cme/cne ensuring the rapid recognition and optimal

PeerView .com /QUN900

Brandon R. Allen, MD, FACEPUniversity of Florida College of Medicine Gainesville, Florida

Anita Rajasekhar, MD, MSUniversity of Florida Gainesville, Florida

Tung Wynn, MDUniversity of Florida Gainesville, Florida

Co-Chairs

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This accredited CE activity has been developed in collaboration with the Hemophilia Foundation of Greater Florida.

CME/CNE

Ensuring the Rapid Recognition and Optimal Management of Hemophilia in the Emergency Department: The Role of Inclusive Decision-Making

What’s Inside

3

12

15

Evolving Therapeutic Landscape for the Management of Hemophilia

Treating Hemophilia in the Emergency Department: What Do Current Guidelines Tell Us?

Best Practices From the Experts: Incorporating Shared Decision-Making Into the Management of Hemophilia

https://www.PeerView.com/QUN900

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Activity Information

Activity Description and Educational ObjectivesIn this activity, experts in hemophilia discuss available and emerging therapeutic approaches for the treatment of patients with hemophilia, as well as current guidelines and treatment protocols for patients with hemophilia presenting to the emergency department.

Upon completion of this activity, participants will be able to:• Assess current data on available and emerging therapeutic approaches for the

treatment of patients with hemophilia• Apply current guidelines for the management of patients with hemophilia in the

emergency department• Develop treatment protocols for suspected bleeding episodes in patients with

hemophilia who present to the emergency department that incorporate shared decision-making

Target Audience This activity has been designed to meet the educational needs of emergency department physicians, nurses, and other clinicians involved in the care of patients with hemophilia.

Requirements for Successful Completion In order to receive credit, participants must view the activity and complete the post-test and evaluation form. A score of 80% or higher is needed to obtain CME credit and 70% or higher to obtain CNE credit. There are no prerequisites and there is no fee to participate in this activity or to receive CME/CNE credit. Statements of Credit are awarded upon successful completion of the post-test and evaluation form.

Media: Enduring MaterialRelease and Expiration Dates: August 18, 2020 - August 17, 2021Time to Complete: 60 minutes

Faculty and Disclosure / Conflict of Interest Policy In accordance with ACCME requirements, the University of Florida College of Medicine has a conflict of interest policy that requires faculty to disclose relevant financial relationships related to the content of their presentations/materials. Any potential conflicts are resolved so that presentations are evidence-based and scientifically balanced. No one else in a position to control content has any financial relationships to disclose.

Co-Chairs Brandon R. Allen, MD, FACEP Clinical Assistant Professor University of Florida College of Medicine Department of Emergency Medicine Medical Director, Adult Emergency Department Gainesville, Florida

Brandon R. Allen, MD, FACEP, has a financial interest/relationship or affiliation in the form of: Consultant and/or Advisor for F. Hoffmann-La Roche Ltd. Grant/Research Support from Beckman Coulter, Inc. and F. Hoffmann-La Roche Ltd.

Anita Rajasekhar, MD, MS Associate Professor University of Florida Department of Medicine Division of Hematology/Oncology Gainesville, Florida

Anita Rajasekhar, MD, MS, has a financial interest/relationship or affiliation in the form of: Grant/Research Support from Alnylam Pharmaceuticals, Inc. (sanofi-aventis U.S. LLC/Genzyme Corporation); BioMarin; Dimension Therapeutics, Inc.; F. Hoffmann-La Roche Ltd; Genentech, Inc.; Janssen Pharmaceuticals, Inc.; and Shire.

Tung Wynn, MD Assistant Professor of Pediatrics Division of Pediatric Hematology and Oncology University of Florida Gainesville, Florida

Tung Wynn, MD, has a financial interest/relationship or affiliation in the form of: Other Financial or Material Support from Novartis Pharmaceuticals Corporation (Wife).

CME Reviewer Michael Marchick, MD Co-Clerkship Director Clinical Associate Professor Department of Emergency Medicine University of Florida College of Medicine

Michael Marchick, MD, has no financial interests/relationships or affiliations in relation to this activity.

Planning Comittee DisclosuresTracy L. Greene, MSN, RN, FNP-C, Nurse Planner, MLI, has nothing to disclose.

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Content/Peer Reviewer DisclosuresThe following Content/Peer Reviewer has nothing to disclose: Gina D. Cravey BSN, RN, CHRC, CCRC

DisclaimerParticipants 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 management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patient's conditions and possible contraindications and/or dangers in use, review of any applicable manufacturer's product information, and comparison with recommendations of other authorities.

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The University of Florida College of Medicine designates this enduring material for a maximum of 1.0 AMA PRA Category 1 CreditTM. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

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Brandon R. Allen, MD, FACEP

Anita Rajasekhar, MD, MS

Tung Wynn, MD




This activity is supported by an educational grant from Genentech.

Dr. Rajasekhar: Hello, and thank you for joining us on a discussion that focuses on how to ensure the rapid recognition and optimal management of hemophilia in the emergency department, with a special attention to the role of inclusive decision-making. This online educational activity is designed for an audience of emergency room physicians and nurses, and the activity will be divided into three segments. The first will focus on evolving therapeutic landscapes in hemophilia, and then we’ll move on to how to best treat hemophilia in the emergency room, highlighting what the current guidelines are. Then finally, we will end with a case-based discussion from our expert panel to understand best practices and how to incorporate shared decision-making into the management of hemophilia.

My name is Dr. Anita Rajasekhar, and I’m an adult nonmalignant hematologist at the University of Florida. Joining me today in this discussion are my colleagues at the University of Florida, Dr. Brandon Allen and Dr. Tung Wynn.

Dr. Allen: Thank you for having me today.

Dr. Wynn: Thank you for inviting me to participate in this talk.

Dr. Rajasekhar: Okay, excellent. Let’s begin by understanding what the current landscape is and what the recent advances have been in the management of hemophilia.

Evolving Therapeutic Landscape for the Management of Hemophilia

1. Mannucci PM, Tuddenham EG. N Engl J Med. 2001;344:1773-1779. 2. Srivastava A et al. Haemophilia. 2013;19:e1-e47. 3. Roberts HR et al. In: Kaushansky K et al, eds. Williams Hematology. 8th ed. New York, NY: McGraw-Hill Companies, Inc; 2010:2009-2029. 4. Butler RB. Basic Concepts of Hemophilia: A Self-Study and Planning Workbook for Families With a New Diagnosis of Hemophilia. Atlanta, GA: CDC; 2007.

Hemophilia A (FVIII deficiency)• Affects 1/5,000 to 1/7,000 males

Hemophilia B (FIX deficiency) • Affects 1/25,000 to 1/30,000 males

Secondary hemostasis disorders • X-linked inherited • Clotting factor VIII (FVIII) or factor IX (FIX) is absent or present in low levels

Congenital Hemophilia1-4

Dr. Rajasekhar: By way of background, congenital hemophilia is one of the most well-known and studied inherited bleeding disorders. Hemophilia affects secondary hemostasis since it involves a deficiency of the clotting factors, namely factor VIII and factor IX. It’s an X-linked inherited disorder, so it predominantly affects males, and mothers and daughters are obligate carriers of inherited hemophilia. You’ll see by these statistics on this slide that hemophilia A is more common than hemophilia B, and that’s because factor VIII is larger and more susceptible to mutations than factor IX.

Dr. Allen: Yeah, Dr. Rajasekhar, this is certainly a rare event in emergency medicine; however, it’s not a never event, and knowing the intricacies of this disease process and how to manage it are going to be vitally important for morbidity and mortality of these patients.

1. https://www.wfh.org/en/page.aspx?pid=643. 2. Van Dijk K et al. Haemophilia. 2005;11:438-443.

Phenotype

Moderate hemophilia

Severe hemophilia

Factor Level

1%-5%

<1%

Clinical Features

• May bleed for a long time after surgery, a bad injury, or dental work • Experience spontaneous bleeding rarely

• Frequent and spontaneous bleeds into muscles or joints (70%-80% bleeds are hemarthrosis); up to 1-2 times/week without treatment

Mild hemophilia >5%-40%• Bleed after severe injury or surgery• Do not bleed often; some may never have bleeding problem

~60% of hemophilia A cases are severe

~44% of hemophilia B cases are severe

Bleeding Phenotype Dependent on Levelof Clotting Factor Deficiency in Hemophilia1,2

Dr. Rajasekhar: It’s really important to understand the bleeding phenotype in these patients, and it varies across spectrums. The variability really depends on the factor level in an individual patient. You’ll see here on this slide that in mild hemophilia patients, which is defined as a factor level between 5% and 40%, they generally have very few bleeding problems unless they’re




challenged with surgery or major trauma. Moderate hemophilia patients, on the other hand, have lower factor levels, somewhere between 1% and 5%, and they tend to have moderate phenotype of bleeding and do tend to bleed after a minor trauma. Then you have our severe hemophilia patients, who have a baseline factor level less than 1%. In these patients, they can have severe hemorrhage, most commonly into the joints and muscles, and they can present very early in childhood. Often, they have spontaneous bleeding without any trauma. It’s really important to note also that our mild and moderate hemophilia patients may not be diagnosed until later in life, when they actually have a hemostatic challenge.

Without treatment, bleed events for patients with hemophilia may be life-threatening orresult in chronic disability from recurrent

hemarthroses and intramuscular bleeding

Target JointRepeated bleeding in the same joint; knees, elbows,

and ankles most frequently affected

Hemophilic ArthropathyPersistent intra-articular blood results

in progressive degeneration of the jointcartilage and bone

Hemarthrosis: A Long-Term Complication With Hemophilia

So while life-threatening bleeds can happen with hemophilia, especially severe hemophilia, the most common bleeds are in joints and muscles. When we see recurrent bleeding into the same joint, we term that joint a “target joint,” and eventually that target joint can be affected by chronic synovitis and progressive degenerative changes of the cartilage and bone. Over time, this can lead to end-stage joint damage with significant pain and range-of-motion deficits, and eventually these patients may require surgical interventions, such as joint replacement or fusion.

Dr. Allen: Dr. Rajasekhar, in this case, certainly seeing the majority of cases being hemarthroses, and the significant disability that can happen with the target joint, as you referenced.

Dr. Rajasekhar: Many of my patients in the adult clinic, I have to end up referring them to the orthopedic surgeons, and they discuss what options exist in terms of replacement and fusions, so it’s certainly a significant morbidity for these patients who are having recurrent bleeds in their joints.

Dr. Allen: It’s definitely a high-risk surgery as well, and it can be quite complicated perioperatively.

1. https://www.hemophilia.org/sites/default/files/document/files/241Prophylaxis.pdf.

