Hemophilia A Medication: Hemostatics, Vasopressin-Related, Antifibrinolytic Agents, Monoclonal Antib
Hemophilia A Medication: Hemostatics, Vasopressin-Related, Antifibrinolytic Agents, Monoclonal Antibodies
Factor VIII (FVIII) is the treatment of choice for acute or potential hemorrhage. Recombinant FVIII concentrate is the preferred source of factor VIII. Prophylactic administration of FVIII is often recommended for pediatric patients with severe disease. The FVIII activity level should be corrected to 100% of normal for potentially serious hemorrhage (eg, central nervous system, trauma related, gastrointestinal [GI], genitourinary, epistaxis) and to 30-50% of normal for minor hemorrhage (eg, hemarthrosis, oral mucosal, muscular).
One unit of FVIII is the amount of FVIII in 1 mL of plasma (1 U/mL or 1%). The volume of distribution of FVIII is that of plasma, approximately 50 mL/kg. The difference between the desired FVIII activity level and the patient's native FVIII activity level can be calculated by simple subtraction and expressed as a fraction (eg, 100% - 5% = 95% or 0.95).
To determine the number of units of FVIII needed to correct the FVIII activity level, use the following formula:
Units FVIII = (weight in kg)(50 mL plasma/kg)(1 U FVIII/mL plasma)(desired FVIII level minus the native FVIII level)
As an example, an 80-kg individual diagnosed with hemophilia with known 1% FVIII activity level presents to the emergency department with a severe upper GI bleed. The correct dose of FVIII to administer in this case would be calculated as follows:
Units FVIII = (80 kg)(50 mL/kg)(1 U FVIII/mL)(0.99) = 3960
The next dose should be administered 12 hours after the initial dose and is one half the initial calculated dose. Minor hemorrhage requires 1-3 doses of FVIII. Major hemorrhage requires many doses and continued monitoring of FVIII activity with the goal of keeping the trough activity level at no lower than 50%. Continuous infusions of FVIII may be considered for major hemorrhage.
The specific factor product that patients use is often part of their individualized treatment plan. Patients, or parents of young children, will usually be well educated on their dosing/products. This information also can be found on institutional treatment center/blood bank databases.
Other medicinal adjuncts to factor VIII (eg, desmopressin acetate [DDAVP], antifibrinolytics) often are useful in achieving hemostasis and can lessen the need for FVIII infusion. Antifibrinolytic agents, such as aminocaproic acid and tranexamic acid, are especially useful for oral mucosal bleeds but are contraindicated as initial therapies for hemophilia-related hematuria originating from the upper urinary tract because they can cause obstructive uropathy or anuria.
FVIII concentrates replace deficient FVIII in patients with hemophilia A, with the goal of achieving a normal hematologic response to hemorrhage or preventing hemorrhage. Recombinant products should be used initially and subsequently in all newly diagnosed cases of hemophilia that require factor replacement. Agents that bypass FVIII activity in the clotting cascade (eg, activated FVII) are used in patients with FVIII inhibitors.
These are synthetic products and are the most commonly used form of treatment when the administration of clotting protein factor VIII is indicated. In hemophilia A patients, it temporarily restores hemostasis
These are pooled plasma products (high purity) with factor VIII, which is necessary for stable clot formation and for maintenance of hemostasis.
This agent is a freeze-dried sterile human plasma fraction with FVIII inhibitor bypassing activity. It contains factors II, IX, and X, mainly nonactivated; and FVII, mainly in the activated form. It may shorten the activated partial thromboplastin time of plasma containing factor VIII inhibitors.
Anti-inhibitor coagulant complex is indicated for prevention and control of spontaneous hemorrhage or bleeding during surgical interventions in hemophilia patients who have autoantibodies or alloantibodies to coagulation factors. It is also indicated for routine prophylaxis to prevent or reduce the frequency of bleeding episodes in patients with hemophilia A or B who have developed inhibitors.
