Take the Latest AccessPharmacy Quick Test on Treatment of Hemophilia!

AccessPharmacy Quick Test AccessPharmacy's Quick Test, sent twice a month, lets you test your pharmacologic knowledge and anonymously compare your results to those of your peers. Quick Test is developed by Terry L. Schwinghammer, PharmD, AccessPharmacy's Editor-in-Chief, from the site's online resources. Your results will be ranked against those of your peers. Quick Test posted on 6.28.11: Treatment of Hemophilia CONGENITAL COAGULATION DISORDERS   Hemophilia   Hemophilia is a bleeding disorder that results from a congenital deficiency in a plasma coagulation protein. Hemophilia A (classic hemophilia) is caused by a deficiency of factor VIII, whereas hemophilia B (Christmas disease) is caused by a deficiency of factor IX. The incidence of hemophilia A is approximately 1 in 5,000 male births. Hemophilia B occurs less commonly, with only one fourth the incidence of hemophilia A. There are no significant racial differences in the incidence of hemophilia. Approximately one-third of patients with severe hemophilia have a negative family history, presumably representing a spontaneous mutation. Both hemophilia A and hemophilia B are recessive X-linked diseases, that is, the defective gene is located on the X chromosome. The disease usually affects only males; females are carriers. Affected males have the abnormal allele on their X chromosome and no matching allele on their Y chromosome, but their sons would be normal (assuming the mother is not a carrier) and their daughters would be obligatory carriers. Female carriers have one normal allele and therefore do not usually have a bleeding tendency. Sons of a female carrier and a normal male have a 50% chance of having hemophilia, whereas daughters have a 50% chance of being carriers. Thus, there is a "skipped generation" mode of inheritance in which the female carriers, who are the children of patients with hemophilia, do not express the disease but can pass it on to the next male generation. Hemophilia has been observed in a small number of females. It can occur if both factor VIII and IX genes are defective, if a female patient has only one X chromosome, as in Turner syndrome, or if the normal X chromosome is excessively inactivated through a process called lyonization. In 1984, researchers isolated and cloned the human factor VIII gene. It is a large gene, consisting of 186 kilobases (kb). More than 900 unique mutations in the factor VIII gene, including point mutations, deletions, and insertions, have been reported (http://europium.csc.mrc.ac.uk). Deletions and nonsense mutations are often associated with the more severe forms of factor VIII deficiency because no functional factor VIII is produced. In 1993, researchers identified an inversion in the factor VIII gene at intron 22 that accounts for approximately 45% of severe hemophilia A gene abnormalities. That discovery has greatly simplified carrier detection and prenatal diagnosis in families with this gene mutation. A more recently discovered inversion mutation involving intron 1 of the factor VIII gene accounts for an additional 5% of severe hemophilia mutations. The factor IX gene, cloned and sequenced in 1982, consists of only 34 kb and thus is significantly smaller than the factor VIII gene. Unlike the factor VIII gene in patients with severe hemophilia A, the factor IX gene in patients with hemophilia B has no predominant mutation. Direct gene mutation analysis is simpler in hemophilia B because of the smaller gene size, and to date more than 900 different mutations have been reported (http://kcl.ac.uk/ip/petergreen/haemBdatabase.html). Most of these mutations are single base pair substitutions. Approximately 3% of factor IX gene mutations are deletions or complex rearrangements, and the presence of these mutations is associated with a severe phenotype. Hemophilia B Leiden is a rare variant in which factor IX levels initially are low but rise at puberty. This phenotype results from a mutation in the promoter region of the gene that apparently is ameliorated by the action of testosterone. Identification of this genotype is clinically important because it confers a better prognosis. Clinical Presentation   The characteristic bleeding manifestations of hemophilia include palpable ecchymoses, bleeding into joint spaces (hemarthroses), muscle hemorrhages, and excessive bleeding after surgery or trauma. The severity of clinical bleeding generally correlates with the degree of deficiency of factor VIII or factor IX. Factor VIII and factor IX activity levels usually are measured in units per milliliter, with 1 unit/mL representing 100% of