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 Table of Contents  
ORIGINAL ARTICLE
Year : 2019  |  Volume : 4  |  Issue : 2  |  Page : 148-153

Platelet compatibility and platelet antibodies detection: A step towards resolving dilemma in management of platelet refractoriness in oncology patients


Department of Transfusion Medicine, Sri Balaji Action Medical Institute, New Delhi, India

Date of Submission26-Aug-2019
Date of Acceptance10-Sep-2019
Date of Web Publication17-Oct-2019

Correspondence Address:
Dr. Sadhana Mangwana
Department of Transfusion Medicine, Sri Balaji Action Medical Institute, New Delhi
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/GJTM.GJTM_51_19

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  Abstract 


Background: Platelet refractoriness complicates the provision of platelet transfusions- a critical and essential part in management of thrombocytopenia in Oncology patients. Platelet refractoriness poses challenge due to alloimmunization to HLA (Class I) and human platelet antigens (HPAs) and is associated with adverse clinical outcomes and increases health care costs. Aim: A prospective, observational study was planned in medical oncology patients having thrombocytopenia to analyse result of platelet compatibility with post-transfusion platelet count increment and to ascertain presence of platelet antibodies as causative factor in platelet refractory patients. Methods: Eighty oncology patients having thrombocytopenia in a tertiary care centre; both solid organ and hematological malignancies, requiring platelet transfusion were included in this study. ABO-compatible, leucoreduced, random donor platelets with less than 72 hours storage and platelet cross matched were transfused. In case of platelet refractoriness and presence of platelet incompatibility, platelet antibody screening test was performed using SPRCA technique. A P-value < 0.05 was considered statistically significant. Results: Study population was 18-85 years with maximum number of cases (31.3 %) in 60-70 years age group with equal number of both genders. 80% cases showed platelet cross-match compatibility, while 20% were platelet cross-match incompatible. Amongst incompatible platelet cross matches, 87.5% cases showed presence of platelet alloantibodies and all cases except one showed platelet refractoriness. Platelet yield in compatible platelet cross match was higher than in patients with incompatible platelet cross match (P-value < 0.001). Previous exposure in the form of Pregnancy (61% cases) and history of transfusion (54% cases) played a vital role in platelet refractoriness and development of platelet alloantibodies. Patients treated with chemotherapy (78.8%) had significant risk of platelet refractoriness and platelet alloimmunization. Conclusion: Platelet cross matching along with testing for anti-platelet antibodies using SPRCA method is an effective, useful tool and rapid, first-line approach for selecting compatible platelets from the local inventory as compared to HLA-matched platelets in the treatment of thrombocytopenic cancer patients. Blood services must be aware of the measures to prevent alloimmunization and correct identification of refractoriness to provide adequate transfusion support for oncology patients reducing hospital length of stay and minimizing health care cost.

Keywords: Oncology, platelet antibodies, platelet cross matching, refractoriness


How to cite this article:
Mangwana S, Kacker A, Simon N. Platelet compatibility and platelet antibodies detection: A step towards resolving dilemma in management of platelet refractoriness in oncology patients. Glob J Transfus Med 2019;4:148-53

How to cite this URL:
Mangwana S, Kacker A, Simon N. Platelet compatibility and platelet antibodies detection: A step towards resolving dilemma in management of platelet refractoriness in oncology patients. Glob J Transfus Med [serial online] 2019 [cited 2019 Nov 12];4:148-53. Available from: http://www.gjtmonline.com/text.asp?2019/4/2/148/269395




  Introduction Top


Platelet transfusion is a critical and an essential part of managing cancer, hematological malignancies, bone marrow failure, and hematopoietic stem cell transplantation.[1],[2] Platelet refractoriness is defined as inappropriately low platelet count increments following two or more, preferably consecutive transfusions.