MASACRecommendations

Concerning Prophylaxis

q Prophylaxis is considered to be optimal therapy for individuals with severe hemophilia A or B

q Prophylaxis should be instituted early (prior to the onset of frequent bleeding), with the aim of keeping the trough FVIII or FIX level above 1% between doses

q Optimal dosing and frequency should be determined for each individual by appropriate laboratory monitoring

q Individuals on prophylaxis should have regular follow-up visits to evaluate joint status; to document any complications, such as inhibitors; and to record any bleeding episodes that occur during prophylaxis

Current Hemophilia Treatment Paradigm1

Dr. Rajasekhar: Absolutely. The National Hemophilia Foundation has the Medical and Scientific Advisory Council, or MASAC, and they issue periodic recommendations and advisories on treatment, research, and other general health concerns for the hemophilia community. Factor prophylaxis is a regular infusion of factor concentrates in order to prevent bleeding. The idea of prophylaxis comes from the observation that people with moderate or mild hemophilia who have factor levels over 1% rarely experienced spontaneous bleeding. Based on that, MASAC has issued recommendations on prophylaxis as the standard of care and optimal therapy for individuals who have severe hemophilia. Prophylaxis should be instituted early and ideally prior to the onset of frequent bleeding. The goal is to keep the factor level above 1% between doses to prevent bleeding.

Now, optimal dosing and frequency should be determined for each individual, and that is an individual case-by-case decision based on appropriate lab monitoring. The bottom line is that it’s not a one-size-fits-all in terms of the factor prophylaxis regimen.

Then finally, MASAC recommends that individuals on prophylaxis should have regular follow-up visits to evaluate joint status; to document any complications of factor infusions, like inhibitors, which we’ll talk about; and to record any bleeding episodes that occur while on prophylaxis. So it’s clear that prophylaxis is not a static treatment and a patient’s regimen may change over time.

Dr. Wynn, I found this guidance that MASAC gives us particularly helpful when I’m talking to patients. I’m curious, do you use these recommendations in your day-to-day discussions in clinic with your patients?

Dr. Wynn: Yeah, I would add that beyond the MASAC guidelines, there are well-established studies that show that early and aggressive use of prophylaxis can delay and, in many circumstances, prevent the development of the joint complications that you’re discussing. These MASAC guidelines, as well as the numerous studies that exist, I use to discuss with my patients about when and how and what form that may take.




q Disease rarity: How frequently is hemophilia encountered in the ED?

q Need for a consult: Is there a hematologist on call?

q Expanding number of available treatments: Does the hospital stock the medicine an individual patient needs?

Although bleeding episodes in patients with hemophilia are frequently and routinely managed at home and/or at specialized hemophilia treatment centers, they do present to local EDs in emergency situations. Potential challenges to optimal management include:

Potential Barriers to the Optimal Managementof Hemophilia in the Emergency Department

Dr. Allen: We’re going to transition into the potential barriers to the optimal management of hemophilia in the emergency department. This is something, as we mentioned, that is a rare disease and you may want to ask yourselves, in your current emergency department setting, what is the number of these that you potentially encounter, and also what kind of resources you have at your disposal when you need something with these patients. The great thing though is that hemophilia patients are very knowledgeable about their disease state and they can routinely be managed at home with specialized treatment centers as a consultant prior to heading to the emergency department.

However, they do present in emergent situations, and expanding the number of available treatments is also something that has to be a consideration where, does your hospital stock the medicine or is the expectation that the patient should have it? Sometimes you have to go kind of off formulary, but we’re going to discuss that a little bit more in future slides, in regards to the approach to this, to keep the patient in the best scenario of wellness.

Dr. Rajasekhar: Brandon, I agree. I think this is mostly an outpatient disease, thankfully, which is probably why many ER providers don’t have a lot of experience with it. I think it’s really important for ER providers to remember that patients really know a lot about their disease, for the most part, and know what works for them, and so when they come in and give you a history and tell you, “This drug has worked for me, this has not worked for me in the past, this is the dose that works for me usually”—I think it’s important to believe that they know that and to really trust the patient from that standpoint.

Sometimes patients, as you mentioned, bring their own medications. Other times, especially in our mild and moderate hemophilia patients, because they don’t either know how to self-infuse or don’t need to self-infuse much because they don’t bleed often, they don’t have drug with them, so we end up having to use whatever is on the hospital formulary. It is important to know what’s on your hospital formulary and how to dose that.

Dr. Allen: Great points, Dr. Rajasekhar. I couldn’t agree more that one of the first things I do in an encounter with a hemophilia patient is to ask them about what they do at home and what

they’ve done in the past that’s worked for them to get out of one of these potential emergent situations.

1. Manco-Johnson MJ et al. N Engl J Med. 2007;357:535-544. 2. Gringeri A et al. J Thromb Haemostat. 2011;9:700-710.3. Valentino LA et al. Haemophilia. 2014;20:398-406.

• Joint Outcomes Study1

• ESPRIT trial2

• Multicenter, open-label study comparing on-demand treatment with prophylaxis3

Hemophilia A

The benefits of prophylaxis in patients with severe hemophiliaare well established

Evid

ence

Hemophilia B

Prophylaxis: The Standard of Care for Hemophilia

Dr. Rajasekhar: Let’s move on to what the evidence is for routine prophylaxis. Dr. Wynn, you alluded to these studies. There have been a few studies that have looked at the benefits of routine prophylaxis. The one that many are familiar with is the Joint Outcomes Study, and that was the first study to really show us that prophylaxis with regular scheduled factor infusions reduced joint bleeds and joint damage on imaging studies and really led the way for this strategy to become the standard of care in severe hemophilia patients. This study was then confirmed by the ESPRIT study, which found that prophylaxis was particularly beneficial in preventing joint damage when started early. Then finally, a similar study documented the benefits of prophylaxis in hemophilia B patients as well.

So Dr. Wynn, I know in my adult hemophilia patients, despite this evidence that shows a benefit to regular prophylaxis, I still see a lot of hesitation on the part of infusing themselves several times a week. Understandably, it’s burdensome, it’s expensive to give two- to three-times-a-week infusions. Do you find resistance in this approach in your pediatric patient population?

Dr. Wynn: In the pediatric population, especially the youngest population of toddlers and newborns, the most difficult challenge is IV access for these patients. The resistance comes in how can we establish the most accessible IV access for them. Generally, patients are very, very compliant in pediatrics because the administration of the factor is provided to them at an early age either by a home health nurse or by the parents themselves. But oftentimes as we transition to self-infusion, in which the patient learns and provides the factor for themselves, the challenge becomes maintaining that compliance to the prophylactic recommendation. The adolescent and teenage population in our practice does face challenges similar to the ones that you’re describing in adults.

Dr. Rajasekhar: That’s why it’s really important, again, to involve the patient in the decision process and really practice shared decision-making because it’s really not helpful if we prescribe something and ultimately on the patient side, they’re not going to take it. We have to have buy-in from them for this prophylaxis




regimen.

Short in vivo half-life of standard replacement factors; adherence can become a major issue because of the need for frequent infusions

Development of inhibitors (neutralizing antibodies) to replacement factors

t½ rFVIII: ~8-12 h

• The most serious complication of hemophilia today• An IgG antibody that inhibits infused factor• Measured in Bethesda units (BU)• Frequency: severe hemophilia A = 20%-30%, mild and moderate hemophilia A = 3%-13%, and severe hemophilia B = 5%

Prior to 2017, only two treatments were approved for patients with hemophilia and inhibitors1. rFVIIa2. Activated prothrombin complex concentrate

t½ rFIX: ~18-24 h

Major Hurdles to the Optimal Management of Hemophilia

What are the other hurdles of prophylaxis and optimal management of hemophilia? Unfortunately, replacement of the missing factor with factor concentrates is short-lived with the traditional standard half-life therapies. Factor VIII’s half-life is about 8 to 12 hours, and factor IX’s half-life is about 18 to 24 hours. This really translates into a burdensome regimen of twice- to three-times-per-week factor infusions for prophylaxis to keep a patient above that over 1% and prevent bleeding. Another challenge in the treatment of hemophilia is the dreaded consequence of inhibitor formation. Inhibitors are these neutralizing antibodies against exogenous factor that is infused, rendering standard factor replacement ineffective.

Dr. Wynn: Dr. Rajasekhar, I would also add that the vast majority of inhibitors, when they develop, develop in young children—infants and toddlers—and usually those patients are within the first 50 doses, the first 50 exposure doses in their lifetime.

Dr. Rajasekhar: That’s right. By the time they come to me in my adult clinic, often they’ve already developed inhibitor, often they’re already on a very good regimen that works for them, so it really is the pediatric hematologists who have the burden of diagnosing and treating these diseases early on.

1. Gouw SC. Semin Thromb Hemost. 2009;35:723-734.

A complex interaction of many variables leadsto inhibitor development in a particular individual

Patient Variables• Disease severity• FVIII gene defect• Ethnicity• FH of inhibitors• HLA type• Individual immune response traits

Treatment Variables• Number and pattern of FVIII exposures• Type of FVIII product• Concurrent immune system challenges• Frequency of monitoring

Inhibitor

Factors Influencing Inhibitor Development1

What are the factors that influence inhibitor development? There are a variety of them, and while we can’t predict who will ultimately develop an inhibitor, there are risk factors that help us understand

who might be high risk, and these are outlined here. These include patient-specific factors on the left-hand side and treatment-related factors on the right-hand side. There’s a lot of work being done in this area to try and predict and minimize the risk of inhibitor formation, but ultimately it’s a complex interaction of many variables that leads to inhibitor development in any individual patient.

• Options – Plasma-derived vs recombinant – First-gen vs second-gen vs third-gen recombinant• Vary in protein structure (full-length, B-domain–deleted or –truncated), cell line, or production techniques• Similar PK profiles with a mean t½ of 12 h (FVIII) or 25 h (FIX) in adults• Typical prophylaxis with SHL – 25-40 units/kg three times weekly (FVIII) – 25-40 units/kg twice weekly (FIX)

Standard Half-Life Factor Concentrates

Let’s discuss what options exist for hemophilia treatment currently. To remind everyone, there’s been an evolution of products over the years. Initially, we had plasma-derived factor concentrates that were introduced in 1969, and they’ve really come a long way in terms of safety, with modern methods of purification. Then came along recombinant or genetically engineered factor concentrates, and these were really developed as a response to the HIV and hepatitis epidemic in our hemophilia patients in the 1980s. The third- and fourth-generation recombinant products have no human or animal protein in the final preparation of the product. Then there are differences in protein structures, including B-domain–deleted and truncated versions of the product compared with full-length factor molecules. Among the standard half-life products, half-lives do not really vary significantly, with the mean half-life of about 12 hours for factor VIII products and 24 hours for factor IX products. So again, this really translates to rather frequent infusions for our patients based on these half-lives.

