglie AM. SEN and sensibility: interactions between newly discovered and other hepatitis viruses?. Lancet. Dec 8 2001;358(9297):1925-6. [Medline].

  108. Millar DS, Steinbrecher RA, Wieland K, et al. The molecular genetic analysis of haemophilia A; characterization of six partial deletions in the factor VIII gene. Hum Genet. Dec 1990;86(2):219-27. [Medline].

  109. Scandella DH, Nakai H, Felch M, et al. In hemophilia A and autoantibody inhibitor patients: the factor VIII A2 domain and light chain are most immunogenic. Thromb Res. Mar 1 2001;101(5):377-85. [Medline].

  110. Peerlinck K, Jacquemin MG, Arnout J, et al. Antifactor VIII antibody inhibiting allogeneic but not autologous factor VIII in patients with mild hemophilia A. Blood. Apr 1 1999;93(7):2267-73. [Medline]. [Full Text].

  111. Nogami K, Shima M, Giddings JC, et al. Circulating factor VIII immune complexes in patients with type 2 acquired hemophilia A and protection from activated protein C-mediated proteolysis. Blood. Feb 1 2001;97(3):669-77. [Medline]. [Full Text].

  112. Moreau A, Lacroix-Desmazes S, Stieltjes N, et al. Antibodies to the FVIII light chain that neutralize FVIII procoagulant activity are present in plasma of nonresponder patients with severe hemophilia A and in normal polyclonal human IgG. Blood. Jun 1 2000;95(11):3435-41. [Medline]. [Full Text].

  113. Gilles JG, Vanzieleghem B, Saint-Remy JM. Factor VIII Inhibitors. Natural autoantibodies and anti-idiotypes. Semin Thromb Hemost. 2000;26(2):151-5. [Medline].

  114. Lacroix-Desmazes S, Moreau A, et al. Natural antibodies to factor VIII. Semin Thromb Hemost. 2000;26(2):157-65. [Medline].

  115. Spiegel PC Jr, Jacquemin M, Saint-Remy JM, Stoddard BL, Pratt KP. Structure of a factor VIII C2 domain-immunoglobulin G4kappa Fab complex: identification of an inhibitory antibody epitope on the surface of factor VIII. Blood. Jul 1 2001;98(1):13-9. [Medline]. [Full Text].

  116. Yamamoto K, Niiya K, Shigematu T, et al. Transient factor VIII inhibitor in a hemophilia patient after staphylococcal septic shock syndrome. Int J Hematol. Dec 2000;72(4):517-9. [Medline].

  117. Stewart AJ, Manson LM, Dasani H, et al. Acquired haemophilia in recipients of depot thioxanthenes. Haemophilia. Nov 2000;6(6):709-12. [Medline].

  118. Fakharzadeh SS, Kazazian HH Jr. Correlation between factor VIII genotype and inhibitor development in hemophilia A. Semin Thromb Hemost. 2000;26(2):167-71. [Medline].

  119. Streif W, Escuriola Ettingshausen C, et al. Inhibitor treatment by rituximab in congenital haemophilia A - Two case reports. Hamostaseologie. May 2009;29(2):151-4. [Medline].

  120. Hoots K, Canty D. Clotting factor concentrates and immune function in haemophilic patients. Haemophilia. Sep 1998;4(5):704-13. [Medline].

  121. Wadhwa M, Barrowcliffe T, Thorpe R. Immunological effects of factor VIII concentrates: characterization of transforming growth factor beta as an immunomodulatory contaminant in factor VIII concentrates. Br J Haematol. Jun 2000;109(4):901-3. [Medline].

  122. Yoto Y, Kudoh T, Haseyama K, Tsutsumi H. Human parvovirus B19 and meningoencephalitis. Lancet. Dec 22-29 2001;358(9299):2168. [Medline].

  123. Narváez Garcia FJ, Domingo-Domènech E, Castro-Bohorquez FJ, et al. Lupus-like presentation of parvovirus B19 infection. Am J Med. Nov 2001;111(7):573-5. [Medline].

  124. Senior K. New variant CJD fears threaten blood supplies. Lancet. Jul 28 2001;358(9278):304. [Medline].

  125. Schneppenheim R, Schroder J, Obser T, et al. The problem of novel FVIII missense mutations for haemophilia A genetic counseling. Hamostaseologie. May 2009;29(2):158-60. [Medline].

  126. Pacheco LD, Costantine MM, Saade GR, Mucowski S, Hankins GD, Sciscione AC. von Willebrand disease and pregnancy: a practical approach for the diagnosis and treatment. Am J Obstet Gynecol. Apr 22 2010;[Medline].

  127. Bajzar L, Manuel R, Nesheim ME. Purification and characterization of TAFI, a thrombin-activable fibrinolysis inhibitor. J Biol Chem. Jun 16 1995;270(24):14477-84. [Medline]. [Full Text].

  128. Bajzar L, Nesheim ME, Tracy PB. The profibrinolytic effect of activated protein C in clots formed from plasma is TAFI-dependent. Blood. Sep 15 1996;88(6):2093-100. [Medline]. [Full Text].

  129. Bouma BN, von dem Borne PA, Meijers JC. Factor XI and protection of the fibrin clot against lysis--a role for the intrinsic pathway of coagulation in fibrinolysis. Thromb Haemost. Jul 1998;80(1):24-7. [Medline]. [Full Text].

  130. Brinkman HJ, van Mourik JA, Mertens K. Persistent factor VIII-dependent factor X activation on endothelial cells is independent of von Willebrand factor. Blood Coagul Fibrinolysis. Apr 2008;19(3):190-6. [Medline].

