In June 2014 the FDA approved a long-acting recombinant FVIII–Fc fusion protein (rFVIIIFc) product (Eloctate) for control of bleeding episodes, management of perioperative bleeding, and routine prophylaxis in patients with hemophilia A. For routine prophylaxis, rVFIIIFC is infused every 4 days, whereas other available recombinant FVIII products are administered every 2-3 days. [54, 55]
The rFVIIIFc product was developed by fusing rFVIII to the Fc portion of IgG1, which allows a naturally occurring pathway to prolong the product's duration of action. FDA approval was based on a study in 164 patients with hemophilia A in which the median rate of bleeding episodes with prophylactic use of rFVIIIFc was 1.6 per year, compared with 33.6 per year in patients receiving on-demand treatment. [54, 55] In an open-label extension study of rFVIIIFc in 211 patients, with included up to 5 years of follow-up, no inhibitors were observed, annualized bleed rates remained low in patients on individualized prophylaxis, and most patients maintained extended-dosing intervals (median of 3.5 days). [56]
Other rFVIII products are also approved by the FDA for routine prophylaxis (eg, NovoEight, Kogenate, Nuwiq, Adynovate, Kovaltry, Afstyla, Jivi). Adynovate and Jivi are pegylated rFVIII products that allow less frequent administration. For prophylaxis, Jivi is administered every 5 days and Adynovate is administered 2 times per week.
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Coagulation pathway.
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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
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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.
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Possible genetic outcomes in individuals carrying the hemophilic gene.
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Photograph of a teenage boy with bleeding into his right thigh as well as both knees and ankles.
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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.
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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.
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Radiograph depicting advanced hemophilic arthropathy of the knee joint. These images show chronic severe arthritis, fusion, loss of cartilage, and joint space deformities.
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Radiograph depicting advanced hemophilic arthropathy of the elbow. This image shows chronic severe arthritis, fusion, loss of cartilage, and joint space deformities.
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Photograph of a hemophilic knee at surgery, with synovial proliferation caused by repeated bleeding; synovectomy was required.
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Large amount of vascular synovium removed at surgery.
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Microscopic appearance of synovial proliferation and high vascularity. If stained with iron, diffuse deposits would be demonstrated; iron-laden macrophages are present.
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Large pseudocyst involving the left proximal femur.
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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.
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Dissection of a pseudocyst.
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Transected pseudocyst with chocolate brown-black old blood.
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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.
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Plain radiograph of the pelvis showing a large lytic area.
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Intravenous pyelogram showing extreme displacement of the left kidney and ureter by a pseudocyst.
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Photograph depicting extensive spontaneous abdominal wall hematoma and thigh hemorrhage in an older, previously unaffected man with an acquired factor VIII inhibitor.
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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.
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Coagulation Cascade