• Approved for hemophilia A – Efmoroctocog alfa (Eloctate) – Rurioctocog alfa pegol (Adynovate) – Damoctocog alfa pegol (JIVI) – Turoctocog alfa pegol (Espercot)• Approved for hemophilia B – Eftrenonacog alfa (Alprolix) – Albutrepenonacog alfa (Idelvion) – Nonacog beta pegol (Rebinyn)• Investigational – BIVV001

Extended Half-LifeReplacement Factor Products

• Approved for hemophilia A with and without inhibitors – Emicizumab-kxwh• Approved for hemophilia A or B with inhibitors – Coagulation factor VIIa (recombinant)-jncw• Investigational – Fitusiran – Concizumab – Gene-replacement therapy strategies for hemophilia A and B

Nonfactor Replacement Strategies

Recent and Potential Advances in Hemophilia A and B

Hemophilia treatment paradigm has expanded considerably over the past 5 years

Extended Half-Life Factors and Nonfactor Replacement Therapies

In the past 5 years, there’s been really an explosion of new therapies available in the pipeline for hemophilia treatment, and




to address the burden of factor VIII and factor IX prophylactic infusions, these extended half-life products were developed. Here you’ll see a list on the left of those that are approved for hemophilia A and B, and we’ve listed here both the generic and brand names since most of our patients and providers in the ED will be familiar with those brand names.

The last product here is a new-generation factor VIII that circulates independently of von Willebrand factor, and so it breaks that von Willebrand factor–imposed half-life barrier. Phase 1 results with this product have been really encouraging, and the half-life has been on the order of 40 hours with weekly or every-10-day dosing.

On the right side, we have a list of all the newly approved products and investigational products that Dr. Wynn will be reviewing shortly in the next section of this presentation.

Dr. Allen: Dr. Rajasekhar, these are certainly names that I think every emergency physician would struggle to pronounce, and I want to underscore the fact that you may not know the exact name of these or what it’s for, but knowing where to gather that information and whom to discuss with from a specialist standpoint is probably of the utmost importance for the emergency physician.

Dr. Rajasekhar: Absolutely. Thanks, Dr. Allen.

1. Peyvandi F et al. J Thromb Haemost. 2013;11(suppl 1):84-98.

• Fc portion of human IgG fused to factor • IgG has a long half-life (~3 weeks)

• Creates “cloud” around attached proteins• Molecule too big to be cleared by kidneys

PEGylation• Albumin has a long half-life (~3 weeks)

Albumin Fusion

PEG

Protein of interest Fc region

PEG

PEG

Protein of interest AlbuminLinker

Protein ofinterest

Protein ofinterest

Fc region

Fc Fusion

Ho o

n

H

Mechanisms of Half-Life Extension in Hemophilia1

Now let’s talk about the mechanisms by which we can extend the standard half-life products’ half-life to an extended half-life product. There are three main mechanisms by which we can extend the half-life of factor concentrates.

The first is Fc fusion, and this was the first extended half-life technology on the market. Here what we have is a fusion of the Fc portion of IgG to the factor molecule, and this promotes half-life extension by altering the normal clearance of the factor. So what you have is the factor VIII molecule linked to the Fc IgG, and that complex then is recycled back into circulation rather than being directed to lysosomal degradation within a cell.

The second method of extension of half-life is PEGylation, and what we’re doing here is they attach a covalent PEG product to the factor molecule itself, and that protects against proteolytic degradation,

thereby reducing the clearance and increasing the half-life of the product. Essentially, PEG creates a cloud around the factor, making it too big for the kidney to clear.

The third method of extending half-life of a factor product is through albumin fusion. Here, the half-life extension builds on the long half-life of albumin itself, which is attributed to its high molecular weight, and also to the Ph-dependent interaction with the neonatal Fc receptor, which then in turn prevents the intracellular degradation. These are all methods of extending the half-life of products, and we’ve had quite good success with these newer products.

1. Powell JS et al. Blood. 2012;119:3031-3037. 2. Konkle BA et al. Blood. 2015;126:1078-1085. 3. Mahlangu J et al; A-LONG Investigators. Blood. 2014;123:317-325. 4. Coyle TE et al. J Thromb Haemost. 2014;12:488-496. 5. Tiede A et al. J Thromb Haemost. 2013;11:670-678.

Efmoroctocog alfa (Eloctate)

Rurioctocog alfa pegol (Adynovate)

Damoctocog alfa pegol (JIVI)

Turoctocog alfa pegol (Espercot)

Fc Fusion

PEGylation

rFVIII EHL rFVIII

12.4 h 19 h

10.4 h 14.3-16 h

13 h 19 h

11.7 h 19 h

1.5-1.7

t½ extension(fold change)

1.4-1.5

1.5

1.6

0 6 12 18 24t½, h

Approved EHL FVIII Replacement Strategies1-5

Here you’ll see that there’s a list of various extended half-life factor VIII products on the market. What you’ll notice here is that with the current methods of extension, it really has not been a homerun; we’ve been able to extend the factor VIII half-life of the product by at most 1.7-fold. This is largely because like native factor VIII, the half-life of extended half-life products is regulated largely by the interaction with von Willebrand factor, so consequently, the half-life of von Willebrand factor, which is about 15 hours, has been the limiting factor to factor VIII products being extended in their half-life. What I think is important to know is that these products are available, that patients are asking about them, and patients are presenting to the ER on these new products, so I think it’s important for ER physicians and nurses to be familiar that these exist.

Dr. Wynn: Dr. Rajasekhar, I think it is also important to note that the half-life extension is very variable between patients. So some patients may have 19 hours, but some patients may have a large variance from that, and a large portion of patients may have much, much shorter half-lives, and some may actually have slightly longer half-lives.

Dr. Rajasekhar: That’s particularly true for your pediatric patients in whom clearance often with these products is much quicker than our adult patients.




1. Mahlangu J et al; A-LONG Investigators. Blood. 2014;123:317-325. 2. Konkle BA et al. Blood. 2015;126:1078-1085. 3. Reding MT et al. J Thromb Haemost. 2017;15:411-419. 4. Giangrande P et al; Pathfinder™2 Investigators. Thromb Haemost. 2017;117:252-261.

• 92% reduction in ABR with individualized prophylaxis• 76% reduction in ABR with weekly prophylaxis• 87.3% of bleeding episodes resolved with 1 injection • No subjects developed inhibitors during the study

Efmoroctocog Alfa (Eloctate)

• 95% reduction in ABR twice-weekly prophylaxis• 95.9% of bleeding episodes treated with 1-2 infusions• No subjects developed inhibitors during the study

Rurioctocog Alfa Pegol(Adynovate)

• 92% reduction in ABR with prophylaxis once every 5 d• 90.6% of bleeds were controlled with ≤2 infusions • No inhibitors were detected during the study

Damoctocog Alfa Pegol (JIVI)

• 96% reduction in ABR with prophylaxis once every 4 d• 83.6 % of bleeds resolved with 1 injection• One patient developed inhibitors after 93 exposure days

Turoctocog Alfa Pegol (Espercot)

Clinical Data on EHL FVIII Products in Hemophilia A1-4

In general, the pivotal data that led to the FDA approval of these extended half-life products are based on studies that compared the product using regular prophylaxis with the extended half-life product and comparing it with on-demand standard half-life products. Most of these studies found that with regular prophylaxis with these newer products, we had a reduction in annual bleed rate, or ABR. You’ll see that the prophylaxis with these agents is much less frequent. It also had good success, and in those who developed a bleed and had to take more factor, typically they only required one or two doses of the extended half-life product to resolve the bleed. Finally, from a safety standpoint, which we obviously need to consider, is the inhibitor formation. From these studies, you’ll see that there was either no inhibitor formation or very rare incidence of inhibitor formation.

1. Powell JS et al. N Engl J Med. 2013;369:2313-2323. 2. Negrier C et al. Blood. 2011;118:2695-2701. 3. Santagostino E et al. Blood. 2016;127:1761-1769.

Eftrenonacog alfa (Alprolix)

Nonacog beta pegol (Rebinyn)

Albutrepenonacog alfa (Idelvion)

Fc Fusion

PEGylation

Albumin Fusion

rFIX EHL rFIX

33.8 h 82.1 h

19 h 93 h

23.7 h 102 h

2.4

t½ extension(fold change)

~5

4.3

0 24 48 72 96t½, h

Approved EHL rFIX Replacement Strategies1-3

Unlike extended half-life factor VIII products, we’ve had much more success with extending factor IX half-life drugs. What you’ll see here is that there are a few factor IX extended half-life products in which their half-lives have been extended up to five times the standard half-life product. Now Dr. Wynn, in your experience, because of this significant prolongation in half-life with the factor IX products, has there been more enthusiasm in the hemophilia community about switching patients from standard half-life factor IX products to these extended half-life factor IX products?

Dr. Wynn: Yes, for all the reasons that you stated, our pediatric patients have been very enthusiastic in switching from a standard half-life factor IX product to an extended half-life factor IX product.

You know, the factor VIII uptake has been a lot slower because the increase in half-life has been more incremental in its nature.

1. Powell JS et al. N Engl J Med. 2013;369:2313-2323. 2. Collins PW et al. Blood. 2014;124:3880-3886. 3. Santagostino E et al. Blood. 2016;127:1761-1769.

Eftrenonacog Alfa (Alprolix)1

• 83% reduction in ABR with weekly prophylaxis• 87% reduction in ABR with interadjusted prophylaxis • 90.4% of bleeding episodes resolved after 1 injection• No subjects developed inhibitors during study

• 93% reduction in ABR with weekly prophylaxis• 99% of bleeding episodes resolved after 1 injection• No subjects developed inhibitors during study

• 100% reduction in ABR with prophylaxis once every 2 weeks• 98.6% of bleeding episodes were treated successfully, including 93.6% that were treated with a single injection• No patients developed antibodies or inhibitors

Nonacog Beta Pegol (Rebinyn)2

Albutrepenonacog Alfa (Idelvion)3

Clinical Efficacy on EHL rFIX Products in Hemophilia B

Right. You know, with the improvement in convenience with these extended half-life products, it’s really important to make sure that they’re still efficacious. So you’ll see here that there have been several pivotal trials leading to the FDA approval of these factor IX extended half-life products that have shown not only a reduction in annual bleed rates with regular prophylaxis, but also for those who have a bleed, they typically again only require one to two doses to control the bleed. In terms of safety, there were no inhibitors that developed in these studies.

1. https://www.fda.gov/news-events/press-announcements/fda-approves-additional-treatment-adults-and-adolescents-hemophilia-or-b-and-inhibitors.