  131. Broze GJ Jr, Higuchi DA. Coagulation-dependent inhibition of fibrinolysis: role of carboxypeptidase-U and the premature lysis of clots from hemophilic plasma. Blood. Nov 15 1996;88(10):3815-23. [Medline]. [Full Text].

  132. Carlborg E, Astermark J, Lethagen S, Ljung R, Berntorp E. The Malmö model for immune tolerance induction: impact of previous treatment on outcome. Haemophilia. Nov 2000;6(6):639-42. [Medline].

  133. Colowick AB, Bohn RL, Avorn J, Ewenstein BM. Immune tolerance induction in hemophilia patients with inhibitors: costly can be cheaper. Blood. Sep 1 2000;96(5):1698-702. [Medline]. [Full Text].

  134. Courter SG, Bedrosian CL. Clinical evaluation of B-domain deleted recombinant factor VIII in previously untreated patients. Semin Hematol. Apr 2001;38(2 suppl 4):52-9. [Medline].

  135. Gharagozlou S, Sharifian RA, Khoshnoodi J, et al. Epitope specificity of anti-factor VIII antibodies from inhibitor positive acquired and congenital haemophilia A patients using synthetic peptides spanning A and C domains. Thromb Haemost. May 2009;101(5):834-9. [Medline].

  136. Greenberg DL, Davie EW. Blood coagulation factors: their complementary DNAs, genes, and expression. In: Coleman RW, Hirsh J, Marder VJ, Clowes AW, George JN, eds. Hemostsis & Thrombosis: Basic Principles and Clinical Practice. 4th ed. Philadelphia, Pa: Lippincott, Williams & Wilkins; 2001:21-7.

  137. Hoffman M, Monroe DM 3rd. A cell-based model of hemostasis. Thromb Haemost. Jun 2001;85(6):958-65. [Medline]. [Full Text].

  138. Jansen M, Schmaldienst S, Banyai S, et al. Treatment of coagulation inhibitors with extracorporeal immunoadsorption (Ig-Therasorb). Br J Haematol. Jan 2001;112(1):91-7. [Medline].

  139. Johannessen M, Andreasen RB, Nordfang O. Decline of factor VIII and factor IX inhibitors during long-term treatment with NovoSeven. Blood Coagul Fibrinolysis. Apr 2000;11(3):239-42. [Medline].

  140. Kemball-Cook G, Tuddenham EGD. The molecular defect in hemophilia A. In: Forbes CD, Aledort L, Madhok R, eds. Hemophilia. London, England: Chapman & Hall; 1997:21-33.

  141. Lee DH, Walker IR, Teitel J, et al. Effect of the factor V Leiden mutation on the clinical expression of severe hemophilia A. Thromb Haemost. Mar 2000;83(3):387-91. [Medline]. [Full Text].

  142. Lynch TJ. Biotechnology: alternatives to human plasma-derived therapeutic proteins. Baillieres Best Pract Res Clin Haematol. Dec 2000;13(4):669-88. [Medline].

  143. Mannucci PM, Tuddenham EG. The hemophilias--from royal genes to gene therapy. N Engl J Med. Jun 7 2001;344(23):1773-9. [Medline].

  144. Mosnier LO, von dem Borne PA, Meijers JC, Bouma BN. Plasma TAFI levels influence the clot lysis time in healthy individuals in the presence of an intact intrinsic pathway of coagulation. Thromb Haemost. Nov 1998;80(5):829-35. [Medline]. [Full Text].

  145. Oliveira B, Arkfeld DG, Weitz IC, Shinada S, Ehresmann G. Successful rituximab therapy of acquired factor VIII inhibitor in a patient with rheumatoid arthritis. J Clin Rheumatol. Apr 2007;13(2):89-91. [Medline].

  146. Pratt KP, Shen BW, Takeshima K, et al. Structure of the C2 domain of human factor VIII at 1.5 A resolution. Nature. Nov 25 1999;402(6760):439-42. [Medline].

  147. Redlitz A, Tan AK, Eaton DL, Plow EF. Plasma carboxypeptidases as regulators of the plasminogen system. J Clin Invest. Nov 1995;96(5):2534-8. [Medline]. [Full Text].

  148. Renault NK, Dyack S, Dobson MJ, et al. Heritable skewed X-chromosome inactivation leads to haemophilia A expression in heterozygous females. Eur J Hum Genet. Jun 2007;15(6):628-37. [Medline]. [Full Text].

  149. Rubinstein R, Karabus CD, Smuts H, Kolia F, Van Rensburg EJ. Prevalence of human parvovirus B19 and TT virus in a group of young haemophiliacs in South Africa. Haemophilia. Mar 2000;6(2):93-7. [Medline].

  150. Sandberg H, Almstedt A, Brandt J, et al. Structural and functional characteristics of the B-domain-deleted recombinant factor VIII protein, r-VIII SQ. Thromb Haemost. Jan 2001;85(1):93-100. [Medline]. [Full Text].

  151. Soucie JM, Richardson LC, Evatt BL, et al. Risk factors for infection with HBV and HCV in a largecohort of hemophiliac males. Transfusion. Mar 2001;41(3):338-43. [Medline].

  152. 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. [Medline]. [Full Text].

  153. Sutor AH, Wulff J, Ritter J, Pollmann H, Schellong G. [Hemostasis and fibrinolysis in acute lymphoblastic leukemia (ALL) in childhood--analysis of life-threatening bleeding]. Klin Padiatr. May-Jun 1984;196(3):166-73. [Medline].

  154. White GC 2nd. Seventeen years' experience with Autoplex/Autoplex T: evaluation of inpatients with severe haemophilia A and factor VIII inhibitors at a major haemophilia centre. Haemophilia. Sep 2000;6(5):508-12. [Medline].

 
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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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