approach in managing thalassaemia from transfusion perspective · 2019-07-13 · hb e beta...
TRANSCRIPT
Approach In Managing Thalassaemia From Transfusion
Perspective
Dr. Nor Hafizah Ahmad
Transfusion Medicine
National Blood Centre
27 June 2019
Outline
Case Illustration
Introduction
Current situation In Malaysia
Malaysia Clinical Practice Guidelines
Risk of alloimmunization
Ensuring safety in multiply transfused patients
Conclusion
Case Illustration
13 years old ,Malay ,girl
Hb E Beta thalassemia on TDT regime (Transfusion dependent Thal)
Juvenile SLE /Suspected panhypopitutarism
Diagnosed in 2010, initially non transfusion dependent
Converted to TDT regime -Hb was persistently <7 with poor growth
No RBC phenotyping taken.
Transfusion History
20 episodes of transfusion (April 2011 -September 2012) before converting to TDT
On regular 4 weekly transfusion since 2012
Mean HB in 2012 was 6-8g/dl, 2013 was 5-9g/dl and in 2014 4-6g/dl
Her spleen was increasing in size, despite being on a TDT regime.
2013
difficulty getting compatible blood
DCT : 4+ for polyspecific AHG, IgG, C3d, Antibody screening : negative
July 2014
Transfusion requirements were more frequent since January 2014
She was pale- persistent low HB of 4-5g/dl requiring 2-3 weekly tx.
Repeat antibody identification :
DCT : 4+ for polyspecific AHG, IgG, C3d
Antibody identification: pan-agglutination ,non –specific auto-IgGAutocontrol positive 4+.
Case was referred to us in July 2014
Anti-C, Anti-Jkb, Auto-IgG, cold agglutinin. Elution showed Auto IgGspecificity.
Phenotype-
Difficulty in getting blood – presence of multiple alloantibodies with auto IgG
Mycoplasma test was positive
Connective tissue screening : C3/C4 and ANA were positive
No hx of prolong fever, hair loss, rash, and no joint pains.
Impression : Juvenile SLE with AIHA
Treated with Methylprednisolone for 3 days, Azathioprine 25mg od, Hydroxychloroquine 100mg od & weaned off to prednisolone 25mg od
December 2014
Back to monthly transfusion, less hemolysis
Hepatosplenomegaly, liver 5 cm and spleen 5 cm
2015
- developed multiple transfusion reaction
- Treatment were optimized ;methylprednisolone pre transfusion & IVIg
- Hb was better sustained
2016
- Developed flare of the disease
- Methylprednisolone for 3 days. Azathioprine was increased to 100mg od & dexamethasone was converted to prednisolone again
- Referred HKL for splenectomy
- Rituximab commence to control the hemolysis
2017 – regular monthly transfusion, on rituximab
2018
- Hemolyis not controlled with rituximab
- Referred to Hosp Ampang for exchange transfusion
- Patient became unstable, passed away in Ampang
Thalassaemia
Heterogenous group of genetic disorder
Reduced rate of synthesis of alpha or beta chain
Abnormal hemoglobin production leads to anaemia
Clinically patient is lethargic and pale, enlarged spleen, jaundice, dark urine, and failure to thrive
Required regular transfusion for survival
Hemoglobin Chain
In α-thalassemias, production of the α globin chain is affected
In β-thalassemia, production of the β globin chain is affected.
Clinical & Genetic Classiffication
Clinically divided into :
a) Major : severe anaemia; no alpha or globin chain is produced. Cannot make hemoglobin
a) Intermedia : moderate anaemia with splenomegaly & iron overload
a) Minor/trait : mild anaemia; slight decrease in normal hemoglobin types
TRANSFUSION REQUIREMENT
http://www.haematologica.org/content/98/6/833
Widely distributed worldwide, more prevalent in certain areas especially among Asians, middle Mediterranean, Middle eastern & Far
Eastern populations (Singer et al, 2009.)
https://clinicalgate.com/hemoglobinopathies-structural-defects-in-hemoglobin/
Thalassaemia In Malaysia
Most common hemoglobinopathies in Malaysia
Estimated 120-350 babies born with Thalassaemia each year (National Screening Program Malaysia, 2016)
Public heath issue ; psychological, social & economical Impact to patient, family and the nation
HbE and Beta- Thalassaemia are the most common inherited haematologic disorders affecting beta globin (Hassan et al, 2004)
Dr. Hishamshah Ibrahim/ MOH/2012
Malaysia Clinical Practice Guidelines
To minimise the likelihood of alloimmunisation,antigen matched blood for ABO, Rh and Kidd andany other antigen negative blood for defined antibody should be given.
