An Overview of Pharmacologic Treatment for Hemophilia
Outlining key differences between prophylactic and on-demand care, the panel of experts reflects on the currently available pharmacologic agents used to aid patients with hemophilia.
Peter L. Salgo, MD: When I hear you guys talking now, I’m hearing about 2 separate aspects of hemophilia care. One is, “I’m going to give you something because you’re bleeding.” You’ve had an injury, you’ve had surgery, or something else. The other is, “I’m going to give you medication because I don’t want you to bleed in the first place.”
Robert F. Sidonio Jr, MD: Sure.
Peter L. Salgo, MD: How do you parse this out? What’s the difference here? How do you approach this?
Robert F. Sidonio Jr, MD: There are 2 approaches, just as you said. For the patients with severe hemophilia, severe hemophilia A and B, or the severe types of von Willebrand disease, the typical recommendation—particularly for hemophilia—is prevention of bleeds. We know they’re going to have 20 to 30 bleeding events per year. That’s obviously unacceptable because that can lead to significant problems. The strategy is—and it has been recommended over the last few decades—to start regular infusions of factor replacement for hemophilia A and B and some forms of severe von Willebrand disease in the first 3 years of life or immediately after the first joint bleed. We’re waiting for data, but a lot of us don’t like to wait for first major bleeding event.
Peter L. Salgo, MD: I was going to say, that would make me uncomfortable. We don’t want joint bleeds. I heard you say that.
Robert F. Sidonio Jr, MD: Yes, and that’s the general recommendation on the data, but obviously we have personal feelings about how we don’t want our patients to suffer from bleeding events. But there are challenges. If it was something like a pill that they could easily take, no big deal. But these are IV [intravenous] therapies predominantly. I know we’ll talk about emerging therapies. The average age for prophylaxis in hemophilia A is about 2 years. That’s a huge time point, 24 months, in which they’re at risk for life-threatening bleeding events. It’s a problem. And then, obviously, when they do have bleeding events, they’ll use the same-factor therapy to treat the bleeding events at different doses. That’s when we send separate scripts for their prophylaxis and for their on-demand acute bleeding treatment, which may be a different dose.
Peter L. Salgo, MD: Now, clearly, the doctor or the nurse isn’t going to be at home every morning to give an IV dose of something.
Robert F. Sidonio Jr, MD: Sure.
Peter L. Salgo, MD: And it’s a 2-year-old. Let’s get real. This is a 2-year-old. This is why I treat grown-ups. Putting an IV in a 2-year-old every few days?
Robert F. Sidonio Jr, MD: Yes, it’s emotionally taxing as a parent as well, just seeing that. This is a group of people who have learned to adapt. Predominantly, the women in the family take charge and they say, “Well, if he can’t do it, my aunt can do it” or “She can do it.” We even see this in the Amish community. All the women know how to stick those children, even in the conditions that they have. It’s pretty amazing. If you’ve ever seen this, we have these bleeding-disorder camps in which they learn how to stick themselves the first time. It’s very emotional to watch this because their mothers aren’t nearby, so they’re just standing there with a butterfly needle trying to stick themselves, and everything is just silent while they do that. It’s very emotional, and they get something called a “big stick” award. These kids remember this [for] the rest of their lives. People who are 40 years old are telling me about it.
Peter L. Salgo, MD: I’m glad that’s your job. I don’t mean that facetiously.
Robert F. Sidonio Jr, MD: Yes, it’s tough.
Peter L. Salgo, MD: It bothers me to see these little kids, but the other option is so horrible.
Robert F. Sidonio Jr, MD: Yes, until recently the option was that there was no other option. It’s either you treat it and you prevent it or not. This is good for the child, but you know that this is emotionally taxing on them.
Peter L. Salgo, MD: Let’s talk about the treatment options. Now, these are the standard old-fashioned options. Let’s go over some of these. We’ve got concentrated factors and prothrombin complex. Walk me through some of this.
