REVIEW ARTICLE
Year : 2014  |  Volume : 20  |  Issue : 2  |  Page : 101-119

Guidelines for screening, diagnosis and management of hemoglobinopathies

Kanjaksha Ghosh¹, Roshan Colah¹, Mamta Manglani², Ved Prakash Choudhry³, Ishwar Verma⁴, Nishi Madan⁵, Renu Saxena⁶, Dipty Jain⁷, Neelam Marwaha⁸, Reena Das⁹, Dipika Mohanty¹⁰, Rajendra Choudhary¹¹, Sarita Agarwal¹², Malay Ghosh¹³, Cecil Ross^14
1 National Institute of Immunohaematology, Indian Council of Medical Research, K.E.M. Hospital, Parel, Mumbai, India
² Department of Pediatrics and Chief, Division of Hematology-Oncology, LTMG Hospital, Mumbai, India
³ Department of Hematology, Sun Flag Hospital, New Delhi, India
⁴ Department of Medical Genetics, Sir Ganga Ram Hospital, New Delhi, India
⁵ Department of Hematology, Former Head, University College of Medical Sciences, New Delhi, India
⁶ Department of Hematology, AIIMS, New Delhi, India
⁷ Department of Pediatrics, Government Medical Hospital, Akola, Maharashtra, India
⁸ Department of Transfusion Medicine, PGIMER, Chandigarh, India
⁹ Department of Hematology, PGIMER, Chandigarh, India
¹⁰ Department of Hematology, Apollo Hospital, Bhubhaneshwar, India
¹¹ Department of Transfusion Medicine, SGPGI, Lucknow, India
¹² Department of Genetics, SGPGI, Lucknow, India
¹³ Department of Hematology, NRS Medical College, Kolkata, India
¹⁴ Department of Hematology, St. John's Medical College, Bangalore, Karnataka, India

Correspondence Address:
Kanjaksha Ghosh
Director, National Institute of Immunohaematology, 13^th Floor, NMS Bldg, KEM Hospital Campus, Parel, Mumbai - 400 012
India

Source of Support: None, Conflict of Interest: None

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DOI: 10.4103/0971-6866.142841

Abstract

The β-thalassemias and sickle cell disorders are a major health burden in India. Diagnosis and management of these disorders both in adults and in newborns using appropriate approaches and uniform technology are important in different regions of a vast and diverse country as India. In view of a National Thalassemia Control Program to be launched soon, a need was felt for guidelines on whom to screen, cost-effective technologies that are to be used as well as for establishing prenatal diagnosis programs in regional centers. Newborn screening for sickle cell disorders is in its infancy in India and uniform approaches need to be followed. Also, included are guidelines for monitoring and managing patients who are now growing older and need comprehensive care as well as management of complications of the disease.

Keywords: Diagnosis, guidelines, hemoglobinopathies, management, sickle cell disease, thalassemia

Introduction

Figure 1: Synthesis of globin chains during development Click here to view

Figure 2: Globin gene clusters Click here to view

Figure 3: The structure of a prototypical globin gene Click here to view

Table 1: Click here to view

• Premarriage screening
• Antenatal screening
• Preconception screening
• Neonatal screening
• Preoperative/preanesthesia screening.

• β thalassemia trait
• δβ thalassemia trait
• Hb S trait
• Hb E trait
• Hb D trait
• Hb Lepore trait
• Hb D-βthalassemia
• Hb Q ^India - β thalassemia.

• β thalassemia major
• δβ thalassemia major
• β-δβ thalassemia
• Hb S-β thalassemia
• Hb E-β thalassemia
• Sickle cell anemia
• Hb SD disease
• Hb Lepore-β thalassemia
• Hb SE disease.

• This should not be used in children <1 year of age and if a blood transfusion is given in the last 3 months
• In severely anemic patients, the Hb should be adjusted by increasing the amount of blood added
• The reagent should be supplied by the District Hospital
  Screening for β-thalassemia should be done at the District Hospital
  Primary health centre (PHC) should refer any child with anemia, irritability, poor growth, or organomegaly to the District Hospital
  PHCs should have the following medicines: Cap. Amoxicillin, Paracetamol, Folic acid, Cifran, MV/BC, Rantac.

