eMedicine Specialties > Hematology > Coagulation, Hemostasis, and Disorders

Factor VIII: Follow-up

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

Follow-up

Further Inpatient Care

  • Patients with factor VIII (FVIII) deficiency (hemophilia A) should be hospitalized for serious complications, for severe bleeding, and for major surgical procedures, all of which require complex interdisciplinary care including timely pharmacy and laboratory support. Constant close clinical evaluation and laboratory monitoring ensure adequacy of factor product replacement, pain relief, testing, and other supportive care. The hematologist must be centrally involved in this management to coordinate all care.

Further Outpatient Care

  • Outpatient and home care treatment are extremely important parts of patient management. Patients require adequate factor replacement product and ancillary supplies at home for product infusion, whether it is on-demand home care or prophylactic transfusions. Outpatient care in the clinic is provided for patients who require closer supervision because of events such as allergic reactions and the inability to self-infuse factor replacement product.
    • Due to the severe stress, difficulty coping, and numerous hurdles faced by patients with hemophilia who also have HIV/AIDS, a pilot study of the feasibility of providing telephone support by a registered nurse for such patients showed the feasibility of this approach.102 As with patients with other serious disorders, the networking brought additional benefits to patients.
    • Annual complete physical examination and laboratory testing for inhibitors, hepatitis, and HIV infection should be performed as needed.
    • Routine care as provided to patients without hemophilia should also be provided, including stool analysis for blood, rectal examination, colonoscopy, prostate-specific antigen (PSA) testing, dental care, and mammography for women. An appointment with a social worker at the same time ensures that all needs are met.
    • Physical therapy may be needed for the long-term care of affected joints.
    • Prophylactic care includes vaccination for hepatitis A and B strains, flu vaccine, and referral to appropriate state and federal agencies for possible economic support. Although hepatitis A is rarely transmitted by transfusions, the superimposition of hepatitis A in a patient with chronic hepatitis carries a higher risk of acute liver failure.108
    • The local chapter of the National Hemophilia Foundation should be notified about the patient so that proper statistics can be provided to the appropriate state and federal agencies to support adequate funding for their care.
    • Provide counseling and classes to encourage questions and to help solve problems, such as possible ways to avoid transmission of HIV to the uninfected spouse and children.

Inpatient & Outpatient Medications

  • Availability of a continuous supply of factor VIII concentrate and the supplies necessary for self-infusion is important. Patients should avoid acetylsalicylic acid (aspirin), NSAIDs, and any over-the-counter herbal medications that can precipitate bleeding.

Transfer

  • If a qualified hematologist and laboratory support are available, most patients with hemophilia can be cared for in a setting close to home. Laboratory support in community hospitals has improved because of the support provided by commercial referral laboratories (which are also being used by tertiary medical centers). Federal and state funding for programs may be available through the center. The costs of care are much higher at medical centers that are associated with universities.

Deterrence/Prevention

  • Hepatitis A and B vaccination is appropriate for all nonimmune patients.
  • Avoiding high-risk activities (eg, boxing, motorbike riding) and NSAIDs reduces the frequency of bleeding. Avoiding alcohol intake helps protect liver function in patients with hepatitis.
  • Use of barrier contraception is important to protect sexual partners of HIV-positive patients.