Recombinant activated factor (FVIIa) is indicated for the treatment of bleeding episodes in patients with hemophilia A and inhibitors. When complexed with tissue factor, this agent can activate the conversion of coagulation factor X to factor Xa as well as coagulation factor IX to IXa. Factor Xa, in complex with other factors, then converts prothrombin to thrombin, which leads to the formation of a hemostatic plug by converting fibrinogen to fibrin and thereby inducing local hemostasis. This process may also occur on the surface of activated platelets.
Desmopressin transiently increases the FVIII plasma level in patients with mild hemophilia A.
Desmopressin causes a transient increase (up to 4-fold) in FVIII plasma levels of patients with mild hemophilia A. It also produces a dose-dependent increase in plasminogen activator. It is useful for minor hemorrhage episodes only. It may be useful in patients with FVIII inhibitors.
Desmopressin Increases the cellular permeability of the collecting ducts, resulting in renal reabsorption of water. Tachyphylaxis may occur even after first dose, but drug can be effective again after several days.
These agents are used in addition to factor VIII replacement for oral mucosal hemorrhage and prophylaxis, as the oral mucosa is rich in native fibrinolytic activity. Their use is contraindicated as initial therapies for hemophilia-related hematuria originating from the upper urinary tract because they can cause obstructive uropathy or anuria. They should not be used in combination with prothrombin complex concentrate (PCC).
This lysine inhibits fibrinolysis by blocking the binding of plasminogen to fibrin and inhibiting plasminogen and conversion to plasmin, resulting in the inhibition of fibrinolysis. The principal drawbacks of this agent are that thrombi formed during treatment are not lysed, and its effectiveness is uncertain. It has been used to prevent recurrence of subarachnoid hemorrhage.
This agent is widely distributed. Its half-life is 1-2 hours. Peak effect occurs within 2 hours. Hepatic metabolism is minimal.
This agent is an alternative to aminocaproic acid. It inhibits fibrinolysis by displacing plasminogen from fibrin. It also inhibits the proteolytic activity of plasmin.
Monoclonal antibodies are used to bind to specific antigens, thereby stimulating the immune system to target these antigens.
Rituximab is a monoclonal antibody directed against the CD20 antigen on B-lymphocytes. It is recommended as second-line therapy in immune tolerance induction regimens for patients with FVIII inhibitors, especially those with high inhibitor titers. This agent binds to, and mediates destruction of, B-cells, thereby decreasing production of FVIII inhibitors and autoimmunization.
Robert A Zaiden, MD Assistant Professor, Division of Hematology/Oncology, Department of Medicine, University of Florida at Jacksonville College of Medicine
Robert A Zaiden, MD is a member of the following medical societies: American College of Physicians, American Society of Clinical Oncology
Coauthor(s)
Emmanuel C Besa, MD Professor Emeritus, Department of Medicine, Division of Hematologic Malignancies and Hematopoietic Stem Cell Transplantation, 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 Society of Clinical Oncology, American College of Clinical Pharmacology, American Federation for Medical Research, American Society of Hematology, New York Academy of Sciences
Mary A Furlong, MD Associate Professor and Program/Residency Director, Department of Pathology, Georgetown University School of Medicine
Mary A Furlong, MD is a member of the following medical societies: United States and Canadian Academy of Pathology
Gary D Crouch, MD Associate Professor, Program Director of Pediatric Hematology-Oncology Fellowship, Department of Pediatrics, Uniformed Services University of the Health Sciences
Gary D Crouch, MD is a member of the following medical societies: American Academy of Pediatrics, American Society of Hematology
Chief Editor
Steven C Dronen, MD, FAAEM Chair, Department of Emergency Medicine, LeConte Medical Center
Steven C Dronen, MD, FAAEM is a member of the following medical societies: American Academy of Emergency Medicine, Society for Academic Emergency Medicine
Acknowledgements
Dimitrios P Agaliotis, MD, PhD, FACP Consulting Staff, Department of Medicine, Baptist Health System
Dimitrios P Agaliotis, MD, PhD, FACP is a member of the following medical societies: American College of Physicians, American Medical Association, American Society of Hematology, and Florida Medical Association
Jeffrey L Arnold, MD, FACEP Chairman, Department of Emergency Medicine, Santa Clara Valley Medical Center
Jeffrey L Arnold, MD, FACEP is a member of the following medical societies: American Academy of Emergency Medicine and American College of Physicians
Disclosure: Nothing to disclose.