the factor found in 1 mL of normal plasma. Normal plasma levels range from 0.5 to 1.5 units/mL. Patients with less than 0.01 units/mL (1%) of either factor are classified as having severe hemophilia, those with 0.01 to 0.05 units/mL (1%–5%) are moderate, and those with greater than 0.05 units/mL (5%) have mild hemophilia (Table 105–3). Patients with severe disease experience frequent spontaneous hemorrhages and joint space bleeding, whereas those with moderate disease have excessive bleeding following mild trauma and rarely experience spontaneous hemarthroses. Patients with mild hemophilia may have so few symptoms that their condition is undiagnosed for many years, and they usually have excessive bleeding only after significant trauma or surgery. Occasionally those with severe disease (less than 1% factor activity) may not display a severe phenotype; conversely, some with milder forms of the disease may have more severe bleeding symptomatology. Patients with hemophilia usually present with clinical manifestations after age 1 year, when they begin to walk and increase their risk of bleeding. Sidebar: Clinical Presentation of Hemophilia   Signs and Symptoms Ecchymoses (palpable) Hemarthrosis (especially knee, ankle, and elbow) Joint pain Joint swelling and erythema Decreased range of motion Muscle hemorrhage Swelling Pain with motion of affected muscle Signs of nerve compression Potential life-threatening blood loss, especially with thigh bleeding Oral bleeding with dental extractions or trauma Hematuria Intracranial hemorrhage (spontaneous or following trauma) Excessive bleeding with surgery Laboratory Testing Prolonged aPTT Decreased factor VIII or factor IX level Normal PT Normal platelet count Normal von Willebrand factor antigen and activity Normal bleeding time DIAGNOSIS   The diagnosis of hemophilia should be considered in any male with unusual bleeding. A family history of bleeding is helpful in the diagnosis but is absent in up to one third of patients. Brothers of patients with hemophilia should be screened; sisters should undergo carrier testing. Advances in molecular genetic analysis have greatly improved the accuracy of carrier status evaluation. Thus, female relatives of patients with hemophilia who are at risk of being carriers for the disorder should be tested. Additionally, the appropriate factor level should be measured in female carriers to identify those with levels less than 0.3 units/mL (30%) who themselves might be at risk for bleeding. Patients with severe hemophilia A should be tested for the common factor VIII gene inversions. If the patient has this mutation, family members should undergo testing to determine if they also have the mutation and thus are carriers. In patients with hemophilia A who lack the inversion mutation, other methods for determining the carrier status of their family members are available. Techniques for determining carrier status in families with hemophilia B are similar, although no predominant mutation like the factor VIII inversion has been found. The smaller size of the factor IX gene facilitates direct DNA mutational analysis. Hemophilia can be diagnosed prenatally by chorionic villus sampling in gestational weeks 10 to 11 or by amniocentesis after 15 weeks' gestation. Fetal blood can be sampled and assayed directly for factor VIII levels by 18 to 20 weeks' gestation. This procedure is less useful for diagnosing factor IX deficiency because factor IX levels are physiologically low in fetuses and infants. Treatment: Hemophilia   The comprehensive care of hemophilia requires a multidisciplinary approach. The patient is best managed in specialized centers with trained personnel and appropriate laboratory, radiologic, and pharmaceutical services. The healthcare team includes hematologists, orthopedic surgeons, nurses, physical therapists, dentists, genetic counselors, psychologists, pharmacists, case managers, and social workers. Patients with hemophilia should receive routine immunizations, including immunization against hepatitis B. Hepatitis A vaccine is also recommended for patients with hemophilia because of the risk (albeit small) of transmitting the causative agent through factor concentrates. Use of a small-gauge needle can prevent excessive bleeding. Some healthcare providers advocate subcutaneous rather than intramuscular immunizations to decrease the risk of hematoma formation. A few special considerations apply to the perinatal care of male infants of hemophilia carriers. Intracranial or extracranial hemorrhage has been estimated to occur in 1% to 4% of newborns with hemophilia. Vacuum extraction and forceps delivery increase the risk of