Complications

  • Factor VIII (FVIII) inhibitors in patients with hemophilia A (alloantibodies)
    • Approximately 20% of individuals with severe hemophilia develop inhibitors to factor VIII-C, with an overall prevalence rate of 5-10% in all persons with hemophilia; 95% of inhibitors develop in patients with factor VIII-C levels less than 5%. The development of an inhibitor is a serious complication, adding to morbidity and mortality. Inhibitor development depends on the specific genetic defect, the type of factor VIII replacement product used, and the patient's immune system. It has been suggested that persons with severe hemophilia who were exposed to and had an induction of immune tolerance to factor VIII in utero by exposure to maternal factor VIII as a consequence of maternal-fetal hemorrhage were less likely to develop inhibitors following replacement therapy. Genetic mutations associated with inhibitor development are discussed under Causes.
    • Approximately 70-75% of patients with large deletions or non-sense mutations involving the A3 domain developed inhibitors, whereas non-sense mutations in the C1 or C2 domain were associated with inhibitors in approximately 25% of patients. Non-sense mutations in the heavy chain are associated with a low frequency of inhibitor formation (~8%). Patients with gross deletions (>2 kb) have 5 times the incidence of inhibitors compared with patients without deletions, based on Southern blot analysis.109
    • Use of rFVIII has been associated with a rate of inhibitor development of up to 29%, with a median of 10 days of exposure to the recombinant product before the development of an inhibitor. However, one third of these were low-titer transient inhibitors, and these patients remained responsive to factor VIII replacement therapy. Inhibitors developing in patients with mild hemophilia follow this pattern, and when replacement product is withheld, the inhibitor tends to disappear spontaneously in 1-3 months and may not reappear with subsequent reexposure to factor replacement product. A study suggested that the A2 domain and light chain of factor VIII confer greater immunogenicity toward the development of an inhibitor.110
    • Patients with low-titer inhibitors (3-5 BU) may be further classified as low responders (25%) or high responders (75%), based on the lack of or a rise in their inhibitor titer following reexposure to replacement products containing factor VIII. The former may disappear, but the latter may persist for years once they are formed, even in the absence of reexposure to factor VIII. Inhibitors appear to be more common in black and Hispanic individuals.
    • A rather unique factor VIII alloantibody developed in 2 unrelated individuals with mild hemophilia who had a mutation in the C1 domain of factor VIII; both patients had significant residual factor VIII activity in their plasma coexisting with anti-FVIII antibodies. One inhibitor was examined in detail and showed the ability to neutralize wild-type but not self-factor VIII and behaved like a type II inhibitor. It was able to differentiate between the mutated factor VIII that the patient had and the wild-type factor VIII because of its epitope specificity.111
    • Thus, patients whose bodies see infused, external normal factor VIII as a novel antigen or as an altered antigen because they have been acclimated only to their own, internal, immunologically altered protein (and not to the normal wild-type protein) are the ones likely to develop an inhibitor.
  • Acquired spontaneously developing factor VIII inhibitors (autoantibodies)
    • As the population ages, a rising frequency of factor VIII inhibitors is expected. Autoimmune diseases (eg, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease), drug reactions (eg, penicillin, interferon alpha), pregnancy or the postpartum state, solid tumors, lymphoproliferative disorders, infections, skin diseases (eg, erythema multiforme, dermatitis herpetiformis), and graft versus host disease have all been associated with acquired factor VIII inhibitors. Approximately 50% of cases may not have an obvious cause.
    • The hypothesis that maternal sensitization to fetal factor VIII antigen during pregnancy is the cause of pregnancy-related autoantibody production has yet to be substantiated.
  • Characteristics of factor VIII inhibitors
    • Patients with severe hemophilia A have a high rate of inhibitor development (~35%), and these persons usually also have low or undetectable antigen levels. The single amino acid mutations R593C and W2229C are also associated with a high incidence of inhibitors (~40%). Hemophilic or acquired factor VIII antibodies primarily destroy factor VIII-C activity. These antibodies usually consist of a mixture of heavy-chain subclasses of IgG4 and IgG1 with kappa or lambda light-chain specificity; the IgG4 subclass normally represents less than 5% of plasma IgG; thus, it shows a particular predilection of the inhibitor for this heavy-chain class. They tend to be species-specific in vitro and in vivo, which is why porcine factor VIII had been used successfully to control bleeding in patients with factor VIII inhibitors.
