Speaker: Denise M. Adams
you you you you you you you you you you you you you you you you you you you you you you you you you you you you you you you you you you and subsequently her MD degree. She then did a year in obstetrics before completing residency in pediatrics of the University of Vermont. She went on to Duke University where she would remain for seven years versus a clinical fellow in hematology oncology and subsequently on staff as an assistant professor. It was a duke that her interest in vascular anomalies really blossomed while still a fellow. She organized the first vascular anomalies clinic at that institution and began what would be a career along interests in the treatments of this group of rare and vexing disorders. She subsequently moved to Cincinnati where she was the medical director of their now internationally known vascular anomalies center growing their database from 500 to well over 5,000 patients. It's safe to say that she transformed the care of the vascular anomalies patient while they are across multiple dimensions from recruiting and building multi-disciplinary teams, creating support networks for patients and families as well as piloting the first prospective trials on the safety and efficacy of surreliness for the treatment of these disorders. These studies are both ongoing through our own funding from the FDA. While there she also developed an outstanding teaching and mentoring portfolio, mentoring dozens of clinical fellows as the supervisor of the hematology oncology fellowship. As a credits of her years of mentoring of fellows, residents and medical students, she was awarded the inaugural George Buchanan Lectureship at the American Society of Pediatric Hematology and Oncology, the same year that she was recruited to our institution. Here she has been, as you can see, the co-director of the vascular anomalies center with an endowed share in vascular anomalies. Her many leadership roles include two decades of leadership as the medical director of the National Organization of Vascular anomalies, chairperson of the program, committee of the American Society, the pediatric hematology oncology, and service on the National Advisory Board for the National Cancer Institute. Please join me in welcoming Dr. Adam Sipodia. Thank you very much. That was a very gracious introduction. So I'm happy to be here again to do a second lecture on vascular anomalies. And I thought that this lecture would be really case-based. So the first lecture was more about our program and what everyone in our program is doing. And this one is really going to be talking about cases that affect you as surgeons. And I wasn't sure whether the anesthesiologists would be here or not, but they have been very important sort of in this role as well. So I have no conflicts. I will be discussing off-label medications and I do not take full responsibility for the complete content of this lecture. So we are going to talk a little bit. I'm going to remind you about a service that we have the vascular anomaly consultation service. We're going to again give you an update on the classification system, just as a reminder of the disorders and the complicated disorders that we take care of. And then we're going to talk about actual vascular anomaly cases. So it is not a dark time for VAC, but one of enlightenment, new invigorating personnel have been hired. Old processes have been abandoned and new ones initiated. Clinical research has been expanded with new drug trials, outcome studies, drug delivery investigation and natural history studies. Excitement reigns throughout the old garden new. You have heard some of these exciting developments and it is time for you to prepare to take care of these patients. And so we are going to examine some cases. Before we do this though, I wanted to remind you about the beginning of VAC. And so the beginning of VAC started with an unbelievable mentor, John Mulligan, who was measuring these wonderful neophytes who started this world recognized vascular anomaly center. We then had the addition of people over the past several years to really expand on this center. I lean you're looking really good in this picture. I don't think I ever looked like this even as a younger person. But we have not only our old guard, but we also have our new guard in a lot of the different specialties to really improve our vascular anomaly center. I just wanted to remind you all before we get started that we do have a vascular anomaly consult service. This was started a couple years ago when I got here, actually even before I got here. And we have a pager, which is 8222 that the nurse practitioners and I run. It really is sort of a weekly pager. There's no one that's necessarily on that over the weekend, but there are those of us that are available for any questions. So we have truly tried to make VAC the home for our vascular anomaly patients. So if you have anyone that is admitted, make sure you give us a call. We're trying to round and see patients who are in the hospital for more than 24 and 48 hours. So it's sort of important to know. And all of the general admissions and the admissions from IR are now going to the hematology service just so we have a consistent place for them to be and they know their issues. So we're going to start a little bit and I know you all have heard about this, but we're going to start with the reminder of the classification system. And John Mulliken taught me a very important thing and that was in the beginning of wisdom is to call things by their right name. And I think that's been so important for vascular anomalies because when I started this, everything was called to hemangioma. And now we know that everything is not a hemangioma. And it was John Mulliken way back when in the 1980s that actually started this very simple classification system where he took vascular anomalies and he divided them into tumors and malformations. Tumors are things that are growing and malformations are things that supposedly are not growing and are not and do not have any proliferative elements to them. And they are broken down into either low-flow lesion like venous malformations or high-flow lesions. This classification system was then updated and it was really the vascular tumor subtypes were really expanded and then they expanded the malformations to be either simple malformations or complex malformations. And this all was done through