What Are The Screening Standards, Rates of Severity in Hemophilia?

NOVEMBER 26, 2018
MD Magazine Staff

Peter L. Salgo, MD: You want to make this diagnosis. How early do you start testing? You don’t test everybody for hemophilia. Or do you?

Christopher E. Walsh, MD, PhD: If there’s a family history, the pediatricians feel we could test the core blood, and they can measure factor levels, which are all low in the core blood. But if it’s particularly low you’ll know that, especially if there’s a severe phenotype in the family. Less than 1% is by definition severe, so that can be tested for. And then the child is followed.

Peter L. Salgo, MD: But I guess what I was getting at is, do you need to test every live birth?

Christopher E. Walsh, MD, PhD: No.

Peter L. Salgo, MD: You test at birth for families with a history.

Christopher E. Walsh, MD, PhD: Right.

Peter L. Salgo, MD: Then later, you look for symptoms and test on symptoms, is that it?

Christopher E. Walsh, MD, PhD: Pretty much, yes. As you probably know, there’s newborn screening for every child that’s born in the United States. Hemophilia is not part of that screening.

Peter L. Salgo, MD: Should it be?

Christopher E. Walsh, MD, PhD: Probably not. Statistically, it probably doesn’t need to be. It would be nice, but from a cost-effectiveness standpoint, it’s probably not necessary.

Peter L. Salgo, MD: What are you doing about lab tests, CRP [C-reactive protein]? Your practice is primarily clotting disorders.

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

Peter L. Salgo, MD: But what about physicians in general? There’s this spontaneous mutation link, and then there’s all this family history. Who gets tested? When? Why? And by the way, with what test?

Robert F. Sidonio Jr., MD, MSc: Ideally, if there’s a family history, it goes back to simple medicine. Get a good history, right? We can have all the fancy tests that we want, but it takes a good physician to get that good history. Is there a family history of hemophilia or bleeding disorder? Oftentimes, we have to use colloquial terms. In the South they say “free bleeders” a lot. They still utilize those terminologies, and sometimes people don’t realize that. We had an example of a kid who bled during tonsillectomy. He came back for his third attempt before somebody finally asked and he said, “Oh yeah, my cousin has hemophilia, do you think that’s related?” And they said, “Yes, probably.”

Peter L. Salgo, MD: Take me back here. A baby is born. Should every live birth be accompanied by some clotting study?

Robert F. Sidonio Jr., MD, MSc: The disorder, even though we talk about it, is still relatively rare. We’re listed in the rare bleeding disorders group. When you think about it, it’s 1 in 5000 males. It’s relatively rare. That’s hemophilia A, and hemophilia B is 1 in 25,000 males. Other disorders like von Willebrand disease are closer to 1 in 1000, and that’s the most common. We still need to use personal bleeding history, family history, to guide it. If there’s a family history, then you could do screening tests.

We talk about PT [prothrombin time] and PTT [partial thromboplastin time] at first, specifically for factor VIII and IX deficiency, so hemophilia A and B. The PTT is still a good screening test, and it’s available at pretty much every hospital. What’s not available is what we call 1-stage factor assay. That’s when somebody says, “Give me a factor VIII level or a factor IX level.” What they’re talking about is factor VIII or IX activity. That isn’t available at most small hospitals, rural hospitals; they’re send-out tests. That’s where they have to rely on the local expertise. They call us up. I get phone calls from rural Georgia and other areas, just like you would get phone calls from the area as well. That’s where you help guide them, if they have a prolonged PTT. Typically, in a hemophiliac, that PTT could be as long as 90 to 100 seconds.

Peter L. Salgo, MD: That’s infinite.

Robert F. Sidonio Jr., MD, MSc: Yes, very, very prolonged. But you have to remember, in the mild hemophiliac, it may not detect that because of the limitations of the PTT. If the factor level is 30%, that may not be picked up on the PTT. That’s when if you have a suspicion, just go ahead and send the factor VIII and IX levels.

Peter L. Salgo, MD: Let’s run through a few basic things.

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

Peter L. Salgo, MD: What’s the associated risk? What are the complications of this disease? It’s historically pretty clear, but let’s spell them out.

