Platelet Transfusion in refractory in patients

Platelet Transfusion in refractory in patients
Respected Examiners, Faculties & my dear colleagues, Good Morning to all ! Today I wish to present my. The thesis was designed to study Dr. R. R.Sharma Professor Department of Transfusion Medicine PGIMER, Chandigarh

Platelet Transfusions are given either to stop bleeding or prevent haemorrhagic complications by maintaining the platelet count above a predetermined threshold. Origin Four-fold decrease (from 63% to 15%) in the incidence of hemorrhagic deaths in leukemic patients following prophylactic platelet transfusion policy as early as 1960’s

Relationship between hemorrhage & platelet count

Trends in Platelet Transfusion Therapy
USA: From platelet transfusion increased by 100% as against 17% increase in use of red cells. Canada: 116% increase in platelet transfusions. Two thirds of all platelet transfusions in tertiary care hospitals are prophylactic transfusions

Trends in platelet preparation at PGIMER, Chandigarh
Year Random Donor Platelets Apheresis platelets 2008 18802 492 2009 19763 777 2010 17338 605 2011 23348 925 2012 21996 1089 2013 25088 1665 2014 28134 1963 2015 26528 1841 2016 31649 1672 2017 29520 2000

Specialty wise utilization of platelets PGIMER,Chandigarh

Challenges with platelet Transfusion therapy
Product Related Availability (acute/Group specific shortage) Limited shelf life Platelet Dose (RDP Vs SDP) Leukoreduced vs. Non leukoreduced Bacterial contamination Other infectious/non-infectious risks Patient Related Transfusion trigger Prophylactic Vs Therapeutic Platelet dose- Large infrequent Vs small frequent Platelet transfusion Refractoriness

Platelet Refractoriness
Platelet Refractoriness occurs in about 20% to 70% of multi-transfused thrombocytopenic patients. Immunological causes ( 20-30%) Non-immunological causes(60-70%) Refractoriness to platelet transfusion is a complex process and poses a great challenge in haemato-oncological patients. Platelet transfusion failure due to refractoriness leads to morbidity and mortality, long hospital stay and the resultant higher cost of patient care Provision of cross-match compatible platelets. Provision of compatible platelets solely based on HLA antibody profile of patient and not matching for patients HLA type. Provision of HLA matched platelets based on HLA type of patient and their HLA antibody profile using a panel of HLA typed donors.

Post transfusion recovery or CCI is less than accepted value after at least two consecutive transfusions. Causative factors: Poor quality of platelets- production/storage Non immune Fever / Sepsis / DIC / Drugs / GVHD Immune Antibodies to ABH / HLA / HPA antigens

Defined as a post-transfusion platelet increment that is less than expected >10000/µl -1hr ≥7500/ µl -1hr ≥4500/ µl -20hr >30% -1hr, > 20% -20hr

Criteria for refractoriness
DGHS AABB BCSH Patient is said to be refractory to platelet transfusion if increment in platelet count at one hour after transfusion is less than 20% of the expected increase in value on 2 occasions. Post transfusion platelet corrected count increment (CCI) of less than after two consecutive transfusions. Post transfusion platelet corrected count increment (CCI) of less than 7.5x109/L at 1 hour and 4.5x109/L at hours.

Prevalence of Platelet transfusion Refractoriness
Authors/references Year of study No. of patients Patient group Prevalence of Refractoriness Klingemann et al. 1987 210 AA 34% TRAP study group 1997 131 AML 16% and 7 % Mathew D 2004 315 Haem-oncology 40% and 23% Slichter et al. 2005 528 27% Bajpai et al(PGIChd) 2006 43 Haem-onc 56% Kumawat etal(PGIChd) 2009 23 AA/AML 56.6% Ferreira et al. 2011 16 54% and 25% Chavan A et al (PGI.Chd 2014 104 Haemat-oncology 55.8% In the pre-leucoreduction era, the incidence of platelet refractoriness ranged from 16% to 40% as reported by Trial to reduce alloimmunization to platelets (TRAP) study group 20 and Mathew respectively. Klingemann et al. has reported a prevalence of 34% (71 of 210) refractoriness in aplastic anaemia patients provided with non leucoreduced pooled random donor platelet transfusions51The incidence of refractoriness in the post-leucoreduction era was reduced to 7% according to Trial to reduce alloimmunization to platelets (TRAP) study group. Only 23% refractory patients were reported by Mathew in post leucoreduction era. Our study found higher percentage of refractory patients in comparison to first four studies mentioned in the table 22 because in all these studies, patient alloimmunized to HLA antibodies prior to enrolment were excluded however we included them in the study, so as to find out overall prevalence of alloimmunization in our patient population.