Tim Boonstra, RPh: Well, currently, with concentrated factor VIII and factor IX, there are essentially 2 different types: There are the standard half-life products and then the extended half-life products. Those are pretty much the standard of care today. There are also the activated prothrombin complex concentrates, which are generally used for patients with inhibitors. I have not seen cryoprecipitate, to be honest, but we do use desmopressin, DDAVP or Stimate, for patients who have a mild factor VIII deficiency. Amicar or Lysteda, aminocaproic acid or tranexamic acid, respectively, are used sometimes for our milder patients and sometimes surrounding dental procedures or menorrhagia in women. Those are pretty much the standard treatments.
Peter L. Salgo, MD: How do you store the stuff?
Tim Boonstra, RPh: Refrigeration. There’s a lot of it, but some of the older products are stable at room temperature for 3 years. We just have to let the families know or the patients know that if you’re going to be traveling, some are good for 3 months out of the refrigerator. If you’re going to go to Europe on a trip, congratulations for going on a trip, and you don’t have to refrigerate your factor. Don’t worry about that.
Peter L. Salgo, MD: That doesn’t apply to fresh frozen agents.
Tim Boonstra, RPh: No.
Robert F. Sidonio Jr, MD: No.
Peter L. Salgo, MD: That’s cold, right?
Robert F. Sidonio Jr, MD: Yes.
Peter L. Salgo, MD: You don’t see cryoprecipitate anymore, or you’ve never seen cryoprecipitate?
Tim Boonstra, RPh: Well, I’ve heard of it. We don’t dispense it to patients out of the pharmacy, though.
Robert F. Sidonio Jr, MD: That typically comes from the blood bank. Thankfully, we try to avoid the use of those products. Typically, they’re given when we haven’t identified a patient. For example, a baby who had circumcision bleeding. They don’t know what’s going on. They think it’s hemophilia, but they don’t know which type, and so somebody says, “Well, I’m going to give cryoprecipitate or plasma.” We’ve been trying to avoid that use because there is potentially a risk for inhibitor development.
Peter L. Salgo, MD: There’s something on this list that shocked me, which is that we still use fibrin glue.
Robert F. Sidonio Jr, MD: We still use it.
Peter L. Salgo, MD: I didn’t know that because I don’t talk to you guys all that often, but surgeons were using it with the best of intentions. It was developed with the best of intentions. But suddenly, you’re seeing antibodies.
Robert F. Sidonio Jr, MD: Yes, yes, and you see this with something like a bovine preparation. You can develop these unusual antibodies that present later, directed actually to factor V and some other factors because it’s what we call a dirtier product. It’s not as clean. Thankfully, there are recombinant forms of these things, but they have this topical thrombin. We still use that a lot for circumcision bleeds. You always tell people that if somebody is bleeding, put pressure on it. Sometimes, the most basic thing happens. Instead of watching it and thinking that you’re waiting for some magical medication, your hand will help stop the bleeding as well.
Peter L. Salgo, MD: You know, I learned that in medical school. Use pressure.
Robert F. Sidonio Jr, MD: Pressure.
Peter L. Salgo, MD: Of course, it may be an hour.
Robert F. Sidonio Jr, MD: Yes. You’re going to be there awhile.
Peter L. Salgo, MD: Walk me through this basic hematology 101. You’ve got platelets. They form a plug, but you need the other factors to stabilize the plug and then create a permanent stop. But will the platelets work right away?
Robert F. Sidonio Jr, MD: When there’s any damage to blood vessels in the body, that exposes collagen and creates a current that changes in the blood. What happens is the von Willebrand factor helps those platelets stick to the surface. It’s like building your basement, and the von Willebrand factor is like the mortar. If you don’t have enough of it or it’s dysfunctional, it doesn’t matter how great your first floor is, right? That’s the base layer.
Peter L. Salgo, MD: With von Willebrand disease, there’s no platelet action.
Robert F. Sidonio Jr, MD: Yes, the platelet adherence or adhesion can be affected, and other critical factors happen. In coagulation, which we all learn about, people forget to say it happens on a platelet surface. That part of it gets left out. And so you need that platelet surface for factor VIII, factor IX, for thrombin generation. Then there’s clot retraction and the cross-linking of fibrin. The whole point is to approximate the wound and allow time for it to heal. What happens in hemophilia and von Willebrand disease is that those components aren’t as good, and guess what happens. The plug just falls off. You start bleeding again. You might stop it, but they come back later, and they’re bleeding again.