Sickle cell disease (SCD) is the commonest monogenetic disease worldwide and its greatest burden is found in Sub-Saharan Africa especially Nigeria [
Care and treatment of SCD patients require expertise commitment, as well as a wide array of therapeutic and prophylactic measures including adequate analgesia, anticoagulation as indicated, transfusion of requisite blood components when necessary, haemopoietic stem cell transplantation, oxygen therapy when needed, routine prophylactic medications (antimalarial, multivitamins supplements, low dose aspirin, and antioxidants), hydroxyurea therapy, adequate hydration, and immunization against infectious pathogens especially in early childhood. Moreover, care of SCD patients requires a multispecialist team including haematologists, orthopedic surgeons, plastic surgeons, urologists, nephrologists, specialist nurses, counselors, and medical social workers [
Carrier detection and genetic counseling have been recommended by World Health Organization for the control of SCD [
Apart from premarital counseling and continuous medical education, a number of other strategies including chronic transfusion have been scientifically proven to reduce complications and improve quality of life in SCD patients. This work therefore is aimed at collecting and summarizing available information on the practice and utilization of hypertransfusion in the care of SCD patients in Nigeria.
Hypertransfusion refers to a chronic blood transfusion regimen with therapeutic intention of reducing sickle haemoglobin levels over a long period of time [
Traditionally, transfusion in sickle cell disease was carried out only in emergencies until the early 1980s when the benefits of chronic transfusion began to gain clinical appreciation [
As a rule, transfusion therapy in sickle cell disease is carried out with haemoglobin AA blood. Besides reducing the level of circulating haemoglobin S, exogenous supply of haemoglobin AA red cells also suppresses endogenous erythropoiesis, thereby suppressing intrinsic sickle haemoglobin levels. The primary event in sickle cell disease pathogenesis is deoxyhaemoglobin precipitation. Normal red cells contain about 200–300 million soluble haemoglobin A molecules. However, red cells in sickle cell disease contain high level (80–90%) of the less soluble sickle haemoglobin which crystallizes out of solution under low oxygen tension. Under conditions of low oxygen tension (PaO2 less than 35–40 mmHg), haemoglobin S molecules undergo nucleation with progressive polymerization of haemoglobin molecules and eventual crystallization into tactoids with seven double strands which cross-links. This gives rise to the crescent shape appearance of the sickled red cells on blood cytology. With reoxygenation, the polymers dissolve. However, with repeated deoxygenation and reoxygenation in different vascular beds, the red cells permanently acquire a sickle shape. This is termed irreversible sickle red cells (ISCs) when seen on peripheral blood smear. Again, the percentage of ISCs has been shown to correlate directly with severity of haemolysis and inversely with frequency and severity of vasoocclusive crisis [
At the molecular level, there is substitution of valine for glutamate at position 6 of the beta sickle haemoglobin chain due to the single base change from adenine to thymidine. The resultant HbS exposes a hydrophobic patch under low oxygen tension and interactions between these patches lead to nucleation and eventual polymerization [
Prevention of first stroke (cerebrovascular disease). Prevention of repeat stroke. Transcranial Doppler (TCD) ultrasonography with cerebral blood flow > 2 m/sec (highly predictive of stroke). Delayed growth and development in children. Frequent acute chest syndrome unresponsive to hydroxyurea. Frequent severe bone pain crisis requiring three or more hospital admissions per annum and unresponsive to hydroxyurea therapy. Severe SCD lacking HLA-matching donor. Sickle chronic lung disease. Chronic vital organ failure. Pregnant women with bad obstetric history and frequent bone pains.
Sickle cell leg ulcers (to improve tissue oxygenation and wound healing and reduce vasculopathy).
Recurrent sickle cell priapism. Preparation for infusion of contrast media. “Silent” cerebral infarct and/or neurocognitive damage.
Steady state (compensated anaemia). Uncomplicated pain episodes. Infections. Minor surgery that does not require general anaesthesia. Aseptic necrosis of the hip or shoulder (unless indicated for surgery). Uncomplicated pregnancy.