Variables related to product quality
Non Immune Causes Variables related to product quality Quality starts with donor Validated PRP preparation protocol Amount of platelets transfused Leukocyte contamination Storage duration Type of storage bags Temperature

What is the standard dose
Type of Platelet product Clinical indication

Platelet Preparations
Single donor platelets (SDPs or APC) Prepared by apheresis Random donor platelets (RDPs) Prepared within 8 hours of whole blood collection Buffy coat method PRP method Donor should not have taken aspirin within last 3 days

Relative Merits of Platelet Preparations
Apheresis platelets Random donor platelets Platelet numbers > 3x >5.5x1010 Plasma volume ml ml Leucocytes < 5x ≥108 Donor exposure Less More HLA/HPA match Possible Not possible Risk of bacterial contamination Less More Special requirements Cell Separators Traditional component Trained staff technology Hemostatic efficacy Comparable Comparable

Physiological platelet loss
Senescence Life span 9-10 days Endothelial support Plugging gaps at junctions / fenestrations Estimated platelet requirement 7.1x109 / L / day Requirement in a 70 Kg adult (Blood Volume-5Ltrs) 5x7.1x109 / L / day = 3.6x1010 Minimum platelet requirement – 4.8x1010 A unit of Random donor platelets

SDAP RDP

Still not licensed in India
Pooled platelets 4-6 RDPs = 1 Platelet pool = 1 Apheresis platelet Increases HLA exposure –Perceived Chances of increased alloimmunization ( No Conclusive evidence found in studies) Still not licensed in India

Temperature of storage of PCs
Optimum temperature ºC Temperature below 20ºC Structural damage disc to sphere change, platelet clumping and lysis Damage can occur within 6 hours at 4ºC,10 hours at 12ºC and 16 hours at 16ºC.

Platelet shape changes
Spherical, irregular, sticky platelets Normal discoid platelets

Effect of Leukoreduction Refractoriness
Alloimmunization rate Refractoriness (overall) Refractoriness due to alloimmunization TRAP Trial Canadian Study Canadian# Study Pre-Leucoreduction 45 % 19 % 16 % 14% 13 % 14 % Post-Leucoreduction 18 % 7 % 4% 3 % 5 % #HLA matched platelet requirements decreased from 14% to 5 % after implementation of universal leucoreduction in Canada TRAP Trial. The New England Journal of Medicine 1997; 337: 1861–1869 Canadian study . Blood2005; 103: 333–339

Role leucocytes in HLA alloimmunization
Factors affecting HLA alloimmunization History of pregnancy ( 9% vs 32%) History of transfusion 3. Primary disease condition Acute leukemia, Aplastic anemia, Myelodysplasia Non-hodgkin’s lymphoma, Mutiple myeloma , Chronic leukemia

Storage duration Platelets stored for <48hrs
Better PPR & CCI than older platelets Fresher platelets has less storage lesions No significant difference in terms of bleeding and overall clinical outcome Platelet storage duration and its clinical and transfusion outcomes: a systematic review Aubron et al. Critical Care (2018) 22:185

Amount of platelet transfused
Prophylactic Platelet transfusion therapy Low dose x1011 /m2 Medium dose x1011 /m2 High dose x1011 /m2 No significant difference in bleeding in any of the groups ;lower dose group required frequent transfusions but overall less number of platelet transfused Slichter et al . N Engl J Med February 18; 362(7): 600–613. doi: /NEJMoa

How to deal with non immunological causes
Product Specifications/Manipulations ABO compatible Increasing dose of platelets Avoiding prophylactic platelet transfusions Less than 48 hour old; fresh platelets Buffy coat derived platelets/ buffy coat pooled platelets Product splitting for prophylactic transfusions Awareness regarding blood component handling and storage

How to deal with non immunological causes
Patient Management Splenectomy for splenomegaly Removing the implicated drug Treating Fever/ Sepsis/ DIC/ Haemophagocytosis Treatment of GVHD & hepatic thrombosis syndromes in BMT patients

Approaches for management of immune platelet refractory patients
A. Selection of an appropriate platelet product Provision of HLA –Matched platelets Antibody specificity Prediction Platelet Cross-matching B. Modifying the Immune Response Intravenous Immunoglobulins Therapeutic Plasma exchange Immunosuppressive Drugs C. Hemostatic agents Recombinant FVIIa , Tranexamic acid(TXA) with the aim of identifying prevalence and factors responsible for platelet transfusion refractoriness in haemato-oncological patients-Dr. Vijay Kumawat et al. especially in thrombocytopenic phases during the induction phase of chemotherapy or related to sepsis. A major part of platelet rich component in the Transfusion Medicine Department is dedicated to support haemato-oncological patients. About 20 percent of haemato-oncology inpatient costs are associated with platelet transfusions.3

HLA matched Platelets Ideal strategy Class-I (A &B) Limitations
Minimum of HLA Typed donors Molecular laboratory set-up Closest match available within time constraints & donor availability in emergency Cost

HLA matched Platelets HLA –MATCHMAKER
Computerized algorithm for evaluation of molecular similarities HLA – Class I ( A & B) epitopes between donor & recipient by Identifying discrete ag binding Sites (eplets)- CREGS HLA mis-match accepted for incompatible unexposed epilets Advantage To refine and expand the platelet donor pool

