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Frequently Asked Questions (FAQs) - Questions submitted to the Web site by patients, clinicians, and others

I'm a Student doing a Paper on Sickle Cell Disease

Question - Help! I need information for a paper I'm doing for school

Answer - See the following pages on our website: Sickle Cell Summary for Patients, World Wide Web Sites, What Teachers and Employers should Know, and Professional Summary about Sickle Cell Disease. Also go to the The Human Genome Project Sickle Cell Education Site at http://www.mcet.edu/genome/sickle.html-

What About Sickle Cell Trait and The Different Sickle Cell Diseases

Question: What problems can I have if I have sickle cell trait and what is the differences in hemoglobin S concentrations

Answer: Sickle trait can cause you to have some blood in the urine and a slight increase in problems with kidney infections. Individuals with sickle trait can have pain if they go to very high altitudes, greater than 12,000 feet. Other than these uncommon problems, there should be not health problems from sickle trait. Individuals with sickle trait may have children with sickle cell disease if their partner also has sickle, thalassemia, or hemoglobin C trait. Please see the NIH guideline about sickle cell trait on our web site at: http://www.emory.edu/PEDS/SICKLE/nihchp22.htm
The mutation that makes the sickle hemoglobin (HbS) confers at least two abnormal properties:
1) when de-oxygenated, HbS polymerizes to forms rods and fibers that cause
the sickle deformation, and
2) when oxygenated, the HbS molecule is more unstable than normal HbA and
may spontaneously decompose ( to met-hemoglobin, or to globin without heme)
These properties are known from decades of research with HbS, and can be
shown in test tubes. They are biophysical properties of the HbS molecule.
What does this mean for the blood and for sickle cell disease manifestations? The composition of hemoglobin in the red blood cells determines their ability to sickle and cause sickle cell disease problems.

I. People with sickle trait have one gene making HbS and one gene making HbA, so you would expect equal amounts of HbS and HbA in the RBC. The unstable property of HbS, however, means that not all of the amount of HbS made in the red blood cell (RBC) stays floating around in the RBC, because some of the HbS decomposes. Therefore, the RBC contents for a person with sickle trait has slightly less than 50% HbS, typically something like 55 to 60 percent HbA and 40 to 45 percent HbS. The predominance of HbA inhibits and dilutes the ability of HbS to show its polymerization property, and so sickle trait is not a form of sickle cell disease. People with sickle trait have no anemia, no painful episodes, no special
susceptibility to infection, and no implications for life expectancy........ it is not sickle cell disease.

II. The most common form of sickle cell disease, HbSS, has no genes for HbA present. A minor hemoglobin (HbA2) may be present in a few percent of the total hemoglobin, and fetal hemoglobin may be present in varying amounts (HbF). However, the vast majority of the hemoglobin in the RBC is HbS, and it will polymerize and cause the sickle cell disease manifestations.

III. Some people with sickle cell disease, as you know, have HbSC, HbSD, HbS- O-Arab etc. One gene makes HbS and the other gene makes another variant hemoglobin ( HbC, HbD, HbO-Arab, etc.) that usually would not cause a disease by itself. There may be equal parts HbS and the other Hb, or slight variation from equal amounts in the RBC. However, the important difference between HbA and these variant hemoglobins is their ability to participate in polymerization with the HbS. When the inside of RBC contains a combination of hemoglobins that will polymerize, then these are types of sickle cell disease, with anemia, pain, spleen and other problems. Differences in disease pattern between these types of sickle cell disease and the pattern for HbSS can be found statistically, but there is so much variability that the exact disease course is impossibleto predict for an individual with sickle cell disease based on Hb subtype.

IV. What gets a little complicated is HbS-beta-thalassemia. The picture in the RBC for people with HbS-beta-zero-thalassemia is the result of one gene making HbS and the other hemoglobin gene is defective and cannot make anything (beta-zero thalassemia). The hemoglobin produced by these two genes is HbS, and then there are minor amounts of HbA2 and HbF. Again, the HbS can polymerize and there is sickle cell disease manifestations statistically similar to HbSS. Another type is HbS-beta-plus-thalassemia, in which one gene makes HbS and the other gene is defective but makes a little bit of HbA. There is less HbA produced than in sickle trait, and so the end result in the RBC is more HbS (70 to90 percent of the total hemoglobin) than HbA (10 to 30 percent of the to tal hemoglobin in the RBC). This amount of HbA is not enough to dilute the HbS and cannot inhibit polymerization completely, so the RBC can still sickle and this is a subtype of sickle cell disease.

So in summary, the percentage of HbS is helpful for determining what the difference between sickle trait and the HbS-beta-plus-thalassemia,

Sickle trait, not a disease ------ HbS approx 40 percent
Sickle cell disease HbSC, HbSD, etc. ----- HbS approx 50 percent
Sickle cell disease HbS-beta-plus-thalassemia ------ HbS approx 70 percent
Sickle cell disease HbSS, HbS-beta-zero-thalassemia ---- HbS approx 95
percent

However, for the subtypes of sickle cell disease like HbSC, the really important fact is that the other Hb is able to participate inpolymerization with HbS, not that the amount of HbS is close to 50 percent.

For clarification, it may be helpful to get in touch with your local genetics office or sickle cell center. Additional information may be found in recent reviews in the New England Journal of Medicine (BunnHF, Sept 1997; Steinberg MH, April 1999), in textbooks: Embury, Hebbel, Narla, and Steinberg - Sickle cell disease - Basic Principles and Practice, Raven Press 1994.............. Bunn and Forget - Hemoglobin and standard hematology textbooks. For HbS polymerization, look for publications by William Eaton, Hofrichter, or Frank Ferrone. For the unstable property of HbS, look for publications by Toshio Asakura in the early 1970s.

Parents with Sickle Cell Trait

Question: My husband and I both have the sickle cell trait. We have one child together and she has only the trait. We were told that if we had more children then they would most likely have sickle cell disease. Is there any way to prevent my child from having the disease before it is conceived or before I cary it. If we have a child with sickle cell disease, what are the treatments available?