cranial bleeding. Elective cesarean section has not prevented intracranial bleeding. There is no clear consensus on the optimal mode of delivery or the use of prophylactic factor replacement in male infants of hemophilia carriers. Circumcision should be postponed until a diagnosis of hemophilia is excluded. Factor levels can be assayed from cord blood samples or from peripheral venipuncture. Arterial puncture should be avoided because of the risk of hematoma formation. If an infant has hemophilia, many clinicians recommend a screening head ultrasound to rule out an intracranial hemorrhage prior to discharge from the nursery. Intravenous factor replacement therapy for treatment or prevention of bleeding is the mainstay of treatment of hemophilia. Families usually learn how to treat patients receiving factor concentrate at home. Parents may learn to infuse factor for younger children, and older children and adult patients may learn self-administration. Home healthcare nursing support may be helpful, particularly for the youngest patients in whom venous access may be difficult. Administration of factor at home is more convenient for families and allows for earlier treatment of acute bleeding episodes. However, serious bleeding episodes always require medical evaluation. History of Hemophilia Treatment   Therapy for hemophilia has undergone dramatic advances over the past few decades. Fifty years ago, administration of fresh-frozen plasma was the only available treatment. The introduction of cryoprecipitate in the early 1960s allowed more specific therapy for hemophilia A. Intermediate-purity factor VIII and IX concentrates became available in the 1970s. Plasma-derived factor concentrates are made from the donations of thousands of people. Contamination of plasma pools with hepatitis B, hepatitis C, and the human immunodeficiency virus (HIV) during the late 1970s and early 1980s resulted in transmission to most patients with severe hemophilia. Since the mid-1980s, plasma-derived concentrates have been manufactured with a variety of virus-inactivating techniques, including dry heat, pasteurization, and treatment with chemicals (e.g., solvent detergent mixtures). Since 1986, no transmission of HIV through factor concentrates to patients with hemophilia in the United States has been reported. Protein purification, introduced in the 1990s, produced high-purity concentrates with increased amounts of factor VIII or factor IX relative to the product's total protein content. Recombinant factor VIII and then factor IX also became available. The first-generation recombinant factor VIII products utilize human and animal proteins in culture and add human albumin as a protein stablilizer. Second-generation recombinant factor VIII concentrates removed albumin as a protein stabilizer, and third-generation products lack human and animal proteins in the culture media. Gene therapy for treatment of hemophilia is now in the early stages of clinical trials. Hemophilia A   Table 105–4 summarizes the factor VIII products currently available in the United States. Most patients are treated with high-purity products. In general, products that have the lowest risk of transmitting infectious disease should be used. Thus, recombinant products, when available, are generally used rather than plasma-derived products. Table 105–4 Factor Concentrates Brand Name Product Type Viral Inactivation or Exclusion Method Other Contents Factor VIII concentrates       Alphanate Plasma Solvent detergent, dry heat Albumin, heparin, vWF Hemophil M Plasma Solvent detergent, monoclonal antibody Albumin Humate-P Plasma Pasteurization Albumin, vWF Koa–te-DVI Plasma Solvent detergent, dry heat Albumin, heparin, vWF Monarc-M Plasma Solvent detergent, monoclonal antibody Albumin Monoclate P Plasma Pasteurization, monoclonal antibody Albumin Advate Recombinant None   Bioclate Recombinant None Albumin Helixate FS Recombinant Solvent detergent Albumin (fermentation only); sucrose Kogenate FS Recombinant Solvent detergent, monoclonal antibody Albumin (fermentation only); sucrose Recombinate Recombinant Monoclonal antibody Albumin ReFacto B domain deleted Recombinant None Albumin (fermentation only); sucrose Factor IX concentrates       AlphaNine SD Plasma Solvent detergent, filtered Heparin Mononine Plasma Monoclonal antibody, ultrafiltration Heparin BeneFix Recombinant None   aPCC       Autoplex T Plasma Dry heat Heparin, IIa, VIIa, trace VIIIa, IXa, Xa Feiba VH Immuno Plasma Vapor heat IIa, VIIa, VIIIa, IXa, Xa PCC       Bebulin VH Plasma Vapor heat Heparin, II, IX, X Profilnine SD Plasma Solvent detergent II, VII, IX, X Proplex T Plasma Dry heat Heparin, II, VII, IX, X