TAILORING PROPHYLAXIS AND TREATMENT OF HEMOPHILIA SANDEEP DEVABHAKTHUNI, PHARM.D.

Transcription

1 TAILORING PROPHYLAXIS AND TREATMENT OF HEMOPHILIA SANDEEP DEVABHAKTHUNI, PHARM.D.

2 TAILORING PROPHYLAXIS AND TREATMENT OF HEMOPHILIA ACTIVITY DESCRIPTION Patients with hemophilia and their health care providers often search for a treatment solution that is just right. The most effective prophylaxis protocols are tailored to the individual based on many factors (such as age, bleeding patterns, joint health and levels of physical activity). The science of treating hemophilia continues to improve; getting the art of individualizing treatment continues to be a challenge. As the bridge between patients and physicians, pharmacists are in the position to play an integral part of a multi-pronged solution to this challenge of individualizing treatment. Because pharmacotherapy and knowledge of a patient s pharmacokinetics play a prominent role in individualizing treating of hemophilia, it is also a perfect opportunity for the pharmacist to be involved. This program will satisfy the education need by creating a program for pharmacists that will enhance their understanding of hemophilia, pharmacotherapy, counseling points, and information needed to work with the patient to maximize the benefits of medications, limit side effects and identify drug-drug or drug-disease interactions. TARGET AUDIENCE The target audience for this activity is pharmacists, pharmacy technicians and nurses in hospital, community, and retail pharmacy settings. LEARNING OBJECTIVES After completing this activity, the pharmacist and nurse will be able to: Outline the many factors such as age, bleeding patterns, joint health and levels of physical activity) that must be considered when tailoring prophylaxis protocols for individual treatment Review the current and emerging pharmacological approaches to the management of hemophilia (pharmacologic profiles, efficacy, side effects, & adverse events) Describe the role pharmacists can play in counseling hemophiliac patients on lifestyle changes, drug treatment strategies and medication adherence to improve quality of life After completing this activity, the pharmacy technician will be able to: List symptoms of hemophilia List treatments available for hemophilia ACCREDITATION PHARMACY PharmCon, Inc. is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. NURSING PharmCon, Inc. is approved by the California Board of Registered Nursing (Provider Number CEP 13649) and the Florida Board of Nursing (Provider Number ). Activities approved by the CA BRN and the FL BN are accepted by most State Boards of Nursing. CE hours provided by PharmCon, Inc. meet the ANCC criteria for formally approved continuing education hours. The ACPE is listed by the AANP as an acceptable, accredited continuing education organization for applicants seeking renewal through continuing education credit. For additional information, please visit Universal Activity No.: H01-P&T Credits: 2 contact hours (0.2 CEU) Release Date: December 15, 2014 Expiration Date: December 15, 2016 ACTIVITY TYPE Knowledge-Based Home Study Monograph FINANCIAL SUPPORT BY Baxter 1

3 ABOUT THE AUTHOR Dr. Sandeep Devabhakthuni is an Assistant Professor in the Department of Pharmacy Practice and Science at the University of Maryland School of Pharmacy. He graduated with a Bachelor of Engineering in Biomedical Engineering degree from University of Pittsburgh School of Engineering and a Doctor of Pharmacy degree from the University of Pittsburgh School of Pharmacy. He then completed his pharmacy practice residency at the University of Maryland Medical Center. He also completed his specialty residency in Cardiology and Critical Care at the University of Pittsburgh Medical Center. Currently, Dr. Devabhakthuni is a board certified pharmacotherapy specialist at the University of Maryland Medical Center, and he has a clinical practice on the Cardiology and Medical Intensive Care services. Sandeep Devabhakthuni, PharmD, BCPS Assistant Professor, University of Maryland School of Pharmacy FACULTY DISCLOSURE It is the policy of PharmCon, Inc. to require the disclosure of the existence of any significant financial interest or any other relationship a faculty member or a sponsor has with the manufacturer of any commercial product(s) and/or service(s) discussed in an educational activity. Sandeep Devabhakthuni reports no actual or potential conflict of interest in relation to this activity. Peer review of the material in this CE activity was conducted to assess and resolve potential conflict of interest. Reviewers unanimously found that the activity is fair balanced and lacks commercial bias. Please Note: PharmCon, Inc. does not view the existence of relationships as an implication of bias or that the value of the material is decreased. The content of the activity was planned to be balanced and objective. Occasionally, authors may express opinions that represent their own viewpoint. Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient or pharmacy management. Conclusions drawn by participants should be derived from objective analysis of scientific data presented from this monograph and other unrelated sources. 2

