Factor VIII Clinical Presentation

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

History

Recurrent spontaneous or minor injury–induced episodes of joint bleeding are common in persons with severe and moderately severe hemophilia, causing severe pain and limitation of joint movement. The repeated presence of blood in the joint leads to synovial hypertrophy, with a tendency for recurrent joint bleeding, which finally results in a destructive chronic synovitis with destruction of synovium, cartilage, and bone. This leads to chronic pain, arthritis, joint stiffness, and limitation of movement due to progressive and permanent severe joint damage with progressive muscle wasting (see images below).

Photograph of a teenage boy with bleeding into hisPhotograph 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 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 aPhotograph 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 arthropatRadiograph 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 arthropatRadiograph 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 sPhotograph of a hemophilic knee at surgery, with synovial proliferation caused by repeated bleeding; synovectomy was required. Large amount of vascular synovium removed at surgeLarge amount of vascular synovium removed at surgery. Microscopic appearance of synovial proliferation aMicroscopic appearance of synovial proliferation and high vascularity. If stained with iron, diffuse deposits would be demonstrated; iron-laden macrophages are present.

Intramuscular hemorrhage, the second most common bleeding event, also leads to acute severe and recurring pain, swelling, and limitation of movement. The hematoma may dissect down into the fascial planes and result in neuropathies due to nerve compression, such as with psoas bleeding; large retroperitoneal bleeding can lead to hypotension.

Mucous membranes can be the site of bleeding, manifesting as epistaxis, oropharyngeal, or retropharyngeal bleeding, which can lead to acute respiratory obstruction. The GI tract may be a source of bleeding in approximately one fifth of patients, with an increasing frequency due to the consequences of cirrhosis and the use of readily available over-the-counter nonsteroidal anti-inflammatory drugs (NSAIDs) for the relief of arthritic pain. Peptic ulcer disease is approximately 5 times more common in individuals with hemophilia than in the general population.

Central nervous system (CNS) hemorrhage (~3-14%) was the major cause of death in persons with hemophilia before the widespread availability and use of factor replacement to prevent bleeding and before the AIDS epidemic.[34] Approximately one third of CNS bleeding episodes lead to death, and at least half result in major, long-term sequelae. Bleeding is usually preceded by head trauma in children, whereas adults may develop CNS bleeding without obvious trauma. Symptoms are typical of any CNS event, with a variety of symptoms such as headaches, seizures, vomiting, and focal neurologic defects. Findings depend on the sites of bleeding.

Spontaneous hematuria can be seen in those with severe hemophilia. The use of NSAIDs, protease inhibitors, or over-the-counter drugs; trauma; exercise; or exertion may precipitate genitourinary (GU) bleeding. Associated clots in the GU system causing acute hydronephrosis may be a complication of the concomitant use of fibrinolytic inhibitors with factor replacement in patients with hematuria. Underlying pathology, such as nephrolithiasis, tumors, or infections, should be excluded when persistent bleeding is present. Indinavir (Crixivan; Merck & Co, Inc, Whitehouse Station, NJ) may be associated with crystalluria or calculi in HIV-infected patients.

Acute and chronic viral illnesses have been transmitted by the less pure blood products that were the only ones available to treat bleeding in the past. HIV-related illnesses and AIDS; repeated viral, fungal, and bacterial illnesses due to AIDS; malignancies, such as Kaposi sarcoma; and the aggressive AIDS-associated lymphomas are life-threatening complications.[35] Despite these problems, plasma-derived products remain a valuable resource without which many persons with hemophilia throughout the world would experience the painful consequences of recurrent bleeding. See Complications for further details.

The availability of newer recombinant products (with no risk of transmission of HIV and hepatitis) for use in home care and in-hospital treatment means that those unexposed to plasma-derived products could conceivably achieve a normal life span.

