A Seminar on Hemophilia

Transcription

1 A Seminar on Hemophilia Amy Thompson, PharmD Conflict of Interest Disclosure As an organization accredited by ACPE, California/Delaware Board of Nursing and Commission for Case Managers, CVS Caremark, LLC requires everyone who is in a position to control the content of an educational activity to disclose all relevant financial relationships with any commercial interest. CVS Caremark, LLC, or its employees or members of the planning committee, do not provide any financial or in-kind support for the educational activity, do not provide any sponsorships, and do not endorse any products. Last reviewed April 14, 2015 The information contained in this communication is provided in summary form. It is not intended for use as the sole basis of clinical treatment, as a substitute for reading the original research, nor as a substitute for the knowledge, skill and judgment of the medical provider. This document contains references to brand-name prescription drugs that are trademarks or registered trademarks of pharmaceutical manufacturers not affiliated. Disclosures of the Faculty and Planners Objectives Faculty Amy Thompson, PharmD Presenter CVS/caremark employee and stock/shareholder No relevant financial relationship with any product manufacturer mentioned At the conclusion of this program, the pharmacist will be able to: Compare and contrast the types of hemophilia Describe the pathophysiology of hemophilia Recall basic information about the severity and inheritance pattern of hemophilia Identify common bleeding sites and symptoms associated with hemophilia Describe the complications associated with hemophilia Identify clotting factor products for the treatment of hemophilia Describe basic treatment protocols for hemophilia 1

2 Objectives Pre-Test Questions True or False? At the conclusion of this program, the technician will be able to: Compare and contrast the types of hemophilia Describe the pathophysiology of hemophilia Recall basic information about the severity and inheritance pattern of hemophilia Identify common bleeding sites and symptoms associated with hemophilia Describe the complications associated with hemophilia Identify clotting factor products for the treatment of hemophilia 1. Hemophilia is not the most common bleeding disorder. 2. Hemophilia is an inherited condition, and most commonly expressed in females. 3. All bleeds experienced by a person with hemophilia are due to trauma. 4. Most persons with hemophilia will use one product to treat bleeds and another product to prevent bleeds. 5. Anti-hemophilia factor products are given intravenously. Overview Overview of Hemophilia Bleeding disorder caused by the absence or deficiency of an essential clotting factor involved in the formation of fibrin Most commonly inherited but may occur spontaneously Affected clotting factor determines type Hemophilia A: factor VIII (FVIII) Hemophilia B: factor IX (FIX) Severity of disease correlates with the level of clotting factor Results in prolonged or unprovoked bleeding Most bleeding occurs internally into the joints or muscles Sources: 1. Guidelines for the Management of Hemophilia. Montreal, Quebec: World Federation of Hemophilia; Accessed February 16, Hemophilia: facts. Centers for Disease Control and Prevention website. Updated August 26, Accessed February 16, Bleeding disorders. PubMed Health website. Reviewed: March 3, Accessed February 16, Hoots WK, Shapiro AD. Clinical manifestations and diagnosis of hemophilia. In: Leung LLK, Mahoney DH Jr, eds. UpToDate, Waltham, MA,

3 Overview of Hemophilia Compare and Contrast: Hemophilia A vs B Rare disorder Affects about 400,000 people worldwide1 Affects about 20,000 people in the United States2 Occurs in an estimated 1 in 5,000-10,000 births1-3 Affects all races and ethnicities Affects more males than females Lifelong condition often diagnosed in infancy Age at diagnosis correlates with severity of disease Normal life expectancy with clotting factor replacement therapy AGE OF DIAGNOSIS AMONG CHILDREN LESS THAN TWO YEARS OF AGE 15.6% 4.7% 2.8% 7.1% Less than one month 1-6 months 7-12 months months Prenatal 69.7% HEMOPHILIA A Classic hemophilia FVIII deficiency 80%-85% of all patients Two-thirds of patients have severe deficiency HEMOPHILIA B Christmas disease FIX deficiency 15%-20% of all patients 1 in 25,000-30,000 births One-half of patients have severe deficiency Sources: 1. Guidelines for the Management of Hemophilia. Montreal, Quebec: World Federation of Hemophilia; www1.wfh.org/publications/files/pdf-1472.pdf. Accessed February 16, Hemophilia: data & statistics. Centers for Disease Control and Prevention website. Updated August 26, Accessed February 16, Hoots WK, Shapiro AD. Clinical manifestations and diagnosis of hemophilia. In: Leung LLK, Mahoney DH Jr, eds. UpToDate, Waltham, MA, Chart source: Sources: 1. Bleeding disorders: what is hemophilia? Hemophilia Federation of America website. Accessed February 16, Guidelines for the Management of Hemophilia. Montreal, Quebec: World Federation of Hemophilia; www1.wfh.org/publications/files/pdf-1472.pdf. Accessed February 16, Hoots WK, Shapiro AD. Clinical manifestations and diagnosis of hemophilia. In: Leung LLK, Mahoney DH Jr, eds. UpToDate, Waltham, MA, Inheritance of Hemophilia Inheritance of Hemophilia X-linked recessive disorder Both FVIII and FIX genes located on the X chromosome Expressed in males Affected females are typically carriers, but can be symptomatic Inactivation or loss of part or all of the unaffected X chromosome Half of carriers have mild hemophilia Impacts menstruation FVIII and FIX genes are prone to spontaneous mutation Approximately 30% of cases have no family history Sources: 1. Hoots WK, Shapiro AD. Clinical manifestations and diagnosis of hemophilia. In: Leung LLK, Mahoney DH Jr, eds. UpToDate, Waltham, MA, Hemophilia: facts. Centers for Disease Control and Prevention website. Updated August 26, Accessed February 16, Guidelines for the Management of Hemophilia. Montreal, Quebec: World Federation of Hemophilia; www1.wfh.org/publications/files/pdf-1472.pdf. Accessed February 16, National Hemophilia Foundation. MASAC recommendations regarding girls and women with inherited bleeding disorders. MASAC Document #197 (Replaces #185). MASAC/MASAC-Recommendations/MASAC-Recommendations-Regarding-Girls-and-Women-with-Inherited-Bleeding-Disorders. Approved April 18, Accessed February 16, MOTHER FATHER CHILDREN Without Hemophilia Non-Carrier With Hemophilia Without Hemophilia Carrier With Hemophilia Sources: 1. Bleeding disorders: what is hemophilia? Hemophilia Federation of America website. Accessed February 16, Guidelines for the Management of Hemophilia. Montreal, Quebec: World Federation of Hemophilia; www1.wfh.org/publications/files/pdf-1472.pdf. Accessed February 16,

