In Focus

Anti-CD36 in Transfusion Medicine

Immune-mediated thrombocytopenia and more

Lilach Bonstein Blood Bank Laboratory and the National Platelet & Neutrophil Immunology Laboratory, Rambam Health Care Campus, Haifa, Israel Read bio >

Nelson H Tsuno Japanese Red Cross Kanto-Koshinetsu Block Blood Center, Tokyo, Japan Read bio >

Wenjie Xia Institute of Blood Transfusion, Guangzhou Blood Centre, Guangzhou, Guangdong, China Read bio >

CD36 is a molecule expressed on platelets and additional cell types, including monocytes, endothelial cells, adipocytes, erythroblast, myeloblasts, and recently also reported to be expressed (weakly) on mature red cells, and was given the red cell antigen classification number ISBT 45.

CD36 is also known to be an isoantigen, which means that individuals who lack its expression may produce isoantibodies to CD36, resulting in various clinical conditions of immune-mediated thrombocytopenia, such as fetal-neonatal alloimmune thrombocytopenia (FNAIT) and platelet transfusion refractoriness (PTR). The first case with anti-CD36 associated PTR was described in Japan1.

Anti CD36 mediated FNAIT FNAIT accompanied by severe anemia and hydrops fetalis (HF) have been reported with anti-CD36 antibodies2-7. The mechanism underlying the HF with anti-CD36 Abs seems to be the significant reduction in CFU-E/BFU-E cell formation by apoptosis of CD34+ erythroid/myeloid precursor cells5.

Anti CD36 mediated TRALI TRALI cases caused by infusion of anti-CD36 have been reported from Japan6,7. Incubation of monocytes with anti-CD36 plasma derived from a female blood donor that induced TRALI in patients resulted in the production of the pro-inflammatory mediators LTB4 and TNF-α6. TRALI induced by anti-CD36 was found to be dependent on monocytes and complement, with no involvement of neutrophils8. The mechanism proposed for anti-CD36–mediated TRALI is the interaction between monocytes and TNF-α–activated lung endothelial cells, which leads to the upregulation of CD36 expression on monocytes, resulting in increased antibody binding, triggering complement activation, ROS generation, and cytokine production, which are all responsible for the severe endothelial dysfunction in TRALI.

Recently, the role of CD36 isoimmunization in hematopoietic stem cell transplantation (HSCT) has also been questioned9-11. It has been confirmed that CD36-incompatible HSCT can be successfully performed provided the appropriate management, especially reduction of anti-CD36 antibody titers, is carried out prior to transplantation.

CD36 frequency and immunogenicity The primary clinical focus is predicting individuals who will produce anti-CD36 antibodies and determining their frequency in the population.

There are two types of CD36 deficiencies: individuals with type I deficiency do not express CD36 in any of the cell types, including platelets and monocytes. In type II deficiency CD36 is expressed on almost all cell types, including monocytes, but not on platelets. Only type I deficient individuals can produce anti-CD36 antibodies and consequently develop antibody-associated clinical conditions. CD36-positive individuals, on the other hand, may develop TRALI when transfused with plasma from a CD36-negative individual containing anti-CD36 antibody.

What is the genetic background of CD36 deficiency?

The genetic background of CD36 deficiency is not well characterized, although many studies have been conducted. There are CD36 variants that are more frequently observed including 268C>T in Japanese, 975T>G in Africans, and 329_330delAC in Chinese populations. The highest frequency of CD36 deficiency is reported in Asian and African populations, with a frequency of 3% to 11% in Asians, 8% in Sub-Saharan Africans, 2.6% in Arabians, and less than 0.4% in Caucasians12-14.

A study was conducted by the ISBT Platelet immunobiology Working Party in Asia, where labs from different countries in Asia were requested to test 200 healthy individuals for CD36 deficiency. The deficiancy was found in all Asian populations, except for Australia, with the highest incidence in Japan, followed by South Korea, and the frequencies decreasing in the southeast part of Asia15. Interestingly, although the highest frequency of CD36 deficiency, including both type I and II, was observed in Japan, individuals with the 268C>T mutation, the most frequent in Japan, do not produce anti-CD36 antibodies. This mystery has been partially solved by confirming that individuals with this type of mutation express very low levels of CD3616.

Who are the individuals who develop immune-mediated thrombocytopenia or cause TRALI in Japan?

Interestingly, it has been confirmed that all of these individuals have the 329_330delAC mutation, which is the most frequently observed in China. In Japan, however, the commercially available CD36 genotyping kit can only detect the 268C>T mutation, which seems not to be clinically relevant. So, why is this kit routinely used in Japan? It is because it can identify CD36-negative or CD36-weak expressing individuals, who can be CD36-negative platelet donors. In fact, type II deficient individuals, who do not express CD36 on platelets, are also a cohort that can donate CD36-negative platelets. Even in Japan, type I CD36 deficiency is very rare (<1.0%), the majority being type II deficient individuals. Based on this population, the Japanese Red Cross has created a registry of CD36-negative platelet donors, which allows the appropriate management of PTR caused by anti-CD36 antibodies.