Pseudotumors are produced by a slow expansion of repeated hemorrhages in bone or soft tissues. They can be restricted by the fascial planes of a muscle, cause resorption of neighboring bone by pressure-induced ischemia, or develop under the periosteum, leading to erosion of the bony cortex. They develop slowly over months to years and often are asymptomatic, unless pressure on the nerves or vascular compromise occurs. Pseudotumors contain a brownish material and can become infected. The buttock, pelvis, and thighs are frequently involved locations for a pseudotumor (see images below).

Large pseudocyst involving the left proximal femurLarge pseudocyst involving the left proximal femur. Transected pseudocyst (following disarticulation oTransected 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. Dissection of a pseudocyst. Transected pseudocyst with chocolate brown-black oTransected pseudocyst with chocolate brown-black old blood. Photograph of a patient who presented with a slowlPhotograph 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 lytPlain radiograph of the pelvis showing a large lytic area. Intravenous pyelogram showing extreme displacementIntravenous pyelogram showing extreme displacement of the left kidney and ureter by a pseudocyst.

Delayed bleeding develops after dental extractions; therefore, patients require appropriate presurgical and postsurgical management. If not treated appropriately, dental bleeding can persist and expand to sublingual, pharyngeal, facial, or dissecting neck hematomas or other serious bleeding.

Co-inheritance of thrombophilic mutations has been suggested as a reason for a reduction in the severity of bleeding in some individuals with severe hemophilia. A study of the correlation between concentrate utilization, incidence of bleeding episodes per year, and prevalence of hemophilic arthropathy in those with severe hemophilia with and without the factor V Leiden mutation (a known thrombophilic mutation in the white population) showed that factor V Leiden carriers indeed had fewer bleeding episodes, but the authors of this study suggested, appropriately, the need to study this issue in a larger cohort with additional testing.[36]

The development of alloantibodies in persons with hemophilia is a serious complication that leads to increased bleeding and a lack of response to the usual therapy, which can be fatal (see images below). See Complications for more information.

Photograph depicting extensive spontaneous abdominPhotograph 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 spontaneoMagnetic resonance image of an extensive spontaneous abdominal wall hematoma and thigh hemorrhage in an older, previously unaffected man with an acquired factor VIII inhibitor.

Acquired factor VIII inhibitors (ie, acquired hemophilia due to an autoantibody in previously hemostatically normal individuals) are a cause of significant morbidity and are associated with a mortality rate of at least 20%, because they affect elderly people who have comorbid conditions. Patients present with extensive bleeding, often life threatening, before it is recognized.

In contrast to persons with severe inherited factor VIII deficiency (hemophilia A), in whom joint bleeding is common, patients with acquired hemophilia present with large intramuscular, retroperitoneal, limb, subcutaneous, GU, GI, or excessive postoperative or postpartum bleeding. Bleeding into an extremity can result in findings that are easily confused with deep vein thrombosis. Massive upper extremity bleeding can be precipitated by a simple venipuncture. Bleeding can develop at any site.

Postpartum inhibitors usually come to attention several months after delivery (2-5 mo), when bleeding symptoms supervene; rarely, the inhibitor may develop during pregnancy.

Because of the unusual characteristics of these autoantibodies, patients may present with significant bleeding despite the presence of detectable amounts of plasma factor VIII-C activity in vitro; this residual factor VIII activity in a patient with active bleeding can mislead the clinician about the seriousness of the factor VIII deficiency.

Bleeding manifestations in homozygous patients with the combined factor V and factor VIII deficiency include variable bleeding after circumcision, ranging from severe to less than severe. Epistaxis can occur, as can gingival bleeding and easy bruising, starting with mild trauma, as occurs during normal childhood activities. Menorrhagia can start at menarche. Hemarthrosis has been reported in approximately 20% of patients; therefore, joint bleeding is less common in this group than in patients with severe hemophilia A or B.

Confusion with joint bleeding may arise when bleeding occurs in a bursa surrounding a joint. For example, bleeding in the olecranon bursa may be misinterpreted as bleeding into the elbow joint.