4 Coagulation Overview of Coagulation Coagulation is the process of blood clot formation Complex, highly regulated stepwise cascade involving as many as 20 plasma proteins Blood vessel constricts Platelet plug forms Fibrin clot forms Limits blood flow Activation Adhesion Aggregation Secretion Clotting factors (I-XIII) Calcium Vitamin K Sources: 1. Leung LLK. Overview of hemostasis. In: Mannucci PM, Tirnauer JS, eds. UpToDate, Waltham, MA, Bleeding disorders. PubMed Health website. Reviewed: March 3, Accessed February 16, Introduction to Blood Coagulation. themedicalbiochemistrypage.org website. Modified November 19, Accessed February 16, Clotting Sequence Normal Clotting vs Clotting in Hemophilia Factor XII Factor XIIa Factor XI Hemophilia B Factor XIa Factor IX Factor IXa Tissue Factor (III) Factor VIIa Factor VII Factor VIII Factor VIIIa Hemophilia A Factor X Factor Xa Factor Va Factor V Prothrombin (Factor II) Thrombin (Factor IIa) Factor XIII Fibrinogen (I) Fibrin (Ia) Stabilized fibrin Factor XIIIa Sources: 1. Introduction to Blood Coagulation. themedicalbiochemistrypage.org website. Modified November 19, Accessed February 16, Leung LLK. Overview of hemostasis. In: Mannucci PM, Tirnauer JS, eds. UpToDate, Waltham, MA, Source: Hemophilia in Pictures, World Federation of Hemophilia, 2005, 4

5 Learning Assessment (Q1) Bleeding is prolonged after an injury because: Diagnosis, Severity, and Sites of Bleeding A. platelet plug cannot be formed B. fibrin cannot be made C. body breaks down fibrin too fast D. all of the above E. none of the above Diagnosis Levels of Severity Family history Signs and symptoms Prolonged bleeding after circumcision, blood draws, or heel sticks Cranial bleeding after forceps or difficult delivery Significant or unusual bruising Laboratory tests Screening tests indicate if blood clots properly Complete blood count (CBC), platelet count, prothrombin time (PT), activated partial thromboplastin time (aptt), fibrinogen test Clotting factor assays determine the type and severity of hemophilia Genetic testing Prenatal diagnosis via amniocentesis or chorionic villus sampling Carrier detection Clotting Factor Level Age at Diagnosis Description of Bleeding Episodes MILD MODERATE SEVERE 5%-<40% of normal 5-40 IU/dL Older 36 months-adulthood Severe bleeding following major trauma or surgery Spontaneous bleeding is rare 1%-5% of normal 1-5 IU/dL Prolonged bleeding following minor trauma or surgery Occasional spontaneous bleeding <1% of normal <1 IU/dL Younger 1-24 months Spontaneous bleeding into joints or muscles without obvious precipitating cause Sources: 1. Hemophilia: facts. Centers for Disease Control and Prevention website. Updated August 26, Accessed February 16, Guidelines for the Management of Hemophilia. Montreal, Quebec: World Federation of Hemophilia; www1.wfh.org/publications/files/pdf-1472.pdf. Accessed February 16, Hoots WK, Shapiro AD. Clinical manifestations and diagnosis of hemophilia. In: Leung LLK, Mahoney DH Jr, eds. UpToDate, Waltham, MA, National Hemophilia Foundation. MASAC guidelines for perinatal management of women with bleeding disorders and carriers of hemophilia A and B. MASAC Document # Hemophilia-A-and-B. Approved October 31, Accessed February 16, Sources: 1. Guidelines for the Management of Hemophilia. Montreal, Quebec: World Federation of Hemophilia; www1.wfh.org/publications/files/pdf-1472.pdf. Accessed February 16, Hemophilia: data & statistics. Centers for Disease Control and Prevention website. Updated August 26, Accessed February 16, Hoots WK, Shapiro AD. Clinical manifestations and diagnosis of hemophilia. In: Leung LLK, Mahoney DH Jr, eds. UpToDate, Waltham, MA,