Refractoriness to platelet transfusion is a complex process and poses a great challenge in the treatment of thrombocytopenic patients. Platelet refractoriness can be due to immune or nonimmune causes. Nonimmune causes such as fever, sepsis, splenomegaly, disseminated intravascular coagulation, graft-versus-host disease, drug-induced, and hemorrhages are involved in 80% of cases, while immune causes consist mainly of sensitization to foreign Class I A or B human leukocyte antigens (HLAs) through pregnancy, transfusion, or transplantation. Two strategies are used to transfuse alloimmunized patients, matching donor–recipient's HLAs, and cross-matching platelets.[2] HLA typing of patients as well as platelet donors is expensive and high technical skills and long turn-around time decrease its utility in some clinical situations. In addition to these drawbacks, HLA matching requires the availability of large number of HLA-typed donors.[2] Platelet cross-matching assays are rapid alternative and a relatively low cost to the HLA-matched option for the management of platelet refractoriness.[3],[4],[5]

Aims and objectives

A prospective, observational study was planned in medical oncology patients having thrombocytopenia to analyze the results of platelet compatibility with post-transfusion platelet count increment and to ascertain the presence of platelet antibodies as a causative factor in platelet refractory patients.


  Materials and Methods Top


This prospective study was conducted at the department of immunohematology and transfusion medicine of a 400-bedded, super specialty, tertiary care institute. Eighty oncology patients having thrombocytopenia, both solid-organ and hematological malignancies, requiring platelet transfusion were included in this study. The study was conducted from April 2017 to September 2018. Inclusion criteria were medical oncology cases with thrombocytopenia requiring only random donor platelet (RDP) transfusion.

The pretransfusion platelet count of the patient was ascertained by automated 5-part hematology analyzer using impedance (Sysmex XN1000, Transasia Biomedical Ltd.,). ABO-compatible, leukoreduced, buffy coat-prepared RDPs with <72 h storage and platelet cross-matched were transfused. Blood samples were collected within 1 h of completing platelet transfusion for corrected count increment (CCI). The CCI was calculated using the following formula:



Patients were considered to be refractory when 1 h posttransfusion platelet count increment was <5000. Platelet cross-match was performed using Capture-P solid-phase red-cell adherence (SPRCA) technique. In case of platelet refractoriness and the presence of platelet incompatibility, platelet antibody screening test was performed on Capture-P Ready Screening using SPRCA technique (Neo, Immucor Inc., USA). Capture-P Ready-Screen detects the immunoglobulin G (IgG) antibodies to either HLA-A, HLA-B or platelet specific antigens in a patient or donor population. Serum is incubated briefly in platelet-coated wells to allow antibodies, if present, to bind to the platelets. Unbound immunoglobulins (Igs) are then washed from the wells and are replaced with a suspension of anti-IgG-coated indicator red cells. Centrifugation brings the indicator red cells in contact with antibodies bound to the immobilized platelets.

Negative test

Button of indicator red cells at the bottom of the test well with no readily detectable area of adherence.

Positive test

Adherence of indicator red cells to the part or the entire reaction surface.

Statistical analysis

Quantitative variables were compared using Mann-Whitney test and qualitative variables were compared using Fisher's exact test. Pearson's correlation coefficient was used to assess the correlation between quantitative variables. P - value < 0.05 was considered statistically significant.

Ethics

This study was approved by the Institutional Ethics Committee.


  Results Top


The study population was between 18 and 85 years (mean: 55.95 years ± 15.8 years) with the maximum number of cases (31.3%) in 60–70 years' age group followed by the age group of 50–60 years (17.5%), followed by the age group of 40–50 years (16.3%) with equal number of cases of both the genders (40 each). Body surface area (BSA) of the study population ranged from 1.3 m2 to 2.18 m2 (mean: 1.63 m2 ± 0.2) with statistically insignificant difference between the two genders.

The mean dose of platelet transfusion in all patients was 0.63 × 1011/L ± 0.98 with statistically insignificant difference between male (0.65 × 1011/L) and female patients (0.69 × 1011/L).

