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Sections Hemophilia B (Factor IX Deficiency)
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Medication

Medication Summary

Factor IX is the treatment of choice for acute hemorrhage or presumed acute hemorrhage. Recombinant factor IX is the preferred source for replacement therapy. The factor IX activity level should be corrected to 100% of normal for potentially serious hemorrhage (eg, central nervous system, trauma related, gastrointestinal, genitourinary, epistaxis) and to 30-50% of normal for minor hemorrhage (eg, hemarthrosis, oral mucosal, muscular).

One unit of factor IX is the amount of factor IX in 1 mL of plasma (1 U/mL or 1%). The volume of distribution of factor IX is approximately 100 mL/kg. To find the number of units of factor IX needed to correct the factor IX activity level, use the following:

Units factor IX = (weight in kg)(100 mL/kg)(1 U factor IX/mL)(desired factor IX level minus the native factor IX level)

The difference between the desired factor IX activity level and the patient's native factor IX activity level is expressed as a fraction. For example, if 100% activity is desired and the patient’s native activity is 5%, the calculation is as follows:

100% - 5% = 95% or 0.95

As an example, an 80-kg person with hemophilia with known 1% factor IX activity level presents to the emergency department with a serious upper GI bleed. The desired factor IX activity level is 100%. The dose of factor IX to administer to the patient would be calculated as follows:

Units factor IX = (80 kg)(100 mL/kg)(1 U factor IX/mL)(.99) = 7920

The next dose should be administered 24 hours after the first and is one half of the initial calculated dose.

Minor hemorrhage requires 1-3 doses of factor IX. Major hemorrhage requires many doses and continued factor IX activity monitoring with the goal of keeping the trough activity level at least 50%. Continuous infusions of factor IX may be considered for major hemorrhage.

Class Summary

These agents are used to correct the patient's native deficiency, with the goals of achieving a normal hematologic response to hemorrhage or preventing hemorrhage. Fresh frozen plasma is no longer used in hemophilia because of the lack of safe viral elimination and concerns regarding volume overload.

Factor IX, recombinant (BeneFIX, Rixubis, Alprolix, Ixinity, Rebinyn)

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Recombinant factor IX (rFIX) uses no human products for stabilization. Each of the brands is FDA-approved for control and prevention of bleeding episodes, and for perioperative management in adults and children. Rixubis, Ixinity, and Alprolix are also approved for routine prophylaxis in adults and children. Alprolix is a long-acting product, it may be administered for routine prophylaxis once weekly or every 10 days. Rebinyn is a glycopegylated long-acting rFIX. Pegylation slows removal of FIX from the blood circulation.

Factor IX, recombinant/albumin fusion protein (Idelvion)

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Recombinant protein that temporarily replaces missing coagulation Factor IX needed for effective hemostasis. Comprised of genetically fused recombinant coagulation Factor IX and recombinant albumin, which extends the half-life of Factor IX. It is indicated for on-demand control and prevention of bleeding episodes, management of postoperative bleeding, and as prophylaxis to reduce the frequency of bleeding episodes.

Factor IX (Mononine, AlphaNine SD)

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Human blood-derived Factor IX indicated for control and prevention of bleeding episodes, and for perioperative management in adults and children.

Factor IX Complex (Bebulin, Bebulin VH, Profilnine SD)

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Human plasma-derived prothrombin complex concentrates. These pooled plasma products (high purity) replace deficient FIX and other coagulation factors.

Class Summary

These agents can activate coagulation factor X to factor Xa as well as coagulation factor IX to IXa.

Factor VIIa, recombinant (NovoSeven RT, Sevenfact)

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This agent is indicated to treat bleeding episodes in patients with hemophilia A or B and inhibitors. It promotes hemostasis by activating the extrinsic pathway of the coagulation cascade, forming complexes with tissue factor, and promoting activation of factor X to factor Xa, factor IX to factor IXa, and factor II to factor IIa.

