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Management of Joint Bleeding in Hemophilia

  • Authors: Mindy L. Simpson, MD; Leonard A. Valentino, MD
  • CME Released: 9/20/2012
  • Valid for credit through: 9/20/2013, 11:59 PM EST
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Target Audience and Goal Statement

This activity is intended for hematologists, radiologists, pediatricians, and other clinicians caring for patients with joint bleeding due to hemophilia.

The goal of this activity is to review the clinical presentation and management of hemarthrosis in patients with hemophilia.

Upon completion of this activity, participants will be able to:

  1. Describe the clinical characteristics of joint bleeding in hemophilia
  2. Describe prophylaxis to prevent joint bleeding in hemophilia
  3. Describe management of acute hemarthrosis in patients with hemophilia


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  • Mindy L. Simpson, MD

    Department of Pediatrics, Hemophilia and Thrombophilia Center, Rush University Medical Center, Chicago, Illinois


    Disclosure: Mindy L. Simpson, MD, has disclosed no relevant financial relationships.

  • Leonard A. Valentino, MD

    Department of Pediatrics, Hemophilia and Thrombophilia Center, Rush University Medical Center, Chicago, Illinois


    Disclosure: Leonard A. Valentino, MD, has disclosed no relevant financial relationships.


  • Elisa Manzotti

    Publisher, Future Science Group, London, United Kingdom


    Disclosure: Elisa Manzotti has disclosed no relevant financial relationships.

CME Author(s)

  • Laurie Barclay, MD

    Freelance writer and reviewer, Medscape, LLC


    Disclosure: Laurie Barclay, MD, has disclosed no relevant financial relationships.

CME Reviewer(s)

  • Nafeez Zawahir, MD

    CME Clinical Director, Medscape, LLC


    Disclosure: Nafeez Zawahir, MD, has disclosed no relevant financial relationships.

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Management of Joint Bleeding in Hemophilia: FVIII & FIX Genetics


FVIII & FIX Genetics

The human F8 gene, cloned in 1984, is located on the most distal band (Xq28) of the long arm of the X chromosome and spans 186 kb divided into 26 exons and 25 introns.[3] FVIII is primarily expressed in the liver, where sinusoidal endothelial cells are the chief source of circulating FVIII,[4,5] although hepatocytes also contain FVIII mRNA. The FVIII protein contains domains of internal homology, and the structure of the mature polypeptide from amino to carboxyl termini is A1-A2-B-A3-C1-C2. The large B domain is excised, and heavy and light chains form the mature FVIII, which is activated by thrombin. Hemophilia A results from multiple mutations in the F8 gene, of which approximately a third are de novo mutations in patients without a family history of the disease (this is also true for hemophilia B).[6] Gross mutations include inversions (e.g., intron 22 inversion); large deletions, which are associated with severe hemophilia and an increased risk for inhibitory antibodies; insertions; duplications and chromosomal rearrangements. Point mutations, small deletions or insertions and nonsense mutations are linked to a variety of disease phenotypes.[3,6,7]

The human F9 gene was cloned in 1982. Located in the subtelomeric region of the long arm of X chromosome, F9 is 34-kilobases long and is divided into eight exons and seven introns.[8] FIX is synthesized exclusively in the liver by hepatocytes and is processed during its secretion into the bloodstream. The mature FIX polypeptide contains three domains in the following structure: Gla – activation peptide – catalytic domain. The activation peptide is released during the conversion to activated FIX, which is then post-translationally modified by hydroxylation and vitamin K-dependent g-carboxylation.[9] Hemophilia B results from multiple mutations in the F9 gene, and patients with this bleeding disorder are classified as cross-reacting material (CRM) positive, defined as normal concentrations of the FIX antigen but reduced FIX activity; CRM reduced, defined as reduced FIX antigen and activity levels and CRM negative, defined as having no detectable FIX antigen or activity.[6,8] CRM-positive patients generally have missense mutations in coding regions or splicing or transcription mutations that result in decreased quantities of FIX. CRM-negative patients typically have frameshift or missense mutations that cause protein instability. In hemophilia B (but not hemophilia A), there is a strong correlation between the presence of partial or complete gene deletions and the development of inhibitors.[9] Intracellular CRM status has recently been proposed as a potential marker for alloantibody formation.[10]