Sixty-four cases (80%) cases showed platelet cross-match compatibility, while 16 cases (20%), 9 male and 7 female patients, were platelet cross-match incompatible (P < 0.001). Among incompatible platelet cross-matches, 14 (87.5%) cases showed the presence of platelet alloantibodies (P < 0.001), and all cases except one showed platelet refractoriness. Of 64 compatible platelet cross-match cases, 38 cases (59.37%) showed platelet refractoriness (CCI <5000) which is statistically significant than cases showing adequate CCI. None of these cases showed platelet alloantibodies. Platelet yield in compatible platelet cross-match was higher than in patients with incompatible platelet cross-match (P < 0.001). Age and gender did not affect the platelet increment. BSA had a negative correlation with platelet increment. Although solid-organ malignancies showed more platelet refractoriness (69.04%; 29 of 42 cases) than in hematological malignancies (63.15%; 24 of 38 cases), they are statistically insignificant.

Previous exposure in the form of pregnancy in female patients (61% cases) and history of transfusion (54% cases) played a vital role in the development of platelet refractoriness and development of platelet alloantibodies. Of 40 females, 36 female patients (90%) had a history of normal delivery or lower segment cesarean sections, while four cases (10%) did not give any history of pregnancy, indicating that 90% of females had probable cause of development of alloantibodies. In females with a history of pregnancy, 22 cases (61%) showed platelet refractoriness of which six patients (27.27%) showed the presence of platelet antibodies, while other 16 female patients did not develop platelet alloantibodies (P = 0.001). Four of these six alloimmunized patients (66.66%) had a previous history of transfusion also, while two patients (33.33%) did not have any previous history of transfusion. There is no correlation of pregnancy and type of malignancy with the development of alloimmunization.

Forty-three cases (54%) had a history of previous transfusion of either packed red blood cells (PRBCs) or platelet concentrates (PCs) and 37 cases (46.3%) had no history of previous transfusion. As shown in [Figure 1], nearly 70% of the cases in each gender (16 males and 14 females) showed platelet refractoriness (P = 0.003), of which 5 (25%) and 4 cases (28.5%) respectively showed presence of platelet antibodies (P = 0.01). Of 30 patients with a previous history of transfusion and showing platelet refractoriness, 13 cases (43.33%) were of hematological and 24 cases (56.66%) of solid-organ malignancies. The frequency of platelet antibodies was not affected much by the type of malignancy (30.76% [n = 4] and 29.41% [n = 5] hematological and solid-organ malignancies, respectively).
Figure 1: Correlation of transfusion history with gender and platelet refractoriness

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In a total of 80 cases in this study, 38 cases (47.5%) were hematological malignancies and 42 cases (52.5%) were solid-organ malignancies. 24 cases (63.15%) out of 38 hematological cases showed refractoriness while 29 cases (69.04%) of 42 cases showed refractoriness in solid-organ cases. In male patients, hematological malignancies were more (60%) than solid-organ malignancies (40%) while in female patients, solid-organ malignancies were more (67.5%, 27 cases) than hematological malignancies (32.5%, 13 cases) [Figure 2].
Figure 2: Correlation platelet refractoriness with gender and type of malignancy

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Patients treated with chemotherapy (63 cases; 78.8%) had a high risk to platelet refractoriness. Of 63 patients receiving chemotherapy, 43 cases (68.2%) showed platelet refractoriness (P < 0.001). In hematological malignancies (n = 19) receiving chemotherapy, three cases (15.78%) showed the presence of platelet antibodies, while in solid-organ malignancies (n = 24), four cases (16.66%) showed the presence of platelet antibodies. There was statistically significant association between chemotherapy and platelet yield (P = 0.045).

Leukocytosis had statistically significant correlation with platelet refractoriness. Eighteen patients (22.5%) had total leukocyte count (TLC) within the normal limits, and in 33 patients (41.3%), TLC was not done, and 29 patients (36.3%) showed leukocytosis signifying that patients leukocytosis could be due to sepsis; one of the nonimmune causes of platelet refractoriness. Among patients with normal TLC, probably immune cases, 77.77% (14 cases) showed platelet refractoriness (P < 0.001). Four of 14 refractory patients (28.57%) showed the presence of platelet antibodies (P = 0.01). Types of malignancies did not have any impact on these cases. Of 29 cases with high TLC, 19 patients (65.52%) showed platelet refractoriness (P = 0.009), of which three cases (15.79%) showed the presence of platelet alloantibodies (P < 0.001), suggesting significant association between platelet alloantibodies and causative factor (P < 0.001).