a wonderful society called the International Society for the Study of Vascular Anomalies. And this is really a wonderful organization that actually Steve was the president of that is truly interdisciplinary. So there are surgeons, there are radiologists, there are now medical people at our last meeting there was over 50 human people. So it's very exciting that this is expanding and it's expanding more towards clinical research and basic science. And then in 2014, this classification system was updated further by a scientific committee that a model Amari and I were part of. It took over a year for this committee to come up with this renewed classification system where we talked about new diagnoses and atomic variants and where we finally started linking the phenotype to the genotype. And this simple or this is no longer a simple classification system, this is pages of classification. And if you're interested in this, you can go to the ISSA site and find this. This was also reported in pediatrics and this classification system will be updated every two years. So now we're going to talk about some vascular anomaly consults because I think it's really important. I'm sort of honing this lecture in on those vascular anomalies that have issues with coagulation. So again, the first talk that I did last year was more about our center and what our center is doing. And this is truly going to be talking about cases that really might affect you all and how we can work together as a team to improve those patients' outcomes. So this is a case that's recent to us and this is a newborn infant who was noted to have a vascular birthmark at birth. So day of life one, this patient was evaluated by the intake pediatrician and the lesion was felt to be pedunculated so it was sort of sticking out of it. It was slightly warm but not extremely warm and there were some areas that were firm but other areas that were not firm. Their metology did go by to see the patient and they had a diagnosis and then labs were done prior to a circumcision and on the lab evaluation the platelets were noted to be 21,000 and the fibrinogen was noted to be 72. So what do you all think about what are some possibilities for this patient and the differential diagnosis and I know you're only seeing a picture but a lot of times sometimes that's all we have is just a picture when we're helping people try to diagnose things. Anybody? Okay, and to some people know what it is. Should I pick on somebody? I don't really wanna do that. Anyway, so what our diagnosis was when we or our differential diagnosis when we actually saw this patient was could this be a congenital hemingioma? So congenital hemingiomas are not infantile hemingiomas. They are hemingiomas that are fully formed at birth so probably started in utero. Our second and you can actually have a transient coagulopathy and we'll talk about this a little bit later. Our second differential diagnosis was could this be a little bit of an unusual composer from hemingioma and a phylioma so in the World Health Organization and that is noted as a low grade or an intermediate grade tumor? Could it be an other vascular tumor like something in the olden days that we used to call a hemingioparycytoma because those also can look somewhat pedunculated and also can trap platelets and also trap cybrinogen or could it be a more serious type of a tumor like an angiosarcoma or even a fibrosarcoma that truly isn't a vascular tumor but sometimes when those tumors are large enough or there's multiple lesions as you can see with angiosarcoma you can actually have the trapping of platelets and also have trapping of fibroinergid. So let's go over that differential diagnosis. So congenital hemingiomas can be divided and I didn't make up these names. These names were formed by looking and looking at the clinical core cities but there's three types of congenital hemingiomas. Again, remember these are not infantile hemingiomas and infantile hemingiomas are usually not present at birth and then they grow and then they stay the same and then they go away. And true infantile hemingiomas are positive for a stain that's called glute one. These are negative for glute one. These are perfectly formed at birth and they either go away and so when they go away we call them a reach or a rapidly invaluting congenital hemingioma except they don't rapidly go away. You know, you think rapid and you think a couple of days, a couple of weeks but actually takes about 14 months for that rapidly invaluting hemingioma to go away but at least you can see a change in it as you follow a patient week by week. Then there's a niche which is a non-involuting congenital hemingioma and then you have these things or a, yeah, and then you have a peach which is a partially invaluting congenital hemingioma which is sort of an in between. So a lot of times when you see these weasions they can be pedunculated, they're there at birth sometimes you can see what we call a halo around the outside of them. Sometimes they can be, they're usually fast flow and so sometimes they can be warm. And sometimes when a child is born you can actually see that the evolution has already started. So in this patient if you were to lift up this lesion you would see a halo around it so an area that's sort of whitish and then in the middle here it almost seems like this lesion is starting to invalute. But we do know that they have some somatic mutations in geneX and they can have a transient coagulopathy. So when we see them on the skin sometimes they can have for a day or two a lower platelet count but the platelet count is usually 60,70,80,000 and sometimes they can have a transient hypofibrinogenemia but not necessarily like the patient that we just reported. When these are seen in the liver because these are noted as single liver lesions and we talked about this the last time I gave this talk. They actually can have a transient coagulopathy that lasts a little bit longer but again usually the platelet count is not lower than about 60,000. So this is a picture of someone that has a rapidly invaluting congenital hemangioma and you can see what it looked like at birth and you see this later area sort of around it. This is what I was talking about the halo. You see this is not you know that our other little patient had a more perporic looking lesion but really it could have been a congenital hemangioma. I'm giving it away