Antibody specificity prediction (ASP) method
Identify the HLA antibody specificity Select platelet DONOR lacking the antigen (AHG-CDC) Donors may be partial /complete HLA mis-match Permissive HLA –MIS-MATCH Identified by the reactivity pattern of patient serum with the HLA antigen coated beads(flow cytometry or luminex bead assay) ,the pattern HLA antigens depicted by the non reacting beads can be an acceptable donor phenotype Expansion of donor pool Disadvantage- Increase in HLA sensitization in long term

CONCLUSION The ASP method of donor selection for refractory alloimmunized patients appears as effective as HLA-matching or cross matching. Far more donors are identified in a file of HLA-typed donors by the ASP method than by HLA matching, and this indicates that the ASP method provides important advantages regarding the availability of compatible platelet components. TRANSFUSION 2000;40:

Platelet Crossmatching
To ascertain the compatibility between the donor and the recipient Provides an in vitro assessment of antigen antibody interaction likely to occur in the potential recipient after receiving a transfusion. Platelet antigen and antibody typing is not done in routine Knowledge of platelet antigens , antibodies & the typing methods is essential

20-25% patients fail to respond to even HLA matched platelets ABO incompatibility Undetected HLA incompatibility Platelet specific antibodies Antigen unmasking during storage Different methods: MAIPA MACE SPRCA Flow cytometry Bead assays

Advantages Eliminates the need for HLA typed donor pool Easy of performance & standardization Lesser inventory logistic issues Efficacy similar to HLA –matched Dis-advantages Risk of alloimmunization for broader HLA - specificities Need for regular ab screening & frequent cross-match

Transfusion episodes (n=73) Transfusion episodes (n=76)
Study Algorithm ( ) Haem-onc patients Suspected platelet refractoriness (CCI at 1 hour on two consecutive transfusion) (N=104 ) Platelet Refractoriness (N=58, 55.5%) no Exclude from study yes Screened for HLA and HPA antibodies Antibody screen positive (N=42, 87.5%) no Exclude from study yes Include in the study (N=38) Group 1:Patients receiving crossmatched platelets (N=22) Transfusion episodes (n=73) Group 2:Patients receiving uncrossmatched platelets(N=16) Transfusion episodes (n=76) A total of 104 multi-transfused haemato-oncological patients suspected of being refractory to platelet transfusions were evaluated for post platelet transfusion response. Those patients found to be refractory were further screened for alloimmunization status .Against 30 proposed refractory alloimmunized patients, we could enroll 38 patients fulfilling the inclusion criteria .The study subjects included 17 (44.7%) males and 21(55.3%) females. Of the 38,22 were assigned in the cross-match platelet transfusion arm and 16 into the regular transfusion arm. For the sake of comparison, the platelet transfusion episodes received by these patients were divided into three groups depending upon the cross-match and compatibility status of platelets Cross-matched compatible (45 SDAP transfusion episodes)-Group I a,Cross-matched incompatible (28 SDAP transfusion episodes- Group I b Uncross-matched (76 SDAP transfusion episodes )-Group II. Results were compared and analyzed to suggest formulation of appropriate strategy for platelet transfusion in multitransfused alloimmunized refractory patients Cross –match compatible transfusion episodes (n=45) Group Ia Cross –match incompatible transfusion episodes (n=28) Group Ib Uncross –matched transfusion episodes (n=76) Group II Analyzed the results and compare the efficacy in terms of PPI,CCI,PPR

Comparison of mean Post transfusion platelet increment (PPI) in
different groups Group Ia vs II p < Group Ia vs Ib p < Group Ib vs II p < 0.3 The PPI in Group Ia ranged from /µL with mean of 32489/µL ±13324 and median being 33000/µL. The post transfusion platelet increment in Group II SDAP transfusion episodes, which ranged from /µL, had mean and median values of 14368±11932 /µL and 9500 respectively. The PPI in Group Ib ranged from /µL with a mean of ±13324 /µL and median being 9000/µL. Group Ia Group II Group Ib

Comparison of outcome indicators among cross-match compatible (Ia) and uncrossmatched group (II)
Forty four (97.8%) of 45 cross-matched compatible platelet transfusion episodes in group Ia showed a satisfactory response in terms of PPI and CCI values as compared to 50 % and 53.9% in uncross-matched group (group II) for PPI and CCI values respectively. Thirty seven (82.2%) of 45 transfusion episodes and 18 (23.7%) of the 76 transfusion episodes in group II qualified for the successful PPR of ≥ 30% in the cross-matched compatible and uncross-matched group respectively. Thus alloimmunized refractory patients receiving cross-matched compatible platelets have 44, 37 and 15 times higher chances of having satisfactory response in terms of post transfusion PPI, CCI and PPR response criteria respectively as compared to patients receiving uncross-matched platelets as revealed by the odds ratio in two groups.