  Discussion Top


Platelet transfusion therapy is life-saving for oncology patients, but platelet refractoriness always poses a challenge due to the alloimmunization to HLA and human platelet antigens (HPAs).[1] There are a number of approaches to address the problem of platelet transfusion refractoriness. One of the most frequently used methods is HLA matching which is highly effective, and routine approach to the management is of refractory patients in the number of institutions.[6] A commonly used alternative to HLA-matched platelets is the transfusion of cross-match-compatible platelets.[5] Platelet cross-matching by SPRCA technique is simple, less time-consuming, and cheaper than HLA typing.[7]

In this study, the age of patient population ranged from 18 to 85 years with a mean age of 55.95 ± 15.8 years, while in a study conducted by Mangwana and Simon, the mean age was 46.87 ± 15.16 years with a range of 8–70 years,[1] and in a study by Kumawat et al., the mean age was 45 years (17–67 years). It was 27.5 years (17–67 years) for aplastic anemia patients and was 49 years (18–64 years) for acute myeloid leukemia patients.[8] The mean BSA of all patients was 1.63 m2 ± 0.20 (range: 1.3–2.18 m2), without any statistically significant difference between males (1.71 m2) and females (1.56 m2). This finding is similar to the findings by Mangwana and Simon who also observed that the mean BSA of all patients was 1.60 ± 0.25 m2 (range: 0.88–2 m2), without any statistically significant difference between males (1.67 ± 0.22 m2) and females (1.51 ± 0.27 m2).[1] There was a negative correlation of varying height, weight, and BSA to the platelet increment, which is similar to the TRAP study, conducted by Slitcher et al., who also observed that increasing weight and height with corresponding increase in blood volume were associated with decreased platelet transfusion count. These effects were independent of gender.[9]

There were 20% of the cases (n = 16) showing incompatible platelet cross-match; 9 male and 7 female patients, out of which 14 (17.5%) cases showed presence of platelet alloantibodies, and all cases except one showed platelet refractoriness finding similar to the study by Elhence et al.[10] who observed that antiplatelet antibodies were responsible for incompatible cross-match in 41% of the cases either alone (26.8%) or with anti-HLA antibodies, and Rebulla[5] found that 15% of the patients had both anti-HLA and anti-HPA antibodies. The frequency of refractoriness varied in the literature from 13.3% to 39.3%,[1],[10],[11],[12],[13] and this varying incidence is due to difference in the population studied, definition of refractoriness, and management of refractoriness by the type of platelet transfusions, RDPs or apheresis platelets. With the use of leukodepleted products, approximately two-thirds of the refractory episodes are due to nonimmune causes with another 20% having a combination of both alloimmune and nonimmune causes.[13],[14] Platelet refractoriness was seen more in solid-organ malignancies than in hematological malignancies which is contrary to the earlier study of the same center, in which platelet refractoriness was seen more in hematological malignancies (25%) than in solid-organ malignancies (5.55%) which could be due to HPAs.[1]

In this study, previous exposure in the form of pregnancy and transfusion played a vital role in platelet refractoriness and formation of platelet alloantibody. These data are similar to the study conducted by TRAP study, which had 37% of the cases with a history of pregnancy.[9] Forty-three cases (53.8%) had a history of previous PRBCs or platelet transfusion. Among both the genders, history of transfusion had a significant effect on platelet refractoriness and the development of platelet alloantibodies. However, there was no correlation between types of malignancy and history of transfusion, leading to platelet refractoriness and platelet alloantibodies. Prior to enrollment in the study, few patients could not give a specific component transfusion history whether it was PRBC or PC, and no data could be obtained for platelet transfusion triggers outside the institute, while in the study conducted by Kumawat et al. and in the TRAP study, 100% of patients had a history of previous transfusion with median of 46 transfusions[8],[9] and Kumawat et al. documented that the majority of previous blood component transfused were RDPs.[8]