    • In in vitro studies, hemophilic inhibitors (alloantibodies) show a linear relationship between antibody concentration and the amount of factor VIII-C neutralized, with a time requirement of up to 2 hours for a low-concentration inhibitor. Initially, the neutralization is rapid, followed by a slow second phase. This is the classic hemophilic type I antibody. The in vivo characteristics of acquired inhibitors (autoantibodies) are different; no linear relationship exists between inhibitor concentration and factor VIII-C neutralized, they do not totally inactivate factor VIII-C in the test tube, and clinical bleeding may be evident, showing a lack of in vivo factor VIII-C activity, even when a reasonable amount of plasma factor VIII-C activity is detected in in vitro tests. This is the type II antibody.112
    • The structural domains (previously discussed) of the antigenic regions of factor VIII are A1-A2-B-A3-C1-C2; the heavy chain has A1-AR1-A2-AR2-B, whereas the light chain has the AR3-A3-C1-C2 domains. Factor VIIIa has A1, A2, and A3-C1-C2 subunits, without domain B. Two thirds of the antibodies to factor VIII bind the A2 and C2 regions, and half of them bind the AR3 region. Neutralizing antibodies usually detect A2, C2, and AR3-A3-C1 epitopes. Approximately two thirds of autoantibodies are directed against a single epitope, whereas only one fifth of hemophilic antibodies are against a single epitope. Anti-A2, anti-AR3-A3-C1, and anti-A2 plus anti-C2 antibodies are found more often in hemophilic patients with inhibitors. Antibodies directed against other epitopes lead to a shorter half-life of the protein without inducing a loss of factor VIII-C activity. In a given patient, the type(s) of inhibitors may change over time.
    • Nonneutralizing antibodies may play a role in the development of immune tolerance. An analysis of the IgG obtained by affinity chromatography on FVIII-Sepharose columns from the IgG fractions of persons with hemophilia who do not have inhibitors and from those whose inhibitor titers did not rise in response to factor VIII infusion (nonresponder inhibitor patients) had similar properties, such as recognition of light-chain epitopes similar to known factor VIII inhibitors, suggesting that factor VIII inhibitors arise from expansion of preexisting natural anti-FVIII clones. Thus, the body appears to have natural antibodies to factor VIII, as it does to other soluble proteins.113
    • It has been suggested that normal immune homeostasis can "be viewed as a network of interacting molecules, idiotypes, and anti-idiotypes: disruption of this equilibrium leads to the development of autoimmunity."114 Other authors suggest the presence of another source of inhibitor production, one that is due to B-cell clones that have "undergone affinity maturation and hypermutation of the V regions of the antibodies they produce."115 The possibility has been raised that this immune interaction could be modulated by passive infusion of anti-idiotypic antibodies or by active immunization with idiotypes.
    • Anti-C2 antibodies destroy factor VIII-C activity, primarily by blocking its interaction with phospholipids. They inhibit factor VIIIa function in the intrinsic tenase complex and, less often, interfere with thrombin-induced release of factor VIII-C from its von Willebrand factor-bound, protected state. Prevention of binding to phospholipid surfaces abolishes the procoagulant activity of factor VIII, whereas prevention of binding of factor VIII to von Willebrand factor by antibodies to factor VIII results in a markedly shortened half-life of factor VIII.
    • A paper demonstrating the crystal structure of the factor VIII C2 domain clarified the mechanism of action of inhibitors directed against the C2 domain and raised the possibility of producing new, recombinantly altered factor VIII specifically to reduce its immunogenicity while preserving its anticoagulant function.116 Circulating factor VIII immune complexes have been detected in patients with autoantibodies (type II) binding to a specific region on the light chain (not to the C2 domain) and which were protected from antigen presenting cell–mediated proteolysis, suggesting another reason for preservation of some factor VIII activity. Antibodies against the A2 domain allow factor VIII to complex with factor IXa but block activation of factor X. Alloantibodies and autoantibodies appear to be directed against similar epitopes, although they arise under different clinical circumstances.