• Hb level <7 g/dl on two successive occasions separated by at least 2 weeks (the patient should be on folic acid replacement and there should be no other aggravating cause, i.e. infection, bleeding, etc.)
• Patient's growth, activity, academic performance, zeal, etc., are hampered
• Unnatural bony growth due to marrow expansion
• Development of organ failure such as cardiac failure, edema
• Even if Hb level is >7 g/dl and <10 g/dl, and above clinical features are present, the patient may need chronic transfusion therapy.

• To ensure adequate Hb level so that O ₂ delivery to the tissue is not hampered. This will be indicated by:
  • Normal growth spurt
  • Increased zeal, energy, enthusiasm, and improved academic purpose
  • Improved appetite
• To suppress over active erythropoiesis leading to bone deformities.

• The amount of red cells transfused so that pretransfusion Hb remains >9 g/dl but posttransfusion Hb does not go above 12 g/dl
• There is no fluid overload
• Transfusion process is over within a reasonable time (4-6 h)
• Frequency of transfusions is not such that it interferes with patient's normal activities
• Reducing the number of Venepunctures (as lifelong transfusion is needed, peripheral veins need to be preserved well).

• Red cell concentrates (HCT around 0.65) is suitable
• Leucodepleted (prestorage) blood is desirable
• Thalassemia patients who develop at least two non hemolytic transfusion reactions (NHTRs) and allergic reactions need saline washed red cell concentrates.

• Pretransfusion Hb is to be estimated
• Weight of the patient is to be recorded
• If the HCT of the red cell concentrate used is 0.65, then 3-4 ml/kg will raise the Hb by 1 g/dl in the absence of hypersplenism
• Generally in a single transfusion an attempt is made to raise the Hb by 4 g/dl if transfusions are scheduled at 3- to 5 weekly intervals.

Table 2: Guidelines for choosing how much blood to transfuse[11] Click here to view

• Alloantibbody screening at regular intervals in necessary and ideally it should be done during pretransfusion testing. Once an alloantibody is detected, it should be identified and antibody negative blood should be crossmatched
• Extended phenotyping of patient's red cells (ABO, CcDEe, Fy, Kell) is desirable. It would be desirable to establish an extended phenotyped donor registry
• Confirmation of a diagnosis of thalassemia major or severe thalassemia intermedia
• If the family is interested in stem cell transplantation, then counseling and early referral to such a centre is justified
• Serum ferritin level is not needed if the child is <2 years
• Serum ferritin levels should be recorded at regular intervals (3 months) after first 10 units of red cells have been transfused and iron chelation should be started and the dose should be adjusted so as to maintain serum ferritin between 500 and 1000 ng/ml
• Before starting chronic red cell transfusions, Hepatitis B vaccination should be completed
• Every 3 months, virus serology should be done to detect viral infection at the earliest
• Ideally patient should receive NAT tested blood product
• Detailed record of red cell transfusions should be kept, that is, date, number of units, origin of those units, any complication, management, etc
• All precautions of grouping/crossmatching and transfusion as is applied to any patient on chronic transfusion therapy should be taken
• Close relatives blood should not be transfused.

• Deferiprone (L1)
• Deferasirox (Asunra).

• To ensure that pre transfusion Hb is maintained between 9 and 10 g/dl
• To detect development of leucopenia or thrombocytopenia
• To monitor iron status by serum ferritin and MRIT2*
• To detect the side effects of transfusion or complications of chelation therapy early
• Early detection and management of transfusion transmitted infections
• Monitoring of cardiac functions by X-ray chest, Echo, or MRIT2* images if required
• To monitor growth and development and institution of therapy at the earliest for growth failure
• Early detection of endocrine problems and institution of appropriate management.

Table 3: Monitoring of thalassemia patients at each transfusion Click here to view

Table 4: Monitoring of thalassemia patients quarterly and annually Click here to view

Figure 4: IAP Growth curve for boys (2 to 18 yrs) Click here to view

Figure 5: IAP growth curve for girls (2 to 17 yrs) Click here to view

• To destroy and prevent regeneration of defective stem cells
• To induce sufficient immune suppression for good engraftment of donor bone marrow cells
• To infuse normal stem cells
• To prevent graft versus host disease (GVHD) with high dose preconditioning, therapy with busulphan, antithymocyte globulin therapy, cyclophosphamide, or total body irradiation. Presently, preconditioning protocols have improved to provide better survival.

• Presence of hepatomegaly (hepatomegaly of 2 cm below costal margin)
• Portal fibrosis
• Iron overload (serum ferritin >1000 ng/ml).