because it wasn't a congenital hemangioma but this is sort of what happens when you follow a congenital hemangioma you see that over time it does invalute. And what you're left with, which is what you're left with with a lot of even infantile hemangiomas is sometimes residual skin and some dilated vessels. This is a picture of a patient that had a single liver lesion and so this was the picture at birth. We obviously had an MRI out also to prove that this was a rapidly invaluting congenital hemangioma and you see what happens just with a KUB at eight weeks of life. So now let's talk about sort of another thing that's on that differential diagnosis. So rare vascular tumors was something that was up there. And remember we really classified KHE or Caposa from the manju and dyslioma as a rare vascular tumor. So these tumors are complicated because their classification and the WHO classification of them have really been the same as adults. And I truly believe that vascular tumors even angiosarcomas in kids are different than they are in adults. So let's talk about KHE lesions. So how many of you just for me to know have ever sort of taken care of a patient that has a KHE lesion? Okay, so sometimes they can be very, very significant and sometimes they are not as significant and we're trying to truly develop a risk stratification for them. We know that sometimes they are associated with a coagulopathy called Casabock Merit Phenomenon. This originally was reported in the 1940s by a radiologist and also a pediatrician who thought that they had a patient with an infantile humanjoma that had profound from the cytopenia and hope hypofrybrinogenemia. And so in the olden days KHE lesions were truly thought to be infantile humanjomas with Casabock Merit. So if you look at the literature, the literature is really muddy because all the old literature, a lot of times talks about humanjomas with a coagulopathy and also the literature talks about vascular malformations also calling them Hemanjomas with the coagulopathy and we'll talk about that a little bit more. So it's not until recently that this coagulopathy and this tumor versus malformation and what's Casabock Merit and what's not has really been identified. But these are two pictures of two very significant composer form Hemanjoo and the Theliumas. Usually they're present at birth but they also can appear postnatally so they can appear sort of when someone is a toddler. They also have been reported in adults. They affect sexes equally. So remember, Hemanjomas are more common in females than males for my other lecture. Hemanjomas or infantile Hemanjomas are more common in the head and neck area. These actually are usually unifocal but they can be on the extremities. They can be on the trunk even though you see a picture of one in the head and neck. They're not as common in the head and neck area. And they actually can grow by insult trading through tissue and crossing tissue planes. Usually the skin is very tense and there's a red deep perporic area. Certainly when they have Casabock Merit and they have thrombocytopenia, it becomes more perporic and you can have extension of this lesion up into other areas. And again, associated with Casabock Merit phenomenon. The radiologic picture of them, again, they can start, this is actually a picture of a patient and I think we presented her in my first lecture where we had a patient who was two months of age and had a small bruise on her leg and then had immunizations into that extremity and after the immunizations, it caused trauma and so the small bruise became what looked like that previous picture. So the leg became totally dark, perporic, indirated and the lesions started going up into the abdomen, around into the GU area and around into the back. So you see how it infiltrates and crosses tissue planes and it can almost look like a demon on the outside. This is a more typical look as we saw in the previous slide but you actually can see lesions in the retroparitinium and we have had some lesions that look pedunculated that have been diagnosed as other things but then after surgical excision, were KH lesions and that's a picture of a pedunculated lesion on the top. When we look at the pathology, there's two things that are involved in the pathology. There really are endothelial cells which are more spindly and they're usually in lobules and so you can sort of see the spindle cells here. You see that there's entrapment of fibrinogen and red blood cells and you can also see entrapment of platelets. One of the most important things about these tumors that have been found is that they also have a lymphatic component. So these endothelial cells are positive for prox1 which is a lymphatic stain and we truly know that what's happening with these lesions are platelets and fibrinogen are being trapped in this lesion. Those products are not being consumed. It's not a consumption of the coagulation factor. It's really more of an entrapment and I think that's because of the lymphatic component but we don't truly know. There are many things about this tumor that we do not know and need to be further investigated. And so because of that, as you all heard from the first lecture that I gave, you know when we talk about treatment for these things, treatment is anything that's been used to treat anything else. And so a lot of the treatment for these different types of diseases have been based on what's been used for human geomas and we're trying to get away from that. We're trying to look at the individual phenotype or disease and try to figure out what should our best treatment be. So in the past for KHE steroids, been Kristen and Drafira, anti-toxane, all combinations of chemotherapy if that didn't work, anti-fibrinolytic agents, perpranolol and then you all know that we have been using serolimus for the treatment of this with good results. The only thing I'll mention about the serolimus and I know you guys saw pictures of this the last time in the good response that we're having from the semitore inhibitor is we now are following kids long term that have this diagnosis and we're finding that serolimus seems to do a wonderful job with the hematologic response and actually a wonderful job with a decrease in the size. But as we try to take patients off of serolimus, they seem to need it for a longer period of time. So when we did our first FDA study, we had 13 patients that actually