Whenever possible, fresh blood of less than 14 days should be given.
Leucoreduced blood should be given to all thalassemia patients.
Alloimmunization In Thalassaemia
Transfusion therapy mainstay of treatment
Needs critical strategy to reduce morbidity & mortality
Risk of alloimmunization to minor red cell antigen which increased with repeated transfusion
No universal agreement or standards for most appropriate strategy for selection of red cells units
Alloimmunization in ThalassaemiaRemains a major challenge in chronic transfusion therapy (Yazdanbakhsh, Ware et al. 2012)
Clinical importance as can lead to Hemolytic Transfusion Reaction (acute & delayed) with different risks of morbidity & mortality
Those who developed antibodies after few transfusion showed an increased risk of additional alloantibodies & haemolytic transfusion reaction. (Yazdanbakhsh, Ware et al. 2012)
Over the last 20 years risk of alloimmunization remains unchanged, while risk of transmissible infection had gone down (SHOT data , 2011)
Rate of alloimmunization
(Matteocci and Pierelli 2014)
Risk of alloimmunizationa) Donor Factorsb) Host Factors
Risk Factors For Alloimmunization
Donor Factors
- Ethnic or racial disparity
- Homogenus population – lower rate compared to heterogenuspopulation
- Extended RBC antigen matching in donors
Host Factors- Duration of transfusion support
- Older age associated with increased rate of alloimmunization
- Splenectomy -significant risk, mechanism is unclear
- Alogeneic white blood cells – implicated in allergic & febrile reaction as well as alloimmunization
Study of Asian patient with Thalassaemia in a single community in US ;rate 20.8% becaouse only 5% of blood donors are Asian
Patients who had a splenectomy had a higher rate of alloimmunization than patients who did not have a splenectomy(36% vs 12.8%;P 5 .06).
Development of AntibodiesLower rate if first transfusion at < 2 years of age compared those who are transfused later (Gupta et al); < 3 years ( Spanos et al).
An immature immune system & some form of acquired immune tolerance to allogeneic red cells held responsible for the alloimmunization risk
Patient without spleen – promote enhancement of autoantibodies
(4.9 % Thompson et al, 11% Ameen et al, 21% Guirat-Dhouin et al)
Foreign blood not filtered due to absence of spleen. Patient without spleen – promote enhancement an autoimmune reaction
Autoimmunization in Thalassaemia
• Zimring et al explained non –exofacialpolymorphism (NEP) exists in some blood group
• NEP is in the cytoplasmic or transmembranedomains & not exposed on intact red cells –contribute to immunogenicity & provide mechanism for the development of autoantibodies
• A number of NEP identified in Kell, Kidd, Duffy
Main antibody specificities
Thompson et al reported 697 patients the incidence is 21.2% in Caucasian & in Asian 13.3% with antibodies directed towards C,E,K antigens
In 382 Chinese patients, Cheng et al showed global red cell alloimmunizationanti-E (39.3%), anti Mia/Mur (30.85%), and anti-c (13%)
Saied et al reported from 95 Egyptian patients with 27 (28.4%) with anti-K and anti-E (23.6%)
In 58 patients, 8.6% of the patients had alloantibodies and 1.7% had autoantibodies. Alloantibodies identified were anti-E, anti-c, anti-K, anti-Jka, anti-N and anti-S ) (Noor Haslina, Ariffin et al. 2006)
Strategies For Prevention Of Alloimmunization
Baseline RBC phenotyping
Extended RBC matching
Leucocyte reduction
Enhanced Donor Recruitment
Baseline RBC phenotyping
- Prospective phenotyping
- Most blood bank offered serological method on recently transfused