    • Transient factor VIII antibodies following infection have been reported after staphylococcal sepsis117 and a clinically significant low-titer factor VIII antibody has been reported with Lyme disease. Two patients reportedly developed anti-FVIII antibodies following injection of depot thioxanthenes, zuclopenthixol, and flupenthixol.118 Allergic or anaphylactic reactions to other drugs such as penicillin have been followed by inhibitor development.
    • Patients with combined factor V and factor VIII deficiency may develop autoantibodies or alloantibodies to factor V. Multiple autoantibodies found in patients exposed to bovine thrombin can be directed against factor V due to contamination of bovine thrombin with bovine factor V. Following exposure to factor replacement product, independent alloantibodies to factor V and factor VIII could arise in a patient who has inherited 2 separate mutations to account for factor V and factor VIII deficiencies.16,51,89,119
    • Therapy with rituximab may be considered for those with congenital hemophilia, high-titer neutralizing inhibitors to factor VIII, and a severe clinical course in whom standard immune tolerance induction has failed.120
  • Other complications
    • With chronic, severe joint deformities and arthritis, NSAID use may lead to an increase in bleeding in patients with hemophilia (see Images 7-10).
    • HIV-positive persons with hemophilia who use protease inhibitors have an increased risk of bleeding.
    • A higher frequency of bleeding risk has been noticed by patients who use St. John's Wort (over-the-counter herbal medicine). Other natural factor replacement products may contribute to excessive bleeding.
    • Intermediate-purity factor replacement products may contribute to immunosuppression more than high-purity products.121,122
    • Allergic reactions to older, less pure coagulation factor concentrates can occur as a result of sensitization to foreign proteins. These reactions reactions include skin rash, fever, headache, and, sometimes, anaphylaxis. Allergic reactions may develop in association with any factor replacement product.
    • Antibody development leads to failure of usually effective therapy to control bleeding, increases morbidity and mortality, and makes even minor surgery difficult.
    • An anamnestic rise in antibody titers can occur following transfusion of replacement products containing factor VIII to patients who already have an inhibitor.
    • Gene therapy may be associated with an increased prevalence of inhibitors.
    • Acute decompensated DIC, myocardial infarction, or stroke can occur with the use of prothrombin complex concentrates or of rFVIIa products used to treat bleeding in patients with inhibitors.
    • Viruses, including hepatitis A, hepatitis C, TT, and parvovirus B19, can be transmitted parenterally, depending on the factor replacement product transfused. Parvovirus B19 can cause a wide variety of illnesses, including bone marrow suppression, aplastic anemia in immunocompromised hosts, meningoencephalitis, vasculitis, and autoimmune illnesses (eg, lupuslike syndrome)123,124 Other unidentified viruses (eg, those possibly present in Chinese hamster ovary cells that are used to produce rFVIII concentrates) could present potential threats.
    • Hepatitis due to viruses A-E, the new hepatitis G virus, non-A non-B hepatitis, cirrhosis, hepatic failure, and hepatocellular carcinoma develop in persons with hemophilia who receive transfusions with older, less pure replacement products.
    • The newly discovered SEN family of viruses is important because of their potential adverse impact in a patient co-infected with other hepatitis viruses; SEN D and H are transmitted parenterally and contribute to posttransfusion hepatitis.86,108
    • TT virus, considered a hepatitislike pathogen, has been found in first-generation recombinant products because of the presence of TT virus in the human serum albumin used in the manufacturing process.54 Second-generation recombinant products, free of human serum albumin, do not contain TT virus.
    • In addition to HIV-1, emerging viruses in this class include HIV-2 and HIV group O viruses when blood or blood-derived products are used.
    • Human herpesvirus 8 is another emerging pathogen.
    • Transmission of other, currently unknown, viruses or other pathogens is possible.
    • Nephrotic syndrome, especially in inhibitor patients undergoing long-term factor replacement for ITI, may lead to renal dysfunction.
    • Anemia, leukopenia, and thrombocytopenia could occur secondary to chronic liver disease, bone marrow suppression by viruses, or they may occur as unintended adverse effects of antiretroviral medications.
    • The potential transmission of prions causing CJD or new vCJD is being closely monitored. As yet, no hemophilic person or other blood product recipient is known to have developed CJD.125
