Practice Pearl 1: Determining Severity and Goals of Therapy


An introduction to practice pearl #1 with identifying severity of disease and determining goals of therapy.

Luigi Brunetti, PharmD, MPH: Our first practice pearl is really, how do I identify the appropriate patients for prophylaxis? And the first step in that of course is understanding the breadth of severity. What are the different severities of disease that you encounter?

Robert F. Sidonio, Jr, MD: There's the traditional severity regimen in which less than 1% factor VIII, either measured by a chromogenic or 1-stage factor assay, is considered severe. And these are systems that were created decades ago, and they may be revised in the future. But it's generally what we have. And then moderate hemophilia is 1% to 5% factor VIII, and then greater than 5% to 50% factor VIII is considered mild hemophilia. So the current standard is that the recommendation for prophylaxis is all severe patients, those who have no measurable factor VIII, should be started on some preventive or prophulactic factor regimen when we talk about hemophilia A.

Hopefully, the ideal is to start before age 3, or after the first joint bleed. And oftentimes we start after any significant bleeding events. If the patient has had a severe bleed, for example, an intracranial hemorrhage, we certainly are going to start prophylaxis and are probably never going to stop it because we know they're at risk. And so sometimes we can identify those patients who we deem are more severe risk and seem to bleed a lot more, because the range is quite interesting. You'll have patients with the exact same severity, and 1 patient will have their first joint bleed at age 6, and the other will have it at age 1; it doesn't make a lot of sense. So clearly identifying those who bleed early and starting prophylaxis is important. There are lots of good papers on starting prophylaxis earlier, and it seems to have benefit a decade later. Obviously what we're trying to do is make sure they have a reasonable life in their 20s and 30s.

Luigi Brunetti, PharmD, MPH: In terms of the goals of therapy, you touched upon this a little bit, even later in life initiating treatment early can have benefits. But ultimately, what are your goals and therapy?

Robert F. Sidonio, Jr, MD: For us, based on the World Health Organization [WHO] and a few papers, the goal is to try to maintain above 1% factor VIII. There was a Peter Collins, MBBS, MD, paper that said for every hour below 1% factor VIII in a week, your bleed rate goes up by 1.4%. And so it makes sense to try to maintain the level as high as you can. And the thought process goes back decades that moderate severity patients generally don't have spontaneous joint bleeds. Some of them do, but the majority don't.

And so if you basically give somebody factor VIII on a regular basis and keep their levels above 1%, you've effectively made them a moderate severity patient, and you hope that that will make their bleeding risk less. So you're trying to prevent these life-threatening bleeds. And for children, you're trying to let them participate in reasonable activities. They want to be able to go with their friends to birthday parties, and it's important that if they're on a prophylactic regimen, the last thing you want is them to get hurt at a party and miss out on what their friends are doing.

Luigi Brunetti, PharmD, MPH: Sure.

Robert F. Sidonio, Jr, MD: You're really trying to allow them to participate in school and daycare and reasonable activities. And it can be a burdensome regimen, but if it's implemented early and the family accepts it, they can have a relatively normal life. It's obviously not normal with infusions.

Luigi Brunetti, PharmD, MPH: Sure. So it sounds like, generally speaking, targeting greater than 1% factor VIII is what you want.

Robert F. Sidonio, Jr, MD: Yes, that’s what we target. And as therapy gets better and better, we know that we’ve been targeting more of our moderate severity patients, those with 1% to 2% factor VIII, particularly those who seem to have joint bleeds. They don’t need as aggressive a prophylactic regimen. But if you look at some of the progressive centers, like in Colorado, they have a significant portion of their moderate patients on prophylaxis as well. And so we continue to see that shift and we keep moving that factor VIII level up. Before it was 1%, and many places are trying to push it into 2%, 3%, 4%, or 5% factor VIII, and that just is advancing care and us learning that there’s probably some benefit of doing that.

Luigi Brunetti, PharmD, MPH: Sure. And Dr Slocum, or either of you feel free to jump in, we had mentioned that some patients may actually require antiplatelets or aspirin, that sort of medication. In those patients, do we still target 1% factor VIII, or would it be reasonable perhaps to consider a higher activity level?

Robert F. Sidonio, Jr, MD: That one is always challenging. There aren’t any formalized studies looking at that. But the general thoughts are, if you’re going to start somebody on something like an antiplatelet agent, they likely need to be on some prophylactic regimen. I don’t think anybody knows exactly how aggressive it should be. People just hope that those patients will at least be on it on a regular basis to limit their bleeding. I think it’s going to be inevitable, but some of them will have some gastrointestinal [GI] bleeding events because that just cannot be prevented because it’s a different mechanism, of course.

But certainly, they have to be on some prophylactic regimen. And you would hope, at least with standard half-life products, they’d be on it at least 2 to 3 times a week to prevent any bleeding. Some people will take the strategy of, “Well, if I have bleeding events, I’ll just escalate it.” Ideally, you’d want to not have those bleeding events. Try to prevent it if you can because those GI bleeding events can be quite dramatic in those patients.

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