Factor VIII (FVIII) is the treatment of choice for acute or potential hemorrhage. Recombinant FVIII concentrate is generally 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.
Antihemophilic factor recombinant (Advate, Adynovate, Afstyla, Eloctate, Helixate FS, Kogenate FS, Kovaltry, NovoEight, Nuwiq, Obizur, Recombinate, turoctocog alfa, Xyntha)
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.
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- Approach Considerations
- Prehospital Care
- Emergency Department Care
- Factor VIII Concentrates
- Management of Bleeding Episodes by Site
- Treatment of Patients with Inhibitors
- Prophylactic Factor Infusions
- Pain Management
- Gene Therapy
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