Emmanuel C Besa, MD Professor, Department of Medicine, Division of Hematologic Malignancies and Hematopoietic Stem Cell Transplantation, 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.
Max J Coppes, MD, PhD, MBA President, BC Cancer Agency, Vancouver
Max J Coppes, MD, PhD, MBA, is a member of the following medical societies: Alberta Medical Association, American College of Healthcare Executives, American Society of Pediatric Hematology/Oncology, and Society for Pediatric Research
Disclosure: Astellas Pharma US Inc Honoraria Chair Endpoint Review Committee
Brendan R Furlong, MD Clinical Chief, Department of Emergency Medicine, Georgetown University Hospital
Brendan R Furlong, MD is a member of the following medical societies: American College of Emergency Physicians and Society for Academic Emergency Medicine
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.
William G Gossman, MD Associate Clinical Professor of Emergency Medicine, Creighton University School of Medicine; Consulting Staff, Department of Emergency Medicine, Creighton University Medical Center
William G Gossman, MD is a member of the following medical societies: American Academy of Emergency Medicine
Disclosure: Nothing to disclose.
Lawrence F Jardine, MD, FRCPC Associate Professor, Department of Pediatrics, Schulich School of Medicine and Dentistry, University of Western Ontario; Head, Section of Pediatric Hematology and Oncology, Children's Hospital of Western Ontario; Associate Scientist, Child Health Research Institute
Lawrence F Jardine, MD, FRCPC is a member of the following medical societies: American Society of Hematology, American Society of Pediatric Hematology/Oncology, Canadian Medical Protective Association, Children's Oncology Group, College of Physicians and Surgeons of Ontario, Hemophilia and Thrombosis Research Society, Ontario Medical Association, and Royal College of Physicians and Surgeons of Canada
Disclosure: Baxter Honoraria Consulting; Bayer Honoraria Consulting; Novartis Honoraria Speaking and teaching
Elzbieta Klujszo, MD Head of Department of Dermatology, Wojewodzki Szpital Zespolony, Kielce
Disclosure: Nothing to disclose.
Adonis Lorenzana, MD Consulting Staff, Department of Pediatric Oncology, St John Hospital and Medical Center
Adonis Lorenzana, MD is a member of the following medical societies: American Academy of Pediatrics and American Society of Pediatric Hematology/Oncology
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.
Saduman Ozturk, PA-C Physician Assistant, Bone Marrow Transplant Center, Florida Hospital Cancer Institute
Disclosure: Nothing to disclose.
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
Hadi Sawaf, MD Director, Pediatric Hematology Oncology, Van Elslander Cancer Center; Clinical Assistant Professor, Wayne State University School of Medicine
Hadi Sawaf, MD is a member of the following medical societies: American Academy of Pediatrics, American Society of Clinical Oncology, and American Society of Hematology
Disclosure: Nothing to disclose.
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
Robert A Schwartz, MD, MPH Professor and Head, Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, Rutgers 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, New York Academy of Medicine, and Sigma Xi
Disclosure: Nothing to disclose.
Karen Seiter, MD Professor, Department of Internal Medicine, Division of Oncology/Hematology, New York Medical College
Karen Seiter, MD is a member of the following medical societies: American Association for Cancer Research, American College of Physicians, and American Society of Hematology
Disclosure: Novartis Honoraria Speaking and teaching; Novartis Consulting fee Speaking and teaching; Ariad Honoraria Speaking and teaching; Celgene Honoraria Speaking and teaching
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
Acknowledgments
The authors gratefully acknowledge the provision of several photographs used in this article by a dedicated colleague from Chicago, Margaret Telfer, MD. The authors 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
Coagulation pathway.