Multiple red cell alloantibodies. Poor venous access.
Decision to initiate a chronic hypertransfusion regimen in a patient should be individualized. Benefit to risk should be carefully assessed and a clear indication must be present. Decision to hypertransfuse should be communicated to the patient and relatives in clear terms (stating the benefits and potential adverse effects) and informed consent should be obtained. Design a clearly written therapeutic plan and all clinical staff must be duly communicated. Blood bank must be duly informed and necessary pretransfusion services commenced. Prehypertransfusion laboratory work-up should include: blood type with extended red cell phenotyping, antibody screening for unexpected antibodies if indicated, serum ferritin levels, screening for hepatitis A, B, and C, retroviral disease status, liver function test, electrocardiogram/echocardiography, and possibly audiologic/ophthalmologic examinations [ Therapeutic goals such as the final (posttransfusion) haematocrit and the target sickle haemoglobin level should be set before each transfusion episode. On the average, most patients will require 2-3 units every 4–6 weeks. As such, transfusion requirement should be established in each individual patient and monitored as changes may occur with time [ Rapid transfusion should be avoided to prevent hyperviscosity. Overtransfusion or supertransfusion (where haemoglobin level is raised above 11 g/dL) should be avoided [ Transfusion requirement will vary from patient to patient depending on quality of the donor unit, associated morbidities, and biologic variables in the patients. The aim is to keep the haematocrit below 35% to prevent hyperviscosity [ If the pretransfusion haematocrit is >35%, chances are that hyperviscosity may be contributing to acute complications like acute chest syndrome, stroke, and chronic complications like chronic pain syndrome, osteonecrosis, and ocular disease [ The patient should report to the outpatient clinic or day-care unit at least 24 hours before each planned transfusion for a full blood count, reticulocyte count, and initial sickle haemoglobin level. Formula for estimation of required transfusion volume and its dilutional effect of transfusion on HbS levels are as follows [
simple red cell transfusions: PRBCV dilutional effects of transfusion on Hb S levels: manual partial exchange transfusion: exchange volume automated exchange transfusion: red cell volume PRBCV: packed red blood cell volume,
TBV: estimated total blood volume in mL (children 80 mL/kg, adults 65–70 mL/kg),
HCTrp: haematocrit of replacement cells (usually 0.7 to 0.8),
Patient should be immunized for hepatitis B and C. Booster doses should be given annually to maintain good antibody levels [ Monitor for iron overload and commence s/c desferrioxamine infusion when serum ferritin > 1000 ug/L or >20 units of red cell concentrate has been administered [ Overall, the managing physician should ensure that the right blood and the right amount are administered to the right patient at the right time in the right place.
The art of blood transfusion is not without potential hazards to its recipients. Awareness of complications associated with blood transfusion and hypertransfusion (in particular) helps to position the clinician with strategies to keep these untoward effects to the barest minimum. Hazards of blood transfusion are vast and may be categorized as acute or chronic, immunologic or nonimmunologic. They may also be categorized as early (arising within 24 hours of commencement), delayed (up to 4 weeks), or long-term. Early complications include allergic reactions, anaphylaxis, febrile nonhaemolytic transfusion reaction (FNHTR), acute haemolysis, volume overload, hypothermia, metabolic derangements including hyperkalaemia, hypocalcaemia, and acid-base disturbances, transfusion related acute lung injury, thrombophlebitis, citrate toxicity, bacterial contamination, air embolism, and clotting abnormalities. Late complications include delayed haemolysis, alloimmunization, transfusion associated graft versus host disease, iron overload, transfusion transmissible infections, post transfusion purpura, and transfusion associated immune-modulation. Suffice to say, red cell alloimmunization and iron overload are peculiar complications of chronic blood transfusion in SCD.