Answer: There is a newly-developed, very experimental, method for very early
testing for sickle cell disease. It was published two months ago in the Journal of the American Medical Assoc, and is highly controversial - doing in vitro fertilization and then testing the embryos for sickle genes before implanting in the mother's womb.
The Journal of the American Medical Association (JAMA)
"Couple Has Twins Born Unaffected With Sickle Cell Disease After Using Genetic Test Prior To In Vitro Fertilization" Technique holds promise for sickle cell carrier couples to have healthy babies CHICAGO — A couple who are both carriers of sickle cell disease, a common human blood disorder that is passed down in families, successfully gave birth to twins who were free of the disorder by using a genetic test on embryos to determine that they do not have the sickle cell mutation before being implanted into the woman's uterus. This is the first successful attempt to use this genetic procedure to enable a couple to have a child unaffected with sickle cell disease, according to an article in the May 12, 1999 issue of The Journal of the American Medical Association (JAMA).

With current practice, bone marrow transplantation for sickle cell disease requires that the bone marrow donor be a sibling who is an immunologic match (HLA type match) and does not have sickle cell disease (can have sickle trait, or no sickle gene). There is a 25% chance that any two siblings will be HLA matches for each other. There is a 75% chance that the offspring will have no sickle cell disease, from a couple who both have sickle trait. This means that there is a 25% x 75% (18.75%) chance of a suitable sibling donor for a child with sickle cell disease. Because of the low chances for a suitable donor, there have been few children with
sickle cell disease eligible for bone marrow transplantation. The procedure itself is also risky, with approximately 5 - 10% chance of death, and another 8 - 12% chance of graft rejection (meaning that you go through the transplant process but end up still having sickle cell disease). These risks have restricted the bone marrow transplant furthe, to children who have serious complications from their sickle cell disease, and feel that the risks are worth taking. We have 6 patients here in
Atlanta with bone marrow transplantation for sickle cell disease (the
largest number of at any center in North America) out of approximately 600
children with sickle cell disease followed here in our center, so you can
see how few transplants there are.

New possibilities in transplantation are now being explored: other types of donors, such as an HLA- matched cord blood from an unrelated person, transplant without as much chemotherapy, transplant in mid-trimester of pregnancy (Children's Hospital of Philadelphia and Wayne State U in Detroit). ( If you are interested in the prenatal transplant and you appear to live in Philadelphia, may I suggest contacting Dr. Kwaku Ohene-Frempong at Children's Hospital of Philadelphia, through pediatric hematology-sickle cell at 215-590-3438) All of these approaches are very new (1 or 2 cases), controversial, and results have not yet been published. More information is expected in the next few years.

Other possibilities are treatment of sickle cell disease with medications.
Hydroxyurea is now in wider use for making people with severe sickle cell
disease have fewer symptoms. Other medications are in active research
and, again, more information is expected in the next few years.

So, overall, there are many possibilities for improvements in sickle cell
disease treatment and cure on the horizon, and the future looks better
than it did just a few years ago. Furthermore, the course of sickle cell
disease is unpredictable, and a child may have a quiet and mild case. I
hope that this information gives you a sense of the possibilities and the
hope.

The First Description of Sickle Cell Disease

Question: When and by whom was the first description of sickle cell disease in the medical literature?

Answer: The first published reports of sickle cell disease in African medical literature were in the 1870s. Savitt and Goldberg (1989) gave a delightful account of investigations into the story of Walter Clement Noel, the first-to-be-described case of sickle cell anemia (Herrick, 1910). Noel, a first-year dental student at the Chicago College of Dental Surgery, was admitted to the Presbyterian Hospital in late 1904 where Ernest E. Irons, a 27-year-old intern, obtained a history and performed routine physical, blood, and urine examinations. He noticed that Knoll's blood smear contained 'many pear-shaped and elongated forms' and alerted his attending physician, James B. Herrick, to the unusual blood findings. Irons drew a rough sketch of these erythrocytes in the hospital record. Herrick and Irons followed Noel over the next 2.5 years through several episodes of severe illness as he continued his dental studies. Thereafter, Noel returned to Grenada to practice dentistry. He died 9 years later at the age of 32. Curiously, Irons, who lived from 1877 to 1959, was not included by Herrick, who lived from 1861 to
1964, in the authorship. Savitt, T. L.; Goldberg, M. F. : Herrick's 1910 case report of sickle cell anemia: the rest of the story. J.A.M.A. 261: 266-271, 1989. 

Herrick, J. B. : Peculiar elongated and sickle-shaped red blood corpuscles in a case of severe anemia. Arch. Intern. Med. 6: 517-521, 1910.

Hemoglobin SC

Question: I have a thirteen year old daughter with SC Diease. I'm trying to find out why she has pain crisis like SS patient have, I was told at some point that she wouldn't have as much pain but she does. Is this possible or do you have anymore input on the trait SC?

Answer: Hemoglobin SC is very definitely a type of sickle cell disease, and is not
asymptomatic. It is described as a type of sickle cell disease in numerous standard medical textbooks, including hematology, pediatrics, and internal medicine texts. Painful episodes for a population of children with HbSC may not be as severe or frequent as in HbSS (homozygous sickle cell disease), but there is wide variation between individuals. In my clinical experience caring for approximately 500 children with various types of sickle cell disease at the Georgia Comprehensive Sickle Cell Center, 2 patients with HbSC are among the 20 patients most frequently seen at the hospital for pain management. After childhood, the complications of HbSC patients increase so that the disease becomes approximately similar in severity to adults with HbSS. Sickle cell pain typically involves bones (including joints and skull), but can affect nearly any part of the body.

In older school-age children and adolescents with HbSC, there is a high rate of two complications of sickle cell disease: damage to the joints (due to sickle cells interfering with blood flow to the heads of the femur and humerus), and damage to the retina of the eye (due to blocked bloodvessels and abnormal growth of fragile new vessels that can bleed spontaneously). We routinely check HbSC children for these problems, and recommend annual retinal examination by an ophthalmologist after age 8 yrs. Other sickle cell complications are less frequent in HbSC than HbSS (stroke, acute lung problems, aplastic crisis) but can occur.