Type of platelet transfused
Platelet cross-matching using Solid phase red cell adherence assay: comparison with other studies Sr. no Author/ References Year Patient category Patient age(yrs) Sample size Definition of refractory Study period Months Selection criteria Type of platelet transfused OutCome Mean outcome Results (%) 1 Gelb et al. 1997 Unselected group of refractory patients 0.5-78 66 CCI <7500 (1hr) 41 RA SDAP CCI ≥7500 9800 59 2 Petz et.al 2000 1 yr-80 114 PPR <30% 42 PPR> 30% 23.38 -- 3 Rebulla et al. 2004 Haemato-oncology 15-95 40 <5000 (24hrs) 33 Pooled BCPC(6) PPI ≥10000/µL (1hr) PPI 32000 68 4 Wiita et al. 2012 Haemato-oncology and solid tumors 49±17 CCI <7500 11 R CCI≥ 7500 7000 5 Salama et al. 2014 37.6 ±13.35 36 20 SDAP/ RDP CCI≥ 5000 13980 72.9 (92.3) 6 PGIMER study 17-78 38 17 CCI ≥5000 32889 19173 97.8 7 Priti Elhence et al SGPGI 6-75 31 CCI <5000 (24 hrs) 24 SDP 93.2 by Rebulla et al. who had taken CCI<5000 (24Hrs) as criteria for refractoriness but PPI ≥10000/µL (1hr) as outcome criteria, reported mean PPI / µL and a satisfactory outcome in 68% of patients. Our results are also consistent with that study with mean PPI 32488/ µL at 1 hour with a satisfactory response in 97.8% which is higher than study by Rubella et al. This could be because in our study, the platelet recovery was followed after SDAP transfusion, whereas in their study pooled Buffy coat platelet concentrates (BCPC) were used. Wiita and osama-Both the above mentioned studies, had addressed refractory alloimmunized haemato-oncology patients irrespective of whether it was due to immune or non immune cause. We have exclusively included alloimmunized refractory patients and excluded the transfusion episodes resulting in poor response due to non immune causes and combination of immune and non immune factors.OUR prevalence of alloimmunization was higher than in study by salama et al(40% ,87.55 in ours) In the study by Petz et al. with a larger sample size, the mean PPR at 1 hour post cross-match compatible transfusion was % in refractory alloimmunized patients as compared to 48.2% in our study. This could be due to the fact that Petz et al. included patients of all age groups and did not focus exclusively on one group.

Conclusions Platelet refractoriness management is challenging
Focus on product quality - Donor selection and component preparation Sensitization of bedside clinical staff regarding good beside transfusion practices; storage ,handling and appropriate use of blood components Pooled platelets is a viable option but requires necessary approvals Splitting of the apheresis product for prophylactic transfusions HLA –Matched platelets –requires laboratory support and HLA typed donor panel Platelet cross-matching is a rapid and cheaper alternative to HLA matched approach Although owing to the short shelf life of platelets, cross-matching may require to be repeated at frequent intervals, knowing the cross-match compatible donors may help in this aspect.

Thank you

Aims and Objectives Aim Objectives
To study the efficacy of cross-matched compatible platelets in multitransfused, alloimmunized haemato-oncology patients refractory to platelet transfusions. Objectives To assess the platelet transfusion refractoriness in multitransfused haemato-oncological patients. To determine the alloimmunization (HLA and HPA) status. Provision of cross-matched compatible platelets to the study group.

Methods Study Design Study setting
Prospective case control study between July, 2013 to November, 2014 Study setting The department of Transfusion Medicine, PGIMER in collaboration with the Haemato-oncology unit of the Department of Internal Medicine and the Department of Immunopathology in a tertiary care setting

Study populations Multi-transfused patients:- Receiving transfusion of cellular blood components on two or more occasions over a period of three months. Patients refractory to platelet transfusions were screened for Alloimmunization by Capture-P® Ready-Screen® Solid Phase assay on automated immunohaematology analyzer, Galileo from Immucor Norcross, GA, USA. Thirty eight patients (N=38, M=17, F=21) with immune cause of refractoriness were included in the study.

Platelet Transfusion response variables
Post transfusion platelet increment (PPI) Post transfusion platelet count-Pre transfusion platelet count Satisfactory response criteria≥ 10000/µl at 1 hour Corrected count increment (CCI) (Post transfusion platelet count – Pre transfusion platelet count) X 1011×BSA (m2) Number of platelets transfused Satisfactory response criteria≥ 5000 at 1 hour Post transfusion platelet recovery(PPR%) (Post transfusion platelet count – Pre transfusion platelet count) X 103× TBV Satisfactory response criteria≥ 30% at 1 hour Of the several methods used to evaluate post transfusion platelet response, corrected count increments (CCI) is the most widely used primary response variable because it takes into account the number of platelets transfused, the dilution factor of platelets in the patient’s blood volume and body surface area of the patient. Alternatively, percent platelet recovery (PPR) which adjusts for platelet yield and patient’s blood volume is also used. Post transfusion platelet increment is an absolute difference in platelet count in the pre and post transfusion period.