Class Summary

These agents are used in addition to factor IX replacement for oral mucosal hemorrhage and prophylaxis, as the oral mucosa is rich in native fibrinolytic activity. These agents are used in prophylaxis for oral surgery and in the treatment of excessive bleeding in the oral mucosa that results from local 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).

Epsilon aminocaproic acid (Amicar)

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This is a lysine analog that binds to natively produced plasmin, reducing its fibrinolytic activity.

This agent inhibits fibrinolysis by inhibiting plasminogen activator substances and, to a lesser degree, antiplasmin activity. 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 (Cyklokapron)

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Tranexamic acid is an alternative to aminocaproic acid. It inhibits fibrinolysis by displacing plasminogen from fibrin.

Class Summary

These agents are used to control bleeding in hemophilia B or FIX deficiency and to prevent and/or control bleeding in patients with hemophilia A and inhibitors to FVIII.

These are used to control bleeding in mild hemophilia and in some forms of von Willebrand disease.

These agents raise endogenous FVIII levels in mild hemophilia A. Increases as much as 3-fold from the baseline are observed, with peak responses at 30-60 minutes after infusion.^[69]

These replace deficient FVIII in patients with hemophilia A. Recombinant products should be used initially and subsequently in all newly diagnosed cases of hemophilia that require factor replacement.

Desmopressin (DDAVP, Stimate)

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The main effect of desmopressin is enhancement of water reabsorption in the kidney and smooth muscle constriction. It causes a dose-dependent increase in plasma FVIII and plasminogen activator.

This agent increases the cellular permeability of collecting ducts, resulting in renal reabsorption of water. Tachyphylaxis may occur, even after first dose, but the drug can be effective again after several days.

Anti-inhibitor coagulant complex (Feiba NF, Feiba VH Immuno)

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This agent is a freeze-dried sterile human plasma fraction with factor VIII inhibitor bypassing activity. It contains factors II, IX, and X, mainly nonactivated; and factor VII, 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.

Human antihemophilic factor (Hemofil M, Koate-DVI)

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FVIII is a protein in normal plasma that is necessary for clot formation and hemostasis. It activates factor X in conjunction with activated FIX; activated factor X converts prothrombin to thrombin, which converts fibrinogen to fibrin, which, with factor XIII, forms a stable clot.

Recombinant human antihemophilic factor (Recombinate, Kogenate, Helixate, Advate)

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Plasma-derived prothrombin complex concentrates/Factor IX complex concentrates (Bebulin, Profilnine SD)

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This agent replaces deficient FIX and other factors in the complex.

Plasma-derived coagulation factor IX concentrate (Alpha Nine SD, Mononine, BeneFIX)

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This agent replaces deficient FIX and other factors in the complex. AlphaNine SD and Mononine contain only FIX. BeneFIX is a recombinant product.

Class Summary

These agents are monoclonal antibodies directed against the CD20 antigen on B cells. They are recommended as second-line therapy in the treatment of factor IX inhibitors, especially in cases with high inhibitor titers.

Rituximab (Rituxan)

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Rituximab binds to, and mediates destruction of, B-cells, thereby decreasing production of inhibitors and autoimmunization.

Class Summary

The first adeno-associated virus-5 (AAV5)-based gene therapy designed to deliver a copy of a gene encoding the Padua variant of human coagulation factor IX (hFIX598 Padua) was approved by the FDA. A single IV infusion results in cell transduction and increase in circulating factor IX activity in patients with hemophilia B.

Etranacogene dezaparvovec (Hemgenix)

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Indicated for adults with hemophilia B (congenital factor IX deficiency) who currently use factor IX prophylaxis, have current or historical life-threatening hemorrhage, or repeated serious spontaneous bleeding episodes.