Bypassing Agents

• Recombinant activated FVII and activated prothrombin complex concentrate• Activated FVII (FVIIa) can directly activate FX, by passing the need for FVIII and FIX• Bypassing agents are indicated for the treatment and control of bleeding episodes occurring in adults and adolescents with hemophilia A or B with inhibitors

Tissue factor

Extrinsic pathwayIntrinsic pathway

Commonpathway VII

VIII

IX

XI

XII

X

VCa+2

Fibrin clot(XIII)

Prothrombin (II) Thrombin

Fibrinogen (I)

Lipids

The Use of Bypassing Agents for Preventing Bleedingin Patients With Hemophilia With Inhibitors1

We’ve spent a lot of time talking about patients without inhibitors and the multiple drugs that are available—standard half-life products, extended half-life products—for these patients. But for patients with inhibitors, infusion of factor concentrates is generally not effective. Limited options exist for these patients, and they include bypassing agents. The purpose of a bypassing agent is to provide essentially a detour to bypass the factors in the coagulation cascade that are blocked by the inhibitor to help generate a fibrin clot. The two available bypassing agents that we use mostly in inhibitor patients are recombinant activated factor VIIa and prothrombin complex concentrates. Dr. Wynn will be discussing advances and treatment options that are particularly exciting for patients with inhibitors in whom we’ve had very few options over the years.




Dr. Allen: This is something that really could be problematic for the emergency physician, when you provide the factor replacement as thought would work and then you’re still running into a potential emergent condition that could require an intervention. Making decisions with these medicines, which are quite expensive and not benign themselves, is definitely going to take some shared decision-making with a specialist.

Dr. Rajasekhar: And it’s important to note that the presentation of an inhibitor may be for the first time in the ED, so it may be that the patient doesn’t know they have an inhibitor. They’ve just been noticing over time that their factor is not working as it previously had or they’re having more bleeds, and they finally come into the ED and there has to be a high clinical suspicion to look for these inhibitors.

Okay, so now I’d like to turn over the presentation to Dr. Wynn. Dr. Wynn, I’m very excited to hear about some of the novel therapies that are coming down the pipeline in the hemophilia space.

1. Hartmann J, Croteau SE. Am J Hematol. 2016;91:1252-1260.

FitusiranSmall inhibitoryRNA-targetingantithrombin

Emicizumab-kxwhBispecific

monoclonalantibody: bridgesFIXa and FX to

restore function ofmissing FVIIIa

ConcizumabMonoclonal

antibody: TFPIinhibition of

FXa/TF/FVIIa

Gene TherapyReplacing the

gene needed forproduction ofendogenousfactor protein

InvestigationalApproved

Novel Nonfactor Therapies for the Managementof Hemophilia With and Without Inhibitors1

Dr. Wynn: Thank you, Dr. Rajasekhar. It’s my pleasure to talk about these new products. As you mentioned at the beginning of your lecture, these are very, very exciting times in the world of hemophilia and the introduction of new products, and these products, which are what we consider novel products, are coming very, very quickly. It becomes important to have expertise to keep up with all of these introductions.

The first in the currently approved novel agent class is a product called emicizumab. Emicizumab is a bispecific monoclonal antibody that acts as a bridge between factor IX and factor X to replace the factor VIII product. Very, very shortly, we will begin using additional agents. Fitusiran is in late development, as well as a product called concizumab. And very, very exciting, all of us are expecting gene therapy to be on the horizon and will be a therapeutic product that patients will be utilizing.

1. Kitazawa T et al. Thromb Haemost. 2017;117:1348-1357.

HC

LCFIXa

HC

LCFX

FVIIIa

A2A1

A3

C1 C2Gla Gla

Phospholipid membrane

FIXa FX

Emicizumab

Gla Gla

Phospholipid membrane

Interactions of Emicizumab-kxwh With FIXa and FX1

First of all, emicizumab, like I mentioned, is a bridging agent, so it acts in replacement of factor VIII by bringing factor IX in close proximity with factor X. Because of the proximity on the phospholipid membrane, they will go ahead and interact and lead to further activation of factor proteins to eventually develop the fibrin clot.

1. Oldenburg J et al. N Engl J Med. 2017;377:809-818. 2. Young J et al. International Society on Thrombosis and Haemostasis 2017 Congress (ISTH 2017). Abstract OC 24.1. 3. Young G et al. Blood. 2018;132:632.

HAVEN 2 study showed emiciziumab-kxwhis effective and well-tolerated in pediatric

patients with hemophilia A and inhibitors2,3

Group CEmicizumab Prophylaxis

(n = 49)

Group BNo Prophylaxis

(n = 18)

Group AEmicizumab Prophylaxis

(n = 35)

All bleeding eventsTreated events of spontaneous bleeding

Bleeding events treated with bypassing agentsTreated events of joint bleeding

Treated events of target-joint bleeding

87% difference in annualized rate of treated bleeding events(risk ratio = 0.13; P < .001)

30

25

20

15

10

5

0Ann

ualiz

ed R

ate

of B

leed

ing

Even

ts(9

5% C

I)

0.1 (0.0-0.6)

0.8 (0.3-2.2)

1.3 (0.7-2.2)

2.9 (1.7-5.0)

5.5 (3.6-8.6)

28.3 (17.0-47.3)

23.3 (12.3-43.9)

16.8 (9.9-28.3)

6.7 (2.0-22.4)

3.0 (1.0-9.1)

0.6 (0.2-1.5)

3.1 (1.2-8.0)

5.1 (2.3-11

.2)

6.5 (3.4-12.4)

0.3 (0.1-1.0)

87% reductionPrior BPA prophylaxis → emicizumab

prophylaxis: 79% fewer bleeds

HAVEN 1 Inhibitors: EmicizumabProphylaxis vs No Prophylaxis

63% vs 6%Zerobleeds, %

ABR

AE ISR = 15%5 thrombosis/TMA

HAVEN 1 and HAVEN 2 Studies1-3

The studies that support the use of emicizumab are the HAVEN series of studies, the 1 through 4. Starting with HAVEN 1, HAVEN 1 looked at patients who have inhibitors and how effective they were in the control of bleeding. The results from HAVEN 1 show that unlike bypass therapies that these patients were on, emicizumab can reduce annual bleeding rates by more than 90%. HAVEN 2 was a follow-up study for those patients, and this was a pediatric study looking at its use in the same population. HAVEN 2 showed similar results compared with the reduction in annual bleeding rates that were provided to adults.

AE ISR = 25%No thrombosis/TMA

1. Pipe SW et al. Lancet Haematol. 2019;6:e295-e305.

No thrombotic events or development ofde novo antidrug antibodies with neutralizing

potential or FVIII inhibitors were observed

0 1 2 3 4 5

ABR, all 4.5

ABR, treatedspontaneous bleeds

ABR, treated joint bleedsABR, treated target

joint bleeds

HAVEN 3 Study HAVEN 4 StudyHAVEN 3 Noninhibitors

Emicizumab Prophylaxis vsNo Prophylaxis

96% reduction

56% vs 0%Zerobleeds, %

ABR 0.6

1.7

1

HAVEN 3 and HAVEN 4 Studies1




The HAVEN 3 study looks at the use of emicizumab in the prevention of bleeding for patients who do not have inhibitors. Similarly to the HAVEN 1 and HAVEN 2 studies, the results do show also a reduction in annualized bleeding rates to greater than 90%. Then finally, HAVEN 4 looks at alternative dosing regimens for emicizumab. The dosing regimens previously approved were to be given once a week, and HAVEN 4 establishes the use of emicizumab dosing once every 2 weeks or once every 4 weeks, and alternative regimens are equally effective to reduce bleeding rates for adults and pediatric patients.

Dr. Rajasekhar: Dr. Allen, I think what’s important for ER providers here to know is that this is becoming widely used in our hemophilia population, that you will be seeing patients on this new medication and that it’s used for prophylaxis, not to treat a bleeding episode. So if a patient on emicizumab comes to the ER and has an acute bleed, you would revert back to using a factor VIII product if they’re a noninhibitor patient or a bypassing agent if they’re an inhibitor patient.

Dr. Allen: These are great points, Dr. Rajasekhar and Dr. Wynn. Knowing about these is probably going to be half the battle with recognition, as you mentioned, and into your treatment strategy where that shared decision-making that we’re going to discuss quite a bit in the near future is going to be paramount to their success in improving morbidity and mortality.

Dr. Wynn: The other major advantage of emicizumab is that it is administered in a subQ fashion, subcutaneous fashion, rather than an intravenous fashion, so it is much, much easier for our patients to learn and perform the infusions.

Dr. Allen: And Dr. Wynn, I imagine that probably improves their quality of life as well.

Dr. Wynn: It improves their quality of life, both because of the route of administration and the frequency of administration, and it has actually increased the compliance of our patients who have switched to it because of those factors, that ease of use.

Dr. Rajasekhar: Then finally, from a safety standpoint, we are really happy to see that this medication is not associated with inhibitor development.

1. Sehgal A et al. Nat Med. 2015;21:492-497.

RNA interference (RNAi)

Lowers antithrombin production

Promotes thrombin generation

Restores hemostasis

Investigational RNAi therapy that specificallytargets antithrombin mRNA (encoded by

SERPINC1) to suppress the production and therebyrebalance coagulation system and promote

hemostasis in hemophilia

Fitusiran

ASGPR(pH >5)

AT

Hemophilia A

Hemophilia B

FVIIIa FX FVIIa FVII

FIXaFXa

FVa FV

Prothrombin Thrombin

Fibrinogen Fibrin

Blood clot

AT

FVIII

FIX

mRNA

RISO

Clathrin-coated

pit

RecyclingASGPR Clathrin-coated vesicle

Endosome

Nucleus

Targeting Antithrombin in Hemophilia With RNAi: Fitusiran1

Dr. Wynn: Moving on from emicizumab and to other nonfactor products that are in development and hopefully soon to be approved, another exciting one is a product called fitusiran. Fitusiran is a product that uses interference RNA, a short snippet of RNA sequence that will block the production of antithrombin 3 by preventing its translation into a protein. It represents a type of therapy that rebalances the hemostatic system rather than directly replacing the factor that is missing. It will reduce the counterbalance to coagulation and put clotting and bleeding into a more even balance.

1. Pasi K et al. N Engl J Med. 2017;377:819-828. 2. Pasi K et al. ISTH 2019. Abstract OC 11.3. 3. https://clinicaltrials.gov/ct2/show/NCT03417102. 4. https://clinicaltrials.gov/ct2/show/NCT03417245. 5. https://clinicaltrials.gov/ct2/show/NCT03974113. 6. https://clinicaltrials.gov/ct2/show/NCT03549871.