4 Introduction Hemophilia A and B are rare congenital bleeding disorders caused by a deficiency or absence of coagulation factor VIII (FVIII) or factor IX (FIX), respectively. 1 Hemophilia is a genetic disorder that affects over 400,000 people worldwide with a majority of them as males. 2 Hemophilia A is the most common form of hemophilia, counting for 80-85% of cases. Because there is no cure for these X-linked disorders, appropriate management is necessary to avoid devastating consequences including crippling arthropathy. The severity of the disorder is typically characterized by the residual endogenous FVIII/FIX concentrations. Patients with a factor level of < 0.01 IU/mL are classified as severe hemophiliacs and represent about half of diagnosed cases. Patients with factor levels between IU/mL and > 0.05 IU/mL have moderate and mild hemophilia, respectively. While the bleeding phenotype may be heterogeneous even in severe hemophilia, this classification by FVIII/FIX concentrations correlates with the severity of clinical symptoms, with spontaneous joint and muscle bleeds being largely confined to patients with severe hemophilia. 3 Hemophilia A and B are difficult to differentiate from clinical presentation. Replacement of hemostatic concentrations of the deficient factor is the mainstay of treatment for bleeding episodes according to type and severity of bleeds. Without proper management, patients can experience recurrent joint bleeds, leading to mobility problems, which was the classic progression of this disease prior to 1970s when coagulation factors were not yet available. 4 Prior to development of coagulation factors, mortality was extremely high, and the life expectancy of people with hemophilia was lower when compared to the general population. 5 Then, the discovery of cryoprecipitate and lyophilized formulations of factor 3

5 concentrates served as a catalyst for the more effective hemophilia replacement therapy. Also, these innovative strategies allowed for increased patient convenience including the possibility of home therapy and treating joint bleeds as soon as possible. This also led to significant reduction in potential complications and improved the quality of life for patients with hemophilia. In the late 1970s and early 1980s, there was a huge concern when widespread bloodborne virus transmission occurred due to use of pooled plasma in manufacturing of factor concentrates. This event triggered a closer inspection to ensure safety of treatment for a population that is at a higher risk of fatal complications. This led to the development of viral inactivation techniques for the production of plasma-derived factor concentrates. Then, recombinant gene technology and protein purification were implemented, which led to the creation of highly purified recombinant FVIII and FIX products, which have become the first-line agents for correction of factor deficiencies associated with hemophilia. 6 These advances in management significantly improved treatment for hemophilia patients and contributed to the increased use of primary prophylaxis, where regular infusion of factor concentrates are administered to prevent bleeding and resulting joint damage. With the development of strategies to improve viral safety, the most serious and challenging complication of treatment is the risk of inhibitory alloantibodies. 7 With recent technological advances, patients with hemophilia may now receive optimal treatment and can achieve excellent quality of life if effective approaches are used to provide multidisciplinary comprehensive care. The objectives of this review are to address current 4

6 advances and emerging pharmacological approaches for treatment of hemophilia and to describe ongoing issues and importance of multidisciplinary comprehensive care. Clinical Assessment of Hemophilia Symptoms of hemophilia can range from mild to severe depending on the amount of clotting factors present in blood. In general, patients with hemophilia bleed for a longer period of time compared to healthy people because of coagulation factor deficiency. Common symptoms can include large bruises, spontaneous bleeding from gums or nose, pain or tightness in joints, and blood in stool or urine. Severe symptoms usually involve bleeding into the joints, brain, or internal organs or substantial bleeding after injury or surgery that could potentially be fatal. Furthermore, bleeding in the joints can develop into swelling that can lead to breakdown of cartilage, resulting in chronic pain and immobility that can be permanent. 8 An accurate diagnosis is essential to ensure that a patient receives the appropriate treatment since different bleeding disorders may have very similar symptoms. A correct diagnosis can only be made with the support of comprehensive coagulation laboratory testing. This testing helps clinicians to understand the clinical features of hemophilia. Using screening tests can identify potential causes of bleeding. For patients with hemophilia, the coagulation tests are characterized by a normal prothrombin time (PT), bleeding time (BT), and platelet count, but the activated partial thromboplastin time (aptt) is prolonged. The reason aptt is prolonged is because this test measures the intrinsic pathway for the coagulation cascade, whereas PT measures the extrinsic pathway. The intrinsic pathway requires adequate sources of both factors VIII and IX to function properly. Since either hemophilia type A or B is 5