Platelet crossmatching by solid phase red cell adherence assay (SPRCA)
Capture-P® Solid Phase System on automated immunohaematology analyzer Galileo Immucor, Inc. Norcross, GA USA. Methodology Donor platelets first bound to the surfaces of polystyrene microplate wells. Serum incubated in platelet coated wells to allow antibodies, if present, to bind to the platelets. Washing to remove unbound immunoglobulins Addition of anti-IgG-coated indicator red cells. Centrifugation Interpretation of results designed to detect the unexpected antiplatelet antibodies (As a consequence of such bridging, the indicator red cells will cover the immobilized platelets in a confluent monolayer.

A positive reaction was characterized by adherence of the indicator red cells over the surface of the well bottom. A negative reaction was indicated by a tight button in the centre of the well bottom. In the case of positive tests, the migration of the indicator red cells to the bottom of the wells is impeded as anti-IgG bridges are formed between the indicator red cells and the platelet-bound antibodies. In the absence of platelet antigen-antibody interactions, the indicator red cells will not be impeded during their migration and will pellet to the bottom of the wells as tightly packed, well-defined cell buttons.

Results

Comparison of mean corrected count increments (CCI) in different
groups Group Ia vs II p < Group Ia vs Ib p < Group Ib vs II p < 0.3 Category Ia -The CCI ranging from 3349 to had mean of ±8960 Category II-The CCI ranged from 1000 to with mean of 8140±6475 Category Ib-The CCI ranging from 1144 to had a mean of 5888 ±3933 Group Ia Group Ib Group II

Comparison of mean percent platelet recovery (PPR) in different groups
Group Ia vs II p < Group Ia vs Ib p < Group Ib vs II p < 0.3 Category Ia-PPR ranged from 7.9 to 98.3% with mean of 48.2±22.1 % Category II- PPR ranged from 0.91 to 74.06% with mean of 20.4±15.9 % Category Ib-PPR ranged from 2.8 to 44.2% with mean of 14.9 ± 9.3% Group Ia Group II Group Ib

Correlation between Panel reactivity on antibody screening and compatibility testing
Percent Panel Reactivity Compatible group Ia (n=45 transfusion episodes) Incompatible group Ib (n=28 transfusion episodes) Total (N=73 transfusion episodes) < 35% 27 (82%) 6 (18%) 33 35% to 70% 12 (71%) 5 (29%) 17 >70% 6 (26%) 17 (74%) 23 A reactivity score was determined by calculating the percentage of number of reactive wells out of 13 cell panel. Based on the percentage panel reactivity, 73 transfusion episodes (group Ia and Ib) for which cross-matching was performed, were stratified into three arbitrary categories: <35%, 35% to 70%, >70% Thirty three of the 73 transfusion episodes had an overall panel reactivity of <35%, of which 27 (82%) were cross-matched compatible and 6 (18%) were cross-matched incompatible, implying that for patients with a panel reactivity of <35%, we found 82% compatible units and 18% incompatible units. Similarly with patients with panel reactivity of 35% to 70%, we found 12 (71%) compatible and 5 (29%) incompatible units. For patients with a panel reactivity of more than 70%, we could only find 6 (26%) compatible units. Thus with the increase in percentage of panel reactivity for HLA and HPA antibodies, the chance of finding a cross-matched compatible platelet unit decreases. Thus with the increase in percentage of panel reactivity for HLA and HPA antibodies, the chance of finding a cross-matched compatible platelet unit decreases.

Future directions In refractory alloimmunized patients, provision of cross-matched compatible platelets is a viable option and provides satisfactory response in terms of post transfusion platelet recovery profile (PPI, CCI and PPR) and should be considered strongly in such patients. An inventory of SDAP of all groups from voluntary donors, on a regular basis, dedicated for haemato-oncological patients, especially those who are refractory and alloimmunized could hasten up the cross-matching procedure and cross-match compatible platelets can be issued to these patients as and when required. Alternatively, a list of platelet compatible donors could be generated by cross-matching prior to the actual need for transfusion for a particular patient, so that the donors may be called for directed platelet donation at the time of need for transfusion. A baseline antibody screening and assessment of alloimmunization status at regular intervals will diagnose the immune cause leading to refractoriness, so as to take appropriate steps in a timely manner. This would optimize the platelet transfusion needs and also decrease the financial burden. Though we have an emergency donor panel for plateletpheresis registered for voluntary donations in the department, the number needs to be increased so as to cater to the increasing requirements of haemato-oncology patients.

Acknowledgements I find words inadequate to express my sense of indebtedness and gratitude to my esteemed teachers and accomplished guides Additional Professor Dr. R.R. Sharma, Prof. Pankaj Malhotra, Prof. Neelam Marwaha and Additional Professor Dr. Biman Saikia for guidance, expert supervision, sustained encouragement and belief in me all throughout this thesis work. My special thanks to entire staff of Department of Transfusion Medicine and Department of Internal Medicine who helped me in several ways. This scientific accomplishment would not have materialized without the support of the patients/next of kin registered in the study, for which I feel heavily indebted.

