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

Major Topics: Sickle Cell Disease , Bone Marrow and Stem Cell Transplant, Sickle Cell Trait and G6PD, Students and Teachers,  Physicians, Nurses and Health Care Providers, Sickle Cell Newborn Screening 

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What About the different types of Sickle Cell Diseases

Question: What is the difference in sickle cell trait and the different types of sickle cell disease? 

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.scinfo.org/nihnewchap3.htm and our guide at http://www.scinfo.org/sickletrait.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.

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.scinfo.org/hemoglb.htm and http://www.scinfo.org/tutorial/Sickle%20Cell/index.htm

Life Expectancy

Question: What is the average life expectancy for  some one with sickle cell disease?

Answer: Median survival of individuals of all ages with sickle cell disease based on genotype and sex (Platt OS, Brambilla DJ, Rosse WF, et al. Mortality in sickle cell disease- Life expectancy and risk factors for early death. N Engl J Med 330(23): 1639-1644 (1994). 

Sex and Genotype Median Survival
Males with Hb SS  - 42 years
Females with Hb SS - 48 years
Males with Hb SC - 60 years
Females with Hb SC - 68 years

Note that this was reported in 1994. Now in 2002 many new advances with the medication hydrea, the new pneumoccocal vaccine Prevnar, stroke prevention with TCD, and cures with bone marrow transplants the life expectancy is increasing.

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.

 Pain with Menses

Question: My daughter has sickle cell pain always arround her period, what can we do?

Answer: Many women with sickle cell disease experience pain around the time of their menstrual periods. Female hormone changes probably affect the way sickle cells and blood vessels interact. The use of ibuprofen at the very onset of the periods is a good idea, but needs to continue around the clock for the duration of the period (600 mg every 6 hours) in order to maintain an effect on reducing inflammation. 
Alternative medications include Naprosyn, another member of the non-steroidal 
anti-inflammatory drug type. This approach may not completely prevent the pain 
episode, so a stronger pain medicine like Tylenol with Codeine should be begun as soon as she is having moderate or worse pain, to try to keep the symptoms from getting too severe. Lastly, for women who have this problem every single month, we have some success with hormone treatments to try to keep the estrogen and progesterone in the body from going to extremes. This would involve the medications usually used for birth control - the oral contraceptive pills or injectable Depo-Provera. Some parents naturally get a little nervous about this approach in their teenaged daughters because of the fear that it gives the child "license" to have sex. This is something that you will need to discuss with your daughter and her primary provider to see if it is an acceptable treatment. Most of the women (young and older) whom we have treated with hormone therapy report a reduction in the pain episodes associated with their periods.

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.

Question - What is the best fluid for a sickle cell patient to drink to prevent pain crisis or during a pain crisis?

Answer The sickle cell centers in Atlanta and Philadelphia recommend water as the drink choice during an episode of sickle cell pain.  The rationales are:
(1) sickle red blood cells tend to be dehydrated, 
(2) test tube studies show that adding water to the sickle red blood cell can lower the hemoglobin concentration and decrease sickle polymer formation. 
(3) a study from the 1960's showed that giving IV fluid without electrolytes (5% dextrose in water, abbreviated D5W) or low in electrolytes (D5  1/4normal saline) was better than IV fluid with electrolytes for sickle cell crisis patients hospitalized for crisis.
(4) kidney damage from sickle cell makes it harder to excrete sodium than the average person, so that continuously adding too much salt to the body may worsen the dehydration of the sickle red blood cells and increase sickle polymer formation.
(5) too much water given IV (in the vein) may cause problems with edema of the lungs or brain, so IV overhydration is not a good idea. A combination of IV and oral fluid intake is preferred, because the patient's hormonal control of thirst can keep electrolytes and volume from getting too far out of line.

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.

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.

Hydroxyurea (Hydrea) for Children with Sickle Cell Disease

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

Answer:  Updated by Dr. Lewis Hsu 7/04 - Hydroxyurea therapy for adult sickle cell patients is commonly accepted therapy, and the United States FDA approved this use since 1997. Hydroxyurea therapy for children had probably made the transition from "experimental therapy" to "commonly accepted therapy," but the FDA has not officially approved hydroxyurea for children because fewer pediatric patients have been studied on hydroxyurea. 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 and adult sickle cell patients on hydroxyurea look like they are similar:
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 early concerns were 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 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. To date (June, 2004), studies of sickle cell patients on hydroxyurea have not revealed an increased cancer rate.
9) birth defects - rats treated with hydroxyurea in the lab have shown a higher rate of birth defects than other rats. So far, about 14 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 contraception). 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. Several years of tracking several dozen children has not revealed developmental problems so far, and their growth may actually be improved on hydroxyurea, but longer experience is needed.

POTENTIAL LONG-TERM BENEFITS IN SICKLE CELL PROBLEMS: So far, hydroxyurea treatment seems to be improving several aspects of sickle cell disease: pain, acute chest syndrome, priapism, and abnormal red blood cell stickiness to the blood vessel wall (endothelium). One study indicates that hydroxyurea increases life expectancy in adults with severe sickle cell disease. Hemoglobin level typically rises by 1 gm/dL (less anemic) and many underweight people gain some weight on hydroxyurea. Small studies indicate that hydroxyurea may provide partial protection from stroke in children who cannot receive blood transfusions. 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, chronic lung disease, and perhaps no impact in avascular necrosis of bones such as the hip & shoulder joint bones. 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 (June 2004) 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 Beta Thalassemia

Question: my nephew was just diagnosed as having Sickle Cell/Thalasemia disease..The 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.

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.

Cold temperature causes reflexes to constrict the blood vessels and slow down the blood flow to hands, feet, & other parts of the extremities, in order to conserve heat for the core functions of the body (brain & trunk). Any condition that slows down blood flow has the potential to trigger sickle cell pain. People can adapt to cold weather and also can dress warmly to reduce heat loss so that blood vessels do not have these reflex constrictions. A few days every winter, however, have severe snow
& ice storms or just severe cold when it is hard to really stay warm no matter what you do.

Warm temperature causes reflexes to open (dilate) blood vessels and send more blood to the skin and extremities to shed heat. This re-distributes blood flow and may shunt blood flow away from parts of the body that need oxygen or need to clear the chemical waste of metabolism. Those parts of the body might then develop sickle cell pain. Sweating helps the body lose heat, but also may lead to dehydration, and dehydration is a common trigger for sickle cell pain. People can adapt to hot
weather by keeping to the shade or air conditioning, by drinking a lot of fluids to avoid dehydration, and avoiding excessive exertion while taking frequent rest breaks.