7 characterized by a deficiency in one of these factors, this leads to problems with the intrinsic pathway, which ultimately can result in bleeding consequences. 8 In addition to evaluating coagulation tests, assessment of factor assays is needed to confirm diagnosis since a deficiency in a coagulation factor can guide clinicians in determining the type of hemophilia. The severity of the disease is correlated with the degree of the deficiency, and the classification of hemophilia severity by the factor concentration is shown in Table 1. 8 The most common hindrance in hemophilia treatment is the production of inhibitors, or antibodies against injected coagulation factor replacement, which can occur up to 20% of patients. 9 In hemophilia patients with suspected inhibitors, testing can be performed using a Bethesda titer to determine presence of antibodies to specific clotting factors. Preventive and Supportive Measures for Hemophilia When managing a patient diagnosed with hemophilia, the goals of therapy include promotion of adequate hemostasis with minimal side effects with deficient clotting factor, prevention of viral transmission, promotion of hemostasis in the presence of inhibitors, and optimizing patient adherence by considering cost and ease of use. Because early recognition is crucial to prevent mobility complications, patients need to be educated on signs/symptoms of bleeding, injury avoidance, prompt self treatment, and need for immunizations against Hepatitis A and B prior to receiving replacement coagulation factors. Acute bleeds should be treated as quickly as possible, preferably within two hours. 8 Most patients should be counseled on home treatment since this strategy can improve quality of life due to less pain and disability, fewer hospitalizations, and decreased time away from work or school. 10 In addition, patients 6

8 should be prepared for any surgical interventions by maintaining factor levels of at least units/ml (50-70%). Dental extraction in hemophiliacs is also associated with a high risk of bleeding and requires a multidisciplinary approach and stringent protocol. 11 Besides considering preventative strategies, patients may require supportive therapy depending on the severity of hemophilia. If patients have significant swelling in their joints, this may lead to either acute pain from bleeding or chronic pain from joint damage due to cartilage destruction. Adequate assessment of the cause of pain is necessary to guide proper management. Hemophilia patients can experience pain due to venous access, joint or muscle bleeding, operation, or chronic hemophilic arthropathy. For appropriate management of pain, clinicians can consider corticosteroids, acetaminophen, and narcotics. 12 For chronic hemophilic arthropathy, cyclooxygenase-2 (COX-2) inhibitors have a greater role in management. If pain is disabling, orthopedic surgery may be indicated Treatment Options for Hemophilia The types of treatment methods available today are plasma-derived products, recombinant coagulation factors, and gene therapy. Dosing for coagulation factors is based on volume of distribution (both intravascular and extravascular compartments), half-life, and factor level required for hemostasis. The available plasma-derived products or recombinant clotting factors are listed in Table 2. Patients who develop an immune response to therapy or have acquired hemophilia are extremely difficult to manage. 17 The treatment options for this complication include prothrombin complex concentrates, activated recombinant factor VII therapies, and immunosuppressive medications. 7

9 Plasma-Derived Coagulation Factors Plasma-derived coagulation factors in whole blood and in plasma fractions are used as replacements for any absent factors in hemophiliacs. 18 Available plasma products include fresh frozen plasma, freeze-dried concentrates, and cryoprecipitate (slowly thawed plasma precipitate). 19 Transfusions with healthy blood were the earliest successful treatment of hemophilia. Blood transfusions provide the patient with missing clotting factors and replenish lost blood volume during bleeds. However, these products need to be used repeatedly in order to replenish live tissue cells. Treatment with these products requires suitable methods to cleanse blood and plasma from pathogens. For plasma-derived products, the most common methods for purification include moderate dry heating, strong dry heating, and wet heating of blood products. The use of these methods decreased the incidence of Human Immunodeficiency Virus (HIV) and Hepatitis C transmission, which are deadly blood-borne pathogens. 17 In the 1980s, 60-80% of patients with severe hemophilia contracted HIV from blood-derived products. Most of the viruses commonly transmitted through blood transfusions have a long, asymptomatic carrier state, which is problematic since healthy donors may actually be carriers of a pathogen. 18 Standard screenings have been placed to remove blood samples with these viruses, but there still is a potential risk for transmission. Viruses can evolve into different strains or different pathogens, which may not be detected by routine techniques. So there is a potential threat of emerging viruses because a pathogen can make contact with a new species or population and establish itself in that vulnerable population, like patients with hemophilia. 8

