Transfusion support in Thalassaemia. Dr.A.keerti 1 st year PG DEPT. OF TRANSFUSION MEDICINE

Transcription

1 Transfusion support in Thalassaemia Dr.A.keerti 1 st year PG DEPT. OF TRANSFUSION MEDICINE

2 Structure of hemoglobin Types of hemoglobins Hemoglobin-Development Switching Thalassaemia- introduction Classification Pathogenesis of beta thalassaemia Clinical Presentations of Thalassaemia Diagnosis Transfusion support in thalassaemia

3 Structure of hemoglobin

4 Types of hemoglobins 1. Embryonic hemoglobins - 3rd to 10th week of gestation ζ2ε2 (Hb Gower 1) α2ε2 (Hb Gower 2) ζ2γ2 (Hb Portland 1) ζ2β2 tetramers (Hb Portland 2) 2. Foetal hemoglobin,hbf (α2γ2 )molecule which is the predominant oxygen carrier during gestation;constitutes % in adults 3. Adult hemoglobin,hba >95% (α2β2), which replaces HbF shortly after birth; 4. A minor component, HbA2 3.5%(α2δ2 )is also present in adults.

5 Hemoglobin-Development Switching

6 Anemias There are various causes of anemias Broadly divided into - Defect in the production - Defect in normal survival of blood cells - Blood loss

7 Thalassaemia It is hereditary disorder of Hb synthesis, where there is deficient synthesis of globin chain Is characterised by increased rate of destruction of red cells resulting in anaemia. Alpha thalassaemia results from large deletions in the alpha gene(s) Pathogenesis is due to the presence of free beta subunits Beta thalassaemia results from mutations in beta gene(s) Pathogenesis due to the presence of free alpha subunits Two classes: β0 and β+

8 Classification: Alpha thalassaemia Beta thalassaemia

9 Pathogenesis of beta thalassaemia

10 Clinical Presentations of Alpha Thalassaemia A single deletion silent carrier state RBC morphology and hemoglobin concentrations are usually normal Two gene deletion (α-thalassaemia trait) Mild microcytic anemia Three gene deletion (hb H disease) Precipitated β chains Patients have moderate anemia, marked microcytosis, splenomegaly, and bone marrow erythroid hyperplasia Four gene deletion (Hydrops fetalis) Not compatible with life Hemoglobin is primarily comprised of γ4 (Bart s), which has a very high affinity for O2 and is a poor oxygen transporter

11 Clinical Presentations of beta Thalassaemia β-thalassaemia major usually presents between 6 to 24 months with osevere hypochromic microcytic anaemia(hb - <5gm/dl), omild jaundice ofailure to thrive ofeeding problems oirritability orecurrent bouts of fever due to hypermetabolic state or inter-current infection oprogressive enlargement of abdomen caused by spleen and liver enlargement β -thalassaemia intermedia(hb 7-10gm/dl) should be suspected in individuals who present at a later age with similar but milder clinical findings. β-thalassaemia trait has no important clinical effects

12 Diagnosis Laboratory Testing CBC with peripheral blood smear Many hemoglobinopathies can be diagnosed using electrophoretic or high performance liquid chromatography (HPLC) techniques, but some may be missed

13 Cont. investigations G6PD level Serum ferritin Total iron-binding capacity Serum iron Red cell folate. Liver enzymes ALT,AST, Bilirubin, LDH should be measured Genetic testing

14 α Thalassaemia Diagnosis Hb gel/hplc migration patterns helpful in Hb H and Hb Barts diagnosis Genetic analysis -Multiplex PCR Alpha globin sequencing -PCR amplification followed by bidirectional sequencing of the complete protein coding sequence with exon/intron boundaries, proximal promoter region, 5 and 3 untranslated regions, and polyadenylation signal

15 β Thalassaemia Diagnosis - HPLC: Elevated HB A2 diagnostic - Molecular analysis: Complete beta globin coding sequence, the splice sites and other intronic regions known to harbor mutations, the proximal promoter region, and the 5 and 3 UTR regions

16 Transfusion support in thalassaemia

17 Goals of Blood Transfusion Therapy Achievement of appropriate haemoglobin level. Use of donor erythrocytes with an optimal recovery and half-life in the recipient. Avoidance of adverse reactions, including transmission of infectious agents

18 Management PRBC Palliative Iron chelation Splenectomy Immunization Vitamin and folic acid supplementation Curative Hematopoietic stem cell transplant (HSCT) Gene therapy

19 Whom to Transfuse Haemoglobin level (Hb) <7 g/dl on 2 occasions, > 2 weeks apart (excluding all other contributory causes such as infections) OR Haemoglobin > 7 g/dl with any of the following: - Facial changes - Poor growth -Fractures -Clinically significant extramedullary haematopoiesis

20

21 Transfusion regimen Supertransfusion Regimen Hypertransfusion Regimen Moderate Regimen Target is Hb- 12g/dl Post transfusion Hb 14g/dl Pretransfusion Hb 9-10 g/dl The post-transfusion Hb should not be greater than 14 15g/dl to avoid hyperviscocity & stroke.