were, that had KHE, 10 of them had Casaboc Marit phenomenon. They all responded incredibly well and that's important because the mortality from this diagnosis is usually because of the coagulopathy but they responded really well. But as we're looking at those patients, we have, we followed them for five years. We're finding that the majority of those patients, so seven out of those 10 are still on a low dose of serolimus. So there again are more things that we need to investigate and more trials that we need to do to sort of figure out the pathology and the biology and the molecular nature of these tumors and we're not quite there yet. So going back to our patients. So a lot of times we really think about whether we should do a biopsy or not on these patients, but I have this little saying that if it looks like a duck and quacks like a duck, it's a duck and if it doesn't biopsy it. Because there are many vascular anomalies that I have had over my 17 years of doing this that really weren't vascular anomalies, that were leukemia, that were a rabdomyocercoma, that were angiosercoma, that were other things. So I think if you're at the right place, you can do a biopsy very safely. And when we saw this child, so half of the team thought that this kid had a congenital hemangioma, but I just was not comfortable with that because of the grade of the thrombocytopenia and the grade of the hypothyroidonogenemia and the consistency that that was still present and it wasn't getting better. And I didn't really have sort of that halo around the lesion. We did an ultrasound and the ultrasound said that it was a hemangioma because it was a high phle lesion. We did an MRI that Dr. Alemari looked at and we both said, you know, this has some atypical features. And so when we have something that has atypical features, we need to biopsy it. So what do you do when you're, when you're, when you need to biopsy something like this and you know that any kind of trauma to this lesion can make that chassebach merit worse. And what do you do when, in my lecture a year ago, I told you that you have to be very careful with giving platelets to a chle lesion because again, they're getting trapped in this lesion and platelets granules are pro-anogenic and so you can really stimulate this lesion. So I've seen people who have a very diffuse chle lesion and you give them platelets because you have to because they're bleeding and you can see the lesion get larger and they have pain in that extremity. So how do you get around that? Because if we're gonna make a cut not only do we need to keep the chybrinogen up but we probably need to get that platelet count up higher than 19,000. And so what you do is you talk to your wonderful friends and surgery and so we did that. So with the help of Dr. Dickie and with Chris and even talking with Steve, we basically felt that yes, let's talk about does this kid need a biopsy? Does this kid not need a biopsy? Yes, we think that this child needs a biopsy. So how are we going to do this in a safe way? So we know that if we give platelets right away they're gonna go into the lesion but we know that we need platelets. We know one of the most important other things is to really get that phybrinogen up. So the night before this kid had surgery we basically gave the child cryo and we tried to get that phybrinogen up to 2000 and that wasn't or 200 and that wasn't a problem. And then the morning of the surgery prior to the surgery we started dripping in a slow infusion of platelets and we did that through the surgery while we were keeping the cryo up at 200. The other thing that we did is we also talked to the team that was taking care of him in the OR. So I talked to the anesthesiologist the day before just to give him a heads up to let him know that this is not a congenital hemendoma. You do not have to worry about heart failure. But these are things that might happen in the OR if the child starts to ooze. You probably need cryo before you need anything else and we kind of went over a plan. And then because I am a little bit of a closet surgeon I always like to go to the operating room. So I went to the operating room when this started and Chris and I kind of looked at the lesion and we decided sort of where would be the safest place to do the biopsy and everything went well. So I think with that preparation you can do these things and the biopsy was a KHE lesion. And basically what happened was the child was put on our studies. We have a study now. Our first study was looking at serolimus for complicated vascular anomalies. The second study is actually comparing serolimus and steroids to being Christian and steroids. And this child was randomized to the serolimus arm and is doing very well. So these are pictures of that I took on Monday. So you can see that the lesion is lighter over on this end. It still sort of is somewhat the same though. This picture doesn't really show you but it's still lighter over here. The platelet count is now 200,000 and the fibrenogen is 120. And so doing well for now on serolimus and the surgical site looks wonderful. Does anyone have any questions about that before we go to the next case? Okay. So this is a case that I came across when I was a young attending at an institution, which was a wonderful institution. But when we were discussing the treatment of this, I actually did call here to sort of talk about this case because this was a pretty significant case. So this was a child too. When they presented to Cincinnati was a year old and had this large lesion that was noted. So when the child was born, the platelet count was 60,000 and the fibrenogen was 80 and the D dimer was very high at 20. Was that another institution? And so they fought with those laboratory values that this was probably a KHE lesion. And so they started the patient on some steroids which didn't help and then they started the patient on some been christened and that didn't help either. And then they called me for advice and looking at the lesion, I said, you know, that's not a KHE lesion. And it probably would be a good idea for you to send the baby to a center that really knows about this type of lesion. So this coagulopathy though did persist. So nothing they did could help it. And the child, you know, was a one year old, ran punctious little boy who was having increased bruising, actually was having some bleeding in different areas because of the