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New Treatments for Sickling Disorders

Sickle cell anemia is characterized by occlusive, painful crises, which are the most common event in sickle cell disease. Most people working in an emergency room think that patients with sickle cell disease have, on average, 30-35 episodes a year sickle cell anemia. It is just not true. Some patients do have 30-35 episodes a year. The average for all patients, 4,000 patients under observation, was about one episode per year.

At the present time we have very little understanding as to why some people have so many more than others. Painful crises due to occlusion are distinct and sudden in onset. They often occur at night when only the emergency room is open. They often occur in several sites and that presumably is because the changes which brought about the endothelial adhesion are not localized, but generalized. They are characterized by increased D-dimer by ELISA and they last anywhere from 5-10 days on average. Anything beyond ten days, and certainly anything beyond two weeks, you must be thinking of other complications such as permanent tissue damage.

Now there is another way in which vascular occlusion can occur which does not involve forming a barricade. And that is the virtual vascular occlusion that comes from increase in blood viscosity that is mal-perfusion, poor perfusion simply because the blood is too viscid. Now the components of whole blood viscosity are several. And the two that we are concerned about are the intrinsic red cell viscosity which is, in patients with sickle cell disease at SC disease, is markedly increased and it is increased because the formation of rods and the formation of even small aggregates markedly increases the intrinsic viscosity of the red cell. That means then that the red cell is not able to, even in its oxygenated state, is not able to bend well. When it begins to get deoxygenated it very rapidly becomes much more viscid.

In variants of sickle cell disease, which we are not going to talk about in great detail, but there are a number of variants in sickle cell disease which are double heterozygotes in which the hematocrit is relatively high. That is, in general, over 30% in many patients. SC disease is by far the most common. As you know the C defect is at exactly the same place as the S defect on the cell, and all the patients with SC disease are descended from a single propositi or propositus. We donít know which. There has only been one mutation, that occurred.

Sickle beta thalassemia, both beta plus and beta zero thalassemia, but particularly beta plus thalassemia will have a high hematocrit. Sometimes patients who have a high F sometimes brought about by therapy, as weíll see, may have a high whole blood viscosity, and those with hereditary persistence of fetal hemoglobin can have a high viscosity. Weíve had patients with HPFH who have had essentially normal hematocrits but have had the difficulties with the high viscosity. In fact, one died from the consequences of high viscosity nevertheless. SD and SO Arab are variants in which the hematocrit tends to be higher than in patients with classic SS disease. What happens when you have high viscosity is that you canít pump the blood through the vessels. This isnít necessarily the smallest vessels, this can be the relatively large vessels,

There are some therapeutic implications for differences and the perfusion problem might be treated with phlebotomy. Weíve done that in several patients with SC disease although the data is rather soft because itís very hard to double blind taking blood out of somebody and we rely on the reports of the patients. But about three-quarters of the patients said that they had

The treatment of pain in sickle cell disease is something everybody thinks they know how to do, but there are some things I think we can keep in mind. For us hematologists as well, but for other people taking care of patients with sickle cell disease there are some things that need to be thought about. One is; consider that the patient is having pain unless there is contrary evidence. Itís very hard to get contrary evidence. Itís very hard to prove that a patient is not having pain,

Iím not going to presume to tell you how to run your emergency room, but we have found that our patients hate universally, have in the past, hated to go to the emergency room. The emergency room people thought that they were running to them at their first sign of pain. Most patients with sickle disease will only go to the emergency room when there is nothing else left. The emergency room needs to understand that they are the point of last resort. We have found it very effective having monthly meetings with emergency room personnel to discuss sickle cell disease in general, and to discuss problems in particular. Part of what has come from that is

In the hospital; again, youíve all dealt with patients but there are some suggestions that I think are becoming standard of practice. Where available, patient-controlled analgesia, PCA, is the best way to give the analgesics. If itís not used then the medications must be given with adequate frequency and strength and that takes knowledge of the pharmacodynamics of the pain medication being used. Most pain medications that are used parenterally donít last more than 2-3 hours at max, so that when the intern writes an inadequate dose of morphine sulfate q. 6 hour, that means that the patient is very likely to have three hours of uncovered pain. Secondly, we

Now what are some of the other complications of viscosity? Well, we talked about pain. The second most common complication in sickle cell disease is acute chest syndrome. Most patients know that as pneumonia and often it is pneumonia. I think the use of the acute chest syndrome is used as a nonspecific term but I will outline what we currently think is the cause, at least for

Now the acute chest syndrome is now defined - at least for the most part - as acute onset of infiltrate in the chest x-ray. A new infiltrate in the chest x-ray. All of you have seen x-rays of patients with sickle cell disease. Oftentimes they have residual findings from previous encounters with this problem. The causes of acute chest syndrome are primarily, I think, sludged circulation. Iíll show you what I mean by that. If it becomes infected it becomes pneumonia. Occasionally in patients having crises, fat embolism has been detected. I have never been entirely sure what that meant, and very rarely a thrombotic embolism, that is an embolism from a distant site occurs.