6 Learning Assessment (Q2) Sites of Bleeding: Hemarthroses Which is FALSE? A. Hemophilia A is less common than Hemophilia B. B. Hemophilia B is FIX deficiency. C. Hemophilia is X-linked recessive and primarily expressed by males. Hallmark feature 70%-80% of bleeds Hinged joints (e.g., ankles, knees, and elbows) Signs and Symptoms Stiffness and warmth Tingling Swelling Acute pain Decreased range of motion and use of affected limb Sources: 1. Hoots WK, Shapiro AD. Clinical manifestations and diagnosis of hemophilia. In: Leung LLK, Mahoney DH Jr, eds. UpToDate, Waltham, MA, Guidelines for the Management of Hemophilia. Montreal, Quebec: World Federation of Hemophilia; www1.wfh.org/publications/files/pdf-1472.pdf. Accessed February 16, Sites of Bleeding: Hemarthroses (cont.) Sites of Bleeding: Muscles Common site of bleed 10%-20% of bleeds Affects any muscle group Signs and symptoms Pain or aching Swelling Tension Functional impairment Need to maintain limb in a comfortable position Iliopsoas hemorrhage Unique presentation Mimics acute appendicitis Pain in lower abdomen, groin, lower back, extension but not rotation of hip joint Source: Hemophilia in Pictures, World Federation of Hemophilia, 2005, Sources: 1. Hoots WK, Shapiro AD. Clinical manifestations and diagnosis of hemophilia. In: Leung LLK, Mahoney DH Jr, eds. UpToDate, Waltham, MA, Guidelines for the Management of Hemophilia. Montreal, Quebec: World Federation of Hemophilia; www1.wfh.org/publications/files/pdf-1472.pdf. Accessed February 16,

7 Sites of Bleeding: Other Complications of Joint and Muscle Bleeds Mucous membranes Mouth and gums Nose Genitourinary tract Intracranial* Neck/throat* Gastrointestinal* Flexion contractures Synovitis Joint arthritis/arthropathy Chronic pain Muscle atrophy Compartment syndrome Neurologic impairment *Life-threatening Sources: 1. Hemophilia: facts. Centers for Disease Control and Prevention website. Updated August 26, Accessed February 16, Guidelines for the Management of Hemophilia. Montreal, Quebec: World Federation of Hemophilia; www1.wfh.org/publications/files/pdf-1472.pdf. Accessed February 16, Source: Guidelines for the Management of Hemophilia. Montreal, Quebec: World Federation of Hemophilia; www1.wfh.org/publications/files/pdf-1472.pdf. Accessed February 16, Learning Assessment (Q3) The most common bleeding sites are: Treatment A. Hip joints, calf muscles, and flexion contractures B. GI tract and deltoids C. Hinged joints and any muscle group D. Mouth and nose 7

8 Treatment Goals General Principles Prevent and treat bleeding with the deficient clotting factor Additional objectives Prevent damage to joints and muscles Manage complications from the disease and treatments Treatment goals are accomplished by Prophylaxis Immediate treatment of acute bleeds Home therapy Patients should be proactive in their care Carry an identification card for emergency situations Maintain an adequate supply of factor therapy on hand at all times Acute bleeds should be treated within two hours If potentially life-threatening severe bleed, treat immediately If in doubt, treat! Emphasize dosing appropriateness Source: Guidelines for the Management of Hemophilia. Montreal, Quebec: World Federation of Hemophilia; www1.wfh.org/publications/files/pdf-1472.pdf. Accessed February 16, Source: Guidelines for the Management of Hemophilia. Montreal, Quebec: World Federation of Hemophilia; www1.wfh.org/publications/files/pdf-1472.pdf. Accessed February 16, General Principles Comprehensive Care Assess patient s health status at least every 12 months Identify new or potential complications early Evaluate/modify treatment plan Reinforce patient education points Treat veins with care 23- or 25-gauge butterfly needles Avoid venous access devices if possible Avoid medications that affect platelet function Maintain good oral health Encourage safe physical activity and exercise Use first aid adjunctive measures Splints Rest, ice, compression, elevation (RICE) Coordinated inpatient and outpatient care from a multidisciplinary team Promotes physical and psychosocial health; quality of life Decreases morbidity and mortality 40% lower mortality and hospitalization rates CORE TEAM MEMBERS Medical director Hematologist or physician Nurse coordinator Musculoskeletal specialist Physiotherapist, occupational therapist, orthopedist Lab specialist Psychosocial specialist Social worker, psychologist ADDITIONAL SUPPORT MEMBERS Chronic pain specialist Dentist Geneticist Hepatologist Infectious disease specialist Immunologist Gynecologist/obstetrician Vocational counselor Source: Guidelines for the Management of Hemophilia. Montreal, Quebec: World Federation of Hemophilia; www1.wfh.org/publications/files/pdf-1472.pdf. Accessed February 16, Sources: 1. Guidelines for the Management of Hemophilia. Montreal, Quebec: World Federation of Hemophilia; www1.wfh.org/publications/files/pdf-1472.pdf. Accessed February 16, Hemophilia: data & statistics. Centers for Disease Control and Prevention website. Updated August 26, Accessed February 16,