- Recently transfused; DNA genotyping for RBC prediction
- Guide serological work in new antibody findings
- Prospective matching especially with multiple alloantibodies
- Not all centre practice; costs outweigh benefit
Extended RBC matching
-Reduction in alloimmunization expected with matched C,E,Kellphenotype (Singer, Wu et al. 2000)
- Minority programme ; include Duffy Kidd, MNS (extended phenotype)
- No consensus recommendation , not universally practiced
- Regional & national variability
- Depend on local inventory size & donor base for the region
Highly antigen matched available from donor of European background screened using molecular method. Found 96 units matched for ABO, Rh K (basic level)34 units if extended to Duffy (mid level)16 units if extended to Kidd & MNS (high level)
Leucocyte reduction
Increasingly being used as universal procedure
Effect discordant (some says reduce alloimmunization, others say no difference)
Benefit -reduce febrile non hemolytic transfusion reaction
- Cytomegalovirus transmission
Enhanced Donor Recruitment
- In populations with non homogenus population ;
- Increase recruitment of donors
- Develop specific programme for donors
- Donors partner with specific patient ( Hillyer et al 2006)
- Recruitment of dedicated donor & limiting number of donors –effective strategy to reduce alloimmunization (Roberts et al, 2012, el-Danasoury et al 2012)
Ensuring safety in multiply transfused patients ; Malaysian Perspective
• Ensuring adequate blood collection
• Improved safety of blood supply by using Nucleic Acid Testing
• Filtered /leucodepleted blood products
• Supplying phenotype matched blood
• Phenotyping/Genotyping blood donors
Phenotype Request Jun-Ogos 2015 according to diagnosis
Improved Safety by using Nucleic Acid Testing
• Thalassaemia patients at higher risks of acquiring transfusion transmitted infections.
• To reduce the risk, it is recommended that Nucleic Acid Testing (NAT) screening is expanded to cover the whole country.
• NAT introduced able to reduce window period
• Baseline screening result & 6 monthly screening
Filtered /leucodepleted blood products
• As outlined by Thalassaemia Guidelines to use packed red blood cells depleted of leucocytes
• Reduce the incidence of patient developing non haemolytic transfusion reaction
• Reduce the risk of alloimmunization to HLA.
Supplying Phenotype Blood
Perform full phenotyping for 15% of our yearly collection
Develop Rare Donor Registry Database
Strategy to recruit new rare donors:
• Mass Screening Project
- Target population eg; Thaipusam mobile, Kwan In Teng temple mobile
• Family screening
• Random phenotyping of daily blood collection
• This year - Embark collaboration with embassy
Annual event UIA ‘Rare Donor Mobile’
Targeted rare phenotype- Fya-b-, SS ( African /Arab )- Jka-b- Indonesian students- Ind B neg, Bombay (Indian)
3346 (44.3%)
1937 (25.6%)
2266 (30.0%)
COMBINATION OF PHENOTYPE JAN-DEC 2018
3122 (41.4%)
4364(57.8%)
63 (0.8%)
Rarity Phenotyped Blood Supplied In Jan-Dec 2018
No. of Common Phenotype
No. of Moderate Rare Phenotype
No. Of Extreme Rare Phenotype
Total ‘18 Total 17
Common Phenotype
3122 (41.4%) 3303 (48.6%)
Moderate Phenotype
4364 (57.8%) 3450 (50.8%)
Extreme Phenotype
63 (0.8%) 44 (0.6%)
Total ‘18 Total 17
Single Phenotype 3346 (44.3%) 3210 (47.1%)
Double Phenotype
1937 (25.6%) 1758 (25.9%)
Multiple Phenotype
2266 (30.0%) 1838 (27%)
Syazana Akmal Sharifudin/PDN/2018
Donor Phenotype Study
Classiffication of Donor Phenotype
Extremerely Rare Phenotype :
PP1Pk -, Ind b negative, Bombay, Parabombay , -D- , Jka-b-, RZRZ, Fya-b-, rh null, Yta negative, MAM negative, Doa.