10 Thus, there have been improvements made in detection methods such as nucleic-acid screening and incorporation of products that reduce viral activity, making blood products safe from HIV and Hepatitis B and C. 18 There is an increased focus on the use of reagents that are completely independent of human plasma. 18 Another concern with plasma-derived factors is the possibility of an adverse immune reaction, leading to decreased efficacy with repeat administration. 17 Blood products are generally cost effective; yet, proper purification techniques are not easily accessible in some third-world countries, which increases the risk of viral transmission and causes complications in hemophilia patients. Approximately 80% of hemophiliacs continue to use plasma-derived factors due to limited resources. 20 Recombinant Coagulation Factors Recombinant coagulation factors treatments deliver clotting factors that hemophilia patients are missing and have become the first-line agents for management of acute bleeds. 17,21 The first generation recombinant factors were derived from DNA by using albumin in the synthetic steps. However, albumin was not included in the final product, which decreases the risk of hypersensitivity reactions. Newer recombinant factors have been produced that use no human proteins in the synthetic or final stages of production. Because of this process, these factors are though to be safer in terms of viral transmission compared to plasma-derived factors; however, the risk is not completely eliminated. 17 The recovery time for patients using recombinant factors has been shown to be slower than those for plasma-derived factors. 22 9

11 A single dose of recombinant factors can eliminate 80% of uncontrolled bleeds and subsequent use increases the success rate to 90-95%. 17 Recombinant factors are considered as effective as plasma-derived coagulation factors. In a study of 95 children with moderate to severe hemophilia A, recombinant FVIII for average of 1.5 years was given in response to excessive bleeds and prior to surgical/dental procedures. The average number of transfusions needed was 34.9 infusions per individual, with effective response and minimal side effects reported. 23 Another study suggested a different method of administration, which was continuous injection of clotting factor to prevent highs and lows in coagulating factor level. This promotes homeostasis and stops large bleeds before they occur. This method also reduces the overall amount of factor required for treatment. 24 Several factors are considered when determining appropriate dosing for recombinant coagulation factors, including site of bleeding, volume of distribution, half-life, and joint health. Dosing for factor replacement is dependent on site of bleed, which helps to determine percent correction to target factor concentration that is needed as well as duration. Guidelines for factor replacement based on site of bleed and need for prophylaxis for surgery are provided in Table 3. Specific dosing instructions for recombinant FVIII and FIX products are provided in Table 4. Because recombinant FVIII concentrates are larger molecules, the volume of distribution is 0.5 so this requires half the amount needed for appropriate recombinant FIX concentrate replacement. Recombinant FIX concentrates also have a longer half-life and require less frequent dosing compared to recombinant FVIII products. These recombinant concentrates should be infused slowly by intravenous injection at a rate not to exceed 3 ml/min in adults and 100 units/min in young children. 10

12 Administration of recombinant factor concentrates requires close monitoring. Important efficacy parameters include plasma factor levels 15 minutes after infusion completed to verify accuracy of calculated dose and control of bleeding. If the target factor concentration is not achieved with appropriate dosing, then testing for inhibitor development is warranted. For monitoring of safety, patients should be educated on the possibility of hypotension, injection site reaction/pain, dyspnea, hypersensitivity, and thrombosis (more common with recombinant FIX products). In addition, recombinant FIX concentrates have an increased risk for hypersensitivity reaction and disseminated intravascular coagulopathy in patients who have liver disease, are undergoing surgery, or are neonates. 25,26 The main concern with recombinant factors is the development of inhibitors (approximately 28-33%). 25,26 For hemophiliac patients, a normally functional coagulation factor is deficient. So the body s immune system will see a recombinant product derived from foreign DNA as a pathogen. Thus, an immune response is mounted to destroy and remove the infused coagulating factor. 27 If not recognized, hemophilia patients with inhibiting antibodies could have an increased bleeding risk that is potentially fatal. 28 The reported incidence of inhibitor development has been variable due to different study designs. A study by Knobe and colleagues tested 116 people with hemophilia for presence of inhibitors after factor replacement treatment that last days. Of these people, 19% of hemophilia A patients developed inhibitors compared to 37% of hemophilia B patients. The study suggested that inhibitor development could be genetically related because all patients who had inhibitors were found to have impaired protein synthesis due to a mutation

