Studies on CD36 deficiency in South China: Two cases demonstrating the clinical impact of anti-CD36 antibodies

Summary

CD36 (also known as GPIV) deficiency is known to be responsible for the production of anti-Nak^a antibodies in different clinical settings such as fetal/neonatal alloimmune thrombocytopenia (FNAIT), platelet transfusion refractoriness (PTR) and post-transfusion purpura (PTP). However, no data regarding the relevance of CD36 immunisation is currently available for China. In this study, healthy blood donors were typed for CD36 deficiency using flow cytometry. Nucleotide sequencing was performed to identify the molecular basis underlying the CD36 deficiency. Anti-Nak^a antibodies in CD36-deficient individuals were analysed by ELISA and flow cytometry. By analysis of 998 healthy blood donors, 18 individuals failed to express CD36 on their platelets. In 5/12 individuals no CD36 expression was detected both on platelets and monocytes. This result suggested that the frequencies of type I CD36 deficiency (platelets and monocytes) and type II CD36 deficiency (platelets only) are approximately 0.5 and 1.3%, respectively. Nucleotide sequencing analysis of type I CD36 deficient individuals revealed eight different mutations; four of them were not described so far. However, 1228–1239de/ ATTGTGCCTATT and 329–330de/AC appear to be the most common mutations related to type I CD36 deficiency in South Chinese population. Further analysis showed that 1/5 type I CD36 deficient individuals developed anti-Nak^a antibodies. In addition, anti-Nak^a antibodies could be identified in two cases of thrombocytopenia associated with FNAIT and PTR. In conclusion, more than 0.5% of CD36 type I-deficient individuals are at risk to be immunised through blood transfusion or pregnancy in China. Testing of anti-Nak^a antibodies should be considered in FNAIT and PTR suspected cases. A registry of CD36-deficient donors should be established to allow treatment of immune-mediated bleeding disorders caused by anti-Nak^a antibodies.

Keywords

CD36 - platelet glycoprotein IV - anti-Nak^a - gene mutation - neonatal alloimmune thrombocytopenia - platelet transfusion refractoriness

• References

• 1 Silverstein RL. Febbraio. CD36, a scavenger receptor involved in immunity, metabolism, angiogenesis, and behaviour. Sci Signal 2009; 09: re3.
• 2 Nergiz-Unal R, Rademakers T, Cosemann JM. et al. CD36 as a multiple-ligand signalling receptor in atherothrombosis. Cardiovasc Hematol Agents Med Chem 2011; 9: 42-45.
• 3 Ikeda H, Mitani T, Ohnuma M. et al. A new platelet-specific antigen, Naka, involved in the refractoriness of HLA-matched platelet transfusion. Vox Sang 1989; 57: 213-217.
• 4 Tomiyama Y, Take H, Ikeda H. et al. Identification of the platelet-specific alloantigen, Naka, on platelet membrane glycoprotein IV. Blood 1990; 75: 684-687.
• 5 Lee K, Godeau B, Fromont P. et al. CD36 deficiency is frequent and can cause platelet immunization in Africans. Transfusion 1999; 39: 873-879.
• 6 Yamamoto N, Akamatsu N, Sakuraba H. et al. Platelet glycoprotein IV (CD36) deficiency is associated with the absence (type I) or the presence (type II) of glycoprotein IV on monocytes. Blood 1994; 83: 392-397.
• 7 Curtis BR, Aster RH. Incidence of the Nak(a)-negative platelet phenotype in African Americans is similar to that of Asians. Transfusion 1996; 36: 331-334.
• 8 Bierling P, Godeau B, Fromont P. et al. Posttransfusion purpura-like syndrome associated with CD36 (Naka) isoimmunization. Transfusion 1995; 35: 777-782.
• 9 Rac ME, Safranow K, Poncyljusz W. Molecular basis of human CD36 gene mutations. Mol Med 2007; 13: 288-296.
• 10 Curtis BR, Ali S, Glazier AM. et al. Isoimmunization against CD36 (glycoprotein IV): description of four cases of neonatal isoimmune thrombocytopenia and brief review of the literature. Transfusion 2002; 42: 1173-1179.
• 11 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.
• 12 Fujino H, Ohta K, Taniue J. et al. Primary refractoriness to platelet transfusion caused by Nak(a) antibody alone. Vox Sang 2001; 81: 42-44.
• 13 Ogata T, Ohto H, Yasuda H. et al. CD36 (Naka) sensitization with platelet-transfusion refractoriness in a liver transplant recipient. Transplantation 2005; 79: 620.
• 14 Nakajima F, Nishimura M, Hashimoto S. et al. Role of anti-Nak(a) antibody, monocytes and platelets in the development of transfusion-related acute lung injury. Vox Sang 2008; 95: 318-323.
• 15 Kashiwagi H, Tomiyama Y, Nozaki S. et al. Analyses of genetic abnormalities in type I CD36 deficiency in Japan: identification and cell biological characterization of two novel mutations that cause CD36 deficiency in man. Hum Genet 2001; 108: 459-466.
• 16 Kashiwagi H, Tomiyama Y, Honda S. 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; 95: 1040-1046.
• 17 Kashiwagi H, Tomiyama Y, Kosugi S. et al. Identification of molecular defects in a subject with type I CD36 deficiency. Blood 1994; 83: 3545-3552.
• 18 Hanawa H, Watanabe K, Nakamura T. et al. Identification of cryptic splice site, exon skipping, and novel point mutations in type I CD36 deficiency. J Med Genet 2002; 39: 286-291.
• 19 Tanaka T, Nakata T, Oka T. et al. Defect in human myocardial long-chain fatty acid uptake is caused by FAT/CD36 mutations. J Lipid Res 2001; 42: 751-759.
• 20 Kankirawatana S, Kupatawintu P, Juji T. et al. Neonatal alloimmune thrombocytopenia due to anti-Nak(a). Transfusion 2001; 41: 375-377.
• 21 Okajima S, Cho K, Chiba H. et al. Two sibling cases of hydrops fetalis due to alloimmune anti-CD36 (Naka) antibody. Thromb Haemost 2006; 95: 267-271.
• 22 Omi K, Ohashi J, Patarapotikul J. et al. CD36 polymorphism is associated with protection from cerebral malaria. Am J Hum Genet 2003; 72: 364-374.
• 23 Hori T, Fukao T, Murase K. et al. Molecular Basis of Two-Exon Skipping (Exons 