Generally, the most frequent transfusion hazard is febrile nonhaemolytic transfusion reaction [
Acute haemolysis (AHTR) is the most dangerous transfusion reaction. It is usually due to incompatible blood components from clerical errors. Transfusion of incompatible units leads to immune response and activation of complement cascade leading to intravascular haemolysis. Also massive release of inflammatory cytokines (cytokine storm) and anaphylatoxins leads to hypotension and acute renal failure. Severe intravascular haemolysis can trigger disseminated intravascular coagulopathy and fatality may ensue. Acute haemolytic transfusion reaction (AHTR) is an emergency. Usually, AHTR begins within few minutes of starting the transfusion. Conscious patients complain of pain or heat at the infusion site, restlessness (akathisia), and loin pain. Fever develops with associated chills and rigor, tachycardia, hypotension/shock, and bleeding tendencies. Hypotension and oozing from venipuncture sites may be the only signs in an unconscious patient.
In event of a suspected AHTR, transfusion should be stopped immediately. Then, maintain plasma volume with crystalloids and manage complications that may arise. Haemovigilance unit should be notified immediately. Investigation of AHTR includes checks for haemolysis (visual examination of patient’s plasma and urine, spherocytosis on blood film, increased serum bilirubin, and LDH levels), checking the compatibility form, blood label and patient’s identity, repeat blood grouping of recipient pre- and posttransfusion blood sample and on donor’s blood unit, repeat cross-matching of donor blood against recipient’s pre- and posttransfusion samples, direct antiglobulin test on pre- and posttransfusion samples, run coagulation profile, D-dimer to rule out DIC, and finally electrolyte/urea/creatinine to rule out acute renal failure [
Urticarias are due to allergens (usually plasma proteins) in the donor blood to which the recipient has been previously sensitized. Patient develops rashes and pruritus within minutes of transfusion. Treatment is to slow the transfusion rate and administer antihistamine. if patient is unresponsive to antihistamines, discontinue transfusion. Anaphylaxis is a form of severe allergy, quite rare, and is associated with immunoglobulin-A deficient recipients. Infusion of immunoglobulin-A containing blood component into the recipient triggers the formation of IgA/anti-IgA aggregates with the activation of alternate complement pathway. Release of anaphylatoxins (C5a and C3a) mediates anaphylaxis. Transfusion should be stopped immediately and patient is given adrenaline, chlorpheniramine/promethazine, and hydrocortisone. Hypothermia, metabolic derangements (hyperkalaemia, hypocalcaemia, and acid-base imbalance), citrate toxicity, and clotting abnormalities are associated with large volume transfusions and are unlikely in hypertransfusion therapy. Thrombophlebitis may occur as in any condition warranting insertion of a peripheral or central venous catheter. Peripheral line should be changed every 3-4 days and removed when not in use.
Delayed haemolysis is an immunological reaction that occurs in alloimmunized individuals with low (undetectable) antibody titre which is often missed during compatibility testing. Implicated antibodies include non-D Rh (E, C, and c), kell, duffy, and kidd antibodies [
Transfusion associated graft versus host disease (GvHD) is associated with immune-compromised recipients. It results from immune attack of recipient tissues by immune-competent donor T lymphocytes. Blood components for immune-compromised persons should be irradiated (25 Gy) before use.
With proper donor selection blood screening for pathogens, the risk of transfusion transmissible infection (TTI) is negligible. However, in developing nations such as Nigeria, TTIs still pose a major challenge. International standards such as predonation questionnaire and ELISA based TTI screening are yet to become a routine in many blood banking facilities. In addition, there is poor haemovigilance reporting; as such there is little or no data for monitoring and evaluation of transfusion services.