13 Despite recombinant factors being more expensive than plasma-based factors by 20-50%, these factors are used by 60-70% of severe hemophiliacs in the United States and all patients in Canada and Ireland use recombinant factors over plasma-derived products. Increased cost is likely due to amount of coagulation factor that can be extracted from a blood sample is only 5-10% of the quantity of factor present in the sample. 17 Although dosing patterns will vary, a typical individual with hemophilia receiving primary prophylaxis will need approximately 2000 IU of clotting factor 3 times per week with the average cost per dose ranging from $1,000 to $2,000. This translates into an approximate monthly cost of $12,000 to $24,000 or $1444,000 to $288,000 per year in medication expenses alone. 30 The discrepancy in price is the reason why it is challenging to provide recombinant factors in developing countries. 31 Methods to decrease amount needed for replacement such as factor clearance receptor antagonist, continuous infusion of product, and increased half-life of recombinant factor may lead to substantial healthcare cost savings. 17,24 Possible solutions to prevent inhibitor development include re-engineering the recombinant factor so that it is less likely to induce an immune response. 32 Adjunctive Therapies for Hemophilia While coagulation factor replacement therapy is the mainstay treatment for hemophilia patients, there are adjunctive therapies that can be used depending on the type and severity of hemophilia. Desmopressin is a vasopressin synthetic analog that causes release of von Willebrand factor and factor VIII, which makes it suitable for treatment of hemophilia A only. 33 Desmopressin is frequently used for treatment of mild or moderate bleeding episodes in patients with hemophilia A with a good response rate of 80-90%. It can be given either 12

14 intravenously by administering 0.3 mcg/kg in 50 ml of 0.9% sodium chloride over minutes or intranasally with mcg per dose (1 spray = 150 mcg). Desmopressin can be given daily for 2-3 days, but a 30% lower response is expected with second dose due to tachyphylaxis. 34,35 Major adverse effects of treatment include flushing (most common), thrombosis (rare), headaches, tachycardia, and hypotension. Because of its antidiuretic effect, desmopressin also promotes fluid retention, which can cause profound hyponatremia so it should be used cautiously in patients with heart failure experiencing fluid overload or existing hyponatremia. 34,35 Antifibrinolytic therapy can be used as adjunctive therapy for procedures expected to cause mucosal bleeding. This type of therapy prevents fibrin breakdown by inhibiting fibrinolytic enzymes found in saliva. Aminocaproic acid can be given as oral or intravenous dose of 100 mg/kg (maximum of 6 grams) every 6 hours. Aminocaproic acid is used less often due to short half-life, low potency and potential for toxicity. Tranexamic acid is 10 times more potent compared to aminocaproic acid so it can be administered as 25 mg/kg (maximum 1.5 grams) orally every 8 hours or 10 mg/kg (maximum 1 gram) intravenously every 8 hours. 36,37 Either agent is usually given for 7 days following dental extractions to prevent post-operative bleeding. They are contraindicated in hematuria since they may cause serious obstructive uropathy and should be avoided in combination with prothrombin complex concentrates due to additive risk of thromboembolism. These agents can cause thrombosis, headache, renal failure (requiring dose adjustments), and hypotension. Aminocaproic acid also can cause rhabdomyolosis, and tranexamic acid has been associated with visual disturbances and increased incidence of anaphylaxis. 36,37 13

15 Another adjunctive therapy for patients with Hemophilia B is the use of prothrombin complex concentrates (PCCs). These products contain non-activated factors II, VII, IX, and X. Activated PCCs contain greater quantities of the activated factors. However, PCCs are not used as first-line for management of patients with Hemophilia B because of lower purity and risk of thrombosis. The risk of thrombosis is higher in patients with hepatic disease, neonates, and patients experiencing crush injury or major surgery. Other adverse effects include dizziness, nausea, hives, flushing, headaches, and hypersensitivity reactions. Other adjunctive therapies include fresh frozen plasma and cryoprecipitate, but neither of these agents is recommended routinely due to concerns about safety and quality. Prophylaxis versus On-Demand Replacement Therapy Current factor treatment regimens include on-demand treatment, which is infusing clotting factor when a bleed occurs, or prophylaxis, where factors are infused to prevent bleeds by maintaining levels of FVIII or FIX at appropriate levels. The use of prophylaxis is intended to prevent bleeding episodes through the administration of regular infusions. The frequency of prophylactic infusion depends on several factors and is determined by the patient and primary care provider. The prophylaxis options are provided in Table 5. Several studies have demonstrated that prophylaxis therapy gives children the best chance to reach adulthood without damage to their joints If patients have recurrent joint bleeds, this can lead to severe and debilitating injuries that often require physical therapy. Also prophylactic administration can convert severe hemophilia into milder form with much lower incidence of chronic arthropathy. 14