Aster RH. Pooling of platelets in the spleen: role in the pathogenesis of 'hypersplenic' thrombocytopenia. J Clin Invest 1966; 45:645.

Comparisons of post transfusion platelet recovery profiles of between group Ia and Ib Groups
Group Ia cross-matched- compatible (n=45 transfusion episodes) Group Ib cross-matched incompatible (n=28 transfusion episodes) Pearson- Chi-square p Mean PPI (95% CI) 32489 ( ) 10893 ( ). <0.0001 Mean CCI (95% CI) 19173 ( ) 5888 ( ) Mean PPR (95% CI) 48.2 ( ) 14.9 ( ) Statistically significant and better platelet recovery in terms of PPI, CCI and PPR was observed at 1 hour post SDAP transfusions with cross-matched compatible platelets than on occasions receiving cross-matched incompatible platelets.

Comparisons of post transfusion platelet recovery profiles of between group Ia and II Groups
Group Ia cross-matched- compatible (n=45 transfusion episodes) Group II Uncross matched (n=76 transfusion episodes) Pearson- Chi-square p Mean PPI (95% CI) 32489 ( ) 14368 ( ) <0.0001 Mean CCI (95% CI) 19173 ( ) 8140 ( ) Mean PPR (95% CI) 48.2 ( ) 20.4 ( ) Statistically significant and better platelet recovery in terms of PPI, CCI and PPR was observed at 1 hour post SDAP transfusions with cross-matched compatible platelets than on occasions receiving uncross-matched platelet units.

Comparisons of post transfusion platelet recovery profiles of between group II and Ib Groups
Group II Uncross-matched (n=76) Group Ib cross matched incompatible (n=28) Pearson- Chi-square p Mean PPI (95% CI) 14368 ( ) 10892 ( ). <0.332 Mean CCI (95% CI) 8140 ( ) 5888 ( ) <0.313 Mean PPR (95% CI) 20.4 ( ) 14.9 ( ) <0.06 There was no statistically significant difference between PPI, CCI and PPR values in the two groups implying thereby that the patients showed a similar post transfusion platelet recovery profile both for uncross-matched as well as cross-matched incompatible platelets.

Limitations of the study
This study was a time bound study with a small sample size. It was not possible to follow all transfusions received by a patient due to time constraints and different hours at which the patients received them.

Approaches for management of immune platelet refractory patients.
A. Selection of an appropriate platelet product Provision of HLA –Matched platelets Antibody specificity Prediction with the aim of identifying prevalence and factors responsible for platelet transfusion refractoriness in haemato-oncological patients-Dr. Vijay Kumawat et al. especially in thrombocytopenic phases during the induction phase of chemotherapy or related to sepsis. A major part of platelet rich component in the Transfusion Medicine Department is dedicated to support haemato-oncological patients. About 20 percent of haemato-oncology inpatient costs are associated with platelet transfusions.3

Hematopoietic cell transplantation (HCT)
Both allogeneic and autologous, is clearly associated with an impaired response to platelet transfusions. Bone Marrow Transplant. 1996;17(6):1035 Hepatic sinusoidal obstruction syndrome associated with intrahepatic thrombosis and platelet deposition in hepatic venules, in patients undergoing HCT, contribute to platelet refractoriness.

Graft-versus-host disease (GVHD)
Risk factor for refractoriness to platelet transfusion in the HCT patient population Thrombotic microangiopathy associated with GVHD Transfus Apher Sci. 2002;27(1):3 Increased incidence of platelet autoantibodies in patients with acute or chronic GVHD, suggesting a possible immune component to increased platelet destruction in this setting Blood. 1989;73(4):1054

Splenomegaly. Approximately one-third of an individual's platelets are sequestered in the spleen where they are in equilibrium with the circulating platelet pool. In cases of extreme splenomegaly, splenic sequestration can be increased to 90 %.

Medication Thrombocytopenia caused by medications is relatively common, with hundreds of drugs implicated Amphotericin has been associated with a reduced corrected count increment (CCI) Drug-induced thrombocytopenia is usually immune-mediated

Sepsis Association with thrombocytopenia is a well known cause of refractoriness to platelet transfusion. The mechanisms are not completely understood. Several hypotheses have focused on immune, non-immune, sequestration, and decreased platelet production. In addition, consumptive processes such as disseminated intravascular coagulation (DIC) and hemophagocytosis may contribute to thrombocytopenia in some septic patients

Cost calculations Random donor platelet (6 Nos) Apheresis platelets
Non-Recurring Equipment 16-20 lacs 20-25 lacs Recurring Manpower Medical Officer / N. Staff Medical Officer N. Staff Consumables Blood bags with Additives Apheresis kit Rs. 400x6 = Rs. 2,400 Rs. 7,500 TTI testing HIV, HBV, HCV, VDRL, Malaria (Rs. 500x6=3,000) Rs. 5,00 Leucofiltration required Rs. 1500 Not required Total Rs. 6900 Rs. 8000