Chemotherapeutic and immunosuppressive agents among other drugs are implicated as triggers of drug-induced immune thrombocytopenia.[15] Various mechanisms by which drugs can cause immune thrombocytopenia are hapten-dependent antibody, drug-induced antibody binding to platelet membranes in the presence of sensitizing drug, drugs reacting with glycoprotein IIb/IIIa to induce conformational change, drug-specific antibody, autoantibody, and the formation of immune complexes. To the best of our knowledge, we could not find any study showing the correlation of platelet alloimmunization and platelet refractoriness with chemotherapy. In this study, 63 cases (78.8%) were previously diagnosed malignancies cases who have received any chemotherapy, while 17 cases (21.3%) were fresh cases without having received any chemotherapy. 63.5% cases (n = 40) with a history of previous chemotherapy showed platelet refractoriness which was statistically significant (P = 0.001). Platelet alloimmunization was seen in seven cases (P < 0.001), three hematology and four solid-organ malignancies. Thus, it is suggested that chemotherapeutic agents must be considered as a cause of platelet alloimmunization leading to platelet refractoriness and such cases should be investigated for the presence or absence of platelet antibodies.

It has previously been reported that ABO compatibility improves post-transfusion platelet responses but does not improve platelet survival, and the transfusion of platelets 48 h old or lesser was associated with an increase in the transfusion interval of 0.19 days as compared with >48 h old. Longer platelet storage times have been reported to decrease posttransfusion platelet viability;[9] however, since in this study, ABO group-specific PCs of <72 h of storage were issued to thrombocytopenic oncology patients, no correlation could be observed between ABO group-specific platelet transfusion on platelet refractoriness.

17.5% incidence of platelet alloimmunization in this study was slightly higher than an earlier study of this center and in concordance with multicentric TRAP study which showed 17%–21% incidence of alloimmunization.[1],[9] This could be due to use of leukoreduced, RDPs and transfusion policy of our blood center, of universal leukodepletion of PRBCs and issuing of Rh-phenotype matched, antigen-negative PRBCs to all oncology patients which has resulted in very low frequency of red cell alloimmunization (0.30%) in our institution,[16] same as evidenced in multicentric TRAP study receiving leukoreduced components and contrary to 45% incidence in patients receiving nonleucoreduced blood components. However, in other studies showing a high incidence of alloimmunization up to 40%, 56%, 66%, and 73.2% are due to formation of HLA antibodies in multi-transfused patients and transfusion of nonleukoreduced RDPs or single donor platelets.[10],[17],[18],[19] Limitation in this study was that further antibody identification could not be performed to differentiate between HLA typing and platelet-specific antibody due to the resource constraints.


  Conclusion Top


Platelet transfusion response in medical oncology patients depends on both clinical and immunological factors. To manage platelet refractoriness in medical oncology patients, platelet cross-matching, similar to red blood cell cross-match, using SPRCA method is an effective, useful tool and rapid, first-line approach for selecting compatible platelets from the local inventory as compared to HLA-matched platelets in the treatment of thrombocytopenic cancer patients. Platelet cross-match along with testing for antiplatelet antibodies are important, less time-consuming, and cost-effective than the molecular testing in the management of oncology patients. Blood services must be aware of the measures to prevent alloimmunization and correct identification of refractoriness to provide adequate transfusion support for oncology patients reducing hospital length of stay and minimizing health-care cost.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Mangwana S, Simon N. Evaluation of the platelet cross-matching in oncology patients. Glob J Transfus Med 2016;1:16-9.  Back to cited text no. 1
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2.
Stroncek DF, Rebulla P. Platelet transfusions. Lancet 2007;370:427-38.  Back to cited text no. 2
    