9 Medication Therapy Factor VIII Products Factor replacement therapy FVIII products for hemophilia A FIX products for hemophilia B Ancillary medications Desmopressin (DDAVP) Stimate Aminocaproic acid Amicar Tranexamic acid Cyklokapron Lysteda Recombinant factors: laboratory-produced synthetic clotting factors First generation: Recombinate Second generation: Kogenate FS, Helixate FS Third generation: Advate, Xyntha, Novoeight Fourth generation: Afstyla, Nuwiq, Kovaltry Long-acting: Adynovate, Eloctate Indicated for the prevention and control of bleeding in patients with hemophilia A; for perioperative management; for routine prophylaxis in adults and children Plasma-derived factors: isolated from pooled human blood Immunoaffinity purified: Monoclate-P, HEMOFIL M Intermediate purity: Koate DVI Indicated for the prevention and control of bleeding in patients with hemophilia A Sources: 1. National Hemophilia Foundation. MASAC recommendations concerning products licensed for the treatment of hemophilia and other bleeding disorders (Revised September 2014). MASAC Document #230 (Replaces #225). Providers/Medical-and-Scientific-Advisory-Council-MASAC/MASAC-Recommendations/MASAC-Recommendations-Concerning-Products-Licensed-for-the-Treatment-of-Hemophilia-and-Other-Bleeding-Disorders. Approved September 20, Accessed February 16, Recombinate with 5 ml Sterile Water for Injection [package insert]. Westlake Village, CA: Baxter Healthcare Corporation; December Recombinate with 10 ml Sterile Water for Injection [package insert]. Westlake Village, CA: Baxter Healthcare Corporation; December Kogenate FS [package insert]. Tarrytown, NY: Bayer HealthCare LLC; May Kogenate FS with BIO-SET [package insert]. Whippany, NJ: Bayer HealthCare LLC; June Kogenate FS with Vial Adapter [package insert]. Whippany, NJ: Bayer HealthCare LLC; June Helixate FS [package insert]. Whippany, NJ: Bayer HealthCare LLC; May Advate [package insert]. Westlake Village, CA: Baxter Healthcare Corporation; April Xyntha [package insert]. Philadelphia, PA: Wyeth Pharmaceuticals Inc.; October Xyntha Solufuse [package insert]. Philadelphia, PA: Wyeth Pharmaceuticals Inc.; October Novoeight [package insert]. Plainsboro, NJ: Novo Nordisk Inc., October Eloctate [package insert]. Cambridge, MA: Biogen Idec Inc.; June Monoclate-P [package insert]. Kankakee, IL: CSL Behring LLC; October Hemofil M [package insert]. Westlake Village, CA: Baxter Healthcare Corporation; April Koate-DVI [package insert]. Research Triangle Park, NC: Talecris Biotherapeutics, Inc.; August Factor VIII Products: FVIII with von Willebrand Factor (vwf) Factor VIII Products: Standard ALPHANATE APPROXIMATELY 1 FVIII: 0.4 VWF:RCOF* HUMATE-P APPROXIMATELY 1 FVIII: 2.4 VWF:RCOF Control and prevention of bleeding in patients with hemophilia A Surgical and/or invasive procedures in adult and pediatric patients with von Willebrand Disease (vwd) in whom desmopressin (DDAVP ) is either ineffective or contraindicated (removed indication for acquired hemophilia) Treatment and prevention of bleeding episodes in adults with hemophilia A Treatment of spontaneous and trauma-induced bleeding episodes and prevention of excessive bleeding during and after surgery in adult and pediatric patients with vwd Intravenous infusion Dose varies depending on type of bleed Ranges from 20 to 50+ units/kg of body weight every eight to 24 hours Half-life: eight to 12 hours Each unit infused/kg of body weight raises serum FVIII level by 2% WILATE 1 FVIII: 1 VWF:RCOF Treatment of spontaneous and trauma-induced bleeding episodes in patients with severe vwd as well as patients with mild or moderate vwd in whom the use of desmopressin is known or suspected to be ineffective or contraindicated No indication for hemophilia A *The ratio of vwf:rcof to FVIII of Alphanate varies by lot. Sources: 1. Alphanate [package insert]. Los Angeles, CA: Grifols Biologicals Inc.; June Humate-P [package insert]. Kankakee, IL: CSL Behring LLC; August Wilate [package insert]. Hoboken, NJ: Octapharma USA Inc.; August Sources: 1. Guidelines for the Management of Hemophilia. Montreal, Quebec: World Federation of Hemophilia; www1.wfh.org/publications/files/pdf-1472.pdf. Accessed February 16, Recombinate with 5 ml Sterile Water for Injection [package insert]. Westlake Village, CA: Baxter Healthcare Corporation; December Recombinate with 10 ml Sterile Water for Injection [package insert]. Westlake Village, CA: Baxter Healthcare Corporation; December Kogenate FS [package insert]. Tarrytown, NY: Bayer HealthCare LLC; May Kogenate FS with BIO-SET [package insert]. Whippany, NJ: Bayer HealthCare LLC; June Kogenate FS with Vial Adapter [package insert]. Whippany, NJ: Bayer HealthCare LLC; June Helixate FS [package insert]. Whippany, NJ: Bayer HealthCare LLC; May Advate [package insert]. Westlake Village, CA: Baxter Healthcare Corporation; April Xyntha [package insert]. Philadelphia, PA: Wyeth Pharmaceuticals Inc.; October Xyntha Solufuse [package insert]. Philadelphia, PA: Wyeth Pharmaceuticals Inc.; October Novoeight [package insert]. Plainsboro, NJ: Novo Nordisk Inc., October Monoclate-P [package insert]. Kankakee, IL: CSL Behring LLC; October Hemofil M [package insert]. Westlake Village, CA: Baxter Healthcare Corporation; April Koate-DVI [package insert]. Research Triangle Park, NC: Talecris Biotherapeutics, Inc.; August Alphanate [package insert]. Los Angeles, CA: Grifols Biologicals Inc.; June Humate-P [package insert]. Kankakee, IL: CSL Behring LLC; August Wilate [package insert]. Hoboken, NJ: Octapharma USA Inc.; August