Other       NovoSeven Recombinant VII None   Hyate:Ca Porcine VIII Freeze-dried Citrate aPCC, activated prothrombin complex concentrate; PCC, prothrombin complex concentrate; vWF, von Willebrand factor. aNo longer available in the U.S. Recombinant Factor VIII   Derived from cultured Chinese hamster ovary cells or baby hamster kidney cells transfected with the human factor VIII gene, recombinant factor VIII is produced with recombinant DNA technology. Because it is not derived from blood donations, the risk of transmitting infections through administration of recombinant factor VIII is low. For this reason, recombinant products are generally favored over plasma-derived products. There still is a small risk of viral infection of the cell lines used to produce the clotting factor. Furthermore, human and/or animal proteins are utilized in the production process of some recombinant products. Therefore, these products have a theoretical risk of transmitting infection, although hepatitis and HIV infection have never been reported with their use. The presence of parvovirus B19 DNA has been reported in recombinant factor VIII products. First-generation recombinant factor VIII products contain human albumin as a stabilizing protein. Second-generation recombinant factor VIII products add sucrose instead of human albumin as a stabilizer, but human albumin is utilized in the culture process. One second-generation product (ReFacto) has deletion of the B domain of the factor VIII gene, yielding a smaller protein product. This B domain does not appear to be necessary for coagulation function. Third-generation recombinant factor VIII products contain no human protein in either the culture or in the stabilization processes. Clinical trials have demonstrated that recombinant factor VIII products are comparable in effectiveness to plasma-derived products. The risk of patients with severe hemophilia A developing an inhibitory antibody to factor VIII with use of recombinant factor VIII is 28% to 33%. This risk is higher than reported with plasma-derived products. The difference may be partly attributable to more frequent screening for inhibitors in the recombinant product trials, with detection of transient inhibitors that might have been missed in the trials with plasma-derived products. However, the incidence of high-responding inhibitors, which are clinically significant, was higher in trials using recombinant factor VIII compared with those using a single plasma-derived product. Plasma-Derived Factor VIII Products   Several different plasma-derived factor VIII products are available (Table 105–4). These products are derived from the plasma of thousands of donors and therefore potentially can transmit infection. Donor screening, testing plasma pools for evidence of infection, viral reduction through purification steps, and viral inactivation procedures (e.g., dry heat, pasteurization, and solvent detergent treatment) all have resulted in a safer product. No cases of HIV transmission from factor concentrates have been reported since 1986. However, isolated cases of hepatitis C infection with use of plasma-derived products have been reported. Additionally, outbreaks of hepatitis A viral infections associated with plasma-derived products, likely because solvent detergent treatment does not inactivate this nonenveloped virus, have been reported. Parvovirus has been reported to be present in both plasma-derived and recombinant factor VIII products. Finally, there remains concern about the possibility of infection with as yet unidentified viruses that currently used methods would not inactivate. Factor VIII concentrates can be classified according to their level of purity, which refers to the specific activity of factor VIII in the product. Cryoprecipitate is a low-purity product. Cryoprecipitate also contains von Willebrand factor, fibrinogen, and factor XIII. Current American Association of Blood Banks standards call for a minimum of 80 international units of factor VIII per pack. This product is no longer considered a primary treatment of factor VIII deficiency in countries where factor VIII concentrates are available because cryoprecipitate does not undergo a viral inactivation process. Intermediate-purity products have a specific activity of factor VIII of 5 units/mg of protein, whereas high-purity products have up to 2,000 units/mg of protein. Ultrahigh-purity plasma-derived products are prepared with monoclonal antibody purification steps and have a specific activity of 3,000 units/mg of protein prior to addition of albumin as a stabilizer. Factor VIII Concentrate Replacement   Appropriate dosing of factor VIII