Questions

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Media Gallery

Coagulation Cascade
Obituary in the Salem Gazette (Massachusetts) of a 19-year-old man, March 22, 1796.
The hemostatic pathway: role of factor IX.
Activation of factor IX and function of the intrinsic tenase complex. Activation of factor IX is followed by formation of the intrinsic tenase complex, which activates factor X to activated factor X, leading to a second and larger burst of thrombin production during activation of hemostasis.
Vitamin K–dependent carboxylation of precursor factor IX to procoagulant factor IX. Carboxylation of glutamate (Glu) to gamma-carboxyglutamate (Gla) residues in the precursor protein of the vitamin K–dependent factors occurs in the endoplasmic reticulum of the hepatocyte. Reduced vitamin K is oxidized in this process. Warfarin prevents the reduction and recycling of oxidized vitamin K.
Cell surfaced-directed hemostasis. Initially, a small amount of thrombin is generated on the surface of the tissue factor (TF)–bearing cell. Following amplification, the second burst generates a larger amount of thrombin, leading to fibrin (clot) formation. (Adapted from Hoffman and Monroe, Thromb Haemost 2001, 85(6): 958-65.)
Knee radiographs in a patient with advanced hemophilic arthropathy demonstrate chronic severe arthritis, fusion, and loss of cartilage and joint space.

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Table 1. Severity, Factor Activity, and Hemorrhage Type

Classification	Factor Activity, %	Cause of Hemorrhage
Mild	>5-40	Major trauma or surgery
Moderate	1-5	Minor trauma or surgery; occasional spontaneous hemarthrosis
Severe	< 1	Lifelong spontaneous hemorrhages and hemarthroses starting in infancy

Table 2. General Guidelines for Factor Replacement for the Treatment of Bleeding in Hemophilia B

Indication or Site of Bleeding	Factor level Desired, %	FIX Dose, IU/kg^*	Comment
Severe epistaxis; mouth, lip, tongue, or dental work	20-50	20-50	Consider aminocaproic acid (Amicar), 1-2 d
Joint (hip or groin)	40	40	Repeat transfusion in 24-48 h
Soft tissue or muscle	20-40	40	No therapy if site small and not enlarging (transfuse if enlarging)
Muscle (calf and forearm)	30-40	40	None
Muscle deep (thigh, hip, iliopsoas)	40-60	40-60	Transfuse, repeat at 24 h, then as needed
Neck or throat	50-80	50-80	None
Hematuria	40	40	Transfuse to 40% then rest and hydration
Laceration	40	40	Transfuse until wound healed
GI or retroperitoneal bleeding	60-80	60-80	None
Head trauma (no evidence of CNS bleeding)	50	50	None
Head trauma (probable or definite CNS bleeding, eg, headache, vomiting, neurologic signs)	100	100	Maintain peak and trough factor levels at 100% and 50% for 14 d if CNS bleeding documented^†
Trauma with bleeding, surgery	80-100	100	10-14 d

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Author

Robert A Zaiden, MD Adjunct Associate Professor, Division of Cancer Medicine, Baptist MD Anderson Cancer Center

Robert A Zaiden, MD is a member of the following medical societies: American College of Physicians, American Society of Clinical Oncology

Disclosure: Nothing to disclose.

Specialty Editor Board

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Chief Editor

Srikanth Nagalla, MD, MS, FACP Chief of Benign Hematology, Miami Cancer Institute, Baptist Health South Florida; Clinical Professor of Medicine, Florida International University, Herbert Wertheim College of Medicine

Srikanth Nagalla, MD, MS, FACP is a member of the following medical societies: American Society of Hematology, Association of Specialty Professors

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Alexion; Alnylam; Kedrion; Sanofi; Dova; Apellis; Pharmacosmos<br/>Serve(d) as a speaker or a member of a speakers bureau for: Sobi; Sanofi; Rigel.

Acknowledgements

Dimitrios P Agaliotis, MD, PhD, FACP Consulting Staff, Department of Medicine, Baptist Health System