Disclosure Hemophilia: The Royal Treatment Nikki Heeren, PharmD PGY1 Resident Avera McKennan Hospital I have had no financial relationship over the past 12 months with any commercial sponsor with a vested interest in this presentation. Objectives Background Pharmacist Design treatment regimens for patients with hemophilia A. Design treatment regimens for patients with hemophilia B. Technician Define hemophilia. Identify routes of administration for hemophilia factor concentrates. Inherited bleeding disorder Spontaneous bleeding Bleeding following injuries or surgery Low levels of either factor VIII or factor IX Severity depends on the amount of factor in the blood History of Hemophilia Epidemiology 1800 s - Queen Victoria of England Hemophilia B carrier 1828 - Hemophilia first described 1940 s - whole blood transfusions given at hospital 1955 - First infusions of factor VIII in plasma form 1968 - First FVIII concentrate available 1980s - Factor VIII and IX genes cloned 1 in 5000 males born in USA Hemophilia A represents 80% of cases ~20,000 males have hemophilia in USA 67% of babies diagnosed have a family history 1
Causes Clinical Manifestations Genetic disorder Recessive trait Located on X chromosome Females can be carriers Mutation with clotting proteins Hemophilia can result in: Bleeding within joints Bleeding in the brain Death Types of Hemophilia Severity of Hemophilia Hemophilia A Lack or decrease of clotting factor VIII Hemophilia B Lack or decrease of clotting factor IX Severity Clotting Factor Level Spontaneous Bleeding Severe < 1% of normal Occurs frequently Moderate 1-5% of normal Occasionally Mild 5-39% of normal Rare Types of Bleeding Frequency of Bleeding Serious Joints Muscles Mucous membranes Joints 70-80% Muscles 10-20% Lifethreatening Intracranial Throat/neck Gastrointestinal Other 5-10% CNS < 5% 2
Factor Replacement Management of Hemophilia Replace the missing blood clotting factor Administer by slow IV injection Maximum 3 ml/min in adults and 100 units/min in young children Recheck patient s factor level 15 minutes after administration Hemophilia A: Factor VIII Hemophilia B: Factor IX Treatment of Choice Dose Half life Hemophilia A Factor VIII concentrates Each FVIII unit/kg will increase the plasma FVIII level by about 2 IU/dl 8-12 hours Treatment of Choice Dose Half life Hemophilia B Factor IX concentrates Each FIX unit/kg will increase the plasma FVIII level by about 1 IU/dl 18-24 hours Agents for the Treatment of Hemophilia Factor Concentrates Fresh Frozen Plasma Desmopressin (DDAVP) Epsilon Amino Caproic Acid (EACA) Cryoprecipitate Tranexamic acid Factor Concentrates Factor VIII and Factor IX Human plasma derived Human recombinant Recombinant human pegylated Recombinant human with Fc fusion Recombinant porcine 3
Fresh Frozen Plasma DDAVP (Desmopressin) One ml of FFP contains 1 unit of factor activity FIX levels above 25 IU/dl are difficult to achieve with FFP alone An acceptable starting dose is 15 20 ml/kg Releases factor VIII from body tissues Can be given IV, subcutaneous, or intranasal Used for treatment of mild or moderate hemophilia A Can increase factor VIII level by three- to six-fold Peak response ~60 minutes after administration Epsilon Amino Caproic Acid (EACA) Cryoprecipitate Can be given IV or by mouth Prevents clots from breaking down resulting in firmer clots Typically administered every four to six hours Maximum of 24 g/day in adults Dose related side effect of gastrointestinal upset Slow thawing of FFP at 4 C for 10-24 hours Precipitate that is separated by centrifugation Contains FVIII and FXIII Does not contain FIX or FXI 1 unit of FFP contains 70 80 units of FVIII Tranexamic Acid Inhibits activation of plasminogen to plasmin Used for bleeding from skin and mucosal surfaces Available as an oral tablet, mouthwash, and IV Excreted by the kidneys Must reduce dose in renal dysfunction Avoid toxic accumulation Use is contraindicated for the treatment of hematuria Treatment of Hemophilia Prophylactic Factor Replacement Management of Acute Bleeds Management of Inhibitors Perioperative Management 4
