Treatment Options, Adverse Effects in Treating Hemophilia

Peter L. Salgo, MD: I want to run down some of the current treatment landscape that we have. We’ve got concentrated factor VIII, factor IX, plotting factor, and human versus recombinant. We have prothrombin complex. We’ve got cryoprecipitate, fresh frozen—you alluded to that—desmopressin, aminocaproic acid, tranexamic acid, and fibrin sealant. I know before we went on the air you were talking specifically about fibrin sealant, something I never knew about. What’s going on?

Christopher E. Walsh, MD, PhD: Many years ago, surgeons, such as yourself, would use it like water in the OR [operating room]. This contained factors derived from cows—bovine factors, factor V particularly—where patients who did not have hemophilia or any such problem would make antibodies to that, and this would cause all sorts of concerns later on when you wanted to use it.

Peter L. Salgo, MD: It’s funny, I used to watch the surgeons squirting this stuff on coronary arteries. We thought it was a gift.

Christopher E. Walsh, MD, PhD: It works great. But since that time, that problem has been eliminated by using purified humic acid.

Peter L. Salgo, MD: What about storage preparation for all of these things?

Christopher E. Walsh, MD, PhD: These are all proteins that can be stored. Now, all the companies can store these for months at a time. There are even certain companies that will advertise that you can leave them in the back of a car at 88 degrees for X number of hours and it’s still stable. They’ve gone to great lengths to stabilize these proteins and to reconstitute them so the volume that you infuse is basically down to just a few CCs [cubic centimeters], when many years ago—we were talking about it earlier—it would take half an hour or an hour to infuse.

Peter L. Salgo, MD: How many CCs would that be?

Christopher E. Walsh, MD, PhD: Depending on your weight because these are weight-based, it would be anywhere from 30, 60, or sometimes even more CCs.

Peter L. Salgo, MD: In the old days.

Christopher E. Walsh, MD, PhD: In the old days.

Peter L. Salgo, MD: Now, it’s just a few CCs.

Christopher E. Walsh, MD, PhD: And now, it’s a few CCs.

Peter L. Salgo, MD: Can you give them push IV [intravenous therapy]?

Christopher E. Walsh, MD, PhD: It’s a push. It’s a slow push.

Peter L. Salgo, MD: There are different formulations out there, right, with different half-lives. What are the risks or the benefits here of these different formulations? What are they, by the way?

Robert F. Sidonio Jr, MD, MSc: First they started off with plasma drive concentrates, and those are factors derived from human plasma. And then, because of the HIV and hepatitis complications, they shifted it to recombinant in the late 1980s and early 1990s.

Peter L. Salgo, MD: About time.

Robert F. Sidonio Jr, MD, MSc: But since then, we’ve actually been able to eliminate that issue from plasma-derived products. I don’t want to state that they’re not safe now; they are safe. But we have those recombinant products. The limitation has always been the half-life. For most factor VIII concentrates, the half-life is somewhere between 8 and 12 hours. You can tell that if you infuse somebody at 100%, within 8 to 12 hours, they’re already down to 50%. By the next morning, they’re down to 25%. You can see the limitations. That has been the practice for a while. About 5 to 10 years ago, the companies started making what we call extended half-life products.

Peter L. Salgo, MD: Right.

Robert F. Sidonio Jr, MD, MSc: For factor IX, they’ve had significant improvement. They’ve been able to increase the half-life 4- to 5-fold, which is a significant increase, so patients could infuse once a week versus 2 to 3 times a week, which is a significant improvement.

Peter L. Salgo, MD: It’s huge, actually.

Robert F. Sidonio Jr, MD, MSc: For kids that’s great, and even for adults as well. But on the factor VIII side, they really haven’t been able to get past that. Typically, it’s 3 times a week or every other day for standard half-life. For extended half-life, they’ve been able to get to twice a week, which is a slight improvement but obviously there’s a limitation. They’ve hit a ceiling in how well they’ve been able to make it.

