Medication Summary
Factor VIII (FVIII) is the treatment of choice for acute or potential hemorrhage. Recombinant FVIII concentrate is generally the preferred source of FVIII. Prophylactic administration of FVIII is often recommended for 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:
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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:
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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. It is important to recall that response to factor replacement and half-life of product varies substantially across the population and that therapy should ideally be individualized for the patient. Peak and trough values drawn after a treatment and just prior to next treatment can be very helpful in individualizing therapy.
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 FVIII (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.
Monoclonal antibodies have entered clinical practice for prophylaxis in patients with hemophilia. They offer the benefit of subcutaneous rather than intravenous administration and, with some agents, efficacy in patients with FVIII inhibitors.
Coagulation Factors
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 (Advate, Adynovate, Afstyla)
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
Antihemophilic factor/von Willebrand factor complex (Alphanate, Humate P, Wilate)
Antihemophilic factor (factor VIII; FVIII) and von Willebrand Factor (vWF) are constituents of normal plasma, which are required for clotting. Temporarily increases the plasma level of FVIII, thus minimizing the hazard of hemorrhage in patients with hemophilia A; FVIII is an essential cofactor in activation of factor X, leading to formation of thrombin and fibrin. Indicated for control and prevention of bleeding episodes for hemophilia A in adults and children (brand dependent). These concentrates have different ratios of the amount of FVIII and vWF in the product, and prescribers should familiarize themselves with these differences to optimize dosing.
Anti-inhibitor coagulant complex (Feiba, Feiba NF)
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 (Factor VIIa, Eptacog alfa, Factor VIIa recombinant-jncw)
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.
Factor VIII, human plasma derived (Antihemophilic Factor (Human), 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.
Monoclonal Antibodies
Class Summary
Monoclonal antibodies are used to bind to one specific substance in the body (eg, molecules, antigens). This binding is very versatile and can mimic, block, or cause changes to enact precise mechanisms (eg, bridging molecules, replacing or activating enzymes or cofactors, immune system stimulation).
Emicizumab (Emicizumab-kxwh, Hemlibra)
Emicizumab is a first-in-class bispecific monoclonal antibody that bridges activated FIX and FX to restore the function of activated FVIII. It is indicated for routine prophylaxis to prevent or reduce the frequency of bleeding episodes in adult and pediatric patients (including newborns) with hemophilia A with or without factor VIII inhibitors.
Rituximab (Riabni, Rituxan, Rituximab-abbs)
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.
Vasopressin-Related
Class Summary
Desmopressin transiently increases the FVIII plasma level in patients with mild hemophilia A.
Desmopressin (DDAVP, Minirin, Nocdurna)
Desmopressin causes a transient increase (up to four-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. This can result in hyponatremia, which can be severe, particularly with repeat dosing. 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).
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 injection (Cyklokapron)
This agent is an alternative to aminocaproic acid. It inhibits fibrinolysis by displacing plasminogen from fibrin. It also inhibits the proteolytic activity of plasmin.
Clotting Factors, Gene Therapies
Class Summary
These therapies are designed to introduce a functional copy of a transgene encoding the human coagulation factor VIII.
Valoctocogene roxaparvovec (Roctavian)
Valoctocogene roxaparvovec is an adeno-associated virus serotype 5 (AAV5)–based gene therapy vector, designed to introduce a functional copy of a transgene encoding the B-domain deleted SQ form of human coagulation FVIII (hFVIII-SQ). The expressed hFVIII-SQ replaces the missing coagulation FVIII needed for effective hemostasis. It is indicated for severe hemophilia A (congenital factor VIII deficiency with factor VIII activity <1 IU/dL) in adults without preexisting antibodies to AAV5 detected by an FDA-approved test.
TFPI Neutralizing Antibodies
Concizumab (Alhemo, Concizumab-mtci)
Tissue factor pathway inhibitor (TFPI) antagonist indicated for routine prophylaxis to prevent or reduce the frequency of bleeding episodes in adult and pediatric patients 12 years of age and older with hemophilia A (congenital factor VIII deficiency) with FVIII inhibitors.
Marstacimab (Hympavzi, Marstacimab-hncq)
Human monoclonal IgG1 antibody directed against tissue factor pathway inhibitor (TFPI). TFPI is the primary inhibitor of the extrinsic coagulation pathway; neutralization of TFPI activity enhances coagulation by inactivating factor Xa/factor VIIa/tissue factor complex protease functions. Marstacimab is indicated for routine prophylaxis in hemophilia A (congenital factor VIII deficiency) without factor VIII inhibitors, in patients aged ≥12 years.
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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 three 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
Tables
Classification |
Factor Activity, % |
Cause of Hemorrhage |
Mild |
>5-40 |
Major trauma or surgery |
Moderate |
1-5 |
Mild-to-moderate trauma |
Severe |
< 1 |
Spontaneous |
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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