Robert F. Sidonio Jr., MD, MSc: When you look back even to the 1960s, the average life expectancy was no more than 15 to 20 years. Patients would die of a devastating bleed. They would fall, have an intraabdominal hemorrhage. We wouldn’t be able to control it, and they would pass away from that. Or, they would hit their head doing something minor and develop an intracranial hemorrhage and die. That was a common way that people died. And then, of course, we developed factor concentrates through the 1970s and 1980s, all the breakthroughs. The mortality rates went down. And then, of course, in the 1980s there was the devastating discovery of HIV and hepatitis. Up to 80% to 90% of those patients were affected. Of course, we lost a whole generation of hemophiliacs.

Peter L. Salgo, MD: I remember that, it was devastating.

Robert F. Sidonio Jr., MD, MSc: There are some good documentaries that are required watching for anybody who goes into our field. Nowadays, the mortality rate is still higher. But if you look at some of the studies in England, people are living almost as long if they don’t have some of the complications like inhibitors. Those patients almost live as long as patients without hemophilia.

Peter L. Salgo, MD: Does everybody get the full-blown disease? Does it come in—I’ll use a word that may not be genetically correct—variable penetrance? I’m not sure that’s the word I’m looking for.

Christopher E. Walsh, MD, PhD: Penetrance isn’t quite right, but what you’re getting at...

Peter L. Salgo, MD: Variable severity.

Christopher E. Walsh, MD, PhD: The disease, depending on the mutation and probably other factors we haven’t really identified, still roughly correlates to the amount of protein in the blood. Less than 1% is severe, while 1% to 5% is moderate, and this means spontaneous bleeding anywhere, but typically joints and soft tissue muscles, that sort of thing.

Peter L. Salgo, MD: The abnormal gene can make some clotting factor, a little clotting factor, or almost no clotting factor.

Christopher E. Walsh, MD, PhD: There you go.

Peter L. Salgo, MD: Depending on how much it makes, that’s what makes the disease more or less severe.

Christopher E. Walsh, MD, PhD: That is correct.

Peter L. Salgo, MD: How does this break down? Of those all-comers, 25,000 or so with hemophilia, how many—what percent—are the real severe patients?

Christopher E. Walsh, MD, PhD: In my own practice, I view severe and moderate as the same while many of my colleagues will split those out, but that’s roughly 70% or 80%. The most severe patients are the bulk of patients. The mild patients, the ones who you’re alluding to—the ones who are picked up later on in life from an injury or when they’re tested—those mild patients are the minority of patients, usually 20% to 30%.

Peter L. Salgo, MD: We’re looking at the quality of life. Untreated versus treated, there’s a difference. Talk to me about both. What is the untreated quality of life, the impact?

Christopher E. Walsh, MD, PhD: The untreated, we see in the third world where they don’t have access to factor. Their mortality rate is significant, from intracranial hemorrhage and from bleeds pretty much anywhere. If they have just joint bleeds, they are all significantly disabled from the arthropathies that occur from that. In the first world, here in the United States, we see some of that depending on how bad the bleeding is and how aggressive the treatment is, but nothing like what’s seen in the third world. Mortality in this group of patients is now no different than any other patient, except if patients have contracted hepatitis C and HIV.

Peter L. Salgo, MD: In terms of the quality of life, right now with what we’ve got, how does this disease impact patients?

Robert F. Sidonio Jr., MD, MSc: It’s definitely impactful. We always joke that when we tell the moms that their child has hemophilia, that’s when she starts getting upset; and then we tell the dads they can’t play contact sports like football, and that’s when the dads start crying. We see that a lot in our states. If you look at the surveys, it’s a lot of missing out on things that they feel are part of a normal childhood. Even being able to do contact sports, just telling children you can’t do that, that’s a big deal. We do allow them to participate in other sports like soccer and basketball and baseball, with some restrictions, of course.

Peter L. Salgo, MD: Soccer worries me.

Robert F. Sidonio Jr., MD, MSc: We don’t allow them to head the ball, and we don’t want them to be goalie. You start to box them in a little bit. When they become more competitive in teenage years, it becomes very dangerous. Those limitations are hard. For those kids, they have recurrent joint bleeds that they have to worry about. They have to travel with their factor products. This idea of being different than other children, obviously it affects them.

Transcript edited for clarity.

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