CD36-negative donor registry

It is important to know the frequency of donors with type I and II deficiencies and prepare a registry of potential platelet donors in each country. Of note: with an increase in ethnic migrations, many individuals of Asian or African descent now live in Western countries, where CD36 incompatibility may occur, requiring the use of CD36-negative platelet transfusions. Therefore this issue is not restricted to Asia and Africa anymore, but it needs to be suspected when an immune-mediated thrombocytopenia or conditions such as TRALI occur in individuals of Asian, African, or Middle Eastern descent.

Each country should consider the risks in their population, and need to prepare to appropriately manage when CD36 deficiency is suspected.

References

  1. H Ikeda, T Mitani, M Ohnuma, H Haga, S Ohtzuka, T Kato, T Nakase, S Sekiguchi. A new platelet-specific antigen, Naka, involved in the refractoriness of HLA-matched platelet transfusion. Vox Sang. 1989; 57(3):213-7. doi: 10.1111/j.1423-0410.1989.tb00826.x.
  2. Kankirawatana S, Kupatawintu P, Juji T, et al. Neonatal alloimmune thrombocytopenia due to anti-Nak(a). Transfusion. 2001; 41:375-377.
  3. Xu X, Li L, Xia W, et al. Successful management of a hydropic fetus with severe anemia and thrombocytopenia caused by anti-CD36 antibody. Int J Hematol. 2017; 107:251-256.
  4. Taketani T, Ito K, Mishima S, et al. Neonatal isoimmune thrombocytopenia caused by type I CD36 deficiency having novel splicing isoforms of the CD36 gene. Eur J Haematol. 2008; 81:70-74.
  5. Wu Y, Chen D, Xu X, et al. Hydrops fetalis associated with anti-CD36 antibodies in fetal and neonatal alloimmune thrombocytopenia: Possible underlying mechanism Transfus Med. 2020; 30(5):361-368
  6. Nakajima F, et al. Role of anti-Nak(a) antibody, monocytes and platelets in the development of transfusion-related acute lung injury. Vox Sang. 2008; 95(4):318–323.
  7. Ando M, et al. Defective CD36 mutations in anti-Naka antibody-positive subjects associated with transfusion-related acute lung injury (TRALI). Japanese Journal of Transfusion and Cell Therapy. 2016; 62(5):587–591.
  8. Da-Wei Chen, Tian Kang, Xiu-Zhang Xu, Wen-Jie Xia, Xin Ye, Yong-Bin Wu, Yao-Ri Xu, Jing Liu, Hui Ren, Jing Deng, Yang-Kai Chen, Hao-Qiang Ding, Muhammad Aslam, Wioleta M. Zelek, B. Paul Morgan, Rick Kapur, Sentot Santoso, and Yong-Shui Fu. Mechanism and intervention of murine transfusion-related acute lung injury caused by anti-CD36 antibodies. JCI Insight. 2023 Mar 22; 8(6): e165142
  9. Tomohiko Sato, Nelson Hirokazu Tsuno, Yasuji Kozai, Hiroki Yokoyama, Shingo Yano, Should unrelated haematopoietic progenitor cell donors be tested for CD36 in Japan? Correspondence to Lancet Haematology 2022; DOI: https://doi.org/10.1016/S2352-3026(22)00296-4
  10. Shuhei Okuyama, Masahiko Sumi, Ryuto Ishikawa, Tsutomu Shishido, Daisuke Koyama, Toshimitsu Ueki, Daisuke Takahashi, Hironori Kobayashi, Hikaru Kobayashi, Nelson Hirokazu Tsuno. Successful allogeneic hematopoietic stem cell transplantation in a patient with type I CD36 deficiency: a case study and literature review. Int J Hematol. 2023 Jul 25. doi: 10.1007/s12185-023-03637-4. Online ahead of print.
  11. Nelson H Tsuno and Miquel Lozano. The role of CD36 antibodies in hematopoietic stem cell transplantation. Vox Sanguinis Commentary 2023 Nov; DOI: 10.1111/vox.13560
  12. Flesch BK, Scherer V, Opitz A, et al. Platelet CD36 deficiency is present in 2.6% of Arabian individuals and can cause NAIT and platelet refractoriness. Transfusion 2021;61:1932-42.
  13. Curtis BR, Aster RH. Incidence of the Nak(a)-negative platelet phenotype in African Americans is similar to that of Asians. Transfusion 1996; 36:331-4.
  14. Wu G, Zhou Y, Li L, et al. Platelet immunology in China: research and clinical applications. Transfus Med Rev 2017; 31:118-25
  15. W. Xia, X. Xu, Y. Fu, X. Ye, N. Tsuno, S. Santoso. CD36 deficiency among South-East Asian populations. ISBT Science Series (2016); 11(S2):33-36
  16. Kashiwagi et al. Molecular basis of CD36 deficiency. Evidence that a 478C-->T substitution (proline90-->serine) in CD36 cDNA accounts for CD36 deficiency. J Clin Invest. 1995 Mar;95(3):1040-6
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