    • Psychosocial impact, including addiction to narcotic analgesics, alcohol, and other substances of abuse, leads to unstable personal and work relationships.
    • Lack of availability of appropriate jobs; an inability to maintain a job due to recurrent illnesses; the need for repeated job absences; and the need for repeated, expensive medical care all lead to the likelihood of an inability of individuals with hemophilia to adequately support themselves economically.
    • Severe arthropathy develops from repeated bleeding of a target joint, with limitation of joint movement and ambulation. Muscle bleeding adds to these problems, and pseudocysts can lead to amputation.
    • Chronic progressive hepatitis leads to hepatic failure and may be associated with hepatocellular carcinoma if the patient survives long enough. Hepatitis can be caused by hepatitis viruses A-E and G and the SEN family of viruses A-H; SEN D and SEN H are transmitted parenterally and cause posttransfusion hepatitis.86,108
    • HIV seroconversion and progression to AIDS are serious problems in 30-90% of patients with hemophilia who were treated with older factor replacement products; this occurred before the recognition and understanding of the role of the HIV virus and its consequences. Based on a retrospective analysis of stored hemophilic plasmas, seroconversion apparently started in 1978, with 70% of patients progressing to clinical AIDS over 11 years. The first individual with hemophilia who also had AIDS was reported from the United States in 1983. Five percent of sexual partners are HIV positive; other household members usually remain negative. Hemophilic patients with AIDS do not develop Kaposi sarcoma, unlike AIDS patients without hemophilia who are prone to Kaposi sarcoma. Emerging pathogens include HIV 2 and HIV group O.85
    • Allergic reactions to factor replacement products, the development of inhibitors, CNS bleeding, and other infections all can lead to death. The development of inhibitors adds further complexity.
    • Cryoprecipitate, which can be used as a backup for emergencies, not only has factor VIII-C, but it also has von Willebrand factor, fibrinogen, and other proteins.
      • Worldwide, most people with hemophilia receive cryoprecipitate as their principal factor replacement product because of a lack of availability, an inability to purchase expensive purified concentrates, or a belief in the better viral safety of cryoprecipitate made by individual blood banks from screened donors. Extreme variability in the safety of cryoprecipitate is evidenced by data indicating that in the United States, there was a 2% risk of being exposed to HIV-contaminated cryoprecipitate, whereas in Venezuela, the risk rose to 40% in persons with hemophilia receiving once-monthly cryoprecipitate made from 15 donors over a lifetime (60 y) of treatment; these estimates were based on a study that attempted to predict the risk of HIV infection following cryoprecipitate therapy.
      • Immune dysfunction from protein overload has been a problem in the past with the use of less pure factor replacement products. Additionally, transforming growth factor beta may be an immunomodulatory contaminant of factor VIII concentrates.
    • A study of the causes of death over a 15-year period in Scotland showed that life expectancy among patients with hemophilia increased despite the widespread prevalence of morbidity related to HIV and hepatitis C infection acquired from old plasma-derived factor replacement product that caused an increase in the use of hospital beds and a fluctuation in the need for hospitalization for bleeding.
    • Parvovirus B19 and TT virus are 2 nonlipid-enveloped viruses that can be transmitted by coagulation factor concentrates. TT virus has been shown to contaminate first-generation rFVIII and factor IX concentrates as a result of the use of human albumin that had been contaminated with TT virus.54 Second-generation recombinant products that do not use human albumin have been free of TT virus. A study of 39 children with hemophilia A and B in South Africa showed that in children exposed to locally produced factor replacement products, there was a risk of transmission of parvovirus B19, but not TTV, when compared with controls. Other emerging viruses include human herpes virus 8.85
    • A review of concerns over classic CJD or vCJD indicated that the FDA's Transmissible Spongiform Encephalopathies Advisory Committee proposal to limit the pool of blood donors and to exclude donors who, since 1980, have traveled in Europe for longer than 5 years or who have spent a total of 3 months or more in the United Kingdom reduces the risk of vCJD contamination of blood supplies. Newer blood tests for the detection of vCJD are expected in the near future.85,125
    • Pseudocysts develop as a result of recurrent slow bleeding and lead to extensive destruction of bone (see Images 14-17).