16 To prevent bleeding and joint destruction by preserving normal musculoskeletal function, the typical goal of infusion is to maintain at minimum of 0.01 units/ml (1%). Studies have shown that this can still prevent joint bleeds even if the goal cannot be achieved For FVIII and FIX, the most common regimens studied are units/kg three times weekly and units/kg twice weekly, respectively. These regimens have been proven to be costeffective long-term because they eliminate the high cost associated with subsequent management of damaged joints and improves quality of life. 30,41 Primary prophylaxis is typically started before 2 years of age with almost no previous history of bleeding episodes and normal joint evaluations. However, this type of prophylaxis is not widely accepted because of high cost, inconvenience to families leading to noncompliance, and risk of infection or thrombosis with central venous access. Secondary prophylaxis after significant joint bleeding is more common and is associated with significant reduction in number of recurrent episodes; however, radiological evidence of joint disease rarely improves and often progresses despite prophylaxis. 41 The National Hemophilia Foundation s Medical and Scientific Advisory Council recommend that prophylaxis be considered optimal therapy for individuals for severe hemophilia A or B. Prophylactic therapy should be instituted early (prior to onset of frequent bleeding) with the aim of keeping FVIII/FIX level above 1% between doses. 42 Treatment Options for Hemophilia Patients with Inhibitors One of the most serious complications of hemophilia is the development of inhibitors or neutralizing antibodies to the infused clotting factor. In some individuals with hemophilia A, the factor product used to prevent or treat bleeds is viewed as a foreign body. This results in an immune reaction by the body to make that infused clotting factor inactive and harmless to the 15

17 system, which leaves the individual unprotected from bleeds. Inhibitors develop in about 30% of patients with severe Hemophilia A and up to 5% of those with hemophilia B. 30 Individuals with inhibitors are certainly at higher risk for serious bleeding episodes and significant joint damage. There are numerous risk factors for the development of inhibitors that have been identified. These risk factors include age, race, type of hemophilia, presence of other immune disorder, and frequency and dose of factor. High-intensity treatment with factor replacement is a major risk factor for inhibitor development. Also, choosing continuous infusion of clotting factor over bolus dosing can increase the risk. Other risk factors include surgical procedure during first 50 exposure days, severe hemophilia A, family history, certain FVIII and FIX genetic mutations, and other genetic factors (African American, Asian, and Hispanic ethnicity). 43 Inhibitor development is more common during the first year of treatment, but it can occur at anytime. Inhibitor development should be suspected with decreased clinical response to factor replacement, and lab testing should be considered in this situation. When hemophilia patients develop inhibitors, treatment goals are to treat acute bleeding episodes and eradicate inhibitor development if possible The decision to treat hemophilia patients with inhibitors is dependent on whether they are having an active bleed. If the patients are bleeding, then treatment strategies are dependent on the degree of inhibitor development. If a low titer < 5 BU is measured, then high-dose factor replacement is the best option, which would require 2-3 times the usual replacement doses more frequently. However, if a high titer > 5 BU is measured, then other alternative strategies are warranted, which include 16

18 the use of the use of PCCs, recombinant FVIIa concentrate, or porcine FVIII concentrate (for patients with hemophilia A only). 45,46 For hemophilia patients with high titers of inhibitors, activated PCCs will be more effective since PCC includes only trace amounts of FVIII and larger amounts of FIX, which is more helpful in patients with hemophilia B. Activated PCCs also contain FVIII Inhibitor Bypassing Activity, which activates the synthesis of thrombin by stimulating prothrombinase, which bypasses the synthesis of FIX and FVIII. Using apccs is an option for either type of hemophilia with inhibitors present. The disadvantages of this treatment strategy is that the products have lower purity, high risk of thrombosis, no suitable monitoring strategy, and possibility of an anamnestic response, which means that the body may develop an immune response upon repeated exposure. For these reasons, recombinant FVIIa (NovoSeven ) is a preferred strategy to manage bleeds in hemophilia patients with high titers of inhibitors. Recombinant FVIIa bypasses the factor deficiency and activates factor X, which can initiate thrombin formation, and it is only active at site of tissue injury. Recombinant FVIIa can be used for prevention and treatment of bleeding. The major limitation of this product is that it has a very short half-life and requires redosing every 2 hours. So continuous infusion is a more convenient and cost-effective method to administer recombinant FVIIa, and the interval can be extended once hemostasis is achieved. There is a less risk of viral transmission and anamnestic response compared to apccs. There are no routine laboratory tests that can accurately measure the efficacy of recombinant FVIIa infusion Recombinant FVIIa has been demonstrated to stop bleeding episodes effectively with one dose as opposed to treatment 17