10 Factor VIII Products: Long-acting (Eloctate) Von Willebrand Factor Product Intravenous infusion Dose varies depending on type of bleed Ranges from 20 to 50 units/kg of body weight every 8 to 48 hours Half-life: 19.7 hours Each unit infused/kg of body weight raises serum FVIII level by 2% Vonvendi Von Willebrand factor (Recombinant) On-demand treatment and control of bleeding episodes in adults diagnosed with von Willebrand disease Sources: 1. Guidelines for the Management of Hemophilia. Montreal, Quebec: World Federation of Hemophilia; Accessed February 16, Eloctate [package insert]. Cambridge, MA: Biogen Idec Inc.; June Sources: 1. Vonvendi [package insert]. Westlake Village, CA: Baxalta US Inc.; December Factor IX Products Factor IX Products: Standard Recombinant factors: laboratory-produced synthetic clotting factors BeneFix, Rixubis, Ixinity Long-acting: Idelvion, Alprolix Plasma-derived factors: isolated from pooled human blood FIX Complexes Bebulin (nanofiltered/vapor heated) Profilnine SD (solvent detergent treated) Coagulation FIX AlphaNine SD (solvent detergent treated/virus filtered) Mononine (monoclonal antibody purified) Sources: 1. BeneFix [package insert]. Philadelphia, PA: Wyeth Pharmaceuticals Inc.; March Rixubis [package insert]. Westlake Village, CA: Baxter Healthcare Corporation; September Alprolix [package insert]. Cambridge, MA: Biogen Idec Inc.; March Bebulin [package insert]. Westlake Village, CA: Baxter Healthcare Corporation; July Profilnine [package insert]. Los Angeles, CA: Grifols Biologicals, Inc.; November AlphaNine SD [package insert]. Los Angeles, CA: Grifols Biologicals Inc.; January Mononine [package insert]. Kankakee, IL: CSL Behring LLC; February Indicated for the prevention and control of bleeding in patients with hemophilia B BeneFix indicated for use in pediatrics and perioperative management Rixubis indicated for use in children, perioperative management, and routine prophylaxis Ixinity indicated for use in adults and children 12 years, control and prevention and perioperative management Mononine has also been studied in pediatric patients Intravenous infusion Dose varies depending on type of bleed Ranges from 20 to 100+ units/kg of body weight Half-life: 18 to 26 hours Each unit infused/kg of body weight raises serum FIX level by 1% Bebulin and BeneFix raise it by 0.8% Rixubis raises it by 0.9% in patients 12 years of age (0.7% in patients <12 years of age) Sources: 1. BeneFix [package insert]. Philadelphia, PA: Wyeth Pharmaceuticals Inc.; March Rixubis [package insert]. Westlake Village, CA: Baxter Healthcare Corporation; September Bebulin [package insert]. Westlake Village, CA: Baxter Healthcare Corporation; July Profilnine [package insert]. Los Angeles, CA: Grifols Biologicals, Inc.; November AlphaNine SD [package insert]. Los Angeles, CA: Grifols Biologicals Inc.; January Mononine [package insert]. Kankakee, IL: CSL Behring LLC; February Guidelines for the Management of Hemophilia. Montreal, Quebec: World Federation of Hemophilia; www1.wfh.org/publications/files/pdf-1472.pdf. Accessed February 16,

11 Factor IX Products: Long-acting Other Factor Replacement Products Indicated in adults and children with hemophilia B for: Control and prevention of bleeding episodes Perioperative management Routine prophylaxis to prevent or reduce the frequency of bleeding episodes Intravenous infusion Dose varies depending on type of bleed Half-life: Alprolix hours Idelvion hours (adults), hours (< 18 year old) Each unit infused/kg of body weight raises serum FIX level by 1% Cryoprecipitate Fresh frozen plasma Sources: 1. Alprolix [package insert]. Cambridge, MA: Biogen Idec Inc.; March Sources: 1. Guidelines for the Management of Hemophilia. Montreal, Quebec: World Federation of Hemophilia; www1.wfh.org/publications/files/pdf-1472.pdf. Accessed February 16, National Hemophilia Foundation. MASAC recommendations concerning products licensed for the treatment of hemophilia and other bleeding disorders (Revised September 2014). MASAC Document #230 (Replaces #225). Products-Licensed-for-the-Treatment-of-Hemophilia-and-Other-Bleeding-Disorders. Approved September 20, Accessed February 16, Other Treatments: Desmopressin Acetate Other Treatments: Tranexamic Acid Synthetic vasopressin Mechanism of action: release of stores of FVIII and vwf from endothelial cells raising serum levels Indication: hemophilia A (FXIII activity levels >5%), vwd Administration Intravenous Subcutaneously Intranasally (Stimate) How supplied:1.5 mg/ml; 2.5 ml bottle--delivers 25 doses of 150 mcg Dosing: every 24 to 48 hours as needed <50 kg of body weight: 1 spray (150 mcg) >50 kg of body weight: 2 sprays (300 mcg) Requires test dose by MD for effectiveness Preferred treatment option for mild (removed reference to moderate) hemophilia A Especially useful for carriers Lower cost No risk of viral transmission Mechanism of action: inhibits activation of plasminogen to plasmin Cyklokapron Lysteda Uses Short-term use (two to eight days) to reduce or prevent hemorrhage and reduce the need for replacement therapy during and following tooth extraction Dosing 10 mg/kg intravenously before tooth extraction and three to four times daily for two to eight days after May also be given orally How supplied 100 mg/ml, 10 ml ampules or vials Use Treatment of women with cyclic heavy menstruation Dosing Two 650 mg tablets taken three times daily (3,900 mg/day) for a maximum of five days during monthly menstruation How supplied 650 mg tablets Sources: 1. Guidelines for the Management of Hemophilia. Montreal, Quebec: World Federation of Hemophilia; www1.wfh.org/publications/files/pdf-1472.pdf. Accessed February 16, National Hemophilia Foundation. MASAC recommendations concerning products licensed for the treatment of hemophilia and other bleeding disorders (Revised September 2014). MASAC Document #230 (Replaces #225). Hemophilia-and-Other-Bleeding-Disorders. Approved September 20, Accessed February 16, Stimate [package insert]. King of Prussia, PA: CSL Behring LLC; June DDAVP Injection [package insert]. Bridgewater, NJ: sanofi-aventis U.S. LLC; July Sources: 1. Cyklokapron [package insert]. New York, NY: Pharmacia & Upjohn Co; December Lysteda [package insert]. Parsippany, NJ: Ferring Pharmaceuticals Inc.; October Guidelines for the Management of Hemophilia. Montreal, Quebec: World Federation of Hemophilia; www1.wfh.org/publications/files/pdf-1472.pdf. Accessed February 16, National Hemophilia Foundation. MASAC recommendations concerning products licensed for the treatment of hemophilia and other bleeding disorders (Revised September 2014). MASAC Document #230 (Replaces #225). Approved September 20, Accessed February 16,