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Rebulla P, Morelati F, Revelli N, Villa MA, Paccapelo C, Nocco A, et al. Outcomes of an automated procedure for the selection of effective platelets for patients refractory to random donors based on cross-matching locally available platelet products. Br J Haematol 2004;125:83-9.  Back to cited text no. 3
    
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Freedman J, Gafni A, Garvey MB, Blanchette V. A cost-effectiveness evaluation of platelet crossmatching and HLA matching in the management of alloimmunized thrombocytopenic patients. Transfusion 1989;29:201-7.  Back to cited text no. 4
    
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Rebulla P. A mini-review on platelet refractoriness. Haematologica 2005;90:247-53.  Back to cited text no. 5
    
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Petz LD, Garratty G, Calhoun L, Clark BD, Terasaki PI, Gresens C, et al. Selecting donors of platelets for refractory patients on the basis of HLA antibody specificity. Transfusion 2000;40:1446-56.  Back to cited text no. 6
    
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Vongchan P, Nawarawong W, Linhardt RJ. Modification of solid phase red cell adherence assay for the detection of platelet antibodies in patients with thrombocytopenia. Am J Clin Pathol 2008;130:455-66.  Back to cited text no. 7
    
8.
Kumawat V, Sharma RR, Malhotra P, Marwaha N. Prevalence of risk factors for platelet transfusion refractoriness in multitransfused hemato-oncological patients at tertiary care center in North India. Asian J Transfus Sci 2015;9:61-4.  Back to cited text no. 8
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9.
Trial to Reduce Alloimmunization to Platelets Study Group. Leukocyte reduction and ultraviolet B irradiation of platelets to prevent alloimmunization and refractoriness to platelet transfusions. N Engl J Med 1997;337:1861-9.  Back to cited text no. 9
    
10.
Elhence P, Chaudhary RK, Nityanand S. Cross-match-compatible platelets improve corrected count increments in patients who are refractory to randomly selected platelets. Blood Transfus 2014;12:180-6.  Back to cited text no. 10
    
11.
Slichter SJ, Davis K, Enright H, Braine H, Gernsheimer T, Kao KJ, et al. Factors affecting posttransfusion platelet increments, platelet refractoriness, and platelet transfusion intervals in thrombocytopenic patients. Blood 2005;105:4106-14.  Back to cited text no. 11
    
12.
Klingemann HG, Self S, Banaji M, Deeg HJ, Doney K, Slichter SJ, et al. Refractoriness to random donor platelet transfusions in patients with aplastic anaemia: A multivariate analysis of data from 264 cases. Br J Haematol 1987;66:115-21.  Back to cited text no. 12
    
13.
Legler TJ, Fischer I, Dittmann J, Simson G, Lynen R, Humpe A, et al. Frequency and causes of refractoriness in multiply transfused patients. Ann Hematol 1997;74:185-9.  Back to cited text no. 13
    
14.
Doughty HA, Murphy MF, Metcalfe P, Rohatiner AZ, Lister TA, Waters AH. Relative importance of immune and non-immune causes of platelet refractoriness. Vox Sang 1994;66:200-5.  Back to cited text no. 14
    
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Aster RH, Bougie DW. Drug-induced immune thrombocytopenia. N Engl J Med 2007;357:580-7.  Back to cited text no. 15
    
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Mangwana S, Kacker A, Simon N. Red cell alloimmunization in multitransfused, oncology patients: Risks and management. Glob J Transfus Med 2019;4:74-8.  Back to cited text no. 16
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Ferreira AA, Zulli R, Soares S, Castro VD, Moraes-Souza H. Identification of platelet refractoriness in oncohematologic patients. Clinics (Sao Paulo) 2011;66:35-40.  Back to cited text no. 18
    
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Bajpai M, Kaura B, Marwaha N, Kumari S, Sharma RR, Agnihotri SK. Platelet alloimmunization in multitransfused patients with haemato-oncological disorders. Natl Med J India 2005;18:134-6.  Back to cited text no. 19
    


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