22 Transfusion protocol STATUS NO CARDIAC PROBLEM CARDIAC PROBLEM PRESENT OR Hb<5g/dl RATE OF TRANSFUSION 5-7ml/kg/hr 2ml/kg/hr AMOUNT OF BLOOD TRANSFUSED 15-20ml/kg 5ml/kg A dose of 20ml/kg will increase 1gm/dl of hemoglobin.

23 Types of blood products for Thalassaemia PACKED RED CELLS less than 6 day old ABO, Rh(D) compatible blood Phenotypically matched for C, E and Kell antigen CMV negative LEUKOREDUCED RBC s: Pre-storage filtration of packed red cells is the preferred method for leucoreduction To prevent febrile non-hemolytic transfusion reaction (FNHTR), To prevent CMV transmission, Alloimmunization with leukocyte antigens.

24 Types of blood products for Thalassaemia WASHED RED CELLS : To prevent allergic reactions FROZEN RED CELLS: For rare blood groups.

25 Irradiation of Blood Components Patients at greatest risk are: Severely Immunosuppressed, Immunocompromised, Receive Blood Donated By Relatives, Or Fetuses Receiving Intrauterine Transfusions Irradiation inactivates lymphocytes, leaving platelets, RBCs and granulocytes relatively undamaged. Used to avoid Transfusion associated graft versus host disease(tagvhd)

26 NEOCYTE TRANSFUSION Neocytes are younger RBCs with an average lifespan of 100 days when compared to matured RBCs with an average lifespan of 60 days. Collected by apheresis method from the donor based on the principle of specific gravity. ADVANTAGES: As the lifespan is more, transfusion intervals are increased. Reduces iron overload. Reduces total blood requirement. DISADVATAGES: cost constraint.(apheresis machine required)

27 Complications due to transfusions: Febrile non hemolytic transfusion reactions - HLAantibodies in patients, cytokine reactions produced by donor leucocytes Transfusion associated graft versus host disease(tagvhd) - avoided by using irradiated blood products Allergic reactions Hyperviscosity Transfusion transmitted infections

28 Alloimmunization - At each transfusion, give ABO, Rh(D) compatible blood. Matching for C, E and Kell antigen is highly recommended. Iron overload -Uncontrolled transfusion iron overload increases risks heart failure endocrine damage liver cirrhosis hepatocellular carcinoma. - Difficult in getting Venous access in repeated transfusions

29 Assessment of Iron overload Serum ferritin Liver iron concentration -liver biopsy -SQUID( superconducting quantum interference device) -MRI MRI assessment of cardiac Iron MRI assessment of Pancreatic Iron overload Liver T and iron overload Grading Hepatic T2(ms) none >6.3 mild moderate severe <1.4 Cardiac T2 and iron overload Grading none >20 Myocardial T2(ms) mild moderate 8-12 severe <8

30 When to start chelation Iron chelation should be initiated as soon as transfusions have caused enough iron accumulation to cause tissue damage Iron chelation is started when following criteria are met in TDT: -Age of child 2 years -after first transfusions -Serum ferritin > 1000µg/L -LIC > 7mg/g dry weight The primary goal should be prevention of iron loading of hepatocytes thus preventing secondary distribution to endocrine organs and heart

31 Iron chelation for transfusion dependent patients Desferrioxamine subcutaneous infusion, Deferiprone, Deferasirox oral iron chelators -Close monitoring for ocular and auditory toxicity is strongly recommended Vitamin C upto 200mg/day one hour after initiating chelation splenectomy is indicated (but not before 6 years of age) if annual pure red cell requirement >200ml/kg/hr

32 Haemopoietic stem cell transplant should be offered to thalassemia patients (and families) at an early age, or before complications due to iron overload have developed if an HLA identical sibling is available Either bone marrow or cord blood from an HLA identical sibling can be used. A matched unrelated donor can be selected, provided high compatibility criteria for both HLA class I and II loci are present. Transplanted after Myeloablation by busulphan and Cyclophosphomide

33 Transfusion therapy in non transfusion dependent thalassaemia(ntdt) Indications of transfusion in NTDT: Persistent severe anaemia During conditions of stress (eg:- pregnancy) Growth failure and delayed puberty Facial changes Pseudotumor, cerebrovascular disease, pulmonary hypertension and leg ulcers Anaemia leading to poor quality of life.

34 Key points for pregnancy care include: Genetic counselling for couples at risk for offspring with homozygous beta thalassemia can be done Check cardiac, liver,thyroid function and gestational diabetes once per each trimester. Transfuse blood periodically to maintain haemoglobin 10-12g/dl. Serial ultrasound scans to monitor fetal growth. Higher incidence of caesarean section. Patients on oral chelators (deferasirox or deferiprone) are should be advised to switch to desferrioxamine prior to induction of ovulation/spermatogenesis

35 Life Span In Thalassemics No treatment : 2-4 yrs With only blood transfusion support:10-12yrs With blood transfusion and chelation: 30-40yrs With blood transfusion support, chelation and splenectomy: yrs With haematopoietic stem cell transplant (HSCT):cure rate 95%.

36 Prevention Birth of Thalassaemia patients can be prevented. Population education Mass screening Genetic counseling Therapeutic abortion after prenatal diagnosis.

37 Thank you