19 with apccs. 47 Due to a reduced need for re-infusion of product, recombinanat FVIIa is overall more cost-effective than apccs. 47 Finally, the last option available to treat an acute bleed for hemophilia patients with high titers of inhibitors is the use of porcine factor VIII. This option is only available for patients with hemophilia A with inhibitor development. Since this is obtained from a foreign source, there is a high risk of a severe allergic reaction when given. Because of the risk of hypersensitivity and thrombocytopenia, porcine factor VIII is no longer commercially available, but it can be obtained for specific patients that have no response to recombinant FVIIa or PCC or have severe hemorrhages. 44 If the hemophilia patient with inhibitors is not actively bleeding and has a low titer < 5 BU, then immune tolerance therapy is recommended so that maintenance factor replacement is a viable option. Providing high doses of factor concentrate therapy as a regular infusion ranging from 25 units/kg every other day to 200 units/kg daily has been shown to eradicate inhibitors. 44,46 High-dose factor treatment has been successful in 70% of patients. 48 Drugs that suppress the immune system have also been investigated for inhibitor eradication in hemophilia patients. Rituximab is an anti-cd20 antibody that destroys existing B-cells, which are present in immune response. 49 Other immunosuppressive agents used to control inhibitors include corticosteroids, cyclophosphamide, immunoglobulin, and prednisone. 46 These drugs can be used alone or in combination to reduce immune activity. However, these treatments are not usually pursued because of notable adverse effects. For example, corticosteroids can cause mood instability, weight gain, hypertension, and hyperglycemia. Because these agents suppress the immune system, patients are higher risk for deadly infections. The process by 18

20 which immune tolerance is induced creates high costs, estimating up to 4 times higher than patients without inhibitors ($697,000 vs. $155,000). 30 In addition, all of these treatments would require adequate monitoring to ensure both efficacy and safety. Gene Therapy In the recent years, there has been a focus on developing gene therapy for management of hemophilia because the disease is usually caused by a single gene defect. 50 The treatment looks promising when tested in dogs and mice with knock-out mutations for the coagulation factor gene. However, when used in human models, the same degree of coagulation factor production was not achieved compared to animal models. 17 Though gene therapy is promising, it is currently not a viable option for mass use among hemophilia patients. Further investigation is warranted to demonstrate universal success of gene therapy. Hemophilia Products in Development For the last three decades, the hemophilia market has been dominated by recombinant clotting factors produced by specific manufacturers including Baxter, Bayer, and CSL Behring. There have been several generations of recombinant coagulation factors. The most recent generation (third-generation recombinant factors) lack bovine or human proteins in the synthesis of coagulation factors or in the final products), which lowers the risk of viral transmission. Aside from this advance in manufacturing, there have been no other major changes that have affected management of hemophilia patients. Table 6 summarizes the products that are currently being developed or recently approved. There are two new recombinant products approved in 2013 (Rixubis and Alprolix ) and one in

21 (NovoEight ). 51,52 Also, there are many longer-acting versions of clotting factors in development, which may be helpful since there has been an increased use of prophylaxis. Comprehensive Care Hemophilia is a rare disorder that is complex to manage and requires optimal care of patients, especially in those with severe forms of the disease. Comprehensive care goes beyond treatment of acute bleeds and is crucial to promote physical and psychosocial health and quality of life and can potentially decrease morbidity and mortality. A multidisciplinary care team is needed to address prevention and treatment, as well as vein and dental care. Because an acute life-threatening bleed can occur anytime at any location patients should carry easily accessible identification indicating diagnosis, type and severity of hemophilia, inhibitor status, type of factor needed for repletion, initial dosage for treatment of mild, moderate, and severe bleeding as well as contact information. 53,54 Adequate emergency care should be available at all times including access to a coagulation laboratory capable of performing clotting factor assays, provision of appropriate clotting factor concentrates, blood products if factor concentrates not available, and casting and/or splinting for immobilization and mobility/support aids as needed. A comprehensive care program is needed to coordinate inpatient and outpatient care and services to patients and their family. Patients should be seen by all multisdisciplinary team members on a yearly basis for a complete hematologic, musculoskeletal, and psychosocial assessment. 8 The management plan should be developed in collaboration with the patient and communicated to all practitioners involved in the patient s care. Communication among 20