Comparison of outcome indicators among cross-match compatible (Ia) and incompatible group (Ib)
Forty four (97.8%) of 45 cross-matched compatible platelet transfusion episodes in group Ia showed a satisfactory response in terms of PPI and CCI values as compared to 39.3% and 42.9% in cross-matched incompatible group(group Ib) for PPI and CCI values respectively. Thirty seven (82.2%) of 45 transfusion episodes and 2 (7.1%) of the 76 transfusion episodes qualified for the successful PPR of ≥ 30% in the cross-matched compatible (group Ia) and uncross-matched group (group Ib) respectively. Thus alloimmunized refractory patients receiving cross-matched compatible platelets have 68, 58.7 and 60.1 times higher chances of having satisfactory response for post transfusion PPI ,CCI and PPR values respectively as compared to patients receiving uncross-matched platelets as revealed by the odds ratio in two groups.

Platelet transfusion policy ,PGIMER, Chandigarh
Single donor apheresis platelets (SDAP) preferred for all haemato- oncological patients. Random donor platelets (RDP)- donor non availability / not affordability ABO identical platelets are given to all patients (48-72hrs ) Transfusion triggers:- Prophylactic platelet transfusions are provided to patients at Platelet counts ≤ 10,000/μL without fever Platelet counts ≤ 20,000/μL with fever For central line insertion ≤ 50,000/μL Therapeutic transfusions are provided to patients with bleeding episodes irrespective of the platelet counts.

Statistical data analysis
The measurable data was presented as mean, standard deviation and range and were further analyzed with appropriate statistical tests The level of significance was kept at < 0.05 for all statistical tests. Ethical justification The Institutional ethics committee of PGIMER, Chandigarh approved the study. Written informed consent was taken form patients to participate in the study.

All the Assay systems for HLA antibody determination can be used for PLATELET antibody detection & cross-matching

To ascertain the compatibility between the donor and the recipient Provides an in vitro assessment of antigen antibody interaction likely to occur in the potential recipient after receiving a transfusion. Platelet antigen and antibody typing is not done in routine Knowledge of platelet antigens , antibodies & the typing methods is essential

Our experience with Platelet cross matching
Our previous studies, Prevalence of platelet transfusion refractoriness & alloimmunization were 56.6%, 83.33% & 66%, 71.4% respectively Prevalence of risk factors for platelet transfusion refractoriness in multitransfused hemato-oncological patients at tertiary care center in North India Asian Journal of transfusion Science. January-June 2015.vol.9 (1):61-64 Platelet alloimmunization in multitransfused patients with Haemato-oncological disorders National medical journal of India. 2005; 18(3): 134.

Global Variations in Blood Safety and Availability Based on WHO Report January 24, 2018
Availability and safety were found to vary by region and income group 112 million units of blood collected worldwide High income countries-47% (19%population) Majority of transfusions for surgery ,trauma and cancers with component support Middle and low income countries ;majority for children<5yrs of age and pregnancy related for women Wide variation in testing , blood component availability & quality practices

Blood supply in India India is a federal union comprising twenty-nine states and seven union territories; a total of 36 states and union territories Population of India 1.32 billion Projected blood need 13.2 million units Annual blood collection 11.6 million units Voluntary blood donation (%) 71 ( ) Component separation (%) 70.9 (0-100) TTI reactivity in donated blood (%) HIV HCV HBV Syphilis Malaria 0.14 (0-0.37) o.34 ( ) 0.87 ( ) 0.17 (0-0.97) 0.06 (0-0.76) Participation in EQAP ( % ) 11-12 Ref: Assessment of blood banks in India-2016 (

Analysis of random donor platelet utilization data (August 2004-2005)
No. of units issued units No. of patients Indication for transfusion Therapeutic units for 5187 patients 80.9%) Prophylactic units for 1696 patients (19.1%) Clinical speciality Hemato-oncology % CTVS % Dengue fever % DIC/Sepsis % Surgical % DTM, PGI, Chandigarh

Trends in platelet preparations at PGI, Chandigarh
Year Random Donor Platelets Apheresis Platelets 1999 6044 105 2000 6250 85 2001 8542 76 2002 5743 106 2003 7521 2004 7057 121 2005 7655 203 2006 15857 241 2007 17602 492 2008 18957 777 2009 16906 605 2010 22430 925 2011 19642 1089 2012 22972 1665

Our experience with platelet cross matching
Two studies on our patients showed prevalence of platelet transfusion refractoriness of 56.6% and 83.33% & alloimmunization as the cause in 66% and 71.4% respectively Platelet crossmatching by solid phase red cell adherence assay (SPRCA) Platelet alloimmunization in multitransfused patients with Haemato-oncological disorders National medical journal of India. 2005; 18: 134. Prevalence of risk factors for platelet transfusion refractoriness in multitransfused hemato-oncological patients at tertiary care center in North India Asian Journal of transfusion Science ;9 :61-64