Damage to the kidneys by sickling can cause inability for the kidneys to concentrate the urine, leading to high urine production through the night(whereas normal kidneys reduce urine production during sleep). Therefore, bedwetting (enuresis) is extremely common in children with sickle cell disease. In my experience, bedwetting as a sickle cell complication does not respond to medications (desmopressin or Tofranil) nor psychotherapy Instead, management focuses on behavioral modification (incentives, bedwetting alarms, alarm clocks) to train the child to get up in the middle of the night and go to the bathroom to urinate. People with sickle cell disease also get dehydrated more quickly, due to the abnormal kidney function, and dehydration will aggravate sickle cell pains or trigger them.

Children with sickle cell disease are more susceptible to certain bacterial infections (Streptococcus pneumoniae) and death from overwhelming infection remains the leading cause of death for people with sickle cell disease, including HbSC. The National Institutes of Health recommends a three-pronged approach for children with sickle cell, and these are in standard medical texts for many years:
1) Give a preventive antibiotic (such as Penicillin VK 250 mg twice a day)
through age 5 yrs
2) Special immunization (Pneumovax for now at age 24 months and 5 years, with an improved vaccine coming on the market soon for administration to infants)
3) Prompt medical evaluation of any fever (examination and empiric injection of antibiotics within a hour or two of the detection of fever)

Children with sickle cell disease can also have any of the other problems of childhood, with no particularly greater or lesser frequency of ordinary infections such as respiratory viruses and pinworms. Therefore, it is important not to lose sight of good primary pediatric care.

In summary, it is my opinion that this child's pains, pneumonia, bedwetting, and school absences are attributable to her sickle cell disease of the HbSC type. Her headaches may represent sickle cell problems. Her frequent upper respiratory infections and pinworms are probably not related to sickle cell disease, although they may accentuate sickle cell pains and problems. I suggest that she should have access to expert care by a physician interested in sickle cell disease, as well as a
primary care provider for ordinary childhood problems and case management.

A recent review was in the New England Journal of Medicine (MH Steinberg,
April 1, 1999, page 1021)

Which chromosome is the sickle mutation found on ?

Question: Which chromosome is the sickle mutation found on?

Answer: Chromosome 11 where the Beta chain of hemoglobin in coded. There is one amino acid substitution, a valine for glutamic acid in the beta 6th position that forms sickle beta chains. Two sickle beta chains combined with two alpha chains and four iron containing heme groups form sickle hemoglobin. See our tutorial
http://www.emory.edu/PEDS/SICKLE/tutorial/blood/sld009.htm

Being 50 Years Old with Sickle Cell Disease

Question: My questions are; As a 50 year old AfricanAmerican woman, is chronic pain and soreness normal? Is my LACK of ability to concentrate normal? What about chronic headaches? Every morning, I feel like the Tin Man in The Wizard of Oz. SO STIFF! My hgb is SS. I no longer work outside of my home, my husband is understanding, (or seems to be) regarding my many hospitalizations. Also, back pain and hip pain can be immensely painful. As we, patients, get older, what can we do to improve our quality of life? Thank you for your kindness and patience in addressing these issues.

Answer: You may be experiencing chronic pain from sickle cell disease and this does occur from chronic dammage from sickling in the bones. I would also think
that you and your doctors should consider other causes for the pain. The fact that it is bad in the morning suggests that it may be related to other types of disease like rheumatoid arthritis. I have a number of older patients that have both and respond very well to the treatment of the arthritis. You should have x-rays of hips and shoulders if they hurt most of the time to make sure you do not have avascular necrosis from sickle cell.

If none of these are present, you may benefit from treatment with hydroxyurea to decrease the rate of pain associated with sickle cell disease. You also may benefit from a good chronic pain management plan if there are not problems that can be directly improved. This can often be done through a pain clinic.

Splenic Sequestration

Question: I am caring for a 1 9/12 y old girl with sickle cell anemia, and now with splenic sequestration. Is chronic transfusion still the treatment of choice in this age group?

Answer: generally, yes. There does not appear to be a consensus of expert practice, but three general approaches. Some experts proceed to splenectomy at this age, others wait to allow a bit of additional maturation of the immune system before splenectomy, and others are trying to find ways to preserve some spleen immune function by performing partial splenectomy.

At our center we would put such a patient on monthly transfusion if there has been one life-threatening splenic sequestration or two episodes of splenic sequestration symptomatic enough to require RBC transfusion. Monthly transfusions would not have a specific hemoglobin goal, nor a target percentage of HbA. Instead, the therapeutic goal is to provide some amount of normal RBC so that acute splenic sequestration will not have a life-threatening recurrence. Splenomegaly usually persists on this transfusion program, and the spleen can fluctuate in size with some dips in the Hb and platelet count, but without symptoms. Our timing approach
is to continue transfusions through age 24 months, then we immunize the patient against Strep pneumoniae (conjugate vaccine is all we have right now) and Neisseria meningitides and refer the patient for elective splenectomy. Splenectomy is timed to occur immediately after a monthly transfusion, for maximal hematologic reserve. The surgeon and anesthesiologist pay close attention to post-operative analgesia to avoid atelectasis and acute chest syndrome, and we give IV hydration until the child is drinking well.

Another approach is to perform partial splenectomy on children with splenic sequestration, in order to reduce the volume of sequestering tissue while trying to preserve some splenocytes for immune function. The Cuban sickle cell group published a few years experience showing no sepsis at all using this approach, but then gave us personal communication that there was a case of sepsis that occured since the time of publication. Very few sickle cell centers provide years and years of long-term transfusions if splenic sequestration is the only indication for transfusion. With increasing recognition that transfusional iron overload is a problem in sickle cell disease just as in thalassemia, limiting monthly transfusions to about 2 years seems to be the most reasonable wayto accomplish the treatment for splenic sequestration while avoiding ironchelation.