Table 5: The frequency of investigations to be done at different ages Click here to view

Table 6: Immunization and medication schedule Click here to view

Table 7: Referral clinic visits Click here to view

• Temperature >38.5°C
• Pain inadequately relieved by home measures
• Significant respiratory symptoms (e.g. severe cough, shortness of breath, chest pain)
• Abdominal pain, distention, acute enlargement of the spleen
• Any neurologic signs or symptoms even if they are transient
• Significant increase in pallor, fatigue, or lethargy
• Significant vomiting or diarrhea.

• Amoxycillin 250 mg tds should be given and adding Augmentin 40 mg/kg should be strongly considered for severe illness or if CNS infection is suspected. Parenteral antibiotics should be given before other procedures, such as CXR
• Paracetamol 250 mg tds should be given for 3 days
• Summary of patient's last comprehensive evaluation should be available and if not, baseline information should be obtained
• A pediatric hematologist or the patient's primary physician with expertise in SCD must be contacted.

• IV+PO 1-1 ½ × maintenance, increased fluids may be needed if patient is dehydrated or if insensible losses are increased, for example, persistent fever, avoid excessive fluids, which may precipitate or exacerbate acute chest syndrome
• Cefotaxime or cefuroxime 50 mg/kg q 8 h IV should be given and it should be substituted with clindamycin 10 mg/kg IV q 6 h for patients with known suspected cephalosporin allergy. Prophylactic penicillin should be discontinued while the patient is receiving broad spectrum antibiotics. Adding vancomycin 10-15 mg/kg IV q 8 h should be strongly considered for severe febrile illness or for proven or suspected CNS infection or a daily dose of Augmentin 40 mg/kg should be started
• Paracetamol 10-15 mg/kg 6-8 hourly must be given as needed
• Transfusion of RBCs should be considered if the Hb is 1-2 g/dl or more below baseline and the patient shows any signs of cardiovascular compromise
• O₂ by facemask, the etiology of a new or increasing supplemental O ₂ requirement should be investigated. Unnecessary O ₂, which could suppress the reticulocyte count, and exacerbate anemia must be avoided.

• Acute exacerbation of baseline anemia:
  • Hyperhemolysis
  • Hepatic sequestration
  • Splenic Sequestration
  • Aplastic crisis
• Severe vaso-occlusive events:
  • Stroke
  • Acute chest syndrome
  • Severe infection
  • Multiorgan failure
• Preparation for procedures:
  • Surgery
  • Radiographs with ionic contrast
  • General anesthesia.

• Mild-to-moderate pain:
  • PCM 10-15 mg/kg daily should be given round the clock for 3 days along with oral fluids
  • If there is inadequate relief within 30 min, then codeine I mg/kg po with PCM - 1 tablet tds should be added
• Moderate-to-severe pain
  • Diclofinac tab 50 mg - 1 tablet tds and oral fluids must be given
  • IV fluids: 10 cc/kg bolus over 1 h should be administered followed by a maintenance rate. Excessive fluids should be avoided unless the patient is judged dehydrated
  • Pulse oximetry to be monitored: O ₂ to be used by a nasal cannula or facemask.

• IV + PO 1 × maintenance. More fluids may be needed if insensible losses are increased (e.g. persistent fever) or to support intravascular volume before transfusion
• Incentive spirometry - 10 breath q 2 h when awake
• Paracetamol 10-15 mg/kg poq 8 h to be given or other antiinflammatory agent if no contraindication is present. If this gives inadequate relief, codeine should be added (PCM + Codeine) or Diclofenac tablets and suppository
• Cefotaxime or cefuroxime 50 mg/kg q 8 h IV to be given. This should be substituted by clindamycin 10 mg/kg IV q 6 h for patients with known suspected cephalosporin allergy. Prophylactic penicillin should be discontinued while patient is receiving broad spectrum antibiotics. Adding vancomycin 10-15 mg/kg IV q 8 h should be strongly considered for severe illness or if large infiltrate with pleural effusion is present
• Pain team consultation should be considered
• O ₂ by face mask to be given as needed
• Heating pads should be offered or other comfort measures previously used by the patient and ice and cold packs should be avoided
• Laxatives should be given for constipation
• Analgesics may be weaned as tolerated by decreasing the dose, and not by prolonging the interval between doses. The change of analgesics must be discussed with the patient/family
• Red cell transfusions should be considered:
  • Simple transfusion for moderately severe illness, especially if Hb >1 g/dl below the baseline (do not transfuse acutely to Hb >10 g/dl, Hct > 30%)
  • Partial exchange transfusion to Hb 10 g/dl and Hb S >30% for severe or rapidly progressive disease (the patient may require transfer to ICU and transfusion medicine consultation for erythrocytapheresis). The femoral or central venous catheters should be removed as soon as possible after the exchange transfusion to reduce risk of thrombosis
• Other clinical care paths to be seen for acute chest syndrome, acute splenic sequestration, aplastic crisis, stroke, priapism if present.