Moderately Rare Phenotype :
Fya-, rr , SS, KK
Common Phenotype :
R1R1, Jka+b+, Fya+b+ Jka+, Jkb +, Fyb+
Molecular Diagnostics (Genotyping)
Benefits of molecular typing :
a) Solve discrepant serological results
b) Clearly define presence or absence of RBC antigens
c) Detect variants of weakly expressed antigen
d) Use when commercial antisera not available
d) Large-scale genotyping to screen donors
(Matteocci and Pierelli 2014)
Molecular Typing In National Blood Centre
91 samples (71 patients and 20 donors) with unresolved results by serologic findings.
Molecular testing to confirm either subgroup, Rh D status or red cell genotyping.
Findings : 22 (24%) out of 91 samples showed discordance results between serological
and molecular testing.
The discrepancies were found in ABO blood group (12), Rh blood group (4) and red cell
genotypes (6) cases
Red blood cell antigen genotyping platforms (ID-CORE XT) for Thalassaemia Patients in Sabah, Malaysia
Results were available for all 81 samples with ID CORE XT.
Out of 68 samples that had serological red cell phenotyping data, 31 samples (45.6%) were found to have discordant in at least one antigen result.
Most of the discordant is due to the weak expression of the antigen that was not detected by serological testing.
Syazana AS, Rozi HM , Nurul MY, NHafizah A, Shahnaz IS, Jamalluddin M, Saliz MZ
CONCLUSION
• RBC allosensitization remains a major challenge in transfusion dependent patient
• Ongoing research needed – mechanism of response
• Technologies- facilitate identification of patients at risk of alloimmunization
• Strategies to increase number of donors
• Serology remains gold standard
• Molecular genotyping is the way forward
AcknowledgementDr. Noryati Abu Amin
Dr. Afifah bt Hassan
State Transfusion Specialists
Immunohematology Staffs
Rare Donor Registry Committee
Paediatric Department Hospital Teluk Intan
Special Thanks
Dato Dr Yasmin Ayob
Dato Roshida Hassan
REFERENCES• Yazdanbakhsh, K., et al. (2012). "Red blood cell alloimmunization in sickle cell disease: pathophysiology, risk
factors, and transfusion management." Blood 120(3): 528-537.
• Matteocci, A. and L. Pierelli (2014). "Red blood cell alloimmunization in sickle cell disease and in thalassaemia: current status, future perspectives and potential role of molecular typing." Vox Sanguinis106(3): 197-208.
• http://www.haematologica.org/content/98/6/833
• Thompson AA, Cunningham MJ, Singer ST, et al.: Red cell alloimmunization in a diverse population of transfused patients with thalassemia Br J Haematol 2011; 153:121–128
• Schonewille H, Brand A: Alloimmunization to red blood cell antigens after universal leucodepletion. A regional multicentre retrospective study. Br J Haematol 2005; 129:151–156
• Cheng CK, Lee CK, Lin CK: Clinically significant red blood cell antibodies in chronically transfused patients: a survey of Chinese thalassemia major patients and literature review. Transfusion 2012; 52:2220–2224
• Sirchia, G., Zanella, A., Parravicini, A., Morelati, F., Rebulla, P. & Masera, G. (1985) Red cell alloantibodies in thalassemia major. Results of an Italian cooperative study. Transfusion, 25, 110–112. Spanos, T., Karageorga, M., Ladis, V., Peristeri, J., Hatziliami, A. & Kattamis, C. (1990) Red cell alloantibodies in patients with thalassemia. Vox Sanguinis, 58, 50–55.
• Noor Haslina, M. N., et al. (2006). "Red cell immunization in multiply transfused Malay thalassemic patients." Southeast Asian J Trop Med Public Health 37(5): 1015-1020.
• Singer, S. T., et al. (2000). "Alloimmunization and erythrocyte autoimmunization in transfusion-dependent thalassemia patients of predominantly Asian descent." Blood 96(10): 3369-3373.
THANK YOU