Are there data about hydroxyurea in children so young and in this indication?
---- I am not aware of hydroxyurea specifically for splenic sequestration, but some centers are offering hydroxyurea to children as young as 2 months (Oakland Children's Hospital, Dr. Lori Styles & Elliott Vichinsky, study in progress to attempt preservation of organ function and maintain high levels of HbF ----- discussed at meetings). Reports on hydroxyurea use for treatment of children with frequent vaso-occlusive pain often comment that spleen may have regenerated in a few patients in the group (study groups led by Drs. Win Wang - St. Jude, J. Paul Scott - Milwaukee, and Russell Ware - Duke University). However, Dr. Peter Lane and colleagues recently reported that RBC pit counts in patients on hydroxyurea did not suggest return of splenic function. Accordingly, I think that there is no strong evidence to suggest that hydroxyurea will be useful for the indication of preventing recurrence of splenic sequestration, and some weak evidence that it may persist.

Foods to Eat for Sickle Cell Patients

Question: What foods should sickle cell patients eat?

Answer: If food is taken in moderation and with a generally balanced selection of foods, I cannot think of many foodstuffs that would be hazardous to somebody with sickle cell disease.
Possible harm from excess iron if somebody already has iron overload from multiple transfusions - so there is generally no need for iron supplements in sickle cell disease. Possible harm from too much diuretic effect if excess caffeine or alcohol is taken, because the fluid lost will make dehydration more likely and more tendency for red blood cells to sickle. Be cautious with medications that tend to dehydrate the body, lower the oxygenation or slow the circulation or enhance clotting.

There is a cookbook that is available, we do not endorse it but it may be of help: Back to Our Roots : Cooking for Control of Sickle Cell Anemia and Cancer Prevention by Dawud Ujamaa
Price: $18.95

Paperback 2nd Rev edition (January 1995) Al Mai Dah Pubns; ISBN: 1884938019
This can be ordered from Amazon.com key word search - sickle cell.
We tell our patients to eat foods rich in folic acid to help build new red blood cells. We have found in a small number of patients that concentrated fish oil (Omega N3 Fatty acid) prevents pain episodes. A large national multicenter study is pending. The best success by our patients is found by staying hydrated with water, good balanced nutrition, no smoking or use of street drugs, and not
over exerting.

Avascular Necrosis Prevention

Question: What can I do to prevent or lessen the chance of avascular necrosis?

Answer: The answer to your question is difficult because there are no studies to help. I can give you some suggestions based on my experience. Exercise is good but it must be low impact for the hips and shoulders. Things that require jumping are not good and jogging is especially bad. Sitting and doing leg lifting type exercises are good as are exercises to keep the shoulders strong. Weights, if used, should be light. A multivitamin with vitamin D and calcium is a good idea. Extra calcium may be good but this should be medically supervised because too much vitamin D and Calcium can cause the calcium to become dangerously high.

Hematuria (Blood in the Urine) and Sickle Cell Trait

Question: I was wondering if I could get your opinion on a patient who I am a physician seeing a patient who has sickle trait and hematuria.

He is a 51 y.o. man healthy all his life who developed substantial hematuria, including passing of blood clots in the urine, in January. Workup at an outside hospital found that he was bleeding from the left kidney, but no source was apparent. He had a renal angiogram that was negative. There was no evidence of papillary necrosis. He had cystoscopy, including cystoscopy of the left ureter post-Stent, which showed blood and clot coming from the area of the left kidney itself. The procedure was limited, however, and no source of bleeding was seen. I saw him for a second opinion in April. The bleeding spontaneously stopped the next day.

Two weeks ago it started again. Cystoscopy here again showed bleeding from the left side. A renal angiogram was negative. All of his clotting parameters are normal.

Any thoughts on a person with massive hematuria and sickle trait. I have only seen minor hematuria with sickle trait, but have been told that this does occur. However, the absence of papillary necrosis seems odd. Thoughts?
Recommendations?
Answer: I have seen a number of cases exactly as you describe. They always seem to
be bleeding from the left side. Older literature suggests they will immediately start bleeding from the right if the left kidney is removed. The episodes are often precipitated by exercise.

Treatment has been very difficult in some of my patients. Strict bed rest appears to be very important for severe hematuria. I use vigorous IV hydration with D5W with 2 amps of bicarb to alkalinize the urine. I usually also give lasix to maintain diuresis and add potassium as needed. If this
does not work, we add epsilon amino caprilic acid once the hematuria is microscopic. Outpatient treatment is the same with oral bicarbonate, water, lasix, and potassium as needed. This usually allows patients to treat most episodes very early and control many without our help. Some use EACA as an outpatient but I do that very rarely.

Prevention is very important. Dancing and basketball seem to be the worse precipitants so hydration before during and after are very important. I usually let the individual decide on limits. Some avoid precipitants and others just put up with the hematuria.

Some cases are very severe and resistant to therapy. I have had an occasional patients that requires transfusion and several that become iron deficient and require chronic oral iron.

Bone Marrow Transplant for Sickle Cell Disease

Question: I have a daughter that have sickle cell. If she would have a step sibling. Could she receive a bone narrow transplant if they match? What risk would it be if they do match an her body rejects the transplant?

Answer: The main concerns with sickle cell bone marrow transplantation are (1) the immunologic match between donor and recipient (HLA types) and (2) the health status of your daughter.

1) A full HLA match between brothers or sisters will have the very best chances for successful bone marrow transplant (BMT). Lesser degrees of match means greater chances of two bad outcomes:
1a) Graft Rejection (your child goes through the BMT process but at the end her own bone marrow grows back and she still has sickle cell disease) or
1b) Graft Versus Host Disease (GVHD - the transplanted marrow attacks the rest of your child's body as foreign tissue and can cause great damage
1c) very seldom will a person have a full HLA match with half-siblings or parents, unless the family tree is very inbred (for example, everyone is from the same isolated village or clan and all are related to each other's cousins. Therefore, your child's step-sister would not have a high chance
of being an HLA-matched donor for BMT.