Progressive acute-chest syndrome is important to recognize because it requires aggressive therapy. When the patient is first seen with infiltrates, antibiotics and oxygen are perhaps enough unless the patient is already having the problems that weíll talk about here. Antibiotics if the patient is febrile. Itís hard to get the house to not give antibiotics when they see a chest infiltration, but it probably isnít necessary unless there is some evidence that the patient is having an infection within the area of sludging and consolidation. On the other hand, if there are signs of progression - progression of the infiltrates - and this can happen very very quickly. You can

Now this is the pie, which weíll come to later, of the cause of death in sickle cell disease. Pain and chest syndrome, and all of these are probably related to acute-chest syndrome. Many of the perioperative deaths as well are related to the problem of getting blood through the chest when it is readily sludged. Again, as you would expect, the incidence of acute chest syndrome is higher in patients with a higher hematocrit. So those patients with SC and patients with sickle cell disease that happen to have a high hematocrit may get into this problem. These can also be, these problems with high viscosity, can also be brought on by transfusion. Even in patients who did not previously have a high hematocrit. If the hematocrit is raised to normal levels or near normal levels, despite the fact that the blood that is being transfused is normal blood, then the

Another syndrome that is not recognized, but again occurs in patients who have high hematocrits, relatively high hematocrits, the so-called multi-organ damage syndrome. And it characteristically is an acute infarcting phenomenon in several organs, probably because of high viscosity impeding perfusion. Most commonly the brain is affected and it leads to a TTP-like syndrome. The patient just gradually goes into a coma and like TTP, if you stick with it and

Another issue in sickle cell disease is stroke. And again, stroke occurs in a number of different forms in sickle cell disease. One is hemiplegic stroke that occurs in childhood. We see them Ö hemiplegic stroke is caused by the fact that sickling occurs in the major vessels, the carotids and the major vessels coming out of the carotids, occurs in the vasovasorum. That then denudes the endothelium from those vessels and clotting occurs in very large vessels and causes hemiplegia. This is a serious complication. Ten percent of children get it, usually between the ages of 10-13 years of age for some reason. Relatively uncommon in adults, although it can occur and it results in prolonged transfusion; because itís been shown that the strokes will recur if transfusion is not

What causes death in sickle cell disease? Well first, when do patients die from sickle cell disease? There is the data that youíve seen in the New England Journal. Half of the patients with SS disease live to about the age of 46. And I think thatís something that should be used. Patients have often been told in the past that they donít live past 20; thatís clearly not true. Many of them live up to their 60ís and 70ís. With SC disease the survival is almost normal, not quite but

The treatment of sickle cell disease; Iím going to discuss two things. Iím going to talk about transfusions and Iím going to talk about hydroxyurea. There are two kinds of transfusions in sickle cell disease. One is a simple transfusion where blood is taken from a blood bank and given to a patient. That is used to increase the hemoglobin or in a chronic transfusion program, as we will see, to maintain a level of normal hemoglobin in a patient. The second form is exchange transfusion, which is to change the composition of the blood. That is to remove the blood that is sickle-able and replace it with blood that is not sickle-able. Now in simple

Chronic transfusion program; simple transfusion is useful in the post-stroke. Occasionally it has been used for repeated painful episodes, but again, because of the things weíve talked about this morning, one wants to keep the number of transfusions down as much as possible. We really are in a problem with stroke because the amount of transfusions that are necessary that it builds up iron so quickly that Desferal therapy is almost universally needed. Many times patients with

There are several non-indications for simple transfusion and again, simple pain episodes are never benefited by transfusion. I think that a lesson that, at least the physicians in North Carolina, have a hard time learning, that it is simply adding iron and not doing a blessed thing for the patient. Secondly it has now become apparent that at least simple transfusion in pregnancy, unless the patient is having physiologic problems with the anemia, is probably not indicated. Several studies out of Chicago and several other places have suggested that the complications of the transfusions are greater than the savings made on the basis of treating the disease. Exchange transfusions, on the other hand, are necessary and important for the acute complications due to viscosity that weíve talked about, and they may be used as well for rapid preparation for surgery. This again, as I say, is controversial. We have been working with the physicians of

Well you all recognize how hydroxyurea works. It has some difficulties which is dose ascertainment. Patients taking the drug - and we use the MCV as a good monitor - got into some trouble though. We were accusing patients of not taking their hydroxyurea because their MCV was not going above normal until we recognized that these were patients with either alpha or beta thalassemia. In those patients the MCV will not exceed normal. It will go up from their standard, but it will not exceed normal. So you have to know what the MCV was when they

Transplantation in sickle cell disease would solve the problem, but the problem that has occurred is that we have only taken the most complicated patients to transplant, and weíve taken them usually well into adulthood. Although there is now a number of studies going on looking at transplantation, particularly in childhood. We know from the data from the transplantations in thalassemia that if you transplant children with thalassemia before they get organ damage, then the prolonged disease-free survival is some 95%. I think most patients with sickle cell disease early age, just as with thalassemia.

What are the prospects of therapy as a result of this? Well, gene therapy I think is everybodyís great hope. Donít hold your breath. It is possible to replace the gene; that has not gone terribly well. To inactivate the sickle gene allowing the hemoglobin A gene, or the products of the