22 healthcare providers is key. In addition, the patient, family members, and other caregivers should be educated on potential consequences to ensure that optimal care is provided. Pharmacist Role Pharmacists play an important role in making sure that patients are receiving appropriate care. The most important responsibility is the evaluation of factor concentrate dosing regimens for treatment and prophylaxis. Pharmacists can also perform medication regimen reviews to ensure that the patient is not receiving non-steroidal anti-inflammatory drugs, aspirin, or drugs affecting platelet adhesion since these can put the patient at a higher risk for uncontrolled bleeding. Pharmacists can also assist with insurance authorizations to secure reimbursement for clotting factors and communicate any issues with the hemophilia comprehensive care team. There are also specialty pharmacies that manage and coordinate care of hemophilia patients, and this is where majority of clotting factors are dispensed. Treatment with clotting factor requires intravenous access, and patients and their caregivers require training on how to infuse clotting factors at home. Pharmacists can provide hemophilia disease education to patients, families, and other involved team members. They can assist families with making treatment decisions to provide effective therapy with minimal side effects. They can minimize barriers to access clotting factors, manage refills appropriately, and provide infusion training techniques and medication education on clotting factor storage, preparation, and reconstitution. Pharmacists should take the initiative to contact patients routinely to assess compliance, especially if patients are on prophylaxis or immune tolerance therapy, to ensure proper adherence. Finally, pharmacists 21

23 can assess each patient s current regimen and determine the best treatment option using evidence-based medicine. Conclusion Hemophilia is a chronic illness that requires complex and comprehensive medical care to optimize patient outcomes including extending life expectancy and improving quality of life. Indeed, if patients receive appropriate comprehensive care at a hemophilia treatment center and follow preventive care, these patients with hemophilia A or B can have a long life expectancy without disability. There have been major advancements in the treatment and prevention of bleeds that have improved quality of life for these patients. In the future, gene therapy may serve as a cure for hemophilia, but further investigation is needed to clarify the place in therapy. Current research is focused on improving treatment administration to increase compliance for patients and allow them to function appropriately in society. Choosing the appropriate therapy is dependent on several factors such as age, bleeding patterns, joint health, and levels of physical activity) and should be determined on an individual case basis. Multidisciplinary healthcare team coordination is necessary to ensure that patients are aware of risks of hemophilia treatment so that they opt for safer methods of treatments. Both the healthcare team and patients must understand the efficacy and safety of each treatment to make an appropriate decision for management of hemophilia. 22

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30 Table 1. Hemophilia Severity Classification by Factor Concentration 8 Classification Factor Concentration* (Units/mL) Clinical Manifestations Mild > Units/mL (>5 40%) Moderate Units/mL (1 5%) Hemorrhage with magor trauma or surgery May go years without diagnosis Occasional spontaneous hemorrhages Hemorrhage with mild trauma/surgery that is prolonged Severe < 0.01 Units/mL (<1%) Frequent spontaneous hemorrhages Life-threatening hemorrhages *Normal plasma range = Units/mL Table 2. Coagulation Factors Available for Treatment of Hemophilia A and B Recombinant Factor VIII Concentrates Human Plasmaderived Factor VIII Concentrates Plasma-derived Intermediate Purity Concentrates a a Also contains von Willebrand Factor b Derived from human plasma c Formulation expires January 2016 d New formulation September 2013 Hemophilia A Treatment Advate (Baxter) 3 rd generation Helixate FS (Bayer) b 2 nd generation Kogenate FS (Bayer) b 2 nd generation Recombinate (Baxter) 1 st generation Xyntha (Pfizer) 3 rd generation Hemofil M (Baxter) c Hemofil M with nanofiltration (Baxter) d Monoclate P (CSL Behring) Alphanate (Grifols) Humate-P (CSL Behring) Koate-DVI (Grifols) Hemophilia B Treatment BeneFIX (Pfizer) Rixubis (Baxter) AlphaNine SD (Grifols) Mononine (CSL Behring) Alphante (Grifols) Humate-P (CSL Behring) Koate-DVI (Grifols) 29