2) In addition to the chances of the two types of problems listed above (Graft Rejection and GVHD), there is a third set of bad problems that are side effects of the harsh BMT treatment process. Death may occur due to overwhelming infection,uncontrollable bleeding, and failure of organs such as liver or kidney or lungs. The chances that these bad side effects will occur are probably greater if your child is in worse health going into transplant. Therefore, the general feeling among sickle cell doctors in North and South America is that the only patients with severe sickle cell complications should be offered BMT (because only then are the high risks worthwhile), but that they be in relatively good physical condition. Your child may or may not meet these eligibility criteria.

If you have further questions, perhaps you could contact the sickle cell BMT centers in your area. The website for a list Sickle Cell BMT centers is at:
http://www.sickle.fhcrc.org/

HLA Matching for Bone Marrow Transplant

Question: What does HLA matched mean?

Answer:The short answer is: HLA match = immunologic match.

The HLA markers on the surface of cells are what allows the body to
recognize that these cells are its own ("self") or somebody else
("non-self"). Usually we test for HLA in three classes: HLA-A, HLA-B, and
HLA-DR, but there are additional surface markers which are not tested for.
Each person has two possible inherited types in each of these classes,
which are designated by numbers such as HLA-A4, A8 HLA-B27, B19 HLA- DR
1, 11. When all 6 of these are identical between a pair of siblings,
they probably inherited all the same immunologic markers from their
parents, and their cells cannot be distiguished as different by the immune
system. This is the ideal set-up for a bone marrow donor and host:
HLA-matched siblings.

Any mismatch in the HLA types of two siblings means that they inherited
different types from their parents, and that would not be a good set-up
for bone marrow transplant.

Finally, HLA-matching of unrelated people can be done, drawing from
computerized registries of tens of thousands of people willing to be bone
marrow donors (e.g. US National Marrow Donor Program, others in other
countries). However, these unrelated people may match at all 6 of the
markers for HLA-A, HLA-B,and HLA-DR but not match at some of the other
surface markers because they are not from the same parents. The donor
cells would have a fairly high chance of being recognized as foreign.

In each case of a mismatch, greater mismatch in HLA type means higher
chances of two bad outcomes: (1) that donor cells would be attacked by the
host immune system (graft rejection), or (2) the immune system that grows
from the donor cells would attack the host (graft vs. host disease). 
Also, children have less risk of graft vs host disease than adults with
BMT.

For this reason, essentially all of the sickle cell BMT have been from
HLA-matched sibling donors, for a child as the transplant recipient. The
graft vs host disease rate has been relatively low for sickle cell
children, but the graft rejection rate is higher (10-12%) than that for
BMT as cancer treatment. Why the graft rejection rate is high for sickle
cell BMT is not understood. Matched unrelated donors from the National
Marrow Registry have not been used for sickle cell BMT, although one
matched unrelated cord blood stem cell from the New York Cord Blood
Registry has been used (Atlanta, Dr. Andrew Yeager)

You might find additional information about bone marrow transplant in
broad terms from the National Marrow Registry website. Info about HLA
typing may be available from organ donation and organ transplant centers,
since the same HLA matching is done for transplants of heart, lungs,
liver, kidney, etc. to prevent rejection of the transplanted organ.

Hydroxyurea (Hydrea) for Children with Sickle Cell Disease

Question: Can hydrea be used to help children with sickle cell disease?

Answer: Hydroxyurea therapy for pediatric sickle cell patients is in transitionzone between "experimental therapy" and "commonly accepted therapy." In comparison to adult sickle cell patients, the number of pediatric patients treated with hydroxyurea has been small. More teenagers have been treated with hydroxyurea than younger children. Therefore, the descriptions of side effects and crisis reduction benefits are going to change as new information comes out in the next several years of additional experience with hydroxyurea for pediatric sickle cell patients.

In general, the side effects for pediatric sickle cell patients on hydroxyurea look like they are the same as for adult patients:
1) COMMON: MILD NAUSEA OR UPSET STOMACH - many patients have this only for the first few weeks at certain dose, then the nausea goes away. Sometimes nausea is less troublesome if the hydroxyurea is taken at bedtime.
2) COMMON: SUPPRESSION OF BLOOD CELL PRODUCTION - Mild suppression is an
intended side effect of hydroxyurea, but hydroxyurea dosing needs to carefully adjusted and blood cell counts (CBC) monitored frequently (we check every 2 - 4 weeks) to make sure that the suppression does not become severe. Hydroxyurea may suppress the white blood cells too much (leading to increased chances of infection), suppress platelet counts too much (leading to increased chances of bleeding), or red blood cell counts too much (leading to worse anemia, with fatigue and problems for heart & lung function).
3) POSSIBLE THINNING OF HAIR
4) POSSIBLE DARKENING OF SKIN & NAILS
5) RARE: DECREASED KIDNEY OR LIVER FUNCTION
6) RARE: OTHER SIDE EFFECTS NOT CLEARLY ATTRIBUTED TO HYDROXYUREA -
patients on hydroxyurea together with other medications sometimes report dizziness, changes in mood or thought, and other side effects. It is not clear whether these are due to the hydroxyurea or to the patient's other medications.
7) RARE: EXCESS CHANCES OF INTRACRANIAL BLEEDING unrelated to platelet counts - some concerns have been raised about this possibility, but it is not clear whether certain people had bleeding due to hydroxyurea or whether they were going to have a bleed even without hydroxyurea. All of these effects are expected to be reversible (1 thru 7) when the hydroxyurea is stopped. Generally, the medication can then be resumed at a lower dose.

