Advances and MASAC Guideline Recommendations for the Treatment of Hemophilia - Episode 5
Peter L. Salgo, MD: Are there any specific precautions you take with any of the medications that we have discussed so far?
Christopher E. Walsh, MD, PhD: Not in the way you’re thinking, but patients need these drugs. There was a study performed in Canada trying to avoid the use of factor by giving another drug called factor VIIa. They used that for a year or 2, then gave patients factor. They still developed a high rate of inhibitors.
Peter L. Salgo, MD: When you’re looking at how to treat a patient, what are the patient factors you consider? We’ve looked at the pharmacologic factors, but what are the patient factors that affect your choice of agents?
Robert F. Sidonio Jr, MD, MSc: Nowadays, we have many more choices. There was a nice randomized study called the SIPPET trial. For many decades, since we have shifted to the plasma-derived products and the recombinant products, people have felt that there is a higher risk for inhibitors. The best way to get at something like that is through a randomized control study. That’s very difficult in hemophilia.
It was an international study, and it clearly showed that plasma-derived products have a lower incidence of inhibitors. There’s were a lot of issues because there’s some difference in ethnicities. There are some risk scores for choosing products, but generally when we have a new baby—we just had one this week—we discuss the options as being plasma-derived products, which could have lower inhibitor incidence; recombinant products, which are our standard of care now; and then another product, emicizumab, which is a subcutaneous drug that just got approved.
Peter L. Salgo, MD: What is an inhibitor, and just in 1 sentence or 2, how does it affect treatment options?
Robert F. Sidonio Jr, MD, MSc: We talked about how a third of patients will develop a neutralizing antibody to factor VIII, and it’s typically an IgG [immunoglobulin G] molecule that’s directed specifically at factor VIII and basically renders it completely useless. It clears it from the system, so it’s like you never gave factor VIII to that child. All of a sudden, something that was very efficacious and prevented bleeding becomes totally useless. Unfortunately, we have to use alternative therapies that don’t work as well and are bypassing agents.
Peter L. Salgo, MD: Such as?
Robert F. Sidonio Jr, MD, MSc: aPCCs [activated prothrombin complex concentrates] are an example of one that has been around for a while. They basically try to go around factor VIII and do as good of a job, but they’re not as effective. And then, there’s recombinant factor VII. That can be used as well. But they have shorter half-lives and are not as effective at treating bleeds.
Peter L. Salgo, MD: Are there patient factors that cause you to use or avoid the aPCCs?
Robert F. Sidonio Jr, MD, MSc: There aren’t specific factors that make us avoid using them, and there have been a few trials to show that. We typically perform trials of both, and for some reason, some families respond better to one versus the other. This has been seen in a couple clinical trials, where up to 20% of patients don’t respond very well to one versus the other. Unfortunately, there’s a little bit of trial and error that we have to go with, which we don’t like to have to do.
Peter L. Salgo, MD: How long have the aPCCs been available?
Robert F. Sidonio Jr, MD, MSc: They’ve been around for decades, and they had some other original uses.
Peter L. Salgo, MD: What was that? I’m curious.
Robert F. Sidonio Jr, MD, MSc: People were using it for treatment of bleeding events when they didn’t know what was going on. You would get a call from a surgeon and they said, “I can’t get him to stop bleeding. I don’t know why he’s bleeding.” It was basically, “Here’s a bunch of different clotting factors. One of them is probably going to fix the problem.” It’s still used off-label for surgical bleeding, but it has an FDA approval and its indication is for inhibitors, specifically high titer inhibitors.
Peter L. Salgo, MD: In your personal experience with aPCCs, what do you think about them? Do they work?
Robert F. Sidonio Jr, MD, MSc: Up until recently, when we developed newer products, it has worked. It has been our only option. We have limited agents in our arsenal to treat inhibitors and when we’re treating the inhibitors, it’s good to put patients on a prophylactic regimen, either the aPCCs or recombinant factor VII. But there are a lot of issues with the volume of aPCCs that can be quite tremendous. If I had to give you a treatment, it could be 100-something mLs of an infusion. Can you imagine starting an IV [intravenous therapy] and infusing 100 mLs? That’s going to take 20 or 30 minutes. If you do that every other day for maybe 3 or 4 years, you can see the issues.