Peter L. Salgo, MD: Are there adverse effects to clotting factor treatments, other than just getting a needle and doing it several times?

Robert F. Sidonio Jr, MD, MSc: Sure. There’s always the chance of hypersensitivity reactions, those are relatively rare in general; and obviously, you have to dose it correctly or you risk things like blood clots. But the biggest risk factor, and the thing that has been a huge problem—still the hugest problem in hemophilia now—is the development of neutralizing antibodies against that exogenous factor or the infused factor.

Peter L. Salgo, MD: The body says, “Wait a minute. I haven’t seen factor VIII,” or whatever factor it is.

Robert F. Sidonio Jr, MD, MSc: Exactly.

Peter L. Salgo, MD: “This is new to me; I’m going to develop an antibody—good luck with that.”

Robert F. Sidonio Jr, MD, MSc: Exactly. If your body doesn’t make something, it’s trained that way. If you don’t make something because you’ve deleted it and you infuse a large amount of this foreign protein, your body sometimes can react and say, “Oh, this doesn’t belong, I’m going to get rid of it.” Just like it would a virus or a bacterium.

Peter L. Salgo, MD: So, you’re making antibodies.

Robert F. Sidonio Jr, MD, MSc: Yes.

Peter L. Salgo, MD: Not only does the stuff not work with those antibodies, the half-life doesn’t change.

Robert F. Sidonio Jr, MD, MSc: Yes. Actually, these are IgG [immunoglobulin G] antibodies. A third of patients with hemophilia A will develop these. Unfortunately, they develop these in the first 10 to 20 exposures. You’re talking about developing it typically in the first 3 years of life and then, some of the antibodies become so strong such that as soon as you infuse it, within 15 minutes, it’s all gone.

Peter L. Salgo, MD: In other words, in the treatment landscape, you’re giving factor VIII to all-comers with hemophilia.

Robert F. Sidonio Jr, MD, MSc: Yes.

Peter L. Salgo, MD: How many of them will get antibodies?

Robert F. Sidonio Jr, MD, MSc: In the severe patients, a third will develop them.

Peter L. Salgo, MD: And two-thirds won’t.

Robert F. Sidonio Jr, MD, MSc: Yes, and two-thirds won’t. About 60% of that one-third will develop high titer inhibitors that are very difficult to clear. About 40% of them, for the most part, we can clear with aggressive therapy. It’s much less common on the hemophilia B side. It’s somewhere in the single digits. But that has its own challenges because they can develop anaphylaxis or nephrotic syndrome, and all kinds of horrible things can happen. We have almost no data.

Peter L. Salgo, MD: I hate that, by the way.

Robert F. Sidonio Jr, MD, MSc: It’s awful, and those are incredibly difficult to treat. We have one patient now. It’s difficult.

Peter L. Salgo, MD: You can give this drug, and the kid falls apart right in front of you.

Robert F. Sidonio Jr, MD, MSc: Yes. And typically, what happens is the mom will say, “He’s not responding; he’s bleeding a lot; he’s oozing a lot.” We come in and we test them, they have an inhibitor, and everything changes. They thought severe hemophilia was bad, and now they’re at a whole other level of badness.

Christopher E. Walsh, MD, PhD: What is known about inhibitors is that the more severe disease you have, genetically, you have a worse kind of mutation where there’s no protein. There’s family history as well. Black patients have a higher inhibitor rate than Asian, white, or Hispanic patients. The field of inhibitors is fraught with the fact that we really don’t understand exactly what’s going on other than that when you introduce this protein, especially to children, for the first 50 infusions you’re at the highest risk for an inhibitor—really the first 20. If you get past that, the odds of you developing inhibitor drop, but never go away. I have patients who are in their 60s who never had an inhibitor and were taking infusions and developed one.

Peter L. Salgo, MD: What are things you do to avoid complications, other than inhibitors? We’ll get to inhibitors, but are there any other complications?

Christopher E. Walsh, MD, PhD: Apart from the bleeding complications, not so much.

Transcript edited for clarity.