There are POTENTIAL SIDE EFFECTS of long-term hydroxyurea therapy that are major worries, but have not yet emerged as definite problems. We expect that only decades of experience with large numbers of patients will be able to determine whether there are increased risks of
8) leukemia - some people on hydroxyurea for other blood disorders seem to have an increased rate of developing leukemia (cancer of white blood cells). However, it is possible that their blood disorder by itself predisposed those people to leukemia, and not the hydroxyurea treatment. Studies in groups of sickle cell patients on hydroxyurea have not revealed increased DNA damage that would make us suspicious of leukemia development.
9) birth defects - rats treated with hydroxyurea in the lab have shown a higher rate of birth defects than other rats. So far, a handful of babies have been born to mothers on hydroxyurea for sickle cell and have not had birth defects. However, the worry about the possibility of birth defects leads most doctors to give hydroxyurea only when there is no possibility of conception (males or females on hydroxyurea should abstain from sex or use excellent contracepion). It is not known whether being on hydroxyurea for a number of years and then stopping before conceiving a baby will avoid the chances of birth defects.
10) growth and development problems - people have worried that hydroxyurea will slow the growth or development of children with sickle cell disease on hydroxyurea treatment. A few years of tracking several dozen children has not revealed growth & developmen problems so far, but
longer experience is needed.

POTENTIAL LONG-TERM BENEFITS IN SICKLE CELL PROBLEMS: So far, hydroxyurea
treatment seems to be improving only certain aspects of sickle cell disease: pain, acute chest syndrome, priapism, and abnormal red blood cell stickiness to the blood vessel wall (endothelium). Hydroxyurea may not completely eliminate the painful episodes, only decrease their frequency. Small studies have shown no impact of hydroxyurea on the sickle cell damage to the spleen, and perhaps no impact in avascular necrosis of bones such as the hip & shoulder joint bones. It is not clear whether hydroxyurea will affect the risk of stroke in sickle cell disease, but studies examining this question will soon begin. Perhaps there will also be studies on effects of hydroxyurea on retinal damage, kidney damage, and other manifestations of sickle cell disease.

IN SUMMARY - hydroxyurea therapy for a child with sickle cell disease has many possible benefits, and several known risks, and several potential long-term side effects. The full details of the levels of these risks are not known at this time, and probably will not be known until there have
been many more years of experience with sickle cell hydroxyurea treatment.

I strongly recommend an individual discussion with your child's hematologist about the risks & benefits for your child. (We generally have two or three sessions to review the child's medical history and present condition and individualized risks & benefits, give some reading material on the risks & benefits, draw a panel of baseline lab tests (blood counts, vitamin B12 and folate levels, kidney function and liver function, check for hepatitis and HIV infection, test for pregnancy), and check a brain MRI scan for any signs of stroke or abnormal blood vessels that might increase the chances of bleeding in the head.) You need to have a doctor who will follow your child very closely for blood counts and monitor for hydroxyurea-related problems and for other sickle cell
problems.

ALTERNATIVES: Besides managing the complications of sickle cell disease as they occur, the only other alternatives to hydroxyurea therapy presently (July, 1998) are:
1) regular transfusions of RBC
2) bone marrow transplantation - marrow donated by an immunologically-matched (HLA-matched) brother or sister without sickle cell disease.
Both of these alternatives have major risks & major benefits and need individualized discussion with your doctor also. More treatments for sickle cell disease are in the research pipeline, but none is likely to be available outside of a clinical research trial for a couple of years.

Sickle Cell Student with a Sprain and School Guidelines

Question: I am a teacher with a student who has sickle cell disease. Do I use ice on an injury or sprain in a sickle cell patient? What else could I do to keep them well and in class.

Answer: There is no clinical study that solidly demonstrates what to do for asickle cell child with a sprain, but what we have been doing at sickle cell summer camp is a cool compress of wet towel, rather than icepack. Otherwise, the basic recommendations for school is to acknowledge that the child has sickle cell disease, but try to let him or her be as normal as possible with a few caveats:
1) avoid dehydration - allow the child to go to the drinking fountain or bring water bottle as necessary
2) allow for increased urination - may need more frequent trips to the restroom
3) allow for decreased endurance - let the child to set his or her own pace during strenuous exercise, and to take rest breaks when fatigued
4) avoid extremes of temperature - encourage child to dress in layers when the weather is changing, or when going from indoors to outdoors.
5) prompt medical attention for fever (most centers say 38.5C or 101.3F) - need to call parents to bring child for medical evaluation within a hour to rule out sepsis, get blood culture, IV or IM antibiotics
6) develop guidelines with parents for how they would like to have painful episodes managed. Often extra fluids, rest break, and Tylenol or Motrin are sufficient.
7) if child has severe sickle cell disease complications and if the family is willing, perhaps educate classmates about sickle cell disease manifestations such as jaundice, frequent medical absences, decreased endurance, and the need for peers to help the child cope with complicated sickle cell disease. On the other hand, some children have so few sickle cell problems that no special education is needed.
8) remind the family that the child should have regular medical care &
take medications as prescribed.

Sickle Cell - Thalassemia

Question: my nephew was just diagnosed as having Sickle Cell/Thalasemia disease
.Another question I have is: my sister's doctor has explained to her that her son is not producing hemoglobin A and therefore its possible that he has sickle cell disease (he is seven weeks old right now). He has said that its possible that he will produce hemoglobin A and therefore, only be a carrier of the trait. What are the odds that if he is not producing hemoglobin A right now that he will in a few months? From what I've read on the internet, a person has the disease from the moment of conception, and he either has it or not. My sister is hanging on this hope and I don't like to discuss this with her. But, this question has bothered me and I was hoping someone could answer it.

Answer: Your nephew's doctor's interpretation sounds appropriately cautious, but your genetics knowledge is correct also. The genes that control whether a child has sickle/beta thalassemia are indeed present from the moment of conception. The key to understanding the cautious interpretation is that hemoglobin genes are turned on and off in a sequence during prenatal life and early infancy, and that the genes that are EXPRESSED produce will produce actual hemoglobin. The genes for embryonic hemoglobin are expressed first during early development in the womb, then the genes for fetal hemoglobin are expressed, and then finally the adult hemoglobins (hemoglobin A, hemoglobin S, and hemoglobin A2 for your nephew are most likely). The transition point for fetal to adult hemoglobin can take several months, with variation from person to person, but age 7 weeks is too early to be absolutely sure that there will be no hemoglobin A produced. The majority of the hemoglobin produced at that age may be mostly fetal hemoglobins. There is a slight hope that the nephew does have sickle trait.

