HYDROXYUREA: A Drug of choice in managing Sickle Cell Disease

Summary of WhatsApp Discussion held on 7th August 2020

Facilitator: Prof Kaladada Korubo

Key words 

People living with sickle cell disease: PLWSCD

Sickle cell diseases: SCD

Hydroxyurea: HU

Fetal Haemoglobin: HbF

Introduction

Previous research shows that different people with SCD have different clinical picture. Some always fall sick and have frequent crises, while others live a relatively normal life. This can also be between two siblings with SCD where one is always ill and the other isn’t.

Research shows that the difference is in the level of Fetal Haemoglobin (HbF)

When there is high percentage of HbF in the presence of HbS (hemoglobin S) in patients of sickle cell anaemia (SCA), the HbF dampens the deleterious effects of HbS and brings about a milder disease.

Once it was shown that a high HbF makes the disease better, the quest to find a drug that will increase HbF began.

In the early 1980s, Hydroxyurea was first used for people living with SCD because the drug was found to increase the level of fetal Haemoglobin. According to the research the HIGHER the HbF, the milder the disease in the person.

Hydroxyurea (HU) which was primarily used as an anti-cancer drug and treatment of blood and cancer was found to increase the percentage of HbF and was tested in 1984 for SCD.

Fetal Haemoglobin

This is the type of Haemoglobin produced in the blood of a fetus as a result of the amniotic fluid present

In individuals with AA and AS genotype, the normal level of HbF is <1%, whereas, individuals with SCD usually have >1% of HbF that is 3%, 5%, 10%, 12%… etc.

What reduces sickling of Red Blood Cells?

Scientifically, some of the things that reduce the likelihood of sickling include;

  • The presence of another type of Haemoglobin in that same blood cell, which explains why people with AS do not sickle, because of the presence of A.

Genetically, individuals with SCD cannot produce Haemoglobin A but can produce HbF. That is, we all have HbF as a result of hydroxyurea which serves as a HbF Inducer

What exactly does Hydroxyurea do?

At birth, our body stops producing HbF leaving it a level of <1%. Then, with the aid of HU production of HbF resumes. When HU is administered, due to increasing level of HbF it helps reduce sickling as well as other benefits.

Common causes of increased likelihood of sickling include;

1. Inflammation: This results to increased white blood cell count

HU reduces the white cell count to a normal level as well as reducing the other cells involved in inflammation that helps in reducing the likelihood of VASOOCCLUSION, which leads to bone pain crises, and so on.

2. Immature red cells (called reticulocytes): In SCD they are STICKY. They stick to the blood vessels and promotes sickling. HU reduces the stickiness of the reticulocytes.

3. Free Haemoglobin: In SCD when the sickled red blood cells are broken down, they release FREE Haemoglobin into the blood, and this free Haemoglobin consumes/ destroys/ mops up what is called Nitric Oxide. This nitric oxide works to make the blood vessels RELAXED.

HU helps to increase more nitric oxide in the blood vessels to prevent sickling as well as CHANGE the clinical picture from a severe disease to a mild disease IN THOSE THAT RESPOND.

Criteria for Prescription of Hydroxyurea

1. The person should have been admitted in the hospital at least 3 times in the year for severe crises.

2. Acute chest syndrome.

3. Those requiring frequent multiple transfusions, and so on.

As a result of increased use and benefits of HU, it is now widely used for SCD including for children

In adults with SCD, sometimes before they start HU, they may have already developed some complications of SCD. But the beauty of starting the drug in children is that they start the drug early, and will grow up without the pains of frequent crises, etc.

In Obodo-Oyibo, HU is now recommended to be started at 2 years old for children. Some centers even use 1 year or 18 months) but here in Nigeria, that is not yet the case, a lot of people with SCD are not on the drug.

Things you should know about Hydroxyurea in Sickle Cell Disease

1. NOT EVERYONE WILL RESPOND: More than 90% of people on HU will respond, but there are some people that won’t respond

2. THE DRUG TAKES A LONG TIME TO WORK: We only say someone did not respond if the person has been on the drug for 6 months and there was no response.

3. RESPONSE IS DIFFERENT FOR EVERYBODY: One person’s response is different from another person’s response

4. THE DRUG HAS SIDE EFFECTS: Some of them include

  • Infertility (more In males than females)
  • Abnormalities in fetus if taken during pregnancy
  • Low blood counts etc.

5. HU SHOULD NOT BE TAKEN BY PREGNANT WOMEN OR THOSE WHO WANT TO CONCEIVE.

6. BEFORE HU IS PRESCRIBED, CERTAIN TESTS HAVE TO BE DONE:

  1. A QUANTITATIVE Genotype Test:  that will tell us the % of HbF, HbS etc. in the blood. The reason is for us to know what the BASELINE HbF is, because test will be repeated  from time to time to make sure there is response.
  2. A baseline full blood count: certain changes happen in the full blood count when someone is responding, so that tells also if someone is responding.
  3. The Blood Film picture: this also tells if someone is responding.
  4. Pregnancy test for females to ensure they are not pregnant.

Pic A shows many sickled cells while Pic B shows fewer sickled cells as a result of HU

7. THERE IS THE FEAR THAT SINCE HU IS USED IN TREATING CANCER, IT CAN ALSO CAUSE CANCER: Science has shown over time that SCD people on HU were not more at risk for developing cancer than those not on HU. In some centers, those who want to start HU are given a consent form.

8. APART FROM LAB TESTS, CLINICAL PARAMETERS ARE USED TO DETERMINE RESPONSE: For example, if someone was having crises every month and is now having crises once in 2 or 3 months or even less, that’s response. Also, what is the SEVERITY of crises? For some people, HU stops crises for them, for others it doesn’t completely stop the crises but REDUCES THE SEVERITY of the crises.

9. HYDROXYUREA IS NOT AN OVER-THE-COUNTER drug: It is PRESCRIPTION ONLY and while on the drug, the person with SCD has to be MONITORED!!!

You CANNOT AND SHOULD NOT start Hydroxyurea on your own!

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