concentrate depends on the half-life of the infused factor, the patient's body weight, and the volume of distribution. The presence or absence of an inhibitory antibody to factor VIII and the titer of this antibody also influence treatment. Recovery studies, which measure the immediate postinfusion factor level, and survival studies, which assess the half-life of the factor, can establish patient-specific pharmacokinetics. The location and magnitude of the bleeding episode determine the percent correction to target as well as the duration of treatment. Serious or life-threatening bleeding requires peak factor levels of greater than 0.75 to 1 units/mL (75%–100%); less severe bleeding may be treated with a goal of 0.3 to 0.5 units/mL (30%–50%) peak plasma levels. Table 105–5 provides general guidelines for the management of bleeding in different locations. Factor VIII is a large molecule that remains in the intravascular space. Therefore, the plasma volume (approximately 50 mL/kg) can be used to estimate the volume of distribution. In general, each unit of factor VIII concentrate infused per kilogram of body weight yields a 2% rise in plasma factor VIII levels. The following equation can be used to calculate an initial dose of factor VIII: The baseline level usually is omitted from the equation because it is negligible compared to the desired level. The half-life of factor VIII ranges from 8 to 15 hours. It is generally necessary to administer half of the initial dose approximately every 12 hours to sustain the desired level of factor VIII. A single treatment may be adequate for minor bleeding, such as oral bleeding or slight muscle hemorrhages. However, because of the potential for long-term joint damage with hemarthroses, 2 or 3 days of treatment is often recommended for these bleeds. Serious bleeding episodes may require maintenance of 70% to 100% factor activity for 1 week or longer. As previously mentioned, factor VIII dosing depends on several variables, and each case must be considered individually. Individual pharmacokinetics may help guide treatment, particularly for serious bleeding episodes. Alternatively, factor VIII can be administered as a continuous infusion when prolonged treatment is required (e.g., in the perioperative period or for serious bleeding episodes). Infusion rates ranging from 2 to 4 units/kg per hour usually are given in fixed-dose continuous infusion protocols, with the aim of maintaining a steady-state level of 60% to 100%. Administration of factor concentrate via continuous infusion may reduce factor requirements by 20% to 50% because unnecessarily high peaks of factor VIII that occur with bolus injections are avoided. A gradual decrease in factor VIII clearance during the first 5 to 6 days of treatment contributes to the lower factor concentrate requirements. Daily monitoring of factor level can help determine the appropriate rate of infusion. Administration of factor VIII concentrate via continuous infusion has been shown to be safe and effective, and it may be more convenient than bolus therapy for hospitalized patients. The advantages of continuous infusion include maintenance of a steady-state plasma level with avoidance of potentially subtherapeutic trough levels and a reduction in cost associated with decreased factor requirements. A potential side effect with continuous infusion is thrombophlebitis at the delivery site. Concomitant infusion of saline or the addition of heparin (2–5 units/mL) to the infusion bag can minimize this risk. Bacterial contamination of the concentrate is another theoretical concern. However, studies have shown that the products can remain sterile for more than 1 week if prepared and kept under appropriate conditions. Finally, concerns about the stability of the formulations appear to be unwarranted, as most high-purity factor VIII concentrates have been shown to remain stable for at least 7 days after reconstitution. Exposure of factor VIII to light for 10 hours post reconstitution can cause a 30% decrease in the activity. It would be prudent to shield the container with foil wrap or an appropriate bag. Other Pharmacologic Therapy   Treatment with desmopressin acetate often is adequate for minor bleeding episodes in patients with mild hemophilia A. A synthetic analog of the antidiuretic hormone vasopressin, desmopressin causes release of von Willebrand factor and factor VIII from endogenous storage sites. It appears to be most effective in patients with higher baseline factor VIII levels (0.1–0.15 units/mL). The recommended dose of desmopressin is 0.3 mcg/kg diluted in 50 mL of normal saline and infused IV over 15 to 30 minutes. Patients