Generally, I have seen many many more families complain of cold weather triggering problems with sickle cell pain, than of hot weather as a trigger. I have seen very few families with sickle cell choose to move northward. 

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?

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.

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. see our research update report by  clicking here

Dental Work 

Question: Please inform me what are the precautions for dental cleanings-prophylaxis without deep subgingival scaling of children with sickle cell anemia? 

Answer: 1) The recommendations for antibiotics before dental work recently changed, because of new evidence that there is not as much bacteria released into the bloodstream as originally believed.

http://jada.ada.org/cgi/content/full/138/6/739
http://www.dentalcompare.com/news.asp?newsid=186088

Since these new guidelines came out last year, our sickle cell center no longer routinely recommends antibiotics for dental work for sickle cell patients -- only for selected situations.

2) We also recommend that any dental care be done with local anesthesia rather than conscious sedation or general anesthesia, because of worry about the risks of low oxygen and sickling in the chest when breathing shallowly under anesthetic.
3) It is wise to check with the child's physician(s) for any additional individual concerns -- most children with sickle cell are in overall good shape, but some have major complications/health issues such as stroke, chronic lung disease, central venous line, anaphylaxing allergies, bone marrow transplant, splenectomy, etc.
4) We strongly encourage regular dental care as a part of good health. To my knowledge, hardly any specific studies have been done on dental problems and sickle cell disease. A blood flow study showed that gingival and dental microcirculatory blood flow is abnormal in adults with sickle cell. A cross-sectional dental exam of 132 children at the sickle cell center in Children's National Medical Center in DC found 20-30% fewer decayed filled teeth than national averages, adjusted for race and socioeconomic status (J MacDonald DMD (2002) Sickle Cell Disease and Dental Caries, abstract 90 at the National Sickle Cell Meeting Sept 2002 in Washington, DC).
5) All of these concerns are greater for children with Hemoglobin SS and Hemoglobin S-beta-zero thalassemia, than for those with other types of sickle cell disease (Hemoglobin SC, Hemoglobin S-beta-plus-thalassemia)

This Question and Answer Section is provided by Duane R. Bonds, M.D. of the NHLBI - Blood Diseases Program

Thiocyanate

Question : Can you please provide me with information on cyanate (1) and
thiocyanate (2) containing compounds? I give a nutritional supplement that
contains thiocyanate to my son who is sickle cell SF.

Answer :
Cyanate was studied in the 1970's and early 1980's in patients with sickle
cell disease. Although cyanate was shown to prevent the sickling of red
blood cells in a test tube (in vitro), its use in human beings was abandoned
after toxicity was reported in sickle cell disease patients. The adverse
events that were seen included nerve damage and eye cataracts.

The U.S. Food and Drug Administration (FDA) does not require testing of
compounds provided that they do not make medical claims, so there are few
studies to show what happens to individuals who ingest many compounds.
Studies of the effects of compounds on cells in test tubes in the laboratory
often do not have the same effects in the human body. This is because of
how the compounds get into the body and what the body does to them in the
process. Also, even though a compound may have the desired action on the
cells, we do not know what other effects it may have on the human body. For
example, high doses of many compounds kill cancer cells in test tubes, but
they cannot be tolerated at those doses in humans. 

1a. Arch Intern Med 1975 Aug;135(8):1043-7; Toxic-therapeutic ratio of
sodium cyanate. Charache S, Duffy TP, Jander N, Scott JC, Bedine M, Morrell
R.

Abstract: Six patients with sickle cell anemia were treated with sodium
cyanate (30 mg/kg/day). In four, treatment was stopped because of definite
or suspected toxicity, and no improvement was seen in the other two. Most
alarming was the sudden development of peripheral motor neuropathy [nerve
damage] in a patient whose red blood cells contained less than 0.6 mols
NCO-/mol of hemoglobin: six months after treatment was stopped, function had
not completely returned in this patient. Safe oral dosage regimens may not
be effective, but extra-corporeal treatment of sickle cells with cyanate, or
other compounds, might circumvent that problem. [The amount of this drug
that can be safely taken by mouth may not be effective, so treating of
sickle blood cells outside of the body was suggested to get around this
problem.]

1b. Arch Ophthalmol 1976 Jun;94(6):927-30; Cyanate-induced cataracts in
patients with sickle-cell hemoglobinopathies. Nicholson DH, Harkness DR,
Benson WE, Peterson CM. 

Abstract: Two young patients developed bilateral posterior subcapsular
cataracts while receiving oral sodium cyanate for treatment of sickle cell
hemoglobinopathy. In one of the patients, lens opacities regressed
spontaneously after cyanate therapy was discontinued.

1c. J Lab Clin Med 1982 Sep;100(3):345-55; Preliminary studies of
continuous extracorporeal carbamylation in the treatment of sickle cell
anemia. Balcerzak SP, Grever MR, Sing DE, Bishop JN, Segal ML.

Abstract: The lack of effective therapy of sickle cell anemia has prompted
investigation of a large number of antisickling agents. The most promising
drug, cyanate, was found in previous studies to be toxic when given
systemically [when put into the body in contrast to treating the sickle
cells outside of the body]. 

2. Thiocyanate toxicity includes vomiting, excitation, delirium,
convulsions; chronic exposure can cause skin rashes, coryza, and CNS
symptoms; cyanide effect does not occur (Merck Index, p. 1042, 8th
edition). There is no published information containing controlled clinical
trial data from patients with sickle cell disease who were given
thiocyanate. There is only data from published studies done in vitro (in
test tubes) showing that thiocyanate may prevent sickling of blood cells,
and a case report on one patient from 1932 who was given many drugs
including thiocyanate.

2a. Proceedings of the 1974 First National Symposium on Sickle Cell Disease,
June 27-29, 1974, Levine, A.S., et al, Perturbants affecting gelation, rates
of aggregation and solubility of sickle hemoglobin, page 147-149; oral
abstract presented during this symposium with data showing that thiocyanate
inhibits sickling of red blood cells in a test tube. 

2b. Lew, V.L., Ortiz, O.E., Bookchin, R.M., Stochastic nature of red cell
population distribution of the sickling-induced Ca 2+ Permeability, J. Clin.
Invest., 99:2727-2735, 1997; calcium activated potassium channels in sickle
red blood cells were studied with the use of a variety of compounds
including thiocyanate in vitro (in test tubes).