In the absence of appropriate factor replacement, dental extractions or other surgeries precipitate bleeding. Intracranial bleeding can develop, even after minor trauma to the head.

Due to higher basal levels of factor V and factor VIII than those found in homozygotes with combined factor V and factor VIII deficiency, only a few heterozygotes manifest excessive bleeding.[37]

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Physical

Physical examination findings may include the following:

  • Severe pain in the target joint(s); bogginess around the involved joint(s) due to an inflamed synovium and the presence of blood and fluid; fullness of joint space and/or surrounding bursa; and varying degrees of limitation of joint mobility
  • Deep muscle hematomas, with pain, tenderness, and limitation of movement
  • Delayed onset of bleeding from sites of trauma and/or surgery
  • Blood in the urine
  • Blood in the stool or upper GI bleeding
  • Changes in neurologic function (eg, headache, focal neurologic deficits)
  • Signs of jaundice, spider angiomas, hepatomegaly accompanied by tenderness, and splenomegaly related to chronic hepatitis or cirrhosis
  • Fatigue, poor appetite, and loss of energy with progression of chronic viral illnesses, including HIV and hepatitis C
  • Weight loss, adenopathy, and opportunistic infections, particularly as a manifestation of AIDS
  • Possible development of anaphylaxis after the start of factor VIII infusions in severely deficient children (although the frequency is greater in patients with severe factor IX deficiency)
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Causes

With the cloning of the factor VIII gene in 1984, a new era began in the understanding of hemophilias. A large number of mutations have been documented in the factor VIII gene and account for hemophilia A, and, in the early part of the 20th century, the prediction that approximately one third of these would have to be de novo mutations not present in the mother's X chromosome was correct. The functional defects of factor VIII-C manifested as hemophilia A are due to structural defects in the factor VIII gene (see images below).

Structural domains of human factor VIII. Adapted fStructural 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. Image depicting the 28q region of the X chromosomeImage 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.

The gene for factor VIII is located on 28q (the most distal arm of the X chromosome), is approximately 186 kilobases (kb) long, and comprises approximately 0.1% of the DNA in the X chromosome; it has 26 exons and 25 introns. The site for factor VIII is linked to the locus for color-blindness and with polymorphisms at the glucose 6-phosphate dehydrogenase (G6PD) locus.

Intron 22 of the factor VIII gene, uniquely, contains 2 other genes. The first is called F8A, which is transcribed in a direction opposite to that of the factor VIII gene itself. The second gene is F8B, which is transcribed in the 3' (normal) direction similar to the factor VIII gene. Sequences called A2 and A3, homologous to the F8A sequence, are present on the X chromosome, 300 kb telomeric to the factor VIII gene.

Homologous recombination of the factor VIII gene, with inversion and crossover involving the F8A sequence in intron 22 and the homologous distal sequence on the X chromosome, results in a split in the factor VIII gene with the 2 parts aligned in opposite directions. This causes a disruption in the normal factor VIII coding sequence, with an inability to transcribe the complete, normal factor VIII protein, resulting in a loss of function. The mutation in intron 22 occurs during spermatogenesis and is a common cause of severe factor VIII-C deficiency, as it is present in approximately 40% of patients. It is easily detected using a Southern blot analysis of the patient's DNA. These patients are more likely to develop an inhibitor to factor VIII.

In one study, all detected inversions originated in a maternal grandparent during male meiosis (spermatogenesis), supporting the hypothesis that an unpaired Xq, rather than a paired X chromosome, is more likely to undergo an intrachromosomal inversion. The majority of mothers of persons with the sporadic, inversion-related severe hemophilia are carriers.[4]

The knowledge of the parental origin of the inversion mutation has important implications for genetic counseling and should help alleviate the severe emotional burden carried by mothers of persons with hemophilia, who are blamed or blame themselves for being the cause of their son's devastating illness.

Several other types of mutations have been described.