Ongoing phase 3 prophylaxis trials• ATLAS-INH: fitusiran vs FVIIa or aPCC in patients with hemophilia A or B and inhibitors3

• ATLAS-A/B: fitusiran vs FVIII or FIX in patients with hemophilia A or B without inhibitors4

• ATLAS-PEDS: fitusiran in patients 1 to <12 years of age with hemophilia A or B5

• ATLAS-PPX: fitursiran in patients with hemophilia A or B previously receiving bypassing agents6

Interim analysis of phase 2 open-label extension study, which included patients with hemophilia A or B with or without inhibitors who completed the phase 1 study, has indicated fitusiran prophylaxis provides sustained AT lowering, results in low ABR over an extended period of time, and is generally well tolerated2

Phase 1 dose-escalation study showed once-monthly subQ administration of fitusiran waswell-tolerated and resulted in dose-dependent lowering of the antithrombin and increasedthrombin generation in participants with hemophilia A or B who did not have inhibitors1

Targeting Antithrombin in PatientsWith Hemophilia A or B With Fitusiran

Dr. Wynn: The development of fitusiran has been years in the making, and currently the process of development has fitusiran in phase 3 trials. The trials are showing good results with good bleeding control, and the most exciting thing is that fitusiran is a therapy that will be not limited to just factor VIII patients, but also can be used to manage the bleeding of factor IX patients as well.

1. Hilden I et al. Blood. 2012;119:5871-5878. 2. Shibata S et al. Proc Natl Acad Sci USA. 2013;110:7838-7843. 3. Shapiro AD et al. ASH 2019. Abstract 1973. 4. Eichler H et al. ASH 2019. Abstract 2417.

Concizumab

• Humanized IgG4 antibody• High affinity for Kunitz-2 domain of TFPI• Complete neutralization of TFPI inhibition of FXa/TF/FVIIa

Concizumab

Xa

TF

XVIIa

TFPI K1 K2 K3

Concizumab: Monoclonal Antibody Directed Against TFPI1-4

The next agent that we wanted to discuss is concizumab. Concizumab is similar to fitusiran in that it hopes to rebalance the coagulation system rather than just simply increase a missing factor. The mechanism of action of concizumab is to block a molecule called tissue factor pathway inhibitor, and thereby allow the production of factor X into production of a fibrin clot.




1. Astermark J et al. ISTH 2019. Abstract LB 01.1.

• ABR (after 24 weeks): 3.0-7.0• All patients chose to continue to extension phase in both trials• Concizumab exposure, free TFPI reduction, and TG potential were similar across all groups• Concizumab exposure was associated with normalized TG potential

Key Safety Findings

• No AE-related withdrawals

• No safety concerns with breakthrough-bleed treatment

Key Safety Findings

Three concizumab studies—phase 2 Explorer 5, global phase 3 Explorer 7,and Explorer 8—are on hold because of thrombotic events

Phase 2 Results of SubQ Concizumab Daily in Hemophilia A and Hemophilia A/B With Inhibitors1

Concizumab also is in development. It is currently in phase 2 trials, and so far, it has shown good results. There are concerns currently of related thrombotic events that have the most recent studies on hold, but those patients hopefully will be starting up real soon once the events have been clarified.

1. Doshi BS, Arruda VR. Ther Adv Hematol. 2018;9:273-293.

AAV-Mediated, Liver-Directed Gene Therapy for Hemophilia

Therapeutic Options

• Plasmapheresis• Empty capsids• Immunosuppression• Novel serotype• Regional delivery

Modifications

• Codon optimization• CpG content

Modifications

• Serotype• Empty capsids• Production system

Therapeutic Options

• Antiviral therapy• Skeletal muscle gene therapy

Therapeutic Options

• Lower vector dose• Immunosuppression

AAV Genome

rAAV Vector Genome

ITR Rep Cap ITR

ITR Promoter Intron Transgene polyA ITR

FVIII/FIX inhibitors

Liver disease

Pediatric patients

Pre-existing neutralizingantibodies to AAV serotype

CD8+ T Cell

Capsid-triggeredcellular immune

response

Proteinproduction

Gene Therapy: Restoring Normal Factor Production1

Then moving on to the most exciting new therapy that providers as well as patients have been hearing for decades about is gene therapy. Gene therapy, unlike any of the other factors, looks to restore normal factor production in our patients. The current generation of gene replacement therapy uses a virus vector called AAV, which has the inability to reproduce itself and is able to be modified to carry a gene to be the template for production of the factor.

The virus will be injected into the body and carry the gene to a producer cell, which is typically a cell in the liver. The DNA will be uptaken and will exist in the nucleus, and the new DNA will use the nuclear mechanisms to translate itself and produce the factor VIII within the patient’s own body. The cells, being living cells, will continue to produce the factor over an extended period of time.

1. Miesbach W et al. Haemophilia. 2019;25:545-557. 2. Doshi BS, Arruda VR. Ther Adv Hematol. 2018;9:273-293.

Gene Therapy for Hemophilia A

Valoctocogene roxaparvovec (BMN 270)

SPK-8011

TAK 754 (BAX 888, SHP 654)

Spark200/LK03

rAAV5

Serotype

rAAV8

Gene Therapy for Hemophilia B

Fidanacogene elaparvove(SPK-9001)Etranacogene dezaparvovec(AMT-061)

SB-FIX

rAAV5

AAV8

rAAV6

Serotype

BDD-FVIII

BDD-FVIII

Transgene

BDD-FVIII

FIX-Padua

FIX-Padua

Zinc finger-FIX

Transgene

30% at 12 wk

52%

Mean Factor Activity Post-Infusion

To be determined

41%

33.7 ± 18.5

To be determined

Mean Factor Activity Post-Infusion

Selected Investigational Gene Therapy for Hemophilia1,2

The gene therapy products that are in development are ongoing. The factor production for these patients has been effective. It has reduced bleeding rates in men who have received the product and has produced stable rates, anywhere from the 20% to 40% range. Some of the studies are still ongoing and the products are still being developed. The BMN agent will probably be the first of many agents to come to be introduced.

Gene therapy also has its limitations. The AAV vector has a limited lifetime, so the production of factor is expected to decrease over time as the cells live their own lifespans. We also know that gene therapy is a single-dose treatment at the current time. Because it is a virus vector, the immune system will develop an immune response against the virus, and the reintroduction of the virus will cause a destruction of the carrier molecule without any uptake into the producer cells. Hopefully, with those obstacles, we’ll be able to address them and overcome those with the introduction of even newer agents.

Dr. Rajasekhar: Dr. Wynn, it strikes me as important as you’re talking about these new pipeline drugs and gene therapy, that if a patient on one of these clinical trials presents to the ER, whether it has to do with bleeding or something else, that it’s important for ER providers to then contact the institution—the principal investigator or the study coordinator—to let them know that a clinical trial patient is in the ER, and so that we can investigate whether this adverse event is related to a product.

Dr. Wynn: That is right, Dr. Rajasekhar.

Dr. Allen: This is very interesting Dr. Wynn and Dr. Rajasekhar. I think the awareness of the emergency physician, as you mentioned, and speaking with the study coordinator or PI would be incredibly important because there also may be some other mitigating factors to severity of illness based off of the study, outside of just the recognition and documentation of a potential event. I think calling a hematologist in these situations is of the utmost importance to start therapy, if anything could be different that’s more in their specialty.

Dr. Wynn: Next, I would like to go ahead and have Dr. Allen present the approach in the emergency department for our patients.




Tung Wynn, MD



1. National Hemophilia Foundation. MASAC Report No. 257. December 5, 2019.

• Treatment for a suspected bleeding disorder is based on clinical history• Physical findings may be NORMAL in the early phases of most hemophilic bleeds• Spontaneous bleeding is common in individuals with severe disease (<1% factor level)

• If the patient or parent of a patient suspects that occult bleeding is occurring, administer clotting factor replacement• Patients often are instructed to carry with them appropriate factor replacement dosing guidelines as advised by their treating hematologist

When in doubt, administer clotting factor replacement immediately; DO NOT DELAY for imaging studies, lab results, or consultations• Treatment decisions should be based on the SUSPICION of a bleeding-related problem

MASAC Guidelines for ED Management: Assessment1

That leads us into the assessment of the patient, and we’re going to do a great clinical history. As mentioned before by Dr. Rajasekhar, it’s really important with this that the patient is incredibly knowledgeable with this disease state. With that comes a lot of help to the emergency physician in regards to what they tried at home, what they know about their factor replacement, do they have any with them, things like that.

It’s also important to point out that in your physical exam, it could be normal in the early phases of someone’s potential emergency and that in severe disease states, as we’re going to talk about in a couple slides on a really nice table, spontaneous bleeding can occur without trauma. I think one thing that’s a little bit of a pitfall for emergency physicians is to think that a hemophilia patient may require trauma to have a potential injury and that’s potentially not the case in these severe disease states. This goes back to the big piece of this slide, which is when in doubt, administer replacement and do not delay for imaging studies, labs, or consultations. I think this is the best way for us to have better outcomes for our patients.

Dr. Rajasekhar: Dr. Allen, if I can just interject here, I think we talked a little bit about when a patient brings clotting factor concentrate with them, it’s generally best to allow them to use that concentrate if at all possible. This recommendation really acknowledges that many emergency rooms, especially at smaller hospitals, do not have the majority of clotting factor options and may not have any clotting factor, for that matter, on their formulary.

Then the other piece is you mentioned that you should infuse factor before imaging and labs, but if a patient is being transported to your ED or transported from your ED to another facility for a step up in care, again, it’s really important to infuse before that transport.

Dr. Allen: Those are such great points, Dr. Rajasekhar. One of the realities of this, too, is that these factor replacements are expensive, and pharmacies at your local hospitals or in your emergency departments may not carry the exact one that the patient may have, but they may have one. And if not, then a referral and transport is of the utmost importance to get them what they need.

with the Hemophilia Foundation of Greater Florida.



This should not delay giving clotting factor concentrate replacement to the patient

Delays in administering factorconcentrate can significantly

impact morbidity and mortality

q Individuals with known bleeding disorders should be triaged urgentlyq Consultation with the patient’s hematologist or a regional HTC professional is strongly advised when possible

MASAC Guidelines for ED Management of IndividualsWith Hemophilia and Other Bleeding Disorders: Triage1

Dr. Allen: Thank you, Dr. Wynn. We’re going to talk about what the current guidelines tell us for the treatment of hemophilia in the emergency department. This should be right in our wheelhouse in regards to the approach, evaluation, and management of these patients.

First, we’re going to start out with the National Hemophilia Foundation MASAC guidelines. If there are any two take-home points I want you guys to know from this is (1) when in doubt, give factor, and (2) treat first, image or diagnose second—these are two things that have really been the standards and the major highlights of these guidelines.

