Transfusion-dependent anemia

Hemoglobin Barts hydrops fetalis is the most severe form of alpha-thalassemia, and individuals with this disease have severe anemia during the fetal stage of development.[15] It has been considered as fatal until advances in treatment were made. Patients that survive hemoglobin Barts hydrops fetalis will become transfusion dependent.[5]

Bata-thalassemia causes decreased functional hemoglobin production, and blood transfusions can be given to maintain a sufficient hemoglobin level. Patients with beta thalassemia major are more affected and are recommended to receive transfusion throughout their lives.[5]

Myelodysplastic syndromes are disorders where defective blood cells are produced by an abnormal bone marrow, resulting in anemia.[4] Severe cases may require ongoing transfusions, and around 70% of people with myelodysplastic syndromes become transfusion dependent at some point.[16][17] Patients who are initially considered to be lower-risk may experience disease progression as a result of becoming dependent on blood transfusion when they become increasingly unresponsive to alternative treatments.[4]

Diagnosis of transfusion-dependent anemia is similar to the diagnosis of all other kinds of anemia, which primarily depends on one's complete blood count. Units of red blood cells required is examined to diagnose transfusion dependent anemia. Patients that need more than 2 units of red blood cells every 28 days are considered transfusion dependent.[6] Diagnosed patients require frequent and regular transfusion for survival.

As 70% of myelodysplastic syndrome patients exhibit transfusion dependent anemia,[17] diagnosis of MDS can also help indicate transfusion dependency. Diagnosis of it is complexed with great diversity of symptoms,[3] and therefore most patients are only diagnosed with myelodysplastic syndromes when seeking clinical advice after experiencing symptoms of anemia.[4]

Beta-thalassemia is a genetic disease mostly caused by beta-globin gene mutations.[18] Clinical diagnosis is based on interpretation of the peripheral blood smear, which examines red blood cell morphology, followed by hemoglobin analysis and confirmed by DNA sequencing. DNA analysis is performed by either mutation-specific detection or genome scanning.[8] Different mutation patterns observed from DNA analysis divide thalassemia patients into three classes: thalassemia major (TM), thalassemia intermedia (TI) and thalassemia minor (TI). Another classification was established in 2012 for easier referral of patients that require frequent transfusion for survival, dividing patients into non–transfusion-dependent thalassemia (NTDT) and transfusion-dependent thalassemia (TDT) by their baseline hemoglobin levels. Thalassemia major is usually manifested in fetus and early life (birth to <2 years old) and all patients are transfusion-dependent from birth in order to survive. Anemia experienced by some thalassemia intermedia patients are also regarded transfusion dependent. Therefore, most transfusion-dependent thalassemia patients can be diagnosed within the first few years of life, which severe anemia, differed growth, jaundice and hepatosplenomegaly can be observed. Parameters for confirmation includes baseline hemoglobin level <7g/dL, enlargement of liver and spleen (>5 cm) and height in the first 10th percentile.[8]

Screening programs are available to identify thalassemia patients among the general public. Couples are in particular the target group of screening for early identification of carriers who bear risks of having children with thalassemia.[8] Screenings targeted at them are done by detecting heterozygotes in the thalassemia gene. Whereas screening of fetus is done by one-tube osmotic fragility test (identification of red blood cells resistance to hemolysis),[8] red blood cell tests (measurement of mean corpuscular volume and mean corpuscular haemoglobin) or dischlorophenol indophenol precipitation tests (detection of mutation).[8]

There are considerable side effects associated with the transfusion of red blood cells. Side effects include iron overloading,[12][4][9][13][5] allergic reactions that lead to skin rashes and infections transmitted through transfusion.[4][12]

The most common side effect is iron overloading, which the severity of overload depends on the frequency, volume, and the amount of blood transfused to the patient.[9] Approximately, 200 to 250 mg of iron is transfused per unit of blood.[4][5] Iron overloading is resulted because human body cannot excrete excess iron from frequent transfusions, leading to accumulation of iron in blood.[4][9] Iron in blood causes damage to important organs, such as the heart, liver, bone tissue and endocrine glands.[4][13] Damage to vital organs leads to morbidities, including cardiovascular diseases and heart failure.[13] The liver is normally involved in iron metabolism and storage and excess iron causes liver diseases, fibrosis and cirrhosis. Complications associated with the endocrine hormones may also occur, including diabetes.[5] The risk of developing transfusion dependency related morbidities increases with patients' ages.[19]

To reduce iron overloading in blood, iron chelation therapy is commonly used together with transfusion.[3] Necessity to initiate iron chelation therapy is determined by blood test and transfusion volume.  Generally, blood with serum ferritin level that exceed 1000 ug/L and a transfusion of 20 units of red blood cells will require iron chelation therapy along with transfusion.[4][9]

There are three common iron chelators, including deferoxamine, deferiprone and deferasirox.[5][9][13]

The 3D structure of deferoxamine

Deferoxamine is injected into the body through the veins and is the most traditional chelation therapy available.[9] This therapy, although effective, especially for patients with heavy iron overload, is considered very inconvenient. The injection has to be performed over a duration of 8 hours, 5–7 times every week.[13] Therefore, low compliance of patients is one of the major concerns of this therapy. Side effects include abnormal growth of bones and kidney damages.[9][13] Deferoxamine is seldom used alone nowadays, but rather in combination with oral deferiprone to increase the effectiveness in reducing iron overload.[9][13]

Deferiprone forms a complex with excess iron in blood in a binding ratio of 3 to 1 (3 deferiprone: 1 iron).[20] Formation of this complex reduce iron overloading.

Deferiprone is an oral drug that is ingested by patients three times a day.[13] Although patients are still required to visit the clinic frequently for complete blood count, the administering process by simply oral intake regularly is still less tedious when compared to deferoxamine.[9] It is also effective in reducing cardiac-related diseases due to iron overloading.[9] Major side effects of this drug are to the gastrointestinal system.[9]

Defasirox is also an oral drug to mitigate iron overloading taken one dose per day by patients.[13] It shares similar benefits of convenience with deferiprone when compared to deferoxamine, but however is of the highest cost. Side effects to the gastrointestinal and urinary system are common.[9]

The use of iron chelation therapy is not without concern. It can also cause skeletal changes that leads to bone disorders such as osteoporosis.[13] Therefore, minimizing the need of transfusion when possible is still the best way in reducing iron overload.[5]

Other than physical side effects brought by transfusion, transfusion also poses stress psychologically and financially. Inconvenience brought by frequent transfusion interferes with the normal social lives of patients. As a result, lack of social ties make patients more vulnerable to psychiatric illnesses like depression.[5] The high cost for repeated transfusion can also cause financial burden on the patient and his/her family. Subjection to physical, psychological and financial stresses brought by frequent transfusions and its related morbidities worsen the quality of life of most patients as the disease progresses.[4][13][3]

As there are a number of drawbacks brought by frequent transfusions, directly treating the cause of anemia (e.g. myelodysplastic syndrome), if available, remains the optimal choice of treatment.[3] Hematopoietic stem cell transplantation is a treatment for thalassemia that minimizes the need of transfusion in long term.[8][13] However, it is not suitable for patients with organs that have already experienced certain degree of iron overload, and it may only be applicable to strong and young patients.[13] While for transfusion-dependent myelodysplastic syndrome patients, lenalidomide is approved for treating lower-risk patients and hypomethylating agents can be used to treat higher-risk patients.[4]