2c. Agbai O. Anti-sickling effect of dietary thiocyanate in prophylactic
control of sickle cell anemia. J Natl Med Assoc. 1986 Nov;78(11):1053-6.
This is a review article that summarizes the work of other scientists and
presents the opinions of the author.

2d. Haywood LJ., Thiocyanate in sickle cell anemia. J Natl Med Assoc. 1987
Oct;79(10):1032. This is a letter to the editor of the Journal of the
National Medical Association which was written by the then former Director
of the Comprehensive Sickle Cell Center in Los Angeles in response to (2c),
pointing out that the failure to observe adults with sickle cell disease in
Africa has been secondary to the high infant mortality of sickle cell
disease patients because of the high rate of infections and malnutrition
rather than the ingestion of thiocyanate containing vegetables. The only way
that thiocyanate could change the appearance of the number of adults with
sickle cell disease would be if it could change the genes of each person who
inherited two sickle genes (Hb SS).

2e. E.G. Torrance, T.G. Schnabel, Potassium Sulphocyanate: A note on its use
for the painful crises in sickle cell anemia, Annals of Internal Medicine,
6:782-788, 1932. A review of the literature and a case report of one patient
who received a long list of drugs including morphine, nitroglycerin,
atropine sulphate, adrenalin chloride, potassium citrate and sodium
bicarbonate with potassium sulphocyanate [thiocyanate]. The authors state
that no conclusions can be drawn from this one case report and that more
studies are needed.

Talk to your son's doctor about using hydroxyurea which does not have these
associated problems and has been approved by the U.S. Food and Drug
Administration (FDA) for use in adults with 3 or more painful crises per
year, but has not been approved for use in children by the FDA. Some
pediatric hematologists in the U.S. are studying the use of hydroxyurea in
children as part of local university research protocols. The National Heart,
Lung, and Blood Institute (NHLBI) is currently studying hydroxyurea in young
children. The results of this major clinical trial should be available in
appx. 4 years.

If your son has fewer than 3 crises per year because he has hereditary
persistence of fetal hemoglobin [you mention that he is 'SF?], he may not
need any additional therapies because his prognosis is good. Again, discuss
this with his doctor.

Thiocyanate and Cyanate

Question:  Are thiocyanate and cyanate the same? I have searched for
literature on thiocyanate and cannot find it. Are we exposed to thiocyanate
by carrots, African yams, legumes and other foods? Are these compounds in
regular foods? 

Answer: The cyanate compounds are related in that they are derived from a
similar molecule that the body converts back and forth after ingestion of
certain vegetables. The earlier reports from 30 years ago suggest possible
significant harm in sickle cell disease patients after cyanate treatment.
There are no studies on thiocyanate other than its effects on sickle red
blood cells in test tubes and one case report from 1932 that describes a
sickle cell patient who received thiocyanate and many other drugs. 

A review of the scientific literature did not reveal any scientific papers
that demonstrated safety and effectiveness of thiocyanate in patients with
sickle cell anemia, nor any animal toxicity or pharmacokinetic [how the body
chemically handles drugs] data that described the blood levels and excretion
pattern of this agent. No randomized comparison of thiocyanate with either a
sugar pill (placebo) or an established drug (hydroxyurea) has been conducted
in enough patients to answer the question of whether or not this therapy
works. Although thiocyanate prevents red blood cells from sickling in a test
tube, this is not sufficient data to recommend its use in any patient with
sickle cell disease.

It is of particular concern that this therapy is being given to young
children in the absence of safety and toxicity data. Children cannot give
informed consent, and must trust the adults in their lives to use judgment
to protect them from harm. If we do not know how much thiocyanate can be
given before it becomes toxic, or how it is eliminated from the body, it
cannot be considered safe. An analogous situation would be the use of
Vitamin A. Vitamin A is a fat soluable vitamin, and it is therefore
difficult for the body to eliminate when too much is taken in. This is very
different from Vitamin C, a water soluable vitamin that when too much is
taken in, the body removes it by excreting it in the urine if the kidneys
are healthy. We do not know how thiocyanate is handled by the body of a
patient with sickle cell disease, nor do we know how much is too much. We do
know that other drugs in this family are quite toxic, so safety of
thiocyanate is yet to be proven.

The major organs of the body that handle chemicals are the kidneys and the
liver. Sickle cell disease patients begin to have damage of the liver and
kidneys in early childhood. This is another reason that it is important to
know how any new drug is handled by the body before it is assumed to be safe
for sickle cell disease patients.

The concept that sickle cell disease is not seen as frequently in Africa as
it is in the U.S. because of thiocyanate ingestion is not supported by the
facts. The reason that individuals with sickle cell disease are not seen as
frequently in Africa is because they die in infancy and early childhood from
bacterial infections, malaria, and malnutrition [Thiocyanate in Sickle Cell
Anemia, Haywood, J., J of National Medical Association, 79:1032, 1987]. In
West and Central Africa, one in 50 newborns has sickle cell disease,
compared with 1 in 400 in the U.S. Approximately 1,200 babies with sickle
cell disease are born in the U.S. annually compared with about 200,000 in
Africa. Sadly, babies and young children with sickle cell disease die unless
they can benefit from the kind of comprehensive medical care and protective
penicillin which is now available to sickle cell disease infants born in the
U.S. An NHLBI project funded in Ghana has demonstrated that comprehensive
care similar to that given in the U.S. can decrease infant mortality of
African children with sickle cell disease [K. Ohene-Frempong, Director of
NHLBI funded Comprehensive Sickle Cell Center, Children's Hospital of
Phila., personal communication].

Other References:
1. Gillette PN, Manning JM, Cerami A. Increased survival of sickle-cell
erythrocytes after treatment in vitro with sodium cyanate. Proc Natl Acad
Sci U S A. 1971 Nov;68(11):2791-3. Cyanate reacts with the amino-terminal
valine residues of hemoglobin S and prevents the sickling in vitro (in test
tubes) of 50-80% of erythrocytes from patients with sickle cell disease.

2. Houston RG. Sickle cell anemia and dietary precursors of cyanate. Am J
Clin Nutr. 1973 Nov;26(11):1261-4. Review article that discusses opinions of
author and work of others; suggesting that sickle cell disease is not seen
in adults in Africa because of dietary intake cyanate and thiocyanate
compounds.