First, you start out with triage, of course. If someone’s to arrive to the emergency department, either by ambulance or into your lobby, they should be urgently triaged if they have a history of hemophilia. Delays in administering factor can significantly impact their outcomes with morbidity and mortality.

The other big take-home point on this little checklist that we have here is urgent and early consultation with the hematologist or a regional center or professional is strongly advised. But that doesn’t take away the responsibility of the emergency physician to perform an appropriate medical screening examination and get therapy started quickly.

Treating Hemophilia in the Emergency Department: What Do Current Guidelines Tell Us?





• Routine joint bleeds DO NOT require imaging• For the established patient, routine surveillance labs (PT, PTT, factor levels) ARE NOT indicated unless requested by the patient’s hematologist• If an invasive procedure is required (ie, lumbar puncture, ABG, lung/joint tap) or if surgery is indicated, clotting factor to raise the patient’s level to 100% must be administered in the ED prior to the procedure

Clotting factor should be given before any diagnostic studies are performed, especially in cases of head trauma, abdominal trauma, or suspected ICH

MASAC Guidelines for ED Management: Diagnostic Studies1

Moving on into diagnostic studies, and there are some “do nots” on here that I think are incredibly important for resource utilization. One thing that we talked about earlier was a target joint and hemarthroses and routine bleeding in those joints do not require imaging. I think that that actually is tough to manage in an emergency department setting, especially if they have decreased range of motion and things like that, but that’s a part of those MASAC guidelines and I think they’re important to point out.

Back to what we were talking about earlier, clotting factor replacement should always supersede any diagnostic studies, especially in the cases of trauma. There are frequent cases of minor trauma that can result in intracranial hemorrhage and abdominal trauma that can result in intra-abdominal injuries and hemoperitoneum.

Dr. Rajasekhar: Dr. Allen, it seems like what you’re saying here is that treatment decisions really should be based on the suspicion of a bleeding-related problem, not documentation necessarily of one. That kind of goes into what you were saying about labs and imaging not being required. Frankly, labs are not expected to guide management and factor levels are not often available in real time, so it’s not really feasible to check some of the specialized labs to guide your treatment decisions.

Dr. Allen: I couldn’t agree more. You know, another thing that we haven’t really touched on is invasive procedures that are very common in the emergency department. There are some examples like a lumbar puncture, arterial blood gas or an arterial line, lung or thoracentesis or even arthrocentesis, or a joint tap, or if major surgery or an emergent surgery is indicated, it’s paramount that you replace and raise that patient’s level to 100% in the ED prior to the procedure, or the risk of complications and hemorrhage increases substantially.


1. Suspected bleeding into a joint or muscle 2. Any significant injury to the head, neck, mouth, or eyes, or evidence of bleeding in these areas 3. Any new or unusual headache, particularly one following trauma 4. Severe pain or swelling at any site5. All open wounds requiring surgical closure, wound adhesive, or wound closure strips6. History of an accident or trauma that might result in internal bleeding7. Any invasive procedure or surgery8. Heavy or persistent bleeding from any site9. Gastrointestinal bleeding10. Acute fractures, dislocations, and sprains

MASAC Guidelines for ED Management: Indications for Factor Replacement Therapy1

This is a nice summary of the MASAC guidelines for ED management, and I think a lot of these indications for factor replacement are self-explanatory and just go ahead and peruse yourself through this list and we’ll move on to the actual management and treating of the patients.

a Calculations based on factor dosing recommendations. Refer to package insert for full dosing information. b Recombinant clotting factor or patient’s product of choice is preferred; plasma-derived concentrate is a suitable alternative in emergency situations when recombinant factors are not available. 1. National Hemophilia Foundation. MASAC Report No. 257. December 5, 2019. 2. Factor VIII Dosing Calculator. https://mprcalc2.usbmis.com/24535.html. 3. Factor IX Dosage Calculator. https://www.empr.com/medical-calculators/factor-ix-dosage-calculator/article/170191.

• Minor – Early hemarthrosis – Mild soft tissue – Mild muscular

• Severe – CNS – Retroperitoneum – Retropharynx – Surgery – GI

• Moderate – Definite hemarthrosis – Moderate muscular – Hematuria – Dental – Epistaxis (rare)

Remember: Treat first, diagnose later

Bleeding Type

MinorModerateSevere

25%50%

100%

12.52550

2550

100-120

Target PercentCorrection

Dose of FVIIIb,units/dL

Dose of FIXb,units/dL

MASAC Guidelines for ED Management: Treating Patients With Hemophilia A or B Without Inhibitors1-3,a

I think one thing that’s outside of the remembering of the “treat first, diagnose later” is about minor, moderate, and severe indications for factor replacement, and then the target percentage of correction. As it states here, these are really nice criteria in which you get into the severe, the moderate, and the minor.

For the severe, I think we should focus on things in regard to the central nervous system, areas where you can have expansion of blood in a space like the retroperitoneum; the retropharynx, which could be quite scary for an airway; any type of surgery; or GI, as we mentioned on the last slide. Then in the moderate, you get into the hemarthrosis, potentially the target joint; dental; and anything to do with hematuria or muscular. Then the minor is obviously the more mild cases of such. I don’t expect emergency physicians to memorize these things, but having to know where to reference this is going to be important for you to be able to manage first and do that “treat first” strategy.

Dr. Rajasekhar: Dr. Allen, there are online calculators that can help calculate what dose to give.

Dr. Allen: We love online calculators. That’s great.




Dr. Wynn: Dr. Allen, one thing to remind everybody is that these patients are oftentimes on prophylactic regimens, as well as they have the ability to self-infuse and sometimes they have levels that are freestanding. Another rule of thumb to keep in mind is that if these patients have ongoing treatment, if you don’t know what the level is, go ahead and treat to the full intended level that you want and assume that the patient is at 0%.

Dr. Allen: Thank you, Dr. Wynn. That’s a great rule of thumb. When in doubt, assume that they’re at 0%. I think we’ll be able to really standardize that.

• Treatment decisions may be more complicated• The care of inhibitor patients should be urgently discussed with the patient's hematologist • If an individual with an inhibitor presents in a life- or limb-threatening scenario, the safest immediate action is to prescribe:


OR aPCC75-100 units/kg

rFVIIa90 mcg/kg

MASAC Guidelines for ED Management: Treating Patients With Hemophilia and Inhibitors1

Moving forward, there’s this challenge with hemophilia and inhibitors that’s worthy of discussion with the ED management. This brings in another complication, and we discussed this a little bit earlier, but this is the patient who may be refractory to your initial factor replacement. This is where a hematologist and discussing with a specialist is paramount to the patient’s success. If someone presents with an inhibitor or presumed an inhibitor and has a life- or limb-threatening scenario, the two options that we have at this point in time are factor VII or prothrombin complex concentrates. This would certainly be shared decision-making, in my opinion, with the specialist to talk about the risks and benefits of both of these, and also the capability of your institution to be able to provide one of these hopefully. If not, you certainly need to transfer the patient to a higher level of care.

NOT used alone in patients withbreakthrough bleeding episodes• Depending on individual’s inhibitor status, patients should be treated with – FVIII replacement product

– Bypassing agents such as rFVIIa or aPCC (with caution)

or

1. Hemlibra (emicizumab-kxwh) Prescribing Information. https://www.gene.com/download/pdf/hemlibra_prescribing.pdf.

Managing Patients With Hemophilia Aon Emicizumab-kxwh Prophylaxis1

Dr. Rajasekhar: Emicizumab is solely used for prophylaxis or prevention of bleeds, and we touched on the fact that if a patient

on emicizumab comes into the ED with a bleed, we should be treating them with factor concentrate, in the case of noninhibitor patients, or a bypassing agent, in the case of an inhibitor patient. The one caveat to that is that recombinant factor VIIa is recommended over one of the prothrombin complex concentrates, and that’s because in clinical trials, prothrombin complex concentrates were noted to have a higher incidence of thrombosis or thrombotic microangiopathy when used in combination with emicizumab prophylaxis.

• Cases of thrombotic microangiopathy and thrombotic events were reported when, on average, a cumulative amount of >100 units/kg/24 h of aPCC was administered for ≥24 hours to patients receiving emicizumab-kxwh prophylaxis• Monitor for the development of thrombotic microangiopathy and thrombotic events if aPCC is administered• Discontinue aPCC and suspend dosing of emicizumab-kxwh if symptoms occur

Thrombotic Microangiopathyand Thromboembolism

• Emiciziumab-kxwh interferes with ACT, aPTT, and coagulation laboratory tests based on aPTT, including one-stage aPTT-based single-factor assays, APC-R, and Bethesda assays (clotting-based) FVIII inhibitor titers • Intrinsic pathway clotting-based laboratory tests should not be used

Laboratory CoagulationTest Interference

1. Hemlibra (emicizumab-kxwh) Prescribing Information. https://www.gene.com/download/pdf/hemlibra_prescribing.pdf.

Warnings and Precautions for Patients With Hemophilia Aon Emicizumab-kxwh Prophylaxis1

Dr. Wynn: While the thrombotic complications of factor choice with emicizumab are well noted, there have been thrombotic events that have been reported when providing acute management for patients on emicizumab. The incidence of thrombosis has been defined as when patients have received an activated prothrombin complex concentrate at high doses, generally greater than 100 units/kg in a 24-hour period of time, and with repeated dosing of those high doses—multiple doses for more than 24 hours. As a result, it is our general recommendation to consider the use of factor VII first for patients on emicizumab.

In addition to the caution of the choice of bypass therapy for an inhibitor patient on emicizumab, we also know that the measurement of factor levels while a patient is on emicizumab can be problematic. The emicizumab causes falsely high levels of the aPTT assay, as well as the one-stage clotting-based factor VIII assays. It’s recommended if you are looking to try to determine a factor level, you should use a chromogenic assay.

Dr. Rajasekhar: Dr. Wynn, for those emergency departments that don’t have recombinant factor VIIa, we would want them to use prothrombin complex concentrates in an inhibitor patient on emicizumab prophylaxis if they come in with a bleed, the point being that you would try to use the lowest possible dose to control the bleed.

Dr. Wynn: Now we’re going to move into our case discussions regarding how to manage these patients in the emergency room. Dr. Allen is going to introduce the first case and discuss it with us.