12 Other Treatments: Aminocaproic Acid (Amicar) Antifibrinolytic Mechanism of action Enhances hemostasis Uses Mucocutaneous bleeding (oral) Dosing 50 to 100 mg/kg every six hours How supplied 500 mg and 1,000 mg tablets 250 mg/ml oral solution Other Bleeding Disorders with Treatment Options Sources: 1. Aminocaproic Acid [package insert]. Marietta, GA: VersaPharm Incorporated; May National Hemophilia Foundation. MASAC recommendations concerning products licensed for the treatment of hemophilia and other bleeding disorders (Revised September 2014). MASAC Document #230 (Replaces #225). Recommendations-Concerning-Products-Licensed-for-the-Treatment-of-Hemophilia-and-Other-Bleeding-Disorders. Approved September 20, Accessed February 16, Guidelines for the Management of Hemophilia. Montreal, Quebec: World Federation of Hemophilia; www1.wfh.org/publications/files/pdf-1472.pdf. Accessed February 16, Overview of Medication Therapy Factor XIII (Fibrin Stabilizing Factor) Deficiency FACTOR XIII DEFICIENCY FACTOR X DEFICIENCY FACTOR I DEFICIENCY ACQUIRED HEMOPHILIA A Corifact (factor XIII concentrate [human]) Tretten (coagulation factor XIII A-subunit [recombinant]) Coagadex (coagulation factor X [human]) RiaSTAP (fibrinogen concentrate [human]) Obizur (antihemophilic factor [recombinant], porcine sequence) Rarest factor deficiency: 1: 5,000,000 births 1 Affects men and women equally Autosomal recessive inheritance pattern 95% of patients have the A-subunit deficiency 1 FXIII stabilizes blood clot formation FXIII is composed of two A-subunits (catalytic) and two B-subunits (carrier) Without FXIII, the formed clot will break down, causing recurrent bleeds Sources: 1. Factor XIII. National Hemophilia Foundation website. Accessed February 17, Corifact [package insert]. Kankakee, IL: CSL Behring LLC; January Tretten [package insert]. Plainsboro, NJ: Novo Nordisk Inc.; April Tretten [package insert]. Plainsboro, NJ: Novo Nordisk Inc.; April

13 Factor XIII (Fibrin Stabilizing Factor) Deficiency (cont.) Factor X Deficiency TREATMENT Corifact (Factor XIII Concentrate, Human) FDA Approval February 2011 December 2013 Indication Dosing and Administration Routine prophylactic treatment and perioperative management of surgical bleeding in adult and pediatric patients with congenital FXIII deficiency 40 IU/kg, adjust dose ±5 IU/kg to maintain 5% to 20% trough level of FXIII activity Routine prophylaxis: administer every 28 days Perioperative management: dosing should be individualized based on FXIII activity level, type of surgery, and clinical response. Intravenous infusion Tretten (Coagulation Factor XIII A-Subunit, Recombinant) Routine prophylaxis for bleeding in patients with congenital factor XIII A-subunit deficiency 35 IU/kg once monthly to achieve a target trough level of FXIII activity at or above 10% Intravenous infusion TREATMENT Coagadex (coagulation factor X [human]) Indicated in adults and children (aged 12 years and above) with hereditary Factor X deficiency for: On-demand treatment and control of bleeding episodes Perioperative management of bleeding in patients with mild hereditary Factor X deficiency How supplied: single use vials containing 250 or 500 IU lyophilized powder Dosing: For bleeds - 25 IU/kg intravenously every 24 hours until bleed resolved Pre/Post-surgery IU/kg before, and appropriate dose to maintain 50 IU/dL after Sources: 1. Factor XIII. National Hemophilia Foundation website. Accessed February 17, Corifact [package insert]. Kankakee, IL: CSL Behring LLC; January Tretten [package insert]. Plainsboro, NJ: Novo Nordisk Inc.; April Tretten [package insert]. Plainsboro, NJ: Novo Nordisk Inc.; April Sources: 1. Coagadex [Package Insert]. Durham, NC, Bio Products Lab. October Factor I (Fibrinogen) Deficiency Factor I (Fibrinogen) Deficiency (cont.) Affects men and women equally Includes three rare inherited fibrinogen deficiencies AFIBRINOGENEMIA HYPOFIBRINOGENEMIA DYSFIBRINOGENEMIA Type Quantitative Quantitative Qualitative Pathophysiology Estimated Prevalence Fibrinogen is absent (<20 mg/dl) Some fibrinogen with normal structure is present but below levels required for normal hemostasis (20 to 80 mg/dl) 1-2: 1,000,000 Unknown, less than afibrinogenemia Inheritance Autosomal recessive Autosomal dominant and recessive Bleeding Severity Symptoms Most severe form and may be life-threatening Bleeding episodes are usually mild Umbilical cord bleeding, cutaneous bleeding, gastrointestinal hemorrhage, intracranial bleeding, articular bleeding Normal amounts of fibrinogen are made by the liver but do not clot properly (200 to 450 mg/dl) 1:1,000,000 Autosomal dominant and recessive Spontaneous bleeding is rare Often asymptomatic, hemorrhage, thrombosis Sources: 1. Factor I. National Hemophilia Foundation website. Accessed February 18, Acharya SS, DiMichele DM. Rare inherited disorders of fibrinogen. Haemophilia. 2008; 14: Congenital fibrinogen (factor I) deficiency. CSL Behring website. Accessed February 18, Types of congenital fibrinogen deficiency. RiaSTAP website. Accessed February 18, RiaSTAP [package insert]. Kankakee, IL: CSL Behring LLC; December TREATMENT RiaSTAP (fibrinogen concentrate [human]) Indicated for the treatment of acute bleeding episodes in patients with congenital fibrinogen deficiency, including afibrinogenemia and hypofibrinogenemia NOT indicated for dysfibrinogenemia How supplied: single use vial containing 900-1,300 mg lyophilized powder Dosing: 70 mg/kg given intravenously, if baseline fibrinogen level is unknown Sources: 1. Factor I. National Hemophilia Foundation website. Accessed February 18, Acharya SS, DiMichele DM. Rare inherited disorders of fibrinogen. Haemophilia. 2008; 14: Congenital fibrinogen (factor I) deficiency. CSL Behring website. Accessed February 18, Types of congenital fibrinogen deficiency. RiaSTAP website. Accessed February 18, RiaSTAP [package insert]. Kankakee, IL: CSL Behring LLC; December