The hemostatic pathway. APC = activated protein C (APC); AT-III = antithrombin III; FDP = fibrin degradation products; HC-II = heparin cofactor II; HMWK = high-molecular-weight kininogen; PAI = plasminogen activator inhibitor; sc-uPA = single-chain urokinase plasminogen activator; tc-uPA = two-chain urokinase plasminogen activator; TFPI = tissue factor pathway inhibitor; tPA = tissue plasminogen activator
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.
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.
Coagulation Cascade
Table 1. Severity, Factor Activity, and Hemorrhage Type
Table 2. General Guidelines for Factor Replacement for the Treatment of Bleeding in Hemophilia
Medication Summary
Factor VIII (FVIII) is the treatment of choice for acute or potential hemorrhage. Recombinant FVIII concentrate is the preferred source of factor VIII. Prophylactic administration of FVIII is often recommended for pediatric patients with severe disease. The FVIII activity level should be corrected to 100% of normal for potentially serious hemorrhage (eg, central nervous system, trauma related, gastrointestinal [GI], genitourinary, epistaxis) and to 30-50% of normal for minor hemorrhage (eg, hemarthrosis, oral mucosal, muscular).
One unit of FVIII is the amount of FVIII in 1 mL of plasma (1 U/mL or 1%). The volume of distribution of FVIII is that of plasma, approximately 50 mL/kg. The difference between the desired FVIII activity level and the patient's native FVIII activity level can be calculated by simple subtraction and expressed as a fraction (eg, 100% - 5% = 95% or 0.95).
To determine the number of units of FVIII needed to correct the FVIII activity level, use the following formula:
Units FVIII = (weight in kg)(50 mL plasma/kg)(1 U FVIII/mL plasma)(desired FVIII level minus the native FVIII level)
As an example, an 80-kg individual diagnosed with hemophilia with known 1% FVIII activity level presents to the emergency department with a severe upper GI bleed. The correct dose of FVIII to administer in this case would be calculated as follows:
Units FVIII = (80 kg)(50 mL/kg)(1 U FVIII/mL)(0.99) = 3960
The next dose should be administered 12 hours after the initial dose and is one half the initial calculated dose. Minor hemorrhage requires 1-3 doses of FVIII. Major hemorrhage requires many doses and continued monitoring of FVIII activity with the goal of keeping the trough activity level at no lower than 50%. Continuous infusions of FVIII may be considered for major hemorrhage.
The specific factor product that patients use is often part of their individualized treatment plan. Patients, or parents of young children, will usually be well educated on their dosing/products. This information also can be found on institutional treatment center/blood bank databases.
Other medicinal adjuncts to factor VIII (eg, desmopressin acetate [DDAVP], antifibrinolytics) often are useful in achieving hemostasis and can lessen the need for FVIII infusion. Antifibrinolytic agents, such as aminocaproic acid and tranexamic acid, are especially useful for oral mucosal bleeds but are contraindicated as initial therapies for hemophilia-related hematuria originating from the upper urinary tract because they can cause obstructive uropathy or anuria.
Hemostatics
Class Summary
FVIII concentrates replace deficient FVIII in patients with hemophilia A, with the goal of achieving a normal hematologic response to hemorrhage or preventing hemorrhage. Recombinant products should be used initially and subsequently in all newly diagnosed cases of hemophilia that require factor replacement. Agents that bypass FVIII activity in the clotting cascade (eg, activated FVII) are used in patients with FVIII inhibitors.
Antihemophilic factor recombinant (Helixate FS, Xyntha, ogenate FS, NovoEight, Recombinate, Advate, Eloctate, Factor VIII [Recombinant])
These are synthetic products and are the most commonly used form of treatment when the administration of clotting protein factor VIII is indicated. In hemophilia A patients, it temporarily restores hemostasis
Factor VIII, human plasma derived (Monoclate-P, Hemofil M, Koate DVI)
These are pooled plasma products (high purity) with factor VIII, which is necessary for stable clot formation and for maintenance of hemostasis.