Tung Wynn, MD



Best Practices From the Experts: Incorporating Shared Decision-Making Into the Management of Hemophilia

with the Hemophilia Foundation of Greater Florida.


q Boy is alert, interactive, and appears wellq Vitals are normalq Does not appear to be in any distressq No scalp hematomaq Neurologic exam is normal for age

Key PE Findings

A boy 7 years of age with a historyof severe hemophilia A

Receives FVIII prophylaxis 2x/wk

Presents to ED after tripping over a rockwhile running and striking his head

Boy’s mother states• He has been complaining of a mild headache • His last FVIII infusion was 2 days ago

Case 1: Head Trauma

Dr. Allen: Okay, thank you Dr. Wynn. This is a head trauma case, a pediatric case, actually, who just rolls into your emergency department. A seven-year-old boy, and he has a known history of severe hemophilia A. He receives factor VIII prophylaxis twice a week, and he tripped over a rock while running and he struck his head. Mother states he’s been complaining of a mild headache, and his last infusion was about 2 days ago. Pertinent findings on exam: he’s alert, interactive. He appears well. Vitals are normal on your first set of vital signs, and he’s not in any distress. You don’t even see a scalp hematoma, and his neurological exam is normal for age.

• Is head imaging warranted?• Does he need FVIII infusion? – If so, when should it be administered and how much?• The patient uses rurioctocog alfa pegol at home, but mother does not have it with her – Your pharmacy only carries efmoroctocog alfa Ø Is it okay to switch them?

How can we incorporate shared decision-makingand individualize hemophilia care?

Key Questions

Let’s talk about some key questions. Is head imaging warranted? Does he need a factor VIII infusion? He uses a factor replacement at

home, but mother does not have it with her. Your pharmacy only carries a different one. Is it okay to switch them?

1. Sorenson B et al. Blood Coagul Fibrinolysis. 2003;14:469-477. 2. Collins PW. Haemophilia. 2012;18:131-135. 3. Oldenburg J. Blood. 2015;125:2038-2044. 4. Valentino LA. Haemophilia. 2014;20:607-615.

A single severity-based therapeutic model does not represent theoptimal treatment strategy for all patients with hemophilia1

Individualization of hemophilia care is recommended

Underscores need for shared decision-making

Factors to consider for individualized treatment1-4

Patient’s bleeding pattern Condition of the patient’smusculoskeletal system

Level and timingof physical activity Individual PK profile

Central venous access Presence of target joint Patient likelihoodof good adherence Psychosocial factors

Every Patient Represents a Unique Challenge

Thankfully, we’ve talked about a lot of these with the MASAC guidelines and I think that it’s really important to talk about how every patient represents a unique challenge. A lot of these are going to require shared decision-making, and this is something that I’m a real advocate of. I try to do this with almost every patient who I have a discussion with in the emergency department when it comes to care options and potentially a safe discharge plan. In this case with hemophilia in this patient, the individualization of care is recommended and encouraged. Here are some factors to consider for individualized treatment. With all these factors that you can see down here, it really underscores the need for shared decision-making.

1. Cramm JM, Nieboer AP. BMJ Open. 2014;4:e005914.

Inform the patient to improve their knowledge about their own illness

Activate the patient to increase the role they assume in illness management

Promote interaction between patient and healthcare professional

Goals of Shared Decision-Making1

What are the goals of shared decision-making? I think it’s to impart knowledge and inform the patient; to activate the patient to increase the role they assume, which means that they have to be in the action phase for their own wellness; and to and to promote interaction between the patient and their health care professionals. That may be you in the emergency department, but it also may be for their follow-up care with their specialist or if they require admission.




1. NQP Playbook™: Shared Decision Making in Healthcare. 2018 National Quality Forum.

Clear, accurate, and unbiased medical evidenceabout reasonable alternatives (including no medical

intervention) and the risks/benefits of each

Clinician expertise in communicating andtailoring that evidence for individual patients

Patients’ values, goals, informed preferences,and concerns, which may include treatment burdens

Recently, the National Quality Forum developed the National QualityPartners Playbook™: Shared Decision Making in Healthcare withinput from a team of experts and recognized leaders committed

to making SDM a standard of care for all patients

NQP Playbook Requirements for SDM

1

2

3

NQP Playbook for Shared Decision-Making1

The National Quality Forum created a playbook for this. It’s called the National Quality Partners Playbook. To get through it and for some basic fundamental requirements for shared decision-making, you want to think about clear and accurate and unbiased medical evidence, so you’re sharing knowledge, and then the clinician expertise in communicating and tailoring that evidence for your patient.

After you understand and are able to impart the knowledge of that evidence, you need to be able to communicate that effectively to your patient, who may have different levels of healthcare literacy. Furthermore, the patient’s values, goals, and preferences have to be considered in these situations. I think we frequently encounter in the emergency department times where patients may not want to follow your exact treatment plan, but your respect of their values and their goals in someone who has capacity should always be considered and encouraged.

1. AHRQ. The Share Approach – Essential Steps of Shared Decision Making. https://www.ahrq.gov/professionals/education/curriculum-tools/shareddecisionmaking/tools/tool-1/index.html.

Seek patient’s participation

The SHARE Approach:

S

Help patient explore and compare treatment optionsH

Assess patient’s values and preferencesA

Reach a decision with patientR

Evaluate patient’s decisionE

Essential Steps of Shared Decision-Making1

What the playbook really encourages, as well as the AHRQ, is the SHARE approach. Seek their participation, help them explore and compare options, and assess their values and preferences. The social history is a big component of this. Reach a decision with the patient, evaluate the patient’s decision. I would add a D to this—document. Document this discussion in your shared decision-making, and this goes a long way to great charting, but also for continuity of care with that specialist in follow-up.

After brief discussion with boy’s mother, efmoroctocog alfaadministered at 50 units/kg to bring his factor level to 100%

Boy admitted to the PICU for serial neurologic exams;consult hematology for his treatment while in the ICU

Head CT scan obtained after efmoroctocog alfa wasadministered shows a small subdural hematoma withoutoverlying skull fracture

1

2

3

Case 1: Management

Now back to that case that we talked about earlier, and we’re going to talk a little bit about the management. As you know, we’ve talked about before, when in doubt, treat prior to seeking a diagnosis. After shared decision-making with the mother of the patient, we’re going to administer factor to get them up to 100% because of their history of severe hemophilia, and we’re going to talk about imaging because of the concern with the mechanism of injury, when he fell and hit his head on a rock.

And guess what? That CT shows a small subdural hematoma without a skull fracture, which makes sense with the physical exam findings of no hematoma externally. The boy is admitted to the pediatric ICU and serial exams and consults hematology while in the ICU. This is a great strategy, and higher level of care is certainly encouraged in these patients getting factor and who have a known injury, which you can then de-escalate as necessary after the necessary consultants are present.

1. http://ashpocketguides.hematology.org/#/app/tools.

• When treating patients with hemophilia, factor replacement takes priority over imaging and other diagnostic tests

• Remember: If you are ever in doubt about how much factor a patient will need—and there is not enough time to touch base with the patient’s hematologist—correct the factor level up to 100%

• If you don't know severity of patient's hemophilia or baseline factor activity, assume patient is <1% and calculate dose based on that using the American Society of Hematology dosing calculator1

• Shared decision-making: Always consult with the patient’s hematologist to coordinate disposition of discharge home vs admission for observation and continued factor infusion

Case 1: Clinical Pearls1

This leads us to our clinical pearls, and I want to bring in Dr. Wynn and Dr. Rajasekhar to really underscore these pieces of that last case and about shared decision-making together.

Dr. Wynn: This is a great case, Dr. Allen. You know, it’s an unfortunate situation that our families can find themselves in sometimes, but I think, as you’re highlighting, good decision-making can prevent further complications and worsening of the situation. I would highlight especially the decision to provide factor replacement for this patient early when they arrive in the




emergency room and to do it before any imaging, based upon the suspicion of the bleeding that the factor was given.

Dr. Rajasekhar: Dr. Allen, I would add that with regards to shared decision-making, it often goes a long way for the ER provider to contact either the patient’s hematologist, if that’s possible, or the hematologist on call at that institution, and for the ER physician to then say, “We’ve discussed this with a specialist.” I think a lot of patients really appreciate that extra level of communication.

Dr. Allen: Those are both really great points, Dr. Wynn and Dr. Rajasekhar. You know, Dr. Wynn, this bullet number two really underscores what you said earlier about when in doubt, correct to the appropriate level and assume that they’re at 0%. And Dr. Rajasekhar, you and I have done this frequently together—have these discussions. The peace of mind, back to the patient and/or their family member, is really large and significant when we do have those discussions. I can say, just like what you said, “I talked to Dr. Rajasekhar, your hematologist, and we’re both on the same page with your treatment plan. How does that sound to you?”

• Man aged 28 years with severe hemophilia A• On prophylaxis with octocog-alfa, but missed his morning dose• Experienced left upper thigh pain after returning from a bike ride• Administered the prophylactic dose of his factor, but the pain continued to get worse• Came to the ED with his home factor when he was no longer able to walk on his leg because it was too painful for him to fully straighten it

Case 2: Iliopsoas Bleed

Dr. Rajasekhar: Absolutely. Well, let’s move on to case two, and letting the cat out of the bag here, it’s titled iliopsoas bleed, but let’s walk through this as if you didn’t know that. So we have a 28-year-old man with severe hemophilia A on prophylaxis with octocog-alfa, but he missed his morning dose. He experienced left upper thigh pain after returning from a bike ride and administered his prophylactic dose of factor. But then the pain continued to worsen, and so he came into the ER with his home factor when he was no longer able to walk on his leg because it was just too painful for him to fully straighten the leg.

• What is the suspected source of the pain?• What studies should be done to determine the source of the bleeding?• What is the initial care provided in the ED?• To hospitalize or not to hospitalize?• What does the continued treatment look like?• What are the significant complications if the treatment is delayed?• What does return to activity look like as he receives treatment?

Key Questions

What are some key questions you should be asking yourself in the ER? Well, what is the suspected source of pain, obviously? What studies should be done, if any, to determine the source of bleeding? What is the initial care provided in the ED? What should that look like? Should this patient be hospitalized or not? What does continued treatment after the initial treatment in the ER look like? What are the significant complications if we don’t treat this patient in a timely manner? Then finally, most adults want to know when they can get back to normal and go back to work or school.

• Suspected source of the pain: hip joint bleed, thigh muscle bleeding, iliopsoas bleed, hernia, testicular torsion, epididymitis• The inability to extend the hip joint is highly suggestive of iliopsoas hemorrhage – Ultrasound and CT s/o similar findings• CBC, FVIII activity, FVIII inhibitor, urinalysis• Initial care: administer the patient’s factor• Labs and imaging are done after infusion has been given• Consider PRBC because a large amount of blood can be lost in this type of hemorrhage• Corticosteroids for paresthesia and pain relief

Case 2: Management

In this case, the suspected source of pain could be anything and while bleeding is certainly high on the differential, we have to think of other things. In the case of a young man with pain in this area, we should be thinking of a hip joint bleed; a thigh muscle bleed; an iliopsoas bleed, which is a very specific type of bleed; as well as other nonhemophilia-related disorders, like hernias, testicular torsion, or epididymitis. The inability of this patient to extend his hip joint is highly suggestive of an iliopsoas bleed, and while you can, again, confirm this with imaging studies, remember treating is paramount early on. Same thing with labs, those should not delay treatment.