with mild or moderate hemophilia A should undergo a desmopressin trial to determine their response to this medication. At least a twofold rise in factor VIII to a minimal level of 0.3 units/mL within 60 minutes is considered an adequate response. In adults with mild hemophilia A, the response rate to desmopressin has been reported to be 80% to 90%. One study reported a lower response rate of 57% in pediatric patients with mild hemophilia A. Furthermore, the response rate was related to age; the mean age of patients who responded to desmopressin was 5.2 years compared with 3 years for those who failed to respond. Seven of the 11 children who failed to respond to desmopressin initially demonstrated an adequate response when the desmopressin challenge was repeated at an older age. Infusion of desmopressin can be repeated daily for up to 2 to 3 days. Tachyphylaxis, an attenuated response with repeated dosing, may develop after that time. The factor increase after the second dose of desmopressin is approximately 30% lower than after the initial dose. Factor concentrate therapy may be necessary if the patient requires additional treatment. Factor levels should be measured to ensure that an adequate response has been achieved. Treatment with desmopressin will not result in hemostasis in patients who have severe hemophilia and those who are only marginally responsive. Desmopressin should not be used as primary therapy for life-threatening bleeding episodes such as intracranial hemorrhage or for major surgical procedures when a minimum factor VIII concentration of 0.7 to 1 units/mL is required. Desmopressin can be administered intranasally via a concentrated nasal spray. It elicits a slower and less marked response, with a peak effect in 60 to 90 minutes after administration, somewhat longer than with desmopressin administered intravenously. The dosage is one spray (150 mcg) for children who weigh less than 50 kg and two sprays (300 mcg) for those who weigh more than 50 kg. The nasal spray may serve as an alternative to the intravenous formulation, especially in patients with mild bleeding episodes. Few adverse effects are associated with desmopressin. The most commonly observed side effect is facial flushing. Less frequently reported side effects include mild headaches, increased heart rate, and decreased blood pressure. Thrombosis is a rare complication associated with desmopressin. Because of its antidiuretic effects, desmopressin has the potential to cause water retention, which may lead to severe hyponatremia. This may be a particular problem in children younger than 2 years, in whom hyponatremic seizures have been reported. Therefore, desmopressin should be used with caution in this age group. Patients with congestive heart failure may be at increased risk for developing hyponatremia with use of desmopressin. Mild fluid restriction and monitoring of urine output are recommended with desmopressin administration. Antifibrinolytic therapy inhibits clot lysis and therefore is a useful adjunctive therapy for treatment of hemophilia. These antifibrinolytic agents are particularly beneficial for treatment of oral bleeding because of the high concentration of fibrinolytic enzymes present in saliva. Two antifibrinolytics are aminocaproic acid and tranexamic acid. Aminocaproic acid is given at a dosage of 100 mg/kg (maximum 6 g) every 6 hours and can be administered orally or intravenously. The dosage of tranexamic acid is 25 mg/kg (maximum 1.5 g) orally every 8 hours or 10 mg/kg (maximum 1 g) intravenously every 8 hours. Hemophilia B   Therapeutic options for hemophilia B have improved greatly over the past several years, first with the development of monoclonal antibody–purified plasma-derived products and then with the licensure of recombinant factor IX. Products currently available in the United States for treatment of hemophilia B are listed in Table 105–4. Recombinant Factor IX   First marketed in the United States in 1999, recombinant factor IX is produced in Chinese hamster ovary cells transfected with the factor IX gene. Blood and plasma products are not used to produce recombinant factor IX or to stabilize the final product; thus, recombinant factor IX has an excellent viral safety profile. Clinical trials have shown the product to be safe and efficacious in the treatment of acute bleeding episodes and in the management of bleeding associated with surgical procedures. Although the half-life of recombinant factor IX is similar to that of the plasma-derived products, recovery is approximately 30% lower. As a result, doses of recombinant factor IX concentrate must be higher than those of plasma-derived