low platelet count. It went down to I think 40,000 at the lowest. So what do you think the diagnosis is? Yeah. Yes, ma'am. Okay. Do you think it's any kind of syndrome? I don't know. Okay. You are so good, such a master. So the differential diagnosis KHE, does anyone think it's KHE so looking at that, it is pedunculated but it is not your perpric firm type of lesion. So, you know, I could tell from a picture that they sent that I truly did not think that it was KHE plus, you know, a platelet count of 60,000 in a lesion that large is not necessarily KHE. And so my differential was a venous malformation and the question of whether this could be Blue River Blebnevis syndrome. So you all probably are very familiar with this. I know Eileen is, I know Steve is, but and I'm sure there have been some other lectures on this, but Blue River Blebnevis syndrome or Bean syndrome is a multiple venous malformations. And how it got the Blue River Blebnevis syndrome is by how it looks. So these patients usually have these small, they can be pinpoint, they can be larger visions that are rubbery. Some people think they look like Nevi, sometimes they're crested and you can have them on your hands, on your feet, you can really have them all over. And most commonly, the skin and the GI track is involved. And these are patients that present with anemia and pretty significant anemia. Interestingly, this child had no other lesions. So this, the large lesion was his only lesion that he had. And there have been other patients that have what we call the mother lesions. So they have a larger lesion and then smaller lesions. And I'm gonna tell you what happened with this child in the end. And these do have somatic mutations that are tied to mutations. And there's actually some interesting cysts and trans sort of information about the mutation that is questioning whether there is a potential for sort of a metastatic kind of a process that happens with these Blue River Blebnevis lesions. So usually these lesions in the past were taken care of with surgery. So because you have to remove all of those lesions that are in the GI track. And if any of you have worked with Dr. Fishman, you spend I guess it's a simple procedure I've been in there when Dr. Dickey has done them. But it takes a long time because you have to remove every single lesion. And we know now that sometimes patients that had those lesions removed at an earlier age can also have lesions that whether they pop up later or they weren't completely removed. Who knows that they can have reoccurrence or new lesions that pop up later on. We know that some of the larger lesions can be treated with claretherapy. And we also know that serolimus has been very helpful not in basically the lesion going away but actually helping with the anemia that happens with the lesion. And so this is a patient that came in at a very young age that had Blue River Blebnevis and was truly having problems with chronic anemia. And the local team that was treating her really was letting sort of this three year old hang around with a hemoglobin of six which wasn't the greatest idea but she was needing a lot of blood transfusions. And you can see this is the hemoglobin level. The stars are where she had blood transfusions so was needing them quite frequently. And then we started serolimus and her hemoglobin stayed stable. We don't know what's gonna happen with this was kid long term. So we know that when we tried to decrease the serolimus dose that the GI bleeding increased, we put the child back on serolimus and she stabilized. So what we're trying to do is get her to after puberty and see what happens after that. And I bet she she'll probably at that point in time need a surgical procedure to get rid of her lesions. So a lot of investigation that still needs to be done with Blue River Blebnevis. Yeah. It's bleeding, GI bleeding, we got red cell poison. Yes, GI bleeding. And you know, it's interesting because so if you really look at these under the microscope, there is a lymphatic component to them. And honestly, serolimus can help a true venous malformation that doesn't have a lymphatic component. But not as great as it helps a lymphatic malformation. So I think in particular, serolimus works best with this because it has a lymphatic malformation. But I don't think it's really destruction. I truly think that these, you know, if you feel them on the skin, they're very, you know, they can, they're just dry, they can scab. And I think that's what happens in the GI tract as well. Do you, do you agree, Steve? Or I don't think we truly know, which is another problem. That's the best mission. Yeah. It's a situation that we, so as a first officer, we'll go through 25, they've got still fixed. Yeah. But it's, it's different than another kind of, of truly straightforward venous malformation. So, and, and we need further study because, you know, certainly we're, it's, I, you know, serolimus is a great drug. M-tore inhibition has been absolutely wonderful, but it's not a great drug if someone needs to be on it lifetime. Because there are other metabolic issues that, that happen with serolimus. And so I think, you know, whether it's dual treatment, dual medication treatment, or it's a combination of surgery, or it's, you know, more interesting things as far as drug delivery that we're actually talking about doing, I think we have a lot more to learn about a lot of these phenotypes. So, this patient, we decided because of the persistent coagulopathy that this needed to be surgically removed. And I was incredibly nervous about this, because this is not, there probably is some consumption, but this is really consumption of coagulation factors. This is, you know, a high-d dimer, a low-fibrinogen. You really, truly need to get that fibregidion up. You need to decrease that fibrenolasis that's happening. And so we pre-medicated this patient with Lovinox, which increased the fibregidion and decreased the D dimer and actually improved the platelet count. And also during the surgery, we infused platelets and we infused cryo. We had a big powwow with everyone who was involved in the surgery beforehand, was there during the surgery to really see how things were going and to discuss what products needed to be used and the child's thing goodness did really well. And so I think that this can happen when you're prepared. And I think communication is the biggest issue for