3: Lambotte C. Letter: Sickle cell anemia and dietary precursors of
cyanate. Am J Clin Nutr. 1974 Aug;27(8):765-6. Written to the editor in
response to reference #2 pointing out that adults with sickle cell disease
are rarely seen in Africa because of high death rate of infants with sickle
cell disease.

4. May A, Bellingham AJ, Huehns ER, Beaven GH. Effect of cyanate on
sickling. Lancet. 1972 Mar 25;1(7752):658-61. The effect on oxygen affinity
of carbamylation of normal red cells has been compared with that of sickle
cells and found to be identical. This is an in vitro (in test tube) study of
cyanate effects on red blood cells.

5. De Furia FG, Miller DR, Cerami A, Manning JM. The effects of cyanate in
vitro on red blood cell metabolism and function in sickle cell anemia. J
Clin Invest. 1972 Mar;51(3):566-74. Description of in vitro study (in test
tubes) of the effect of cyanate on sickle red blood cells.

6. Cerami A. Cyanate as an inhibitor of red-cell sickling. N Engl J Med.
1972 Oct 19;287(16):807-12. Review article discussing early work of others
and the author previously published on the effects of cyanate on sickle red
blood cells.

Dietary Supplements 
Question : I am part of the same forum that promotes thiocyanate. There
was also mention that the following herbal supplements were good: Hemp Seed
Oil (Omega 3and 6), Flax Seed Oil (Omega 3 and 6), Prickly Ash Bark
(circulation), Vitamin E, Ginko Biloba (circulation). Are any of the above
dietary supplements dangerous? My daughter is 6 months old with SS. 

Answer :
I hope that if I take a moment to explain to you what is involved in
obtaining reliable evidence that a therapy works, I hope that this
information will reach patients and families with sickle cell disease.

Establishing the safety of drugs is important. Giving drugs is prohibited
without such information. In order for therapies to be recommended, a
lengthy process of developing evidence for their effects must be followed.
This process has 3 to 4 phases. The first phase starts with safety in
animals. Nearly everything that we take into our bodies can be harmful at
high enough levels. Initially, animal models are used to find the doses
that are harmful to animals. Then, the animal doses are converted to human
doses, and the therapy is tested in humans for safety and how the body
processes these drugs. If after this information is obtained, small studies
(designed to minimize the number of patients exposed to new drugs in case
they are harmful) are done to further show safety and see if the drugs do
what they are supposed to do. If they appear to work, then they are tested
in larger studies to prove that they have the desired results. Lastly,
after they are approved and placed on the market, to further insure patient
safety, many patients are followed to insure that small numbers of
unexpected results were not missed. 

Dietary supplements are not required to undergo this process. Many
suppliers of dietary supplements are very careful not to advertise medical
benefits. As long as they do not make claims that their supplement cures
this or that, they can avoid this rigorous testing process. That does not
mean that they are safe. A current example is the dietary supplement
ephedrine. This compound has been used in many dietary supplements for
weight loss. We are now finding out that a number of patients died from
this compound contained in dietary supplements.

Whenever a therapy is proposed for sickle cell disease patients, we look at
the previously published scientific articles on the proposed therapy,
usually in small numbers of patients [this includes drugs, blood
transfusions, or dietary supplements]. We then ask the question, is there
enough evidence that this therapy may hold promise so that the National
Heart, Lung, and Blood Institute (NHLBI) [one of the Institutes of the
National Institutes of Health] should sponsor a randomized, controlled,
phase III clinical trial [a large confirmatory study with human subjects who
are assigned to receive a study drug or placebo/comparison drug by the 'flip
of a coin'] to test if the therapy works? Until a phase III clinical trial
is done to prove that a therapy is effective, we cannot know if the therapy
does what the scientists say that it might, nor do we know if the therapy is
safe. It is important to test all therapies in a sufficient number of
patients with a proper control group to get an answer before a therapy is
adopted for use. If a therapy shows benefit in one patient, that could have
happened by chance because sometimes patients get better taking a pill just
because they think that the pill will work. This is called the placebo
effect. This is why we compare a proposed new therapy against a placebo or
an established therapy in a randomly assigned group of patients to be sure
that the beneficial effect is not occurring just because of luck or chance.

I know that penicillin prevents pneumococcal sepsis in infants with sickle
cell anemia because NHLBI sponsored a phase III clinical trial during the
1980's that proved that it works (Prophylactic Penicillin Trial I or PROPS I
- done in 215 infants). In addition, I know that hydroxyurea is effective in
decreasing the rate of painful crises, acute chest syndrome, transfusions,
and hospitalizations in adults with sickle cell anemia because NHLBI
sponsored a phase III clinical trial that ended in 1995 demonstrating that
it works (Multicenter Study of Hydroxyurea or MSH - done in 299 adults).
Finally, I know that blood transfusions given to children at risk for stroke
can prevent stroke because NHLBI sponsored a phase III clinical trial that
ended in 1997 demonstrating that chronic transfusions work (Stroke
Prevention Trial in Sickle Cell Anemia or STOP I - done in 130 children).

When someone proposes any new therapy, we look at the scientific articles
that have been published to see if a phase III clinical trial should be done
to prove that the proposed therapy is safe and effective. A phase III
clinical trial is defined as a comparison of a new drug to a sugar pill with
the patients in the trial and their doctors not knowing which drug is being
given until the trial is over (double-blind placebo controlled) or an
equivalency trial where a new drug is compared to an established drug that
has already been proven to be effective. A single case report of a drug
working in one or 2 patients is not considered proof of effectiveness
because this observation could have happened by chance. Any investigator
who proposes a new drug for use in patients must obtain proof of
effectiveness by studying enough patients with a given problem (example:
lowering of the sickle cell crisis rate) when the new drug is compared to
the sugar pill (placebo) or the established drug. A statistical test is done
on this hypothesis [an assumption] of lowering of the crisis rate when the
new drug group is compared to the sugar pill group, and only if this test
shows that the chance of the observed difference being wrong is less than 5%
is effectiveness proven. In the case of hydroxyurea, the only drug that has
been approved for use in lowering the rate of sickle cell crisis in adults
by the FDA, 299 patients were studied from 1992 to 1995. The crisis rate in
the hydroxyurea group was decreased by 50% when the data was analyzed at the
end of 1994. 

Small human studies of cyanate demonstrated that it was NOT safe, and
therefore a phase III clinical trial in a larger number of patients did not
go forward on this agent. Many respected and caring doctors who had spent
years in sickle cell disease clinical research were very disappointed that,
although cyanate prevented sickling of red blood cells in test tubes, IT WAS
NOT SAFE TO GIVE TO PATIENTS. Thiocyanate has not been carefully studied in
sickle cell disease patients in either small dosing studies or a phase III
clinical trial with a large number of patients and a control group.