products to achieve equivalent plasma levels. Because individual pharmacokinetics may vary, recovery and survival studies should be performed to determine optimal treatment. Recombinant factor IX is often considered the treatment of choice for hemophilia B. Plasma-Derived Factor IX Products   High-purity factor IX plasma concentrates have been available in the United States since the early 1990s. These products are derived from plasma through biochemical purification and monoclonal immunoaffinity techniques. Other viral inactivation measures, such as solvent detergent or chemical treatment, are also used. Before the high-purity products were approved for use, hemophilia B patients were treated with factor IX concentrates that also contained other vitamin K–dependent proteins (factors II, VII, and X), known as prothrombin complex concentrates (PCCs). These products contain small amounts of activated factors generated during processing, and their use has been associated with thrombotic complications, including deep–vein thrombosis, pulmonary embolism, myocardial infarction, and disseminated intravascular coagulation (DIC). The risk of such complications is highest in patients who are receiving high or repeated doses of PCCs, in those who have hepatic disease (the liver removes the activated factors from circulation), in neonates, and in patients who have experienced crush injuries or who are undergoing major surgery. Concomitant use of PCCs and antifibrinolytics should be avoided because of the risk for thrombosis. Because of the lower purity of PCCs and their thrombogenic potential, these products are not first-line treatment of hemophilia B, although they still are used for treatment of patients with hemophilia A or B who have developed inhibitory antibodies against factor VIII or factor IX, respectively. High-purity factor IX concentrates have excellent efficacy in the treatment of bleeding episodes and in the control of bleeding associated with surgical procedures. Their viral safety profile has been reported to be excellent, and the risk of thromboembolic complications is low. Factor IX Concentrate Replacement   Factor IX is a relatively small protein. Unlike factor VIII, it is not limited to the intravascular space; it also passes into the extravascular compartment. This results in a volume of distribution that is about twice that of factor VIII. In general, for plasma-derived factor IX concentrates, each unit of factor IX infused per kilogram of body weight yields a 1% rise in the plasma level of factor IX (range 0.67%–1.28%). The following equation can be used to calculate the initial dose: As with the similar calculation for factor VIII dosing, the baseline level term can be omitted from the formula. Because recovery of recombinant factor IX is lower than that of the plasma-derived products, the following adjustment is made: Pediatric dosing: Adult dosing: A recovery study to determine optimal dosing is recommended for patients who receive recombinant factor IX because of the wide interpatient variability in pharmacokinetics. Because the half-life of factor IX is approximately 24 hours, dosing can be less frequent than with factor VIII. Table 105–5 provides general guidelines for dosing factor IX, based on the site and severity of the bleeding episode. As with factor VIII replacement therapy, individual pharmacokinetics may vary, and monitoring the patient's factor IX levels helps optimize therapy. About AccessPharmacy | Core Curriculum | Subscription Information | Advisory Board | Contact Us | Help | Privacy Notice | Terms of Use | Notice | Additional Credits and Copyright Information Copyright © 2011 The McGraw-Hill Companies, Inc. All rights reserved. Any use is subject to the Terms of Use and Notice. For further information about this newsletter, contact onlinecustomer_service@mcgraw-hill.com. You have received this message because you opted-in to receive information and special offers from McGraw-Hill Professional. We hope you enjoyed receiving this message. However, if you would like to unsubscribe from receiving emails from McGraw-Hill Professional, please follow this link. UNSUBSCRIBE If you would like to update your preferences, please visit: http://www.mhprofessional.com/account/?mode=interest&action=unsub&e=ignoble.experiment@arconati.us . You can also write to us at: Privacy Officer, McGraw-Hill Professional, 1221 Avenue of Americas, 46th Floor, 10020. View our Corporate Privacy Policy at http://www.mcgraw-hill.com/privacy.html. To learn more about how McGraw-Hill Professional applies this Policy, you can contact privacy@mhedu.com. Copyright © 2011, The McGraw-Hill Companies, Inc. Subscribe