14 Acquired Hemophilia A Acquired Hemophilia A (cont.) Rare, potentially life-threatening bleeding disorder Affects approximately 2:1,000,000 1 Typically affects older adults Caused by the production of antibodies directed against FVIII that is synthesized by the body Autoantibodies cause inactivation of FVIII Inability to clot normally results in excessive bleeding Onset may be associated with other medical conditions Patients typically experience bleeds in the skin, muscles, and soft tissue TREATMENT Obizur (antihemophilic factor [recombinant], porcine sequence) Indicated for the treatment of bleeding episodes in adults with acquired hemophilia A Dosage and administration Dose, frequency, and duration of treatment depend on location and severity of bleeding, target FVIII levels, and patient s condition Initial recommended dose is 200 units per kg with subsequent dosing every 4 to 12 hours Dose and frequency should be titrated based on clinical response and FVIII levels Administered as an intravenous injection Supplied in single-use vials containing 500 units per vial Development of inhibitors to porcine factor VIII has occurred in clinical trials Sources: 1. Acquired hemophilia. World Federation of Hemophilia website. Accessed February 23, FDA approves Baxter s Obizur for acquired hemophilia A. National Hemophilia Foundation website. Published October 29, Accessed February 23, FDA approves new treatment for rare form of hemophilia. U.S. Food and Drug Administration website. Updated October 24, Accessed February 23, FDA approves Baxter s Obizur [antihemophilic factor (recombinant), porcine sequence], for acquired hemophilia A. Baxter website. Accessed February 23, Source: Obizur [package insert]. Westlake Village, CA: Baxter Healthcare Corporation; October Hemophilia Factor Treatment Regimens Factor Treatment Regimens On demand treatment Prophylaxis treatment Primary Secondary Tertiary Short-term Source: Guidelines for the Management of Hemophilia. Montreal, Quebec: World Federation of Hemophilia; www1.wfh.org/publications/files/pdf-1472.pdf. Accessed February 16,

15 Treatment Regimen: On Demand Learning Assessment (Q4) Only active bleeds are treated Dose based on Patient s weight Type and site of bleed Factor should be administered promptly Preferably within two hours Which of the following would NOT be an appropriate choice for on demand treatment of a patient with severe Hemophilia A? A. Desmopressin B. Advate C. Xyntha D. Monoclate-P Source: Guidelines for the Management of Hemophilia. Montreal, Quebec: World Federation of Hemophilia; www1.wfh.org/publications/files/pdf-1472.pdf. Accessed February 16, Treatment Regimen: Prophylaxis Treatment Regimen: Prophylaxis (cont.) Goal: Prevent anticipated bleeding and joint destruction to preserve normal musculoskeletal function Optimal therapy for patients with severe hemophilia A or B Reduces the frequency of bleeding and may slow down progression of the joint disease Does not reverse established joint disease Scheduled infusions of factor concentrates Generally two to four times per week, preferably in the morning Long-acting factor concentrates administered less frequently (every four to ten days) To keep trough FVIII or FIX levels at 1% to 3% May need to treat breakthrough bleeds Use of implanted ventricular assist device (VAD) necessary in some individuals No clear guidelines regarding discontinuation of prophylaxis therapy PRIMARY PROPHYLAXIS SECONDARY PROPHYLAXIS TERTIARY PROPHYLAXIS SHORT-TERM OR INTERMITTENT PROPHYLAXIS Regular continuous treatment ( 45 weeks per year) Initiated prior to documented joint damage, second large joint bleed, or the age of three Recommended for patients with severe hemophilia Regular continuous treatment ( 45 weeks per year) Initiated prior to documented joint damage or after 2 large joint bleeds Consider for patients with recurrent bleeds as a result of physiotherapy or intracranial hemorrhage Regular continuous treatment ( 45 weeks per year) Initiated after the onset of joint disease Treatment for fewer than 45 weeks per year Given to interrupt a bleeding cycle (four to eight weeks) Typically in a target joint Sources: 1. National Hemophilia Foundation. MASAC recommendation concerning prophylaxis (regular administration of clotting factor concentrate to prevent bleeding). MASAC Document #179 (Replaces #170). Approved November Accessed February 18, Guidelines for the Management of Hemophilia. Montreal, Quebec: World Federation of Hemophilia; Accessed February 16, Hoots WK, Shapiro AD. Clinical manifestations and diagnosis of hemophilia. In: Leung LLK, Mahoney DH Jr, eds. UpToDate, Waltham, MA, Manco-Johnson MJ, Abshire, TC, Shapiro, AD. Prophylaxis versus episodic treatment to prevent joint disease in boys with severe hemophilia. N Engl J Med. 2007;357(6): Eloctate [package insert]. Cambridge, MA: Biogen Idec Inc.; June Alprolix [package insert]. Cambridge, MA: Biogen Idec Inc.; March Sources: 1. Guidelines for the Management of Hemophilia. Montreal, Quebec: World Federation of Hemophilia; www1.wfh.org/publications/files/pdf-1472.pdf. Accessed February 16, Coppola A, Franchini M, Tagliaferri A. Prophylaxis in people with haemophilia. Thromb Haemost. 2009; 101: Tagliaferri A, et al. Effects of secondary prophylaxis started In adolescent and adult haemophiliacs. Haemophilia. 2008;14:

16 Learning Assessment (Q5) Which of the following is an appropriate treatment for a patient with hemophilia B? Complications Associated with Hemophilia Treatment A. BeneFix B. Bebulin C. AlphaNine SD D. All of the above E. None of the above Complications Associated with Hemophilia Treatment Treatment Complications: Inhibitors Inhibitors Antibodies to replaced clotting factors Blood-borne pathogens HIV/AIDS Hepatitis Parvovirus B19 vcjd Antibody against infused FVIII or FIX FVIII: 15% to 30% FIX: 2% to 5% Diagnosis: Screening or inadequate response to treatment Measured in Bethesda Units (BU) One BU is the amount of inhibitor that will neutralize 50% of factor activity when 1 ml of plasma is incubated at 37 C for two hours Therefore, each BU of inhibitor consumes a 50% level Can be low responding (<5 BU/mL) or high responding ( 5 BU/mL) 41% to 53% are high responding Sources: 1. Guidelines for the Management of Hemophilia. Montreal, Quebec: World Federation of Hemophilia; www1.wfh.org/publications/files/pdf-1472.pdf. Accessed February 16, The challenges of inhibitors. National Hemophilia Foundation website. Accessed February 18, Measuring inhibitors. National Hemophilia Foundation website. Providers/Measuring-inhibitors. Accessed February 18,

17 Treatment Complications: Inhibitors (cont.) Treatment Complications: Inhibitors (cont.) TREATMENT OF BLEEDING EPISODES Low responding inhibitor High dose FVIII or FIX High responding inhibitor By-pass therapy Prothrombin complex concentrates (PCC)/Activated prothrombin complex concentrates (APCC) PCC: Bebulin, Profilnine APCC: FEIBA Recombinant factor VIIa NovoSeven RT (rfviia) IMMUNE TOLERANCE Goal is to eradicate the inhibitor through regular high dose infusions of factor Administered over weeks to years, then tapered down to lowest possible maintenance dose May include immune suppression Effective in up to 80% of cases Sources: 1.Guidelines for the Management of Hemophilia. Montreal, Quebec: World Federation of Hemophilia; www1.wfh.org/publications/files/pdf-1472.pdf. Accessed February 16, Feiba NF [package insert]. Westlake Village, CA: Baxter Healthcare Corporation; November NovoSeven RT [package insert]. Princeton, NJ: Novo Nordisk Inc.; July National Hemophilia Foundation. MASAC recommendation regarding the use of bypassing agents in patients with hemophilia A or B and inhibitors. MASAC Document # Approved April 22, Accessed February 18, National Hemophilia Foundation. MASAC recommendations concerning products licensed for the treatment of hemophilia and other bleeding disorders (Revised September 2014). MASAC Document #230 (Replaces #225). Approved September 20, Accessed February 16, Treatment. National Hemophilia Foundation website.. Accessed February 18, Source: 1. Guidelines for the Management of Hemophilia. Montreal, Quebec: World Federation of Hemophilia; www1.wfh.org/publications/files/pdf-1472.pdf. Accessed February 16, Immune tolerance. National Hemophilia Foundation website. Accessed February 18, Treatment Complications: Blood-Borne Pathogens Learning Assessment (Q6) Concern with plasma derived products Safety has been increasing as a result of improved manufacturing processes Donor screening Solvent detergent scrubbing Pasteurization No new HIV or hepatitis cases since 1998 Hepatitis vaccinations are recommended Parvovirus B19 has been transmitted There is some concern regarding Creutzfeldt-Jakob disease (CJD)/variant CJD due to lack of screening tests or methods for removal or inactivation. Donors diagnosed with or at risk for CJD or vcjd should be deferred from donating blood and plasma. Which of the following is NOT a complication of hemophilia? A. Arthropathy B. Transmission of blood-borne pathogens C. Development of factor inhibitors D. Otitis media Sources: 1. Hemophilia: data & statistics. Centers for Disease Control and Prevention website. August 26, Accessed February 16, Hoots WK, Shapiro AD. Clinical manifestations and diagnosis of hemophilia. In: Leung LLK, Mahoney DH Jr, eds. UpToDate, Waltham, MA, National Hemophilia Foundation. MASAC recommendations concerning products licensed for the treatment of hemophilia and other bleeding disorders (Revised September 2014). MASAC Document #230 (Replaces #225). Recommendations/MASAC-Recommendations-Concerning-Products-Licensed-for-the-Treatment-of-Hemophilia-and-Other-Bleeding-Disorders. Approved September 20, Accessed February 16, Guidelines for the Management of Hemophilia. Montreal, Quebec: World Federation of Hemophilia; www1.wfh.org/publications/files/pdf-1472.pdf. Accessed February 16,