Some people illustrate this process of sequential gene expression with having 3 cassette tapes and 3 tape players. You play first one tape (embryonic hemoglobin gene), then overlap with turning on another (fetal hemoglobin gene), then turn on the third (adult hemoglobin genes) while you turn off the first, then turn off the second and end up playing only the third tape (Adult hemoglobin genes). You have all the information on the tapes (the genes) but the product (the hemoglobin) is not detected until the player is turned on. If the second tape player is overpoweringly loud (high expression of feta hemoglobin), then it may be difficult to tell whether the third tape is a solo instrument piece (only sickle hemglobin, no hemoglobin A produced) or a piece with two instruments (sickle and hemobglobin A).

In general, the possible medical issues for sickle cell disease type HbS
beta-plus-thalassemia are the same as for sickle cell HbSS disease:
unpredictable severe pain, more susceptible to certain infections,
possible emergencies from problems with the lungs trapping the sickle red
blood cells, anemia and poor endurance and overall less "reserve energy"
to deal with physical stress. Compared to sickle cell HbSS disease,
people with HbS beta-plus-thalassemia are more likely to have the
following sickle cell problems:
1) eye problems - damage to the light-sensing cells of the retina at the
back of the eye 
2) joint problems - sickle red blood cells clogging the blood flow inside
the bones of the shoulder and hip joints, leading to a poor fit of the
ball-and-socket joint, limitation of movement and pain in that joint
3) spleen sequestration - trapping sickle red blood cells in the organ in
the upper left abdomen that ordinarily tries to filter blood cells. 
Sudden trapping of more sickle cells can make the spleen swell many times
its normal size, and trap so much blood in the spleen that the blood in
circulation is decreased - this can be an emergency - symptoms are sudden
paleness, fatigue, sometimes tenderness in the spleen area and headache
from lack of blood flow to the brain. The family and patient should know
how to feel for the enlarged spleen and go promptly to the Emergency
Department if they feel a large spleen and these symptoms are present.

For each particular person, it is unpredictable which of these sickle cell
problems may occur, and how often. We therefore continue to push the
"wellness model," that people with sickle cell should try to recognize
that problems may occur, but try to live in moderation and not be
paralyzed with worry about potential problems. When problems do occur, we
encourage coping and empowering the patient and family to do what is
necessary to return to normal function. 



Leg Ulcers

Question: I am a hematologist/oncologist at the Montreal Children's Hospital and
have recently assumed care of a 17 year old girl with SS disease. She
also has a chronic skin ulcer involving her medial malleolus which has
been present for several months. Needless to say it is quite painful.
It measures about 3.5 x 3.5 cm and there is no edema. There doesn't
appear to be any underlying osteomyelitis by radiographic assessment.
Her care, aside from an exchange transfusion program and a protective
dresssing, I have to admit, has been suboptimal in terms of trying to
heal the ulcer and I would like to start from scratch. I was wondering
what protocols you are using for such patients at present and whether
you have routinely incorporated the RGD matrix as part of your therapy
and if so where does it fit in with respect to other dressings, such as
wet-to-dry and hydrocolloid. Have you started using topical oxygen
regularly? Lastly, for patients without a lot of edema, to what extent
do you place them on bedrest?
Thank you in advance for taking the time to address these issues.

Answer: We have used a very conservative approach to treating leg ulcers and I feel
that there are many ways to heal these ulcers that work if they are done
regularly and consistently. the care has to be meticulous and constant.
The two major factors in healing are debridement and improving blood supply
by improving venous return. The two primary ways we achieve debredment are
saline wet to dry or Duoderm dressing. The saline wet to dry will only work
if done regularly and correctly. The gauze must be cotton sticking type and
it must be allowed to dry completely and be ripped off. Many patients will
not do this because of the pain. The Duoderm works well for us but I am
sure many other semi-occlusive dressings would also work. The principle is
that an environment must be created that allows natural dissolving of the
eschar by leukocytes. We use duoderm because it seems to do this well. The
other advantage is that the dressing reduces pain for most patients. The
dressing is changed twice a week or when there is breakage and the fluid
leaks out. The patients must be warned that the ulcer will first increase
in size. This occurs because all non-viable tissue is dissolved.

The edema/blood flow problem is more difficult. I truly believe that every
ulcer could be healed in 6 to 8 weeks if the patient were placed on strict
bed rest with the leg elevated above heart level in a way that does not
restrict venous return. I have seen this repeatedly in patients at bed rest
for other problems. This is usually not practical but must still be
stressed with the patient so that they do this as much as possible. We use
Unna boots, zinc oxide paste casts, to control the edema and help provide a
healing environment in patients who are ambulatory. These are changed once
or twice a week and work fairly well. Support stockings, elevation and
elastic wraps are used in patients to prevent recurrence after healing and
occasionally in active ulcers when there is considerable edema.

All patients receive zinc oxide PO 220 mg B.I.D. RGD matrix, PDGF, and
other such preparations may well help speed healing but we have not been
able to use them because of cost.

We have not used topical oxygen because I do not believe any study of leg
ulcers that does not have a blinded control arm. Regular attention, a
number of hours of bed rest, drying and a number of other factors may be
responsible for the uncontrolled observation that oxygen helps.

I hope this information is helpful. We have a regular clinic time for leg
ulcer patients and we really sell the treatment. Our results seem good in
the patients that are regular participants but it takes time. Good Luck
with your patient.

Avascular Necrosis of the Hip

Question: HELLO I AM A SICKLE CELL PATIENT. I RESIDE IN NY, AND I AM 25 YEARS OLD. I AM EXTREMELY CONCERN WITH THE FACT THAT I'VE SEEN MOST OF THE PATIENTS AT THE SICKLE CELL CLINIC I ATTEND TO SUFFER FROM NECROSIS IN THEIR HIPS, AND HAVE BEEN EXPOSED ALREADY TO SURGERY. I HAVE NOTICED THAT THE PATIENTS THAT USUALLY HAVE THIS PROBLEM ARE FROM AGE 30 AND UP.