Anti-inhibitor coagulant complex (Feiba NF, Feiba VH Immuno)
This agent is a freeze-dried sterile human plasma fraction with FVIII inhibitor bypassing activity. It contains factors II, IX, and X, mainly nonactivated; and FVII, mainly in the activated form. It may shorten the activated partial thromboplastin time of plasma containing factor VIII inhibitors.
Anti-inhibitor coagulant complex is indicated for prevention and control of spontaneous hemorrhage or bleeding during surgical interventions in hemophilia patients who have autoantibodies or alloantibodies to coagulation factors. It is also indicated for routine prophylaxis to prevent or reduce the frequency of bleeding episodes in patients with hemophilia A or B who have developed inhibitors.
Factor VIIa, recombinant (NovoSeven RT)
Recombinant activated factor (FVIIa) is indicated for the treatment of bleeding episodes in patients with hemophilia A and inhibitors. When complexed with tissue factor, this agent can activate the conversion of coagulation factor X to factor Xa as well as coagulation factor IX to IXa. Factor Xa, in complex with other factors, then converts prothrombin to thrombin, which leads to the formation of a hemostatic plug by converting fibrinogen to fibrin and thereby inducing local hemostasis. This process may also occur on the surface of activated platelets.
Vasopressin-Related
Class Summary
Desmopressin transiently increases the FVIII plasma level in patients with mild hemophilia A.
Desmopressin (DDAVP, Stimate)
Desmopressin causes a transient increase (up to 4-fold) in FVIII plasma levels of patients with mild hemophilia A. It also produces a dose-dependent increase in plasminogen activator. It is useful for minor hemorrhage episodes only. It may be useful in patients with FVIII inhibitors.
Desmopressin Increases the cellular permeability of the collecting ducts, resulting in renal reabsorption of water. Tachyphylaxis may occur even after first dose, but drug can be effective again after several days.
Antifibrinolytic Agents
Class Summary
These agents are used in addition to factor VIII replacement for oral mucosal hemorrhage and prophylaxis, as the oral mucosa is rich in native fibrinolytic activity. Their use is contraindicated as initial therapies for hemophilia-related hematuria originating from the upper urinary tract because they can cause obstructive uropathy or anuria. They should not be used in combination with prothrombin complex concentrate (PCC).
Epsilon aminocaproic acid (Amicar)
This lysine inhibits fibrinolysis by blocking the binding of plasminogen to fibrin and inhibiting plasminogen and conversion to plasmin, resulting in the inhibition of fibrinolysis. The principal drawbacks of this agent are that thrombi formed during treatment are not lysed, and its effectiveness is uncertain. It has been used to prevent recurrence of subarachnoid hemorrhage.
This agent is widely distributed. Its half-life is 1-2 hours. Peak effect occurs within 2 hours. Hepatic metabolism is minimal.
Tranexamic acid (Cyklokapron, Lysteda)
This agent is an alternative to aminocaproic acid. It inhibits fibrinolysis by displacing plasminogen from fibrin. It also inhibits the proteolytic activity of plasmin.
Monoclonal Antibodies
Class Summary
Monoclonal antibodies are used to bind to specific antigens, thereby stimulating the immune system to target these antigens.
Rituximab (Rituxan)
Rituximab is a monoclonal antibody directed against the CD20 antigen on B-lymphocytes. It is recommended as second-line therapy in immune tolerance induction regimens for patients with FVIII inhibitors, especially those with high inhibitor titers. This agent binds to, and mediates destruction of, B-cells, thereby decreasing production of FVIII inhibitors and autoimmunization.