• Hospitalization
• Associated symptoms should be documented
• Intake + output should be recorded and the daily weight taken
• Any oxygen requirement must be reviewed and, baseline oxygen sats determined
• History of asthma, current medication, and drug allergies must be reviewed.

• CBC, DLC, PLT count and reticulocyte count should be done initially and then daily until there is improvement
• CXR should be done initially and repeated for evaluation of clinical deterioration
• Typing and crossmatching of blood should be considered for severe illness or if the Hb is >1 g/dl below baseline. If available, minor antigen-matched, sickle-negative, and leukocyte depleted RBCs should be kept ready
• A blood culture should be done if the patient is febrile or has history of recent fever
• Blood gas analysis should be considered for severe illness
• Renal and liver function tests are needed for severe illness or if diffuse encephalopathy is present.

1. General Care and Treatment: Maintain "euvolemia".IV + p.o. 1--1 ½ - maintenance., more fluid is appropriate only if patient is dehydrated or insensible losses are increased
2. Incentive spirometry -10 breath q 2 h when awake
3. Encourage ambullation, activity
4. Oxygen to pulse oximetry >92% 0or >baseline value if >92%
5. Acetaminphen 15 mg/kg po 6 hr or prn T >38 ⁰ C (max dose 60 mg/kg/day)
6. Ibuprofen 10 mg/kg po 6--8 hr if no contraindication is present like gastritis, ulcer, coagulopathy, renal impairment). Limit more frequent dosing to 72 hr maximum duration
7. Cefotaxime or cefuroxime 50 mg/kg q 8 hr IV.substitute clindamycin 10 mg/kg IV q 6 h for patient with known suspected cephalosporin allergy. Prophylactic penicillin should be discontinued while patient is receiving broad spectrum antibiotics
8. Azithromycin 10 mg/kg po first dose then 5 mg/kg qd, erythromycin 10 mg/kg q 6 h po, or other macrolide antibiotic
9. Strongly consider adding vancomycin 10--15 mg/kg IV q 8 hr for severe illness or if large infiltrate with pleural effusion present
10. Consider one dose of fuosemide 0.5- -1.0 mg/kg IV if sign of fluid overload present
11. Consider trial of bronchodilators especially if patient has history of reactive airway disease or wheezing on examination
12. Consider positive pressure ventilation
13. Consider red cell transfusion:
    • Simple transfusion for moderately severe illness, especially if Hb >1 g/dl below baseline (do not transfuse acutely to Hb >10 g/dl, Hct >30%)
    • Partial exchange transfusion to Hb 10 g/dl and Hb S >30% for severe or rapidly progressive disease (may require transfer to ICU and transfusion medicine consultation for erythrocytapheresis). Remove femoral or central venous catheters as soon as possible after exchange transfusion to reduce risk of thrombosis
14. See other clinical care paths for acute splenic sequestration, aplastic crisis, stroke, priapism if present.