Importantly, if a patient is an inhibitor patient, you would use bypassing agents, and if they were a noninhibitor patient, you would use factor. As we’ve talked about before, if they bring those with them to the ED, you should use the patient’s if at all possible. Then one thing to remember about these specific bleeds in the iliopsoas muscle is that these are deep muscles and they can hold a lot of blood in terms of amount, and it sometimes is not noticeable




until the patient clinically deteriorates. Often, you’ll have to use corticosteroids for paresthesias and pain relief. In this case, again, having that iliopsoas bleed on the differential and just thinking about it is really critical.

1 Rurioctocog alfa pegol administered at 50 units/kg to bring his factor level to 100% for 48 hours, then 60% for remainder of 1 week

Maintain 60% levels for longer during physical therapy

CT scan obtained after rurioctocog alfa pegol was administered shows an iliopsoas bleed2

3

Begin prophylaxis regimen thereafter4

Case 2: Management

This patient received a factor replacement at 50 units/kg to bring his factor up to 100% for about 48 hours, and then he was kept on factor replacement to a target goal of 60% for the remainder of the week. A CT scan was eventually obtained after factor replacement and again confirmed what you suspected as an iliopsoas bleed. During periods of physical therapy, which this patient will likely require, it’s important to maintain factor levels so as not to exacerbate bleeding and take two steps backwards. In general, we like to keep factor levels around 60% during aggressive physical therapy, and once physical therapy is complete, the patient can then go back to their normal prophylaxis dosing.

• Common symptoms of iliopsoas bleed: pain (abdominal, back, groin, hip, or thigh)• Signs: flexion contracture, distal paresthesia• Hospitalization – Mild bleeds: manage at home, bedrest, and pain control – Moderate to severe bleeds: hospitalized• Complications of untreated iliopsoas bleed: rebleeding with too rapid of return to activity, femoral nerve compression, or nerve palsy• Amount of activity while on treatment – Strict bedrest for the first 48 hours – Gradual return to activity over 2-3 weeks – Physical therapy is often needed to rehab

Case 2: Clinical Pearls

It’s important that these patients also have strict bedrest initially, and ambulation should really be discouraged initially, even if it’s with crutches, because any form of ambulation requires contraction of that iliopsoas muscle.

So Dr. Wynn, Dr. Allen, I know you’ve seen these types of bleeds before. Any thoughts that you have on these patients presenting to the ER with symptoms specific to an iliopsoas bleed?

Dr. Allen: Yeah, these are definitely sinister and can be certainly occult, but I really liked how we kept a broad differential diagnosis

in the beginning to prevent from some diagnostic anchoring, too, while still keeping that mindset of treat first, find a diagnosis later.

Dr. Wynn: Yeah, I think the greatest point that this case highlights is to keep a high index of suspicion for the bleed, and knowing what the key physical findings are for how an iliopsoas bleed presents can be very, very important for an emergency room physician.

Dr. Rajasekhar: Importantly, sometimes when you give factor, it can be both therapeutic and diagnostic. So if it helps the patient after you give them factor, that’s a clue that this really was a bleed and not something else that was not hemophilia related.

• Boy 15 months of age with severe hemophilia A presents with right knee bleeding• You remember him when he presented to the ED as an infant with hemorrhage for a circumcision done before he was known to have hemophilia. He was treated for 7 days in the hospital at that time and the family thanked you when he was discharged• He had a port placed last week and began 2x/week prophylaxis with moroctocog alfa and had received his second dose this morning

Case 3: Patient With Inhibitor and Bleeding

Dr. Wynn: Okay, I will go ahead and start the third case. Our third case presents, interestingly, with a 15-month-old boy who is known to have severe hemophilia A, and he is experiencing a right knee bleed. You, as the emergency physician, know the family because you can remember when he comes to you that he came as an infant, and at that time, he had a hemorrhage following a circumcision. It was eventually determined that he had hemophilia and he was admitted to the hospital. Your memory of him is jogged by the fact that the family actually walked down to the emergency room and thanked you for helping them when he was discharged previously.

Since that time, he has had a port placed, and last week they began prophylaxis. The prophylaxis is with rurioctocog alfa, and the patient has been receiving that twice a week. He received his second dose of prophylaxis this morning and then developed the bleed.




• What are the reasons that he is bleeding despite prophylaxis?

• What are risk factors for inhibitor?

• What are the laboratory tests that demonstrate the presence of an inhibitor?

• How would you treat the child’s bleeding?

• How would the family manage an inhibitor long-term?

Key Questions

In this case, questions that we want to be asking are, what are the reasons why he is bleeding despite starting on prophylaxis? What are the risk factors that might cause an inhibitor to develop? To determine the inhibitor, what laboratory tests are important? How would this affect your treatment choice for the child’s bleeding? And lastly, what does the family need to know in order to manage the inhibitor for his early childhood and long term?

1 Given the complexity of this patient’s case, you decide to consult with the patient’s hematologist

After a discussion with parents of the patient and his hematologist, a shared decision is made to administer FVII

The patient is observed in the ED for 2 hours and parents report significant improvement in his swelling and pain; he is discharged home with close follow-up and strict return precautions

High-titer inhibitors (>5 BU/mL) to rFVIIIa2

3

4

Case 3: Management

The outcome of this case, given the complexity of the presentation, you decide to go ahead and consult with the patient’s pediatric hematologist. It’s determined and suspected that he has an inhibitor, and in discussing the treatment options for bypass therapy, it was decided to go ahead and provide this patient with activated factor VII. The patient was observed in the emergency room for 2 hours and the parents note that he has improved. He was eventually discharged home with consultation by the hematologist to have a very, very close follow-up and precautions on when to return for further treatment. So Dr. Rajasekhar and Dr. Allen, how do you think the management for this patient proceeded?

• Reasons for bleeding despite prophylaxis – Underdosed: more rapid clearance in children than adults – Injury: breakthrough bleeding on prophylaxis – Training: family or provider not properly trained – Storage: factor will lose efficacy if not stored properly – Inhibitors: antibody-neutralizing factors• Laboratory tests that demonstrate inhibitors – Lower-than-expected FVIII activity – Lack of aPTT correction to normal – Mixing study that does not correct – Nijmegen Bethesda assay for inhibitor quantification

Case 3: Clinical Pearls

Dr. Rajasekhar: I think it was really important and critical that the ER physician, recognizing that this was not a straightforward case, involved the hematologist, and I think that’s how we got to the diagnosis of inhibitor early on. It’s important also to know that not many institutions will have inhibitor assays available in real time. So, one thing that can be done is look at the PTT and if it does not correct, you would expect in that case that this patient has indeed developed an inhibitor, as opposed to a patient without an inhibitor, in which case the PTT should correct on mixing.

Dr. Allen: Really great points, Dr. Rajasekhar. I think it’s safe to say that any emergency physician would be anxious and a little nervous with this patient arriving to their ED. I think that the first bullet point with some reasons [for bleeding] and factor replacement—maybe it’s been underdosed at home, maybe there’s an issue there.

• Treatment for bleeding – Bypass therapy – Recombinant FVIIa – aPCC – Supertherapeutic dose of FVIII – Porcine factor• Long-term management of inhibitors – Low titer – Supertherapeutic factor with spontaneous resolution – High titer: emicizumab, prophylaxis only, needs bypass therapy for bleeding; caution with aPCC >100 units/kg for >24 hours – Immune tolerance: to eradicate the inhibitors

Case 3: Clinical Pearls (Cont’d)

But having that awareness that an inhibitor could be the etiology is why I think this is a big part of this educational activity that we’re having today, too, is to build that awareness around some of these things, and the whole mindset of “treat early and consult early” when you start to get into a potential predicament in which it’s going to impact their outcome.

Dr. Wynn: Yes, and I think the fact that the emergency room physician consulted and brought in the involvement of the hematologist early on in the evaluation in this case is a very, very important point to highlight.




• The treatment of hemophilia has evolved considerably over the past several years• Advances in biotechnology have permitted the development of EHL replacement clotting factors for prophylaxis in patients with hemophilia A or hemophilia B• Novel rebalancing therapies are being evaluated in hemophilia A and hemophilia B• MASAC guidelines for ED management of hemophilia recommend that suspected bleeds be treated first and diagnosed second• In this regard, patients with hemophilia and family members are often very well educated in the disease and its management, which can significantly reduce morbidity and mortality and underscores their role in SDM• SDM has been shown to increase the use of the treatment option that is most clearly associated with health benefits

Summary

To summarize our discussion today, the treatment of hemophilia has evolved, and it’s evolved very, very rapidly and considerably over the past several years. The advancement in what we know has permitted the development of extended half-life factors, as well as its use in prophylaxis for hemophilia A and B. Newer therapies that look at rebalancing therapies for our patients also now exist. MASAC guidelines for treatment of hemophilia in the emergency room do recommend that you treat these patients based upon the suspicion of bleeding, and diagnostic testing and imaging remain secondary in treatment. In regards to family members, remember that a shared decision-making approach is very, very important because our patients are very, very well-educated in their disease, as well as managing the bleeds that may develop. By listening to the family, you can arrive at a treatment much more quickly, and it will reduce the morbidity and mortality that could complicate the situation. Shared decision-making will also increase the amount of treatment options that patients may know to be available to them, and it may actually be associated with increased health benefits.

hemophiliaflorida.org800-293-6527

Education

Information

Referralservices

Improvingquality of life

for patients withhemophilia and

their families

Advocacy

Research

The Hemophilia Foundation of Greater Florida

We wanted to take a minute to acknowledge the Hemophilia Foundation of Greater Florida. The Hemophilia Foundation supports patients and families who have hemophilia and all bleeding disorders in the greater Florida area. They provide all manner of support to these patients. To find out more about what the Hemophilia Foundation does, you can visit their website or you could call their 1-800 number.

This ends our discussion for today. Thank you, Dr. Rajasekhar and Dr. Allen, for your insights during our discussion. We hope that you found this activity informative and useful to your practice and we also highly encourage you to earn extra credit by participating in PeerView’s “Optimal Management of Hemophilia in the Emergency Department Quality Improvement” module. Assess your practice, set your goals, and improve the level of your care for your hemophilia patients.

Dr. Allen: Thanks, everybody.

Dr. Rajasekhar: Thank you.

Narrator: This activity has been jointly provided by University of Florida College of Medicine and PVI, PeerView Institute for Medical Education; the activity is also co-provided by Medical Learning Institute, Inc.


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