Robert A Zaiden, MD Assistant Professor, Division of Hematology/Oncology, Department of Medicine, University of Florida at Jacksonville College of Medicine
Robert A Zaiden, MD is a member of the following medical societies: American College of Physicians, American Society of Clinical Oncology
Coauthor(s)
Emmanuel C Besa, MD Professor Emeritus, Department of Medicine, Division of Hematologic Malignancies and Hematopoietic Stem Cell Transplantation, 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 Society of Clinical Oncology, American College of Clinical Pharmacology, American Federation for Medical Research, American Society of Hematology, New York Academy of Sciences
Mary A Furlong, MD Associate Professor and Program/Residency Director, Department of Pathology, Georgetown University School of Medicine
Mary A Furlong, MD is a member of the following medical societies: United States and Canadian Academy of Pathology
Gary D Crouch, MD Associate Professor, Program Director of Pediatric Hematology-Oncology Fellowship, Department of Pediatrics, Uniformed Services University of the Health Sciences
Gary D Crouch, MD is a member of the following medical societies: American Academy of Pediatrics, American Society of Hematology
Chief Editor
Steven C Dronen, MD, FAAEM Chair, Department of Emergency Medicine, LeConte Medical Center
Steven C Dronen, MD, FAAEM is a member of the following medical societies: American Academy of Emergency Medicine, Society for Academic Emergency Medicine
Acknowledgements
Dimitrios P Agaliotis, MD, PhD, FACP Consulting Staff, Department of Medicine, Baptist Health System
Dimitrios P Agaliotis, MD, PhD, FACP is a member of the following medical societies: American College of Physicians, American Medical Association, American Society of Hematology, and Florida Medical Association
Jeffrey L Arnold, MD, FACEP Chairman, Department of Emergency Medicine, Santa Clara Valley Medical Center
Jeffrey L Arnold, MD, FACEP is a member of the following medical societies: American Academy of Emergency Medicine and American College of Physicians
Disclosure: Nothing to disclose.
Emmanuel C Besa, MD Professor, Department of Medicine, Division of Hematologic Malignancies and Hematopoietic Stem Cell Transplantation, 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.
Max J Coppes, MD, PhD, MBA President, BC Cancer Agency, Vancouver
Max J Coppes, MD, PhD, MBA, is a member of the following medical societies: Alberta Medical Association, American College of Healthcare Executives, American Society of Pediatric Hematology/Oncology, and Society for Pediatric Research
Disclosure: Astellas Pharma US Inc Honoraria Chair Endpoint Review Committee
Brendan R Furlong, MD Clinical Chief, Department of Emergency Medicine, Georgetown University Hospital
Brendan R Furlong, MD is a member of the following medical societies: American College of Emergency Physicians and Society for Academic Emergency Medicine
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.
William G Gossman, MD Associate Clinical Professor of Emergency Medicine, Creighton University School of Medicine; Consulting Staff, Department of Emergency Medicine, Creighton University Medical Center
William G Gossman, MD is a member of the following medical societies: American Academy of Emergency Medicine
Disclosure: Nothing to disclose.
Lawrence F Jardine, MD, FRCPC Associate Professor, Department of Pediatrics, Schulich School of Medicine and Dentistry, University of Western Ontario; Head, Section of Pediatric Hematology and Oncology, Children's Hospital of Western Ontario; Associate Scientist, Child Health Research Institute
Lawrence F Jardine, MD, FRCPC is a member of the following medical societies: American Society of Hematology, American Society of Pediatric Hematology/Oncology, Canadian Medical Protective Association, Children's Oncology Group, College of Physicians and Surgeons of Ontario, Hemophilia and Thrombosis Research Society, Ontario Medical Association, and Royal College of Physicians and Surgeons of Canada
Disclosure: Baxter Honoraria Consulting; Bayer Honoraria Consulting; Novartis Honoraria Speaking and teaching
Elzbieta Klujszo, MD Head of Department of Dermatology, Wojewodzki Szpital Zespolony, Kielce
Disclosure: Nothing to disclose.
Adonis Lorenzana, MD Consulting Staff, Department of Pediatric Oncology, St John Hospital and Medical Center
Adonis Lorenzana, MD is a member of the following medical societies: American Academy of Pediatrics and American Society of Pediatric Hematology/Oncology
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.