I know that some doctors have been studying the Omega 3 fatty acid
supplements in small numbers of adult patients, and although the early
reports are promising, these studies are ongoing. [Thromb Haemost 2001
Jun;85(6):966-74; Reduction of pain episodes and prothrombotic activity in
sickle cell disease by dietary n-3 fatty acids. Tomer A, Kasey S, Connor WE,
Clark S, Harker LA, Eckman JR. Department of Hematology and Oncology,
Winship Cancer Institute, Emory University School of Medicine and Georgia
Sickle Cell Center of Grady Memorial Hospital, Atlanta 30303, USA.]

With regard to the other dietary supplements, I have no information from the
scientific literature that I can quote to you that demonstrates that even
small human studies have shown any benefit in preventing sickling. At this
time, my conclusion would be that dietary supplements should not be used
until they are properly studied and proven to be safe and effective or shown
to not be effective or safe.

Bottom line: be skeptical, and ASK for the scientific evidence. Make anyone
who tells you that they have something that will work prove it to you and to
us here at NIH. We are sponsoring basic science and clinical research to
find a cure for sickle cell disease.

Duane R. Bonds, M.D.
Blood Diseases Program
DBDR, NHLBI
6701 Rockledge Drive, MSC - 7950
Bethesda, MD 20892-7950
301-435-0055 (voice); 301-480-0868 (fax)
INTERNET:db56g@nih.gov

Adoption

Question: My husband and I want to adopt a child with sickle cell disease. What should we expect?

Answer: - Thank you for your questions, and for considering adoption.1) The bottom-line answer to your question about what to expect is that sickle cell disease is
unpredictable. There may be frequent hospitalizations, or not. It may be very hard to tell that she hassickle cell, or it may have a big role. Home care and regular medical checkups with a medical teamexperienced in comprehensive care of sickle cell disease are the main parts of sickle cell care. You willlearn to give daily medications such as penicillin and folic acid, feel for whether the spleen is enlarged,and avoid triggers for sickle cell pain (dehydration, exhaustion, extremes of temperature). Fever is an emergency in children with sickle cell, and there may be other emergency visits for pain as well as home care for pain management. It is helpful to have a flexible family schedule, transportation, and a fair amount of support from extended family & friends. 
If the developmental delay resolves, then intellectual function should be normal, and you can expect her to grow up, finish school, and become a productive member of society. Your family needs to walk the balance between (a) completely denying that the child has special healthcare needs and (b) overprotecting the child & keeping her in a bubble.

2) We do not expect developmental problems as part of sickle cell disease, and I am not sure why this child has developmental delay that needs PT, OT, and speech therapy. It might be good to ask whether she has had stroke, or whether the developmental delay is part of her previous home situation (we would then expect good catch-up with the rehab services and a loving family).

3) Some studies have tried to identify predictors for severe sickle cell complications. Predictive factors include: low baseline Hemoglobin level (less than 8 gm/dL), high white blood cell count ( > 15 or 20,000/cu mm), pain early in infancy (< 6 months) with the hand-foot swelling pattern, low oxygen at night, and absence of the inherited alpha thalassemia or high fetal hemoglobin. These are statistical factors, however, and cannot predict exactly what will happen in an individual.

4) Many people with sickle cell overcome their disease or live with their disease with very good quality of life (lawyers, business owners, doctors, ministers, grandmothers, golf pro, recording artists, etc). Life expectancy is much better than before, studies published in the 1990's listed life expectancy for HbSS in the mid-40's and HbSC in the mid 60's --- these are probably better now. Hydroxyurea has increased life expectancy, and there are slowly increasing options for cure by bone marrow transplant . Additional new treatments and cures for sickle cell are in research, and the future looks bright.

Folate or Folic Acid

Question:  Why should I take the vitamin Folate (Folic Acid)

Answer: Our practice has been to prescribe folate supplement 1mg by moth every day from the initial diagnosis, for all patients regardless of age or hempoglobin type or transfusion status. 

1) For HbSS this is the standard of care. (NIH guidelines 2002 - available on-line. Also see the Problem-Oriented series from the Georgia Comprehensive Sickle Cell Center on-line)

2) It is mildly controversial to prescribe folate supplements in the types of sickle cell disease with lower level of reticulocytosis (HbSC, HbS beta-plus thalassemia, HbSS with hereditary persistence of fetal hemoglobin): 
a) some doctors think that the more prescriptions are added to the regimen the less likely the family will comply with the most important Rx of penicillin prophylaxis. 
b) some doctors think that emphasizing good dietary folate intake is good enough because the need for folate is lower than HbSS
c) there are a few reports that vitamin B12 deficiency can be masked by folate supplementation in sickle cell and other hemolytic anemias
d) folate supplementation of bread and other cereal foods, mandated in the US since a couple years ago due to concern about fetal neural tube defects, provide more dietary folate than just naturaly-occuring folate in fruits & vegetables.

My rationales for widespread use of folic acid are:
1) It is cheap (9 cents per 1mg pill), not particularly bad-tasting, no toxicity or allergies. The  pill can be crushed and put into anything - really does not hurt
2) typical American kids' diet is not high in fruits and vegetable sources of folate. It is generally good in B12.
3) sickle cell high-grade hemolysis requires daily high level of RBC production requires lots of folate and the consequences of folate deficiency include cognitive delay, which may not be reversible
4) excess folate is just excreted in urine - no harm
5) nutritional status in sickle cell disease, especially HbSS, is already marginal in terms of protein & calories. Folate is not stored in the body, and needs daily replenishment. Why make diet recommendations more complex by requiring high-folate foods as well as protein-calorie supplements? Instead, just give folate as a pill and stick to protein-calorie focus for diet.
6) the Jamaican Sickle Cell Center noted years ago that their patients ate so much fresh fruit and vegetables that no folate supplements were needed. However, when a hurricane came through and wiped out the usual food supply, Jamaicans resorted to canned and preserved food and many of the sickle cell patients became folate deficient.
7) homocysteine and low folate are implicated in cardiovascular problems, and sickle cell is increasingly recognized as a vascular disease as well as hematologic disease. This includes HbSC and HbS beta-plus thalassemic. Folate may help this aspect of sickle cell disease, above and beyond the supplement needed for RBC production.
8) We check folate and vitamin B12 levels only before starting a patient on hydroxyurea; I have yet to find a pediatric sickle cell patient with deficiency of Vitamin B12 on this regimen in 9 years of practice. I think that B12 deficiency is a rare situation that does not require modifying the treatment for a whole population of sickle cell patients.
9) I do not think that it interferes with families remembering the penicillin prophylaxis. They either remember both, or forget both.