how this can happen in the right way. And then interestingly enough, when this lesion was taken off, six months later, the patient returned and had those small blue lesions. So on his feet, a few on his hand, someone is back. And then a year later came back and had anemia and on a GI evaluation had lesions in the GI tract. This was before the time of serotonous. So it's kind of interesting. It raises that question about, is there some sort of, do we have this big lesion that's keeping things in check like due to Folkman's theory of metastasis? So hopefully with the tie-2, we might have tie-2 inhibitors in the future that we'll be able to treat these children with and do a better job. So this is another case. And this is a case of a four-year-old that was complaining of pain and swelling in an upper extremity. So it had little nodules that were very painful, that were sort of like flabitis. This lesion was diagnosed at birth and was diagnosed as a hemangioma. So unfortunately this child spent a long time being diagnosed as a hemangioma. I think this kid had prednisone when they were smaller and mom didn't really truly know what to do because she kept thinking that it would go away. And this was a very simple family who didn't know enough until they met someone in a grocery store that basically had some insight because their child had a vascular malformation who told them that I don't think your baby has a hemangioma or your toddler, you really truly need to go to one of the vascular centers. And so they found the patient support group and went to one of the vascular centers. So this baby though had a phybrinogen, this toddler of 60 and a de dimer of greater than 20. So what do you think that this patient has? This is pretty easy. The different than bluer were bloodnevis, which was a venous malformation, but with the little this is truly more of a venous malformation, of a true venous malformation. So this baby had a diffuse venous malformation. So sometimes we call them Bacchanhymers lesions because they're so, so diffuse. These truly can involve the skin, the bone, the soft tissue. They can be very devastating as far as increased pain because of the flabitis. You can absolutely have a coagulopathy. Sometimes it truly leads to really disuse of a hand, of an arm. And so there's multiple things that we actually can do. So we can do sclerotherapy, we can do surgery. And sometimes that gets people to where they need to be, but unfortunately I don't think we're really there yet with long-term issues. We see a lot of these kids that come in that even get an amputation because they're having so much pain and dysfunction from their extremity. When we're going to do a procedure though, for this type of patient that has a coagulopathy because it's consumption of factors, we actually do need to prepare them as well. And so just like we did the Blue River Blood Nevis patient, if you have someone like this that's walking around with a with a fibrinogen of 60, even another type of surgical procedure that's not related to the vascular malformation, you probably need to think about that. And I have to tell you there've been several cases that the pre-op screening has really picked up because the pre-op screening MPs have looked at patients and looked back in their records and said, yeah, I know this kid is coming in for a tonsillectomy or a hernia repair or whatever, but I think they had a coagulopathy way back when do we need a hematology consult? And I think that's been really extremely helpful catching some of those patients because you don't wanna do any kind of surgery if someone has a fibrinogen of 60. And sometimes we don't routinely check those labs. So those are the things that you have to think about when someone has a really diffuse venous malformation. And so these are some pictures of what a diffuse venous malformation looks like. And you can see that we talk about skin, bone, it interferes with the joints, there's some chronic issues. And also you have to worry about the multiple venous malformations as well. So this is another case, and I'm telling you what this child has. So there is something called clothes and this is a three year old patient that has clothes that comes into your office for evaluation and the mother sort of is talking to you about a debulking procedure. So there are things that you should think about when someone has clothes and we're gonna talk about in a minute what clothes is, but one of the biggest things to think about is ectatic veins. And so a lot of these patients will have large and brianic veins that actually can need to thrombosis. And if you are doing a procedure where you're causing either inflammation or you're taking them to the OR where they have an increased risk for clotting, it's really important to know whether they have those large ectatic vessels or not. So clothes is, the CLOVES stands for a congenital lipominous overgrowth. These patients can also have vascular anomalies so that picture that I showed you that patient did not per se have any vascular abnormalities that patient mostly had lipominous overgrowth. But we can see capillary venous lymphatic malformations, we can see pretty significant vascular anomalies with patients that have clothes. They can have epidermal anomalies such as an epidermal nevis. They can have skeletal anomalies. They can also have spinal anomalies. And the majority of clothes are caused by a somatic mutation of pic-3CA. So this is what we're talking about the ectasia and the reflux that they can have from these vessels. And so when we see someone that has clothes and Dr. Alamari with someone that sort of came up with what our standards of practice are for these patients, we look at certain things, we look at the spine. We look for these ectatic vessels when they're younger because it's easier to take care of them and get rid of them when they're younger than when they're older. Closed patients can also have a slightly higher risk for Wilms tumor and so we know that we need to look for that. But this is very significant to know this before a surgical procedure is done. And here we have our people who take care of those ectatic veins. So those are IR blasters that get rid of those ectatic veins for us. And I think that's been extremely helpful to us. And I think it also is something that needs to be reported and needs to be studied more. Because we know from experience that we've