Peter L. Salgo, MD: Let me bring you back to factor VII. We see a lot of bleeding in different settings, such as post—open heart surgery. When I hear somebody received factor VII, I say, “Katy, bar the door; fasten your seatbelts.” It’s a dangerous drug.
Robert F. Sidonio Jr, MD, MSc: Yes.
Peter L. Salgo, MD: And it can result not in bleeding, but hyper-clotting.
Robert F. Sidonio Jr, MD, MSc: Yes, exactly.
Peter L. Salgo, MD: We see strokes with that.
Robert F. Sidonio Jr, MD, MSc: Sure, sure.
Peter L. Salgo, MD: Do you see that in the hemophilia cases?
Robert F. Sidonio Jr, MD, MSc: We don’t typically see that in hemophiliacs because for the patients who you’re referring to where you are using it as an off-label agent—somebody who’s bleeding to death, and we feel like we have to do something—you might be able to stop the bleeding, but you might overcorrect.
Peter L. Salgo, MD: Sure.
Robert F. Sidonio Jr, MD, MSc: Remember, those are normal patients who you’re giving a highly efficacious clotting factor to. We’re talking about a population that bleeds a lot. The risk is much lower. When you look at the risk of clots, it’s really pretty low.
Peter L. Salgo, MD: There’s the anti-inhibitor coagulant complex, or aPCC.
Christopher E. Walsh, MD, PhD: Right.
Peter L. Salgo, MD: That’s something you can use in the treatment of hemophilia. We’ve got the inhibitors, but now we’re going to these anti-inhibitor coagulant complexes. What are they?
Christopher E. Walsh, MD, PhD: If you think of the clotting cascade as dominos, once you start the dominos down a hill they spread and basically cause clotting at the end. Along this path of different factors that have to be turned on, you can bypass this—interdict this pathway—and that’s what aPCC is. It’s a combination of activated factors that are vestal and pass the blocks. If you’re missing factor VIII or IX, you can add factors that jump over that step and move down the path.
Peter L. Salgo, MD: But if you do that, you still have all these factors that have to be triggered. If you’re bypassing this and you take those early dominos out, what triggers the clotting?
Christopher E. Walsh, MD, PhD: These aPCCs are actually activating prothrombic concentration.
Peter L. Salgo, MD: Right.
Christopher E. Walsh, MD, PhD: All these factors—factor VIII, IX, all of them—are in an inactive form that has to be cleaved in your body to be activated, enzymatically turned on. There’s a percentage of activated factor in these compounds. That means that they’re ready to go. A small amount is there to basically turn on the cascade.
Peter L. Salgo, MD: A trigger.
Christopher E. Walsh, MD, PhD: Plus, you’re adding more. You’re adding pharmacologic levels of these other bypassing agents.
Peter L. Salgo, MD: The key thing here, if I understand you correctly, is that this is a treatment paradigm, not a prophylaxis paradigm. Is that fair?
Christopher E. Walsh, MD, PhD: No, it’s both. You use it as a treatment and you use it prophylactically. Patients who you can’t tolerize to factor VIII or IX are chronically on these drugs to bypass and allow clotting to occur.
Peter L. Salgo, MD: How do you use this in a treatment paradigm?
Christopher E. Walsh, MD, PhD: In patients who have inhibitors, there’s a 2-track system. These patients have a higher mortality rate than non-inhibitor patients. They have the worst kind of bleeding. We talked about intracranial hemorrhage. They have that, and they have GI [gastrointestinal] bleeding. They bleed everywhere: the genital urinary tract, around their spinal cord, or anywhere defined as a really terrible bleed. That’s where they can have it. That’s why I view these patients as distinct.
The 2 tracks include putting them on bypassing agents. We talked about aPCCs. There’s another drug, NovoSeven or activated factor VIIa, that does the same thing and jumps around the block and allows clotting to occur. At the same time, you try to get rid of these inhibitors. How’s that done? Basically, if you have a peanut allergy or poison ivy, you go to the allergist. They try to desensitize you with tinctures of those proteins or of the antigen and then increase it to where you’re not sensitive to it anymore. That’s what’s done in these patients. They get daily doses of these factors in the attempt to tell the immune system not to make any more antibodies.
Transcript edited for clarity.