Therefore my opinion is that folic acid may help people with sickle cell, can't hurt, and is quite simple to take. 

Spleen

Question: Why is the spleen removed in some patients?

Answer The main function of the spleen is to filter the blood, and take out damaged red blood cells and bacteria. People with sickle cell disease lose this spleen filtering function very early in life, because the sickle red blood cells clog the filters all of the time. When a spleen gets to be large in a person with sickle cell disease, it is probably not doing any useful filtering at all. The enlarged spleen may only be causing problems of pain or trapping blood without filtering it. Studies show that having the spleen removed by surgery does not change the blood counts or the chances of infection (which are high in sickle cell disease, with or without spleen surgery).

Bedwetting

Question: Is bedwetting common in sickle cell patients

Answer: Yes, bed-wetting can be related to sickle cell disease. The kidney is damaged by sickling from early in childhood, and cannot hold onto fluids normally. The kidney produces urine through the night, more than for a normal child, and the urinary bladder fills up during the night. Then the child has to urinate, either waking up to go to the bathroom or urinates while still asleep. Medications that help other children with bed-wetting usually do not help those with sickle cell disease. Usually, the solution is
to persuade the child and train the child to wake up during the night (reward system, calendar of "dry nights," having the child wash the sheets, setting alarm clocks, using alarm devices that awaken the child when the underwear is a little wet, having nightlights between the bedroom & the bathroom). Cutting back on drinking fluids for a couple hours before bedtime and going to the bathroom before going to sleep are also helpful.

Developmental Delay

Question: Is there a developmental delay in children with sickle cell disease?

Answer: Mental retardation or developmental delay are not characteristic of sickle cell disease, unlike genetic conditions such as Downs syndrome. However, two common complications of sickle cell disease are linked to cognitive problems.

1) Stroke (tissue death in parts of the brain, due to lack of blood flow) can occur in sickle cell children as early as 2yrs. Stroke due to damaged blood vessels can affect 10- 20% of children with the SS type of sickle cell disease. For other types of sickle cell, the rate of stroke is much lower. Stroke is diagnosed clinically when there is loss of motor or sensory function, but is confirmed by brain imaging such as CT scan or MRI scan. Some children have problems with cognitive function detectable on formal neuropsychologic/developmental testing, and abnormal CT or MRI brain scan, without loss of motor or sensory function -- this is called Silent Infarct and is also common in sickle cell disease. Both Stroke and Silent infarct in sickle cell disease are linked to abnormal narrowing of major arteries supplying blood to the brain -- this can be detected by MRA scan.

2) Chronic anemia seems to be associated with slower development & cognitive function, but not in a straightforward way. Not all patients with sickle cell and very low red blood cell counts have cognitive problems -- some can be very high-achievers in school & go on to careers in education, medicine, law, business, etc. Statistically, however, children with more severe anemia in sickle cell disease have slightly lower IQ, and tend to lose IQ as they age. Growth delay and fatigue are also associated with more severe anemia. Anti-sickling therapy such as hydroxyurea can probably reverse these trends.

I should mention that a child with sickle cell disease could also have any other medical problem that causes developmental delay in other children (brain tumor, other genetic defects, birth/prenatal hypoxia, etc.) as well as environmental/social problems that occur in other children (lead toxicity, neglect, abuse, malnutrition, etc.).

If a student with sickle cell disease has developmental delay, then the child's physician should be notified promptly. We would generally do a careful developmental history and neurologic exam and a MRI/MRA scan to check for stroke.
a) Therapy for a child with sickle cell and stroke in the USA would a program of monthly blood transfusions to prevent further strokes, or some other anti-sickling therapy such as bone marrow transplantation. 
b) Therapy for a child with sickle cell and silent infarct would probably be similar, but there is a clinical study (the SITT Trial) still underway to test this.
c) Therapy for a child with cognitive problems but normal brain MRI/MRA is not well defined, but I would generally push for individualized special education services and discuss antisickling therapy options with the family.

Sickle cell disease usually does not cause developmental delay.
However, there can be significant growth delay - low weight, low body mass index, delayed puberty -and there is some research underway to determine whether cause(s) include a metabolic derangement or simply the high energy requirements of hemolytic anemia, high red blood cell turnover, high cardiac output, and multiple illnesses. The Jamaican and Nigerian sickle cell centers have made attempts at developing a sickle-cell-disease ethnic-specific growth curve for children (Medline search Graham
Serjeant). Nutritional supplementation (multivitamins, anti-oxidants, trace minerals, nocturnal nasogastric feedings to increase protein-calorie intake) has met varying degrees of success, in my personal view. Most people with sickle cell disease reach approximately the adult height of their other family members, but puberty may be very delayed. This pubertal delay can be a problem for self-esteem, socialization, and body image. Exercise tolerance may b! e poor, but pilot studies indicate that aerobic conditioning is possible. Search Medline for authors Deborah Kawchak, Ellen Fung,
Virginia Stallings, Jacqueline Hibbert, MS Buchowski, Kristy Woods.

In addition, there can be cognitive deficits due to stroke and subclinical brain ischemic damage ("silent strokes"). Neurocognitive testing (like IQ tests) found a range of scores in the sickle cell population, but slightly lower mean testscore compared to non-sickle peers - both in the US and in France. That is the population average -- there are definitely intellectually brilliant adults with sickle cell disease who
hold advanced degrees. I know people with sickle cell disease who are high-powered professionals in law, medicine, business, ministry, and education. Detection of a child with neurocognitive deficits should trigger a work-up for stroke, and possible anti-sickling therapy. Sometimes the child will have a specific learning disability, & this can be important for the school to detect & help with coping skills - Medline search author Dan Armstrong, Ronald Brown, Winfred Wang, and F Bernaudin.

The big 3 categories of anti-sickling therapies (chronic RBC transfusions, hydroxyurea therapy, and bone marrow transplantation) are associated with weight gain & catch-up growth in those with low weight, and preserve neurocognitive function from worsening, plus some degree of protection from most sickle cell problems.  Other authors to search in Medline are: Graham Serjeant, Kwaku Ohene-Frempong, Mark Walters.