had patients with thrombotic issues, but we don't know who should be classified as high risk or not. We know that probably these things need to be taken care of earlier than not, but we need to get that out into the literature. And so we really are trying as a VAC team to drive the research and to hold people accountable for getting all of these things out there. Because it's important for us to do that, mostly because it's important for us to share our knowledge with other centers and other people. Because I think in general it helps with the care of these patients and it helps improve our outcomes for all of these patients. So let's just review sort of what we learned about with vascular anomalies and coagulopathy. So it's very interesting because when I first started doing this, when we started using low molecular weight heparin before surgery or when someone was actually having active bleeding, it was very hard for people to understand why do we do that. And it's truly because you have this coagulation cascade and you have one part of the cascade that makes a clot and one part that gets rid of it. And remember when anything is really severely affected in that cascade, it makes everything go haywire. So these patients truly are at risk for bleeding and they're also at risk for clotting. And this also, I don't know if you remember when I first came here and within the first year, we actually had a patient that had a total body venous malformation and he's still sort of out there that we did a surgical procedure on and we did have some time that we gave this child low venox beforehand, but still after that procedure because of his low fibrinogen and his consumption and his activation of his fibrinolidic process, he still continued to have bleeding after that. And it wasn't until we sort of jumped on him post-op where we really kept his platelets high and we kept his fibrinogen high that the bleeding stopped. And this patient sort of then came back and had another episode where he had a retroperitoneal bleed and needed to be back on his low molecular rate heparin, but you know, people really, we were having a hard time convincing people that he needed to do that. So we know that there is this triad that we have all heard about. So in the triad really, the regulation system and the vascular system depend on what's the vessel wall, like what's the blood flow, like what's the blood composition, like, and we know that for all of this, it just is a mess with vascular anomalies. So you can look at a venous malformation and you can do an EM on that malformation and you can see that the endocelial cells have gaps in between them, that the muscle layer in some places in normal is normal and some places there's too much muscle and some places there's no muscle. And we know that elasticity over time of that vessel worsens. So a vascular anomaly, sort of every part of this triad is sort of in disarray. So we have an abnormal endocelium, we have abnormal blood flow going through this vessel and we actually, if you stick and needle in a vascular anomaly and if you do a PTPT, you have a DIC type of a picture. And so this was called localized intravascular coagulopathy and I'm hoping eventually we are going to change that when we know more about it, because it's not really localized because I'm telling you that these children systemically can have low fiber antigens and low platelet count. So it does become a disseminated picture and if you don't prepare people for surgery and if you go into these lesions, you can make this a true DIC. And so it's really important to know and understand that. So what do we know? We know that patients have these hematological complications. We know that they're at increased risks for having worsening of this when they have surgery directly to these lesions or if they have invasive radiologic procedures. So not a simple sclerotherapy, not even a simple removal of an ectatic vein, but a more vigorous radiologic procedure. We know that the pathogenesis of this is poorly understood. I'm mostly an oncologist versus a hematologist and I've been trying to have the hematology people really look at this. Like what is going on with this coagulopathy? We have so many biomarkers for thrombosis, biomarkers for platelets and platelet micro particles. And I think we're trying to finally get a study going where we look at these things. So we can might be able to predict who are the high risk people who are not, because now we just know from the diagnosis and from labs who are high risk and we need a little bit more than that. We know that this coagulopathy has truly is misunderstood but it's misreported. So again, I told you that whenever anyone had a low-fibreinogen or a low-played account, no matter what kind of diagnosis they had, it was all called Casabuck Merit. And it's not Casabuck Merit. So very simply, and John Mulligan was sort of put a chart like this together in a key series that he had in the New England Journal where he was talking about KHE. But we can compare KHE to vascular malformations and we can see that in KHE, we have profound thrombocytopenia. Usually a true KHE is going to have a platelet count that's absolutely less than 50,000, usually less than 20,000. With vascular malformations, the thrombocytopenia is not that low. Fibreinogen can be decreased in both of these. Sometimes the PTPT can be very normal in a KHE lesion versus prolonged in malformations. The D dimer can be high in both, but it's much more elevated in the malformations than it is the KHE. And we think that the pathogenesis, we sort of know the pathogenesis here is platelet trapping and then consumption of fibrinogen. But this is more stasis and activation of thrombin and the abnormal vasculature that's causing the coagulopathy. And then management is totally different for these two diagnoses. And that's why it's so important to know. So we as hematologists, oncologists, got together. We have a meeting that happens at the American Society of hematology and we try to start talking about who are the patients that we really think are at high risk? What are the diagnosis? So we talked about the venous malformations, not a single venous malformation, but more of a diffuse. These are all really diffuse lesions. Capillary lymphatic venous malformations. So these are the patients that have clippetronone syndrome. And then the diffuse, the venous lymphatic