Prognosis

  • The prognosis of individuals with factor VIII deficiency (hemophilia A) depends on the type of complications a patient develops; it also depends on the type of factor product replacement the patient receives and the viral infections the patient accumulates over the years.
  • Newly diagnosed patients must receive recombinant products that ensure maximum safety.
  • Primary prophylaxis may be the best way to preserve joint function. Joint replacement is likely in the older patients with severe arthropathy. Patients with inhibitors are now able to undergo orthopedic procedures.
  • Early and complete genetic testing may help patients prepare for possible inhibitor development.
  • Blockade of T-cell activation may reduce the anamnestic rise in inhibitor titers.
  • Gene therapy is still in its infancy, but it is the best long-term solution. See Medical Care for details.

Patient Education

The following are desirable for those affected by factor VIII conditions:

  • Registration with the local chapter of the National Hemophilia Foundation
  • Attendance at educational seminars
  • One-on-one discussions of all issues, including type and mode of inheritance of the genetic defect, with patient and family members
  • The help of a psychosocial worker
  • Molecular genetic testing for factor VIII (FVIII) mutations is desirable, because determination of FVIII activity cannot reliably identify female carriers.126 Establishing the molecular diagnosis in each index case is also valuable, along with expression studies of novel mutations to prove their causative nature.

Miscellaneous

Medicolegal Pitfalls

  • Medicolegal pitfalls include making wrong diagnosis, using the wrong factor replacement product, administering of inappropriate therapy, and creating inordinate delays in replacing factor.
  • Missing the diagnosis of HIV is another concern.
  • The development of severe allergic or anaphylactic reactions may precipitate legal concerns, but a well-educated patient and family will understand that reactions related to the genetic mutation will occur in certain patients. However, prompt attention to allergic reactions is essential, and proper and adequate monitoring of patients in the appropriate setting, particularly in young children who are just starting therapy, is crucial.

Special Concerns

  • Patients with hemophilia should undergo genetic testing so that the type of defect in the family is known; that information would then be available to carriers for use in prenatal testing. Carriers with a sibling with hemophilia or those who have seen other members in the family with this disease are more likely to undergo prenatal testing. A woman who has given birth to a child with hemophilia is more likely to have fewer children than women who have undergone prenatal testing.
  • Manage pregnancy, labor, and delivery based on the patient's factor VIII level and bleeding. Ensure prompt therapy (ie, hydration, epinephrine, antihistaminics) for allergic reactions. Awareness of the possible development of thrombotic complications during factor product replacement and the need for anticoagulants is important.
 
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.



More on Factor VIII

Overview: Factor VIII
Differential Diagnoses & Workup: Factor VIII
Treatment & Medication: Factor VIII
Follow-up: Factor VIII
Multimedia: Factor VIII
References
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Keywords

factor VIII, hemophilia, von Willebrand, von Willebrand disease, von Willebrands, hemophilia A, factor 8, blood coagulation factor VIII, factor VIII coagulant activity, F8, coagulation factor VIII, F VIII-C, FVIII-C, F VIII clotting activity, FVIII clotting activity, antihemophilic globulin, blood disease, blood disorder, hematologic disorder, bleeding disorder, hemostatic system, plasma coagulation system, hemophilia B, haemophilia, hemorrhagic disorder, coagulation disorder, clotting disorder, blood clotting, coagulopathies, coagulopathy, cryoprecipitate, plasma concentrate, F8A gene, F8B gene, ERGIC53 gene, combined deficiency of FV and FVIII, PLAS+SD, Advate, DDAVP, Stimate, EACA, AMCA, Cyklokapron

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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, UMDNJ-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.

Medical Editor

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.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

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

CME Editor

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 Osteopathic Internists, 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: Abbott Grant/research funds Speaking and teaching; Genzyme Honoraria Consulting; Amgen Honoraria Speaking and teaching; Ortho Biotech Honoraria Speaking and teaching

Chief Editor

Emmanuel C Besa, MD, Professor, Department of Medicine, Division of Hematologic Malignancies, Kimmel Cancer Center, 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 Hematology, and New York Academy of Sciences
Disclosure: Nothing to disclose.

 
 
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