Saduman Ozturk, PA-C Physician Assistant, Bone Marrow Transplant Center, Florida Hospital Cancer Institute
Disclosure: Nothing to disclose.
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
Hadi Sawaf, MD Director, Pediatric Hematology Oncology, Van Elslander Cancer Center; Clinical Assistant Professor, Wayne State University School of Medicine
Hadi Sawaf, MD is a member of the following medical societies: American Academy of Pediatrics, American Society of Clinical Oncology, and American Society of Hematology
Disclosure: Nothing to disclose.
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
Robert A Schwartz, MD, MPH Professor and Head, Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, Rutgers 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, New York Academy of Medicine, and Sigma Xi
Disclosure: Nothing to disclose.
Karen Seiter, MD Professor, Department of Internal Medicine, Division of Oncology/Hematology, New York Medical College
Karen Seiter, MD is a member of the following medical societies: American Association for Cancer Research, American College of Physicians, and American Society of Hematology
Disclosure: Novartis Honoraria Speaking and teaching; Novartis Consulting fee Speaking and teaching; Ariad Honoraria Speaking and teaching; Celgene Honoraria Speaking and teaching
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
Acknowledgments
The authors gratefully acknowledge the provision of several photographs used in this article by a dedicated colleague from Chicago, Margaret Telfer, MD. The authors 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
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- Federici AB. The factor VIII/von Willebrand factor complex: basic and clinical issues. Haematologica. 2003 Jun. 88(6):EREP02. [Medline].
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Coagulation pathway.
The hemostatic pathway. APC = activated protein C (APC); AT-III = antithrombin III; FDP = fibrin degradation products; HC-II = heparin cofactor II; HMWK = high-molecular-weight kininogen; PAI = plasminogen activator inhibitor; sc-uPA = single-chain urokinase plasminogen activator; tc-uPA = two-chain urokinase plasminogen activator; TFPI = tissue factor pathway inhibitor; tPA = tissue plasminogen activator
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.
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.
Coagulation Cascade
- Table 1. Severity, Factor Activity, and Hemorrhage Type
- Table 2. General Guidelines for Factor Replacement for the Treatment of Bleeding in Hemophilia
Table 1. Severity, Factor Activity, and Hemorrhage Type
| Classification | Factor Activity, % | Cause of Hemorrhage |
| Mild | >5-40 | Major trauma or surgery |
| Moderate | 1-5 | Mild-to-moderate trauma |
| Severe | < 1 | Spontaneous |
Table 2. General Guidelines for Factor Replacement for the Treatment of Bleeding in Hemophilia
| Indication or Site of Bleeding | Factor level Desired, % | FVIII Dose, IU/kg | Comment |
| Severe epistaxis; mouth, lip, tongue, or dental work | 20-50 | 10-25 | Consider aminocaproic acid (Amicar), 1-2 d |
| Joint (hip or groin) | 40 | 20 | Repeat transfusion in 24-48 h |
| Soft tissue or muscle | 20-40 | 10-20 | No therapy if site small and not enlarging (transfuse if enlarging) |
| Muscle (calf and forearm) | 30-40 | 15-20 | None |
| Muscle deep (thigh, hip, iliopsoas) | 40-60 | 20-30 | Transfuse, repeat at 24 h, then as needed |
| Neck or throat | 50-80 | 25-40 | None |
| Hematuria | 40 | 20 | Transfuse to 40% then rest and hydration |
| Laceration | 40 | 20 | Transfuse until wound healed |
| GI or retroperitoneal bleeding | 60-80 | 30-40 | None |
| Head trauma (no evidence of CNS bleeding) | 50 | 25 | None |
| Head trauma (probable or definite CNS bleeding, eg, headache, vomiting, neurologic signs) | 100 | 50 | Maintain peak and trough factor levels at 100% and 50% for 14 d if CNS bleeding documented |
| Trauma with bleeding, surgery | 80-100 | 50 | 10-14 d |
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