malformations like the blue rubber blab, and either if they're diffuse or if they're multiple lesions. And when do we worry about this? When should we as hematologists, oncologists think about this? So we think about this when someone is having surgery, when someone is having an extensive interventional radiology procedure. We think about it as someone has a traumatic event that happens because this coagulopathy can get worse with trauma. We think about it when someone comes in with infection because sometimes our patients can do that. Or if they come in with an illness. And there are some baseline screening labs that we recommend, obviously, a CBC and the COAD screen. And then we truly think that if someone has one of those high risk lesions, then a heme on person really truly needs to be involved. And so I think in our clinic, because there's two of us now, Cameron, Trenner, and I work together, we really try to have a medical person see the complicated patients so that we can think about those kinds of things, either whether they're having a procedure or not. And also because we have other treatment options that we're thinking about as well. And I truly think that our role is communicating with you all so that we as a team can come up with a plan for these patients. So we talked a little bit about indications for low molecular weight heparin. So this seems to be the best anti-coagulant to use, sort of pre and post. We are basically talking about other anti-coagulants can use some of the new oral anti-coagulants that sort of work very similarly to low molecular weight heparin. And that's a study that's being developed right now that we're going to be looking specifically at our patients with bascular anomalies. Some people have used anti-fibrolinic agents, and I have when you need them, if someone's using particularly in the mouth area for CHE, anti-platelet agents have been used. And NOVO 7, or Factor 7A, has been used in situations where there's this extreme amount of life threatening bleeding. And no one can really take away the importance of, particularly when you have a venous malformation, the importance of compression, sometimes physical therapy, hydrotherapy, those kinds of things. And so what we did as a hemon group is we had a consensus meeting that happened last year where we talked about, what are the diagnoses, what abnormalities should you look at with the blood values, but also now adding ectasia to that. And we came up with sort of a low risk and a high risk and what to do with that. And then we also added the addition of ectasia and compression stockings because we felt that they were very important for this as well. And with that, I want to thank my wonderful team. You look pretty good there, Steve. And I'll take any questions. Thank you. Thank you. So it was a wonderful summary of a very complex topic. You make it all sound so easy. So one question for the neophyte. So you showed a patient with clothes, grossly when you're comparing a patient with clothes with Casabac mer, no, what with the clipal trinonics and how do you differentiate between those? Yeah, so that's a very good question. So we think of clipal trinonics as a capillary, lymphatic venous malformation where there's overgrowth of the extremity. Clothes has different sort of different characteristics that we see as well. So a lot of times with clothes they'll have abnormalities sort of a web base, but in larger foot and abnormalities of the toes. Also, when you see a patient with clothes, they might have the vascular malformation, but they also might have a component of that that looks more like pulmitus. So you can sometimes clothes will have abnormalities of the hands as well. You can see an epidermal nevi as well, and that kind of leans you into that area. And that's important to us because we need to make sure when we have that diagnosis of clothes, we need to check the spine. Sometimes patients with clothes can have aviams of the spine. We know about the increased risk for willms tumor that's slightly increased with clothes versus it doesn't appear to be with clipal trinonics. But I want you to all understand that there's a lot of heterogeneity with all of these diagnoses. And when we look at the tissue, so clothes patients have pic-3CI mutations, but clipal trinonics patients have clips pic-3CI mutations as well. So there is a lot of heterogeneity amongst those diagnoses. But does that help? I mean, typically there are other clinical characteristics that we can see that we say, know this looks like clothes. Sometimes patients come in and they might have a capillary malformation, which is subtle or diffuse. They might have overgrowth. They might have a few abnormalities of the toe. And sometimes now we say this is something called pros. So pros is, so PROS is a pic-3CI related overgrowth syndrome. So there's another type of syndrome, too, that has capillary malformation and macrasephalase, so we call it MCN macrasephaline capillary malformation. Those fit into the PROS category, too, because they have pic-3CI somatic mutations. So I think that's why, I mean, the classification and the names help us. I think that when we learn more about the genotypes, we're going to be able to correlate phenotype with genotype and hopefully put them in a box and know how to treat them. But I still think because there's so much heterogeneity, there are going to be those that look a little like this and a little like this and we're not going to know. So we are truly trying that every time someone has a surgical procedure to actually do genomic testing on them. So we are part of the Dana Farber Enca panel or profile because we think of these, they're not cancer. Some of them truly can get cancer, but a small majority. But they're abnormalities in the growth pathway, just like cancer is. So we are able to send our tissue off for Enca panel. And that has helped us a lot because we really truly want to know what the genotype is of our patients. And I think that I'm hoping in the future that we are not only going to have better surgical and radiologic options, but we're also going to have a repertoire of medicines that can be tailored to not only what a patient has, but what their genotype phenotype is. Additional questions for Dr. Adams. I think you've got us all snowed. Denise, thank you so much for another small moment. Thank you.
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