  • Point mutations can lead to mild, moderate, or severe deficiency of factor VIII-C, depending on the effect of that mutation on factor VIII gene function.
  • Missense mutations, such as the G-to-A single-base substitution, alter the amino acid composition of the molecule, producing a dysfunctional molecule (FVIII antigen, present with reduction in FVIII-C). These mutations are associated with mild, moderate, or severe factor VIII-C reductions and are associated with the development of factor VIII inhibitors. Intracellular accumulation of factor VIII induced by Arg 593→Cys and Asn 618→Ser missense mutations also result in reduction of cross-reacting material in severe hemophilia A.
  • Gene deletions lead to factor VIII-C deficiency, and large gene deletions result in severe hemophilia, with no detectable factor VIII antigen; such patients are more susceptible to inhibitor development. Insertions are apparently uncommon in the factor VIII gene, but they usually lead to severe hemophilia A.[38]
  • Non-sense mutations and abnormal splicing may also occur.

Modification of the clinical severity of the bleeding disorder resulting from a specific factor VIII mutation by co-inheritance of thrombophilic genes is increasingly recognized as a cause of the variability in bleeding manifestations within a single family with hemophilia A.[36, 39, 40] Additionally, keep in mind that phenotypic variations can be found in patients with the same genotype in a variety of hematologic disorders.[41] The case-control design has been suggested as an appropriate type of clinical study to elucidate genetic-environmental interactions.[42]

The role of genetic polymorphisms, particularly intragenic polymorphisms, should be recognized when providing genetic counseling for families with unknown mutations. Some polymorphisms are universal, whereas others appear to be restricted to particular ethnic groups; the latter situation will change as ethnic intermarriages increase with the increased globalization of populations.

Studies of a heterogeneous population in India have identified a higher heterozygosity index of polymorphic variants of 2 new variants of the multiallelic locus DXS52(St14) of the human X chromosome[43, 44] ; other intragenic polymorphisms have also been reported in this population and are of obvious use in prenatal diagnosis.[45] Data published for a Korean population showed a higher occurrence of low molecular weight (LMW) alleles in Korean persons than in white persons.[46]

Some cases of the combined deficiency of factor V and factor VIII are caused by mutations in the ERGIC53 gene, with loss of splicing or insertion of a nucleotide leading to a frameshift; both mutations identified to date result in an altered ERGIC-53 protein in the endoplasmic reticulum–Golgi apparatus. ERGIC53 has an affinity for the glycosylated B domains of both factor V and factor VIII, and the ERGIC-53 protein transports factor V and factor VIII through the secretory processes in cells.

In families with known mutations, allele-specific hybridization studies show the difference between homozygotes and heterozygotes. Because of a single error in a common processing mechanism affecting both factor V and factor VIII, a similar degree of reduction in plasma levels of factor V and factor VIII occurs in homozygotes, with levels varying 5-30%.[4, 5, 17, 26]

Other causes of this disorder remain to be identified. The Haemostasis Research Group Website (The Haemophilia A Mutation, Structure, Test and Resource Site [HAMSTeRS]) has a continually updated database of genetic defects related to hemophilia A.[47]

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Contributor Information and Disclosures
Author

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

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

Disclosure: Nothing to disclose.

Coauthor(s)

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

Disclosure: Nothing to disclose.

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

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

Disclosure: Nothing to disclose.

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

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

Disclosure: Nothing to disclose.

Specialty Editor Board

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

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

Disclosure: Nothing to disclose.

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

Disclosure: Medscape Salary Employment

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

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

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

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

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

Disclosure: Renal Ventures Ownership interest Other

Chief Editor

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

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

Disclosure: Nothing to disclose.

Additional Contributors

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

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



FVIII-C Activity



Dose and Duration of Therapy
Minor



Uncomplicated



hemarthroses



Superficial large



hematomas



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



Hematoma with dissection



Oral/mucosal hemorrhages and epistaxis*



Hematuria



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



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



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



Pharyngeal/retropharyngeal



Retroperitoneal



GI bleeding



CNS bleeding surgery



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



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



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