Oredugba FA, Savage KO.  Anthropometric finding in Nigerian children with sickle cell disease. Pediatr Dent. 2002 Jul-Aug;24(4):321-5. 

Callahan LA, Woods KF, Mensah GA, Ramsey LT, Barbeau P, Gutin B.
Cardiopulmonary responses to exercise in women with sickle cell anemia.
Am J Respir Crit Care Med. 2002 May 1;165(9):1309-16. 

Buchowski MS, Simmons LA, Chen KY, Flakoll PJ, Mellen BG, Turner EA. 

Plasma leptin association with body composition and energy expenditure in sickle cell disease. J Am Coll Nutr. 2000 Apr;19(2):228-36. 

Barden EM, Zemel BS, Kawchak DA, Goran MI, Ohene-Frempong K, Stallings VA.
Total and resting energy expenditure in children with sickle cell disease.
J Pediatr. 2000 Jan;136(1):73-9. 

Yellow Eyes or Jaundice

Question: What causes yellow eye color or jaundice in sickle cell patients?

Answer: The yellow color of his eyes is due to his sickle cell disease. The sickle red blood cells break down quickly as the blood moves around the body, and the hemoglobin released from the red blood cells is converted to bilirubin, which has a yellow-orange color. The bilirubin is normally cleared out of the body through the liver and then out the kidney into the urine. People with sickle cell disease have more
bilirubin than normal people. 

If you see his eyes getting more dark yellow than usual, the first thing to try is to give more water to drink and flush the bilirubin out the kidneys by urinating more. That extra fluid passing through his body should make the eyes a lighter yellow color. 

If the yellow does not get back to usual with more water, then probably something is making the red blood cells break down faster than normal. This could be caused by infection or sickle red blood cells getting trapped in lungs or other parts of the body, and he may need to get to a doctor.

Dental Work

Question: Are there any precautions to do before dental work

Answer: I can only tell you what our practice has been for children receiving
dental care. I reviewed textbooks and did an electronic literature search today, and I think there is no evidence-based guideline for premedication of people with sickle cell disease. I am sure that there is no need for pre-medication in children with sickle trait and no other medical history. 

Our practice in Atlanta has been:

1) to give SBE prophylaxis according the American Heart Association guidelines, as a precaution and physician preference. We decided that the (a)cardiac hypertrophy, (b) high flow turbulence, (c) lack of spleen function, and (d) possible valve distortion due to hypertrophy would theoretically put sickle cell cell patients at moderate risk for endocarditis.
Standard general prophylaxis
Amoxicillin  children: 50 mg/kg orally 1 h before procedure
http://www.americanheart.org/presenter.jhtml?identifier=1745
2) If the dentist plans something more extensive than general dental cleanings, especially if there is consideration of general anesthesia or deep conscious sedation, then we ask to coordinate the pre-op planning between hematology, anesthesiology, and dentistry. On a case-by-case review of the child's medical condition (frequent acute chest syndrome, stroke, frequent pain, asthma, other underlying problems) and the duration of the anesthesia planned, we may recommend a pre-procedure blood
transfusion to achieve Hb = 10, or just IV hydration for several hours before the procedure. 
3) We discourage the use of In-office general anesthesia because the situation may not have sufficient medical back-up. 
4) We discourage adding epinephrine to local anesthetics, because the epinephrine vasoconstriction may trigger sickle vaso-occlusive pain. 
5) we encourage regular dental care, because there may be increased dental problems in people with sickle cell disease (caries, osteomyelitis). In addition, facial pain in a person with sickle cell disease can be due to a dental problem or vaso-occlusion, keeping all the dental problems fixed will make diagnosis & treatment of pain more straightforward. 

Growth

Question: My son has sickle cell and is shorter than his teenage peers. Can  steroids help?

Answer:

1) Most people with growth delay related to sickle cell are treated with human growth hormone (HGH) injections. This is not a steroid. The HGH treatment should be prescribed & monitored by an endocrine specialist. The treatment is very expensive and is given by injection. Most people have no side effects. The most common side effects are hypoglycemia (low blood sugar level) and inadequate thyroid function. HGH for people with sickle cell should be used before puberty, while bones can still grow longer, and its use  Other rare side effects include diabetes, heart enlargement, high blood pressure, and enlargement of the kidneys.

I have seen some sickle cell children treated with HGH by endocrine specialists and they did OK. Antisickling therapy with hydroxyurea or chronic transfusion was discussed as part of the treatment plan. A nutritional assessment and X-rays of bone growth were also part of the treatment plan.  HGH is not at all the same as with anabolic and androgenic steroids.

2) Androgenic steroids are not the first choice for a pre-pubertal person to grow taller, because they can cause permanent short stature by stopping the bones from growing longer. These steroids can be prescribed by endocrine doctors in special circumstances at controlled doses.  For people with sickle cell, androgenic steroids might be used to help trigger puberty. A particular problem for androgenic steroid use in sickle cell is that they could raise the blood count and blood viscosity excessively and make vaso-occlusive episodes more frequent.... so the blood counts would need to be monitored to make sure that they do not go too high.  I have seen one sickle cell teen treated by androgenic steroids to help with puberty for a few months, and he did OK.  Antisickling therapy, nutrition, and X-ray monitoring of bone growth were also part of the plan.

3) Anabolic steroids are in the sports news for alleged illegal use by American baseball players to induce muscle growth & increase sports performance, available on the black market & Internet with no control of dose.  The hazards of their black market use is found at the National Institutes of Health website (http://www.nida.nih.gov/Infofacts/Steroids.html):  "Anabolic steroids are man-made substances related to male sex hormones. “Anabolic” refers to muscle-building, and “androgenic” refers to increased masculine characteristics. “Steroids” refers to the class of drugs. These drugs are available legally only by prescription, to treat conditions that occur when the body produces abnormally low amounts of testosterone, such as delayed puberty and some types of impotence. They are also prescribed to treat body wasting in patients with AIDS and other diseases that result in loss of lean muscle mass. Abuse of anabolic steroids, however, can lead to serious health problems, some irreversible....
 

Health Hazards

The major side effects from abusing anabolic steroids can include liver tumors and cancer, jaundice (yellowish pigmentation of skin, tissues, and body fluids), fluid retention, high blood pressure, increases in LDL (bad cholesterol), and decreases in HDL (good cholesterol). Other side effects include kidney tumors, severe acne, and trembling. In addition, there are some gender-specific side effects:

• For men — shrinking of the testicles, reduced sperm count, infertility, baldness, development of breasts, increased risk for prostate cancer.
   