Alloimmunization to donor red cell antigens and iron overload from repeated transfusions poses a serious challenge to effective hypertransfusion therapy. One unit of red cell concentrate contains about 200–250 mg of iron. Daily physiological loss of iron (through desquamation of skin and mucous membrane) is only about 1 mg. As such, the repeated transfusions and heightened haemolysis in sickle cell disease create a positive iron balance, leading to transfusion siderosis over time. Excess iron in the body will get deposited in virtually every organ in the body, most especially the heart, liver, skin, and endocrine organs and gonads. That would lead to heart failure, diabetes mellitus, skin pigmentation, and gonadal failure. It is advised that iron status of such patients should be monitored every 6 months. Iron chelation therapy should be commenced early when liver iron store exceeds 7 mg/g in adults or 4 mg/g in children [
Recipient alloimmunization is another serious problem that occurs with multiple transfusions. It reduces the chances of a successful transfusion at subsequent times. As a rule, patients being planned for hypertransfusion should have an extended red cell typing to identify other clinically significant blood group antigens including Rh, kell, kidd, and duffy [
Predating this paper, I found sparse local data on the prevalence and pattern of blood use in Nigerian SCD population. Barbara Otaigbe recently reported a high rate of blood use among paediatric SCD patients in south-south Nigeria and noted the commonest indication for simple transfusions to be severe anaemia [
Furthermore, there is dearth of scientific data on the level of awareness, knowledge, and practice of hypertransfusion in SCD among Nigerian general duty doctors and specialists alike. As such, its current challenges may include poor awareness, poor knowledge, and lack of technical expertise among health care givers. Insufficient supply of blood and blood components due to inefficient blood banking services even at tertiary health care levels is a major challenge in our blood banks [
Moreover, the cost of instituting iron chelation therapy adds to the overall cost of hypertransfusion therapy. Invariably, hypertransfusion therapy may cost beyond the reach of most eligible Nigerian SCD patients. The option of erythrocytapheresis is relatively inaccessible and unaffordable. Thus, the practice of hypertransfusion in Nigeria may be bewildered by suboptimal transfusion services and complications such as monitoring and treatment of iron overload. It behooves us to say that its successful use in the Nigerian context cannot be disconnected from general improvements in our national transfusion service. As well, specialized supports including financial aids, trained professionals, and comprehensive sickle cell centers/clinics should be dedicated to treatment of SCD. Better government commitment to the treatment and prevention of sickle cell disease is necessary to expedite proper healthcare delivery to affected persons.
Hypertransfusion is an effective disease modifying strategy in the management of SCD patients. Despite its applicability, there is still little data on its utilization in Nigeria. The reason for the scarcity of information on this treatment modality could be nonusage of the strategy, low acceptance rate, and/or poor attitude to documentation and analysis of such data.
Considering the potential benefits of chronic blood transfusion on quality of life and overall survival in sickle cell disease, we advocate that selected Nigerian patients with adequate resources should be offered hypertransfusion following proper patient education and informed decision on its potential benefits, complications, and cost of therapy. Apheresis for red cell exchange should be provided, accessed, and used when indicated.
Other disease modifying strategies in management of sickle cell disease such as haemopoietic stem cell transplantation are either not readily available or not affordable in developing countries. Therefore, this paper serves as a wake-up call to physicians in Nigeria to practice and promote judicious use of hypertransfusion therapy.
The term hypertransfusion is not exclusive to treatment of SCD alone. There are other clinical indications that may warrant a chronic transfusion regimen, conditions such as major thalassaemia, refractory myelodysplastic syndrome, and aplastic anaemia. However, the strategic therapeutic choice for hypertransfusion in SCD is freshly donated (less than 24 hours), sickle negative, leucodepleted, phenotypically matched, cytomegalovirus negative, and perhaps a minority and racially matched red cell concentrate.
Further efforts should be directed at educating professionals involved in sickle cell disease management at all levels of healthcare to boost their technical knowledge and expertise. Amongst the few disease-modifying interventions that are currently available in SCD care, only haemopoietic stem cell transplantation (HSCT) is potentially curative. However, because of its potential toxicities, HSCT tends to be employed more readily in patients with severe sickle cell disease aged less than 16 years and having a matched sibling donor [
The authors declare that there is no conflict of interests regarding the publication of this paper.