AML/ Haemato-oncology
Alloimmunization to platelet antigens: comparison with other studies Authors/ references Year of study no. of patients Patient group Method/methods used Prevalence of alloimmunization (%) Slichter et al. 1990 32 Haemato-oncology LCT 40 Godeau et al. 1992 50 LCT, PSIFT, MAIPA 28 Kurz et al. 1996 81 LCT, MAIPA 54 TRAP study group 1997 530/131 AML/ Haemato-oncology ELISA 45 Kiefel et al. 2001Germany 25 LCT, PAIFT, MAIPA 44.8 Kumawat et al. 2009 30 AA/AML 83.33 Salama et al. 2014 SPRCA Present study 38 87.5 This likely points to the use of non-leucoreduced random platelet concentrates in our institution.Slichter et al. (1990) reported an incidence of HLA alloimmunization of 40% using Lymphocytotoxicity test (LCT), while Godeau et al. (1992) found 28% alloimmunization among 50 multitransfused haemato-oncology patients. In another study by Kurtz et al. (1996) has reported 40% HLA antibody positivity in 81 haemato-oncological patients using MAIPA. 19 TRAP study group reported the incidence of HLA antibodies to 45% in patients receiving non leucoreduced blood components.20 Of the 252 multitransfused haemato-oncology patients, Kiefel et al. (2001) has reported an incidence of HLA alloimmunization of 42.9% using Lymphocytotoxicity test (LCT) and Monoclonal antibody-specific immobilization of platelet antigens assay (MAIPA).39 In 2014, Salama et al. has shown 40% alloimmunization to the HLA-A and HLA-B antigens found on platelets and to platelet-specific antigens using SPRCA.55 In a study conducted by Kumawat et al. in our institute in 2009, 83% of alloimmunization was found in the study population using ELISA. In our study, we also found almost similar prevalence (87.5%) of alloimmunization using SPRCA. This high prevalence of alloimmunization among studies conducted at our institute could be attributed to non leucoreduced multiple transfusions received by the patients prior to being referred to this tertiary care institute. In this institute also, patients receive both non leucoreduced and leucoreduced blood components depending on their affordability. Thus leucoreduction of blood components has played a significant role in bringing down the rate of platelet refractoriness and alloimmunization in multitransfused haemato-oncology patients and has become a part of standard care in management of these patients in different parts of the world.We have used an assay which can detect alloimmunization to both HLA and HPA. All these figures that we see using different tecnique were used to detect anti HLA antibodies and missed out on anti-platelet specific antibodies. Despite the fact that salama used a similar technique ,we still have a higher incidence of alloimmunization which means that it does not depend on the technique but our incidence is more Despite the fact that different techniques were used to asses alloimmunization, AND DESPITE THE FACT THAT and the tecniques employed weredetecting only HLA antibody and missed out on anti platlet specific antibodies,our incidence was more.There can be various reasons.

Platelet Non-Specific Antigens Can lead to refractoriness
Red cell antigens on platelets ABH : GPIIb (CD41) & PECAM (CD31) Rh antigen is not expressed on platelets - Higher expression : 5%-10% in non-O group individuals Immune complex formation Immune destruction > Platelets Non-ABH antigens Lewis li P, Pk Cromer Can lead to refractoriness

Platelet Non-Specific Antigens
HLA Antigens on platelets HLA Class I Antigens( A & B ; C ) Anti-HLA antibody formation 21-28 days for primary immunization 4 days after secondary exposure Sensitization: 18 % to 70 % Underlying disease of the patients ( AA >AML >ALL ) Immunosuppression due to treatment regimens Number of leukocytes present in the product

Study Algorithm Established platelet refractoriness (CCI at 1 hour on two consecutive transfusion) Platelet Refractoriness no Exclude from study yes Screened for HLA and HPA antibodies Antibody screen positive no Exclude from study yes Include in the study Group 1:Patients receiving crossmatched platelets Group 2:Patients receiving uncrossmatched platelets A total of 104 multi-transfused haemato-oncological patients suspected of being refractory to platelet transfusions were evaluated for post platelet transfusion response. Those patients found to be refractory were further screened for alloimmunization status .Against 30 proposed refractory alloimmunized patients, we could enroll 38 patients fulfilling the inclusion criteria .The study subjects included 17 (44.7%) males and 21(55.3%) females. Of the 38,22 were assigned in the cross-match platelet transfusion arm and 16 into the regular transfusion arm. For the sake of comparison, the platelet transfusion episodes received by these patients were divided into three groups depending upon the cross-match and compatibility status of platelets Cross-matched compatible (45 SDAP transfusion episodes)-Group I a,Cross-matched incompatible (28 SDAP transfusion episodes- Group I b Uncross-matched (76 SDAP transfusion episodes )-Group II. Results were compared and analyzed to suggest formulation of appropriate strategy for platelet transfusion in multitransfused alloimmunized refractory patients Cross –match compatible Group Ia Cross –match incompatible Group Ib Uncross –matched Group II Analyzed the results and compare the efficacy in terms of PPI,CCI,PPR

Platelet Agitator – Incubator

Platelet Transfusion in refractory in patients

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Platelet Transfusion in refractory in patients

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