I AM A BIT SCARE ABOUT THE FACT THAT I MAY HAVE TO FACE THE SAME PROBLEM. WOULD YOU PLEASE LET ME KNOW THE CHANCES I SHOULD BE PREPARE FOR IN THIS MATTER? AND IF IS A COMMON PATERN IN SICKLE CELL PATIENTS TO SUFFER FROM NECROSIS?

Answer: Avascular necrosis of the hip is a common complication in older patients
with sickle cell disease. The best data in this country comes from the
Cooperative Study of the Clinical Course in Sickle Cell Disease published in
the New England Journal of Medicine 325:1476-1481, 1991. The estimates from
that study would suggest that about 50% of Hb SS patients would develop this
complication by age 35. Patients with sickle beta plus thalassemia are more
likely to develop the problem and it occurs at a younger age. Patients with
Hb SC develop the complication later and the complication may also occur
less commonly.

Cold Temperature and Pain Events

Question: Iam a 23 yr. old black female with sickle cell anemia and my question is
why certain things cause the red blood cells (RBCs) to sickle. I read in your site that the
cells sickle upon release of oxygen but I have problems with crises when
I swim in water that is too cold or cold weather (among other things),
but I don't seem to have problems if I swim in warm water. What is it about
the cold that increases sickling? Is my body using more oxygen in
the cold? Another question is are some of my RBCs sickled all of the the
time and if so why am I not in a constant crisis? Thank you for answering
my questions.

Answer: You are experiencing a very common problem in sickle cell patients. Most
patients find that cold causes the onset of pain. The cold does not
directly increase sickling of the red cells but it has two effects on the
body that explain the association. Cold increases the use of oxygen by the
muscles and this reduces the amount in the red cells. Shivering is an
example of the extreme of this effect. Cold also causes the blood vessels
to contract down and become smaller to preserve body heat. This directly
reduces blood flow and any sickling of red cells causes further slowing of
flow. The slower blood flow also reduces further oxygen in the blood and
low oxygen causes increased sickling. Dress warm with hat and gloves. Swim
only in warm heated pools. You also need to drink lots of water in real
cold weather and when swimming because both can also cause dehydration that
will increase sickling..

There are some cells that remain sickled at all times. Chronic pain is not
well understood but is real and likely results from damage to the bones. If
the pain is localized, this is very likely to be the case. The causes of
pain that occurs all of the time is not well understood.

Air Travel and Sickle Cell Disease

Question - I have sickle cell and I will be flying to NJ in July. I was wondering
if there is any info on preventing crisis after flying. I have flown
several times in the past and have always wind up in an emergency room a
few hours/days later...there has to be some sort of connection??!! Any
advice will be appreciated. I ralize that plenty of water
before/during/after the flight is need. However, what about oxygen
during the flight?? Please respond!!

Answer - There is definitely a connection with sickle crisis and flying in some
patients. The major problem is a decrease in oxygen in the cabin air. The
aircraft is only pressurized to about 7,000 feet which is low enough to get
some people with sickle cell in trouble. The other problem is related to
dehydration. The humidity in the aircraft is very low and fluid intake
needs to be markedly increased before and during the flight.
If you have had trouble flying, I would recommend supplemental oxygen at 2
liter per minute. Most airlines are willing to provide this but there will
likely be a charge and you have to make arrangements well in advance. The
airlines I have dealt with require two weeks notice and a doctors letter
that establishes the need for oxygen and also specifies the rate of flow.
You need to talk to the airlines as soon as you have a time scheduled and
find out their requirements. They will need to know your flight number, but
I would check their requirements immediately.
I would also get an aisle seat and plan to be able to drink a pint of water
an hour during the flight. This will also likely require you to carry on
fluids.

The take off and landing are not the critical periods. Because the cabin pressure is
reduced, the period of concern is when the plane is at greater than 10,000
feet or approximately 3,000 meters. This means that oxygen will need to be
used for the majority of the flight. We generally recommend 2 liters/minute
but this is not based on direct measurements of hemoglobin oxygen
saturation. This will require 120 liters/hour or about 720 liters for the
flight. This information should be available from the airline.

I would recommend that you make sure you have a supply of all of the
medicines you will need for the duration of your visit. You should also
have a letter from their doctor that summarizes the disease complications
and the most recent laboratory results so that if they do get sick the
treating doctors will know what is average for them. It is also important
that all vaccinations are up to date.

Taking in lots of fluids is important. Brief exercise will help but should
be short in duration because they will be without oxygen.

I hope all goes well. You must understand that some of my patients fly all
over the world without any of these precautions and do well, but that the
children could still have problems despite you efforts.

Sickle Trait and G6PD
Question - My wife and have a question that local doctors can not seem to answer;
we were wonder if perhaps someone here could help. My wife has Sickle
Cell Trait while I have G6-PD blood deficeincy. We are worried that
there might be health problems for a baby being conceived with our blood
disorders. Your help is greatly appreciated. thank you

Answer - If the parents know that mother has sickle trait and father has no
abnormal hemoglobins, then the children might have either sickle trait or
normal hemoglobin. It would be important for father to have his hemoglobin
type confirmed.

If the father has G-6PD deficiency and mother does not, there is a small
chance that children would have G-6PD deficiency also - probably less than
50% chance for girls, hardly any chance for boys. The genetics of G-6PD
are co-dominant for females.
If some child has both sickle trait and G-6PD deficiency, it is not a
bigger deal than G-6PD deficiency alone.
Overall, these hematologic conditions should not be regarded as major
worries that would bar a couple from having children

New Treatments
Question - My son is a sickle cell patient. He is 19 years old. I recently heard that a cure was being developed. I was wondering if you could send me any information on the
research and how fast it is developing.

Answer - The only true cure today is bone marrow transplant to replace the
factory that makeds the red blood cells with a matched donor, usually a
brother or sister with out sickle cell disease. There are medications
like hydroxyurea that decrease pain episodes and complications. New
research is under way for better treatments and a cure for all.

Ask a question - contact the Sickle Cell Center staff at aplatt@emory.edu

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