to: Post Comments (Atom) Label Cloud Technology (1464) News (793) Military (646) Microsoft (542) Business (487) Software (394) Developer (382) Music (360) Books (357) Audio (316) Government (308) Security (300) Love (262) Apple (242) Storage (236) Dungeons and Dragons (228) Funny (209) Google (194) Cooking (187) Yahoo (186) Mobile (179) Adobe (177) Wishlist (159) AMD (155) Education (151) Drugs (145) Astrology (139) Local (137) Art (134) Investing (127) Shopping (124) Hardware (120) Movies (119) Sports (109) Neatorama (94) Blogger (93) Christian (67) Mozilla (61) Dictionary (59) Science (59) Entertainment (50) Jewelry (50) Pharmacy (50) Weather (48) Video Games (44) Television (36) VoIP (25) meta (23) Holidays (14) Popular Posts (Last 7 Days) Delete Immediately After Reading (DO NOT SHARE) For your weekly reading, we bring you the week's most popular stories from Wealth Daily and our sister site, Energy and Capital… ͏  ͏  ͏... Year-End Spotlight: All Eyes on (DEVS) Tomorrow Morning—Here’s Why ... S&P 8000 January 15, 2026   |   Read Online       You’ve seen this movie… A spaceship drifts too close to a black hole. Light bends. Time warps. W... Search Subscribe To Posts Atom Posts Comments Atom Comments Blog Archive ►  2026 (1606) January (1606) ►  2025 (36923) December (3112) November (3051) October (3119) September (3044) August (3122) July (3132) June (3089) May (3135) April (3022) March (3128) February (2819) January (3150) ►  2024 (37020) December (3113) November (3111) October (3171) September (2998) August (3166) July (3125) June (2991) May (3125) April (2971) March (3189) February (2970) January (3090) ►  2023 (34451) December (3112) November (3102) October (3142) September (2918) August (3061) July (3023) June (2897) May (2988) April (2806) March (2815) February (2202) January (2385) ►  2022 (26749) December (2527) November (2659) October (2668) September (2681) August (2788) July (2649) June (2464) May (2483) April (2148) March (1824) February (939) January (919) ►  2021 (18627) December (1600) November (1802) October (1805) September (1895) August (1767) July (1502) June (1433) May (1157) April (1184) March (1245) February (1392) January (1845) ►  2020 (4239) December (710) November (877) October (679) September (655) August (524) July (414) June (378) February (2) ►  2017 (2928) February (784) January (2144) ►  2016 (17180) December (1848) November (1487) October (1535) September (1463) August (1550) July (1513) June (1405) May (1492) April (1460) March (1507) February (1351) January (569) ►  2015 (16493) December (200) November (1418) October (1507) September (1459) August (1416) July (1533) June (1499) May (1543) April (1450) March (1547) February (1397) January (1524) ►  2014 (15565) December (1541) November (1488) October (1550) September (400) August (921) July (1545) June (1482) May (1502) April (1475) March (789) February (1342) January (1530) ►  2013 (17748) December (1454) November (1455) October (1543) September (1487) August (1495) July (1559) June (1472) May (1492) April (1504) March (1514) February (1261) January (1512) ►  2012 (17322) December (1547) November (1475) October (1527) September (1422) August (1483) July (1359) June (1395) May (1469) April (1434) March (1415) February (1389) January (1407) ▼  2011 (16904) December (1427) November (1435) October (1323) September (1381) August (1366) July (1386) June (1353) May (1405) April (1458) March (1523) February (1385) January (1462) ►  2010 (16340) December (1070) November (1488) October (1432) September (1459) August (1425) July (1413) June (1383) May (1345) April (1295) March (1426) February (1256) January (1348) ►  2009 (16054) December (1435) November (1354) October (1361) September (1318) August (1334) July (1367) June (1347) May (1285) April (1335) March (1442) February (1227) January (1249) ►  2008 (5752) December (1272) November (1160) October (1249) September (789) August (696) July (361) June (182) May (40) March (1) February (1) January (1) ►  2007 (1) May (1) ►  2006 (1310) December (1) May (63) April (803) March (436) January (7) Popular Entries (All Time) One stock to own before Nat Gas 2011 becomes law From the individual investor resource Wired magazine calls "sharp, up-to-the... Jay Leno's Trillion Dollar Investing Tip -- It's No Joke Jay Leno's Trillion Dollar Investing Tip Wall Street know-it-alls laughed when we said the host of The T... The death of diesel & the ONE STOCK to play it The individual investor resource Wired magazine calls "sharp, up-to-the-minute financ... All shared content is the the property of the original owner. No infringement intended. Theme images by luoman. Powered by Blogger.