• For women — growth of facial hair, male-pattern baldness, changes in or cessation of the menstrual cycle, enlargement of the clitoris, deepened voice.
   
• For adolescents — growth halted prematurely through premature skeletal maturation and accelerated puberty changes. This means that adolescents risk remaining short for the remainder of their lives if they take anabolic steroids before the typical adolescent growth spurt.
   

Scientific research also shows that aggression and other psychiatric side effects may result from abuse of anabolic steroids. Many users report feeling good about themselves while on anabolic steroids, but researchers report that extreme mood swings also can occur, including manic-like symptoms leading to violence. Depression often is seen when the drugs are stopped and may contribute to dependence on anabolic steroids. Researchers report also that users may suffer from paranoid jealousy, extreme irritability, delusions, and impaired judgment stemming from feelings of invincibility."  

-Lewis Hsu, MD, PhD
Pediatric Hematologist

Question: 

My eight year old child with hemoglobin SS has been receiving blood transfusions every three weeks for a year and a half now
 because of having an abnormal TCD  The  most recent TCD was normal. Can we stop the transfusions

Answer: 

 A group of sickle cell centers in the STOP study group collected a lot of information and published several papers that you might go over with your doctor. At least 2 papers tried to answer your question and examined whether children with sickle cell disease and abnormal TCD could be taken off transfusion after the TCD became normal. The "STOP 2" study (paper #1 below) showed that many (14 out of 41 children) taken off transfusion developed abnormal TCD again and 2 out of the 41 children actually had stroke, all within 10 months of coming off transfusion. Neither of these events occurred in the 38 children who continued to receive transfusions. In another paper (#2 below), the STOP study group presented the results of over 5 years of follow-up of a variety of children with abnormal TCD, some with transfusions and some not on transfusion. About 25% of the children with abnormal TCD and no transfusion developed stroke, but hardly any strokes occured more than 3 years after TCD abnormality was detected. Higher TCD velocity means a higher risk of stroke. One stroke occured among the 63 children who were on transfusion with abnormal TCD. Transfusions generally cut down the rates of sickle cell pain, sickle cell acute chest syndrome, and other sickle cell problems. Bone marrow transplantation can cure sickle cell disease. 

1. Adams RJ, Brambilla D; Optimizing Primary Stroke Prevention in Sickle Cell Anemia (STOP 2) Trial Investigators. Discontinuing prophylactic transfusions used to prevent stroke in sickle cell disease. New England Journal of Medicine. 2005 Dec 29;353(26):2769-78. http://content.nejm.org/cgi/content/abstract/353/26/2769

2. Lee MT, Piomelli S, Granger S, Miller ST, Harkness S, Brambilla DJ, Adams RJ; STOP Study Investigators. Stroke Prevention Trial in Sickle Cell Anemia (STOP): extended follow-up and final results. Blood. 2006 Aug 1;108(3):847-52.
http://bloodjournal.hematologylibrary.org/cgi/content/full/108/3/847

I think that the evidence is pretty strong that coming off transfusion means probably 25% risk of stroke. A clinical research study are in progress to compare transfusions vs hydroxyurea as treatment to prevent stroke in children with abnormal TCD -- there are no results yet.

I think that you might try to schedule an appointment with your doctor to discuss these papers and how closely they describe your child's situation. I think that the options include chronic transfusion, hydroxyurea treatment, or bone marrow transplantation.

Question: 

Which is better erythrocytopheresis or simple blood transfusion for the prevention of childhood stroke?

Answer: 

Nobody has hard data on the number of sickle cell patients in the USA, but the estimate from the Sickle Cell Disease Association of America is 100,000.  The estimate is that 10% of the children with sickle cell disease SS are at risk for stroke and will benefit from chronic transfusion as primary or secondary stroke prevention.

Some studies comparing costs of chronic simple transfusion plus iron chelation vs bone marrow transplant also include erythrocytapheresis.  The costs depend fairly strongly on whether the target HbS is 30percent or 50 percent.

As you know, the use of RBC exchange is far better than simple transfusion in terms of iron overload but requires technical expertise and a good cost structure. When I was practicing in Atlanta, we wrote numerous business plans about setting up sickle cell erythrocytapheresis centers for the many pediatric sickle cell patients. The limiting factors were:
1) nursing expertise for venous access. Some children requiring erythrocytapheresis may be as young as 2yrs. Not every patient can maintain an indwelling catheter for pheresis, often they get infected or clotted.  The pheresis service needs superb nurses who can place a large-bore peripheral IV in any patient.
2) most insurance companies paid the same amount for erythrocytapheresis as for a simple blood transfusion - which covered costs for neither but was much less favorable from a financial perspective for erythrocytapheresis.
3) greater demand for specially matched PRBC (negative for C, E, Kell antigens and negative for sickle hemoglobin) would strain the Blood Bank supply. Many pheresis units require partnering with a special donor recruitment programs to increase blood donations by African-Americans who are more likely than Caucasians to have RBC that are negative for C, E, Kell.  The PRBC demand depends fairly strongly on whether the target HbS is 30percent or 50 percent.

My impression is that medical centers offering erythrocytapheresis combine it somehow with hemodialysis units or some other service to help break even. Or the medical centers just eat the cost because it is better for the patients and perhaps feature this service as a marketing tool.

Dr. Hae-won Kim at Children's Hospital of Philadelphia has the largest erythrocytapheresis center for sickle cell patients that I have seen. She taught many centers how to set up sickle cell erythrocytapheresis.

Sincerely,
Lewis Hsu, MD, PhD
Pediatric Hematologist

Question: 

I can not afford the medications prescribed for me, Are there ant programs that can help?

Answer: 

There are some very good programs that help such as

http://www.needymeds.com/
http://www.rxassist.org/
https://www.pparx.org/Intro.php

Work with your clinician to see if these programs can help

Famous People with Sickle Cell Disease

• Miles Davis, jazz musician.
• Paul Williams, singer (The Temptations)
• Georgeanna Tillman, singer (The Marvelettes)
• Tionne "T-Boz" Watkins, singer (TLC)
• Prodigy, rapper (Mobb Deep).

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

Send mail to aplatt@emory.edu with questions or comments about this web site.
Copyright © 1997 Sickle Cell Information Center
Last modified: September 17, 2008