• IV + PO 1 × maintenance, more fluids may be needed if insensible losses are increased (e.g. persistent fever) or to support intravascular volume before transfusion
• Incentive spirometry 10 breath q 2 h when awake if on parenteral narcotics
• RBC transfusion 10 cc/kg for Hb <4-5 g/dl and signs of cardio vascular compromise. Transfusion may be needed for Hb <7-8 g/dl for patients with relatively high baseline Hb levels (e.g. Hb SC disease). In severe cases, urgent initiation of transfusion prior to inpatient admission may be life-saving. A posttransfusion Hb level <8-9 g/dl is generally recommended to avoid the risk of hyperviscosity that may occur several days later when RBCs sequestered in the spleen may return to the circulation and increase the Hb 1-2 g/dl above posttransfusion levels
• Cefotaxime or cefuroxime 50 mg/kg q 8 h IV if febrile, substitute clindamycin 10 mg/kg IV q 6 h for patient with known suspected cephalosporin allergy. Strongly consider adding vancomycin 10-15 mg/kg IV q 8 h for severe febrile illness or for proven or suspected CNS infection
• If applicable, continue Prophylactic penicillin. Prophylactic penicillin should be discontinued while patient is receiving broad spectrum antibiotics
• O ₂ by nasal cannula or face mask if needed to keep pulse oximetry >92% or patient's baseline value, if >92%. The etiology of a new or increasing supplemental O ₂ requirement should be investigated
• Acetamonophen 15 mg/kg po q 6 h (max daily dose 60 mg/kg) and ibuprofen 10 mg/kg po q 8 h for any fever and mild pain (Hyperthermia may exacerbate cardiovascular compromise with severe anemia)
• See other clinical care paths for vaso-occlusive pain, acute chest syndrome, aplastic crisis, stroke, priapism if present
• If more than two sequestration crisis, child >5 years, Pnemococcal prophylaxis followed by splenectomy.

• IV + PO at 1 × maintenance
• Partial exchange transfusion or erythrocytapheresis to Hb 10 g/dl and Hb S (patient's RBC) <30%. Remove femoral or central venous catheter as soon as possible after exchange transfusion to reduce risk of thrombosis
• Simple transfusion with RBCs to Hb approximately 10 g/dl may be considered as an alternative to partial exchange transfusion for stable patients with Hb 6-7 g/dl (do not transfuse acutely to Hb >10 g/dl, Hct >30%)
• Rx seizures if present
• Treatment increased intracranial pressure if present
• O ₂ by nasal cannula or face mask if needed to keep pulse oximetry >92% or patient's baseline value, if >92%. The etiology of a new or increasing supplemental O ₂ requirement should be investigated
• Cefotaxime or cefuroxime 50 mg/kg q 8 h IV if febrile, substitute clindamycin 10 mg/kg IV q 6 h for patient with known suspected cephalosporin allergy. Strongly consider adding vancomycin 10-15 mg/kg IV q 8 h for severe febrile illness or for proven or suspected CNS infection
• If applicable, continue Prophylactic penicillin. Prophylactic penicillin prophylaxis should be discontinued while patient is receiving broad spectrum antibiotics
• See other clinical care paths for pain, acute chest syndrome, aplastic crisis, stroke, priaprism if present

• Admission for three or more severe vaso-occlusive crisis pain event/year
• Admission for three or more blood transfusions/year
• CNS manifestations
• Acute chest syndrome
• Avascular necrosis of bone.

• Pregnancy
• Inability to comply with daily dosing and frequent lab monitoring.

• CBC every month with a watch on the plt count
• Reticulocyte count
• LFT, KFT every 3 months
• HPLC for HbF levels.

Conclusions and Recommendations

• Screening for identification of carriers of hemoglobinopathies should be done before marriage or after marriage before conception or during the early antenatal period
• Neonatal screening is important for sickle cell disorders and should be done among the tribal and nontribal population where the prevalence of the sickle gene is high
• Preoperative screening should also be done in communities where the sickle gene is prevalent
• Measurement of red cell indices and quantitation of HbA ₂, Hb F and other variant Hbs are recommended for diagnosis of β-thalassemia carriers and heterozygotes of other Hb variants using automated HPLC. Capillary electrophoresis is also emerging as a suitable technique for screening and can be used
• Facilities as defined should be available at different levels staring with the Primary Health Centre, Rural Hospital, District Hospital, Tertiary Centre and finally the Reference Centre
• Centers managing β-thalassemia patients must first establish the need for transfusion, determine the amount of the appropriate blood product required and the frequency of red cell transfusions
• Pretransfusion testing, which includes extended phenotyping of the patients red cells, testing for viral infections, and estimation of serum ferritin as indicated should be done once chronic transfusion therapy has to be started. Hepatitis B vaccination should also be given and detailed records maintained
• Iron-chelation therapy should be started after the serum ferritin levels cross 500 ng/ml and patients should be monitored regularly
• A comprehensive health care program for children and adolescents with SCD should include all systemic examination, Hb analysis and biochemical investigations as indicated and immunization as per the schedule mentioned
• Both outpatient and inpatient management should be available for management of acute illness and other complications as mentioned in these guidelines.

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