Prophylactic Factor Replacement Prophylactic Factor Replacement Prevents anticipated bleeding and joint destruction Goal : preserve normal musculoskeletal function Repeated bleeding may use 4-8 weeks prophylaxis Prophylaxis protocols: Typically 15-40 IU/kg per dose Given three times weekly for hemophilia A Given twice weekly for hemophilia B Factor Replacement Protocols Protocol Definition Episodic Given at time of bleeding Primary Started after first large joint bleed Secondary Started after second large joint bleed Tertiary Started after onset of joint disease **Large joints: ankles, knees, hips, elbows, shoulders** Management of Acute Bleeds Management of Acute Bleed Management of Acute Bleed Treat as quickly as possible Preferably within two hours If in doubt, treat! DDAVP can quickly raise FVIII levels to three to six times baseline levels in patients with hemophilia A Measure patient s baseline factor level Determine desired factor level based on type of hemorrhage Determine patient s required factor dose Administer dose Recheck factor level 15 minutes after administration Re-dose if needed for adequate bleeding control Determine duration of factor replacement needed 5
Example: Joint Hemorrhage Management of Inhibitors Inhibitors Management of Inhibitors 15-20% of people with hemophilia develop an inhibitor 20% of people with hemophilia A 3% of people with hemophilia B Prevents clotting factors from stopping the bleeding Inhibitors can develop at any time Most often appear during the first 50 treatments with clotting factor concentrates Treatment of bleeding episodes becomes difficult Low Titer Inhibitors High Titer Inhibitors High-Dose Clotting Factor Concentrates Bypassing Agents Immune Tolerance Induction (ITI) Therapy Perioperative Management Perioperative Management Pre-operative assessment Inhibitor screening Assess bleeding risk of surgery Obtain adequate quantities of clotting factors Scheduling surgeries Early in the week and early in the day Optimal blood bank and lab support 6
Perioperative Management Summary Hemophilia is a disorder related to absence of clotting factors Factor concentrates are the treatment of choice Prophylaxis Management of acute bleeds Perioperative management Be aware of resources for management of hemophilia Technician Question #1 Assessment Questions Hemophilia is a disorder related to: A. Skin B. Lungs C. Blood D. Kidney Technician Question #1 Technician Question #2 Hemophilia is a disorder related to: A. Skin B. Lungs C. Blood D. Kidney Factor concentrates are given via which route for factor replacement therapy? A. Topical B. Oral C. Subcutaneous D. Intravenous 7
Technician Question #2 Pharmacist Question #1 Factor concentrates are given via which route for factor replacement therapy? A. Topical B. Oral C. Subcutaneous D. Intravenous A patient presents to the emergency department with complaints of joint pain and loss of mobility after slipping on ice while walking outside. The patient states she has hemophilia A. The ER physician asks you how to best manage this patient s joint hemorrhage. Which of the following is an appropriate treatment regimen for a patient with hemophilia A? Pharmacist Question #1 Pharmacist Question #1 Which of the following is an appropriate treatment regimen for a patient with hemophilia A? A. Factor VIII B. Factor IX C. FFP D. PCC Which of the following is an appropriate treatment regimen for a patient with hemophilia A? A. Factor VIII B. Factor IX C. FFP D. PCC Pharmacist Question #2 Pharmacist Question #2 A patient with hemophilia B is being discharged from the hospital following their second large joint hemorrhage. The provider would like to start secondary prophylaxis in order to future hemorrhages. Which of the following is an appropriate agent for a patient with hemophilia B? Which of the following is an appropriate agent for a patient with hemophilia B? A. Factor VIII B. Factor IX C. FFP D. PCC 8
Pharmacist Question #2 Which of the following is an appropriate agent for a patient with hemophilia B? A. Factor VIII B. Factor IX C. FFP D. PCC Questions? Nikki Heeren, PharmD PGY1 Avera McKennan Nicole.heeren@avera.org References US Department of Health and Human Services. Hemophilia. Centers for Disease Control and Prevention. December 2017. Mayo Clinic. Hemophilia. Patient Care & Health Information: Diseases & Conditions. September 2014. Guidelines for the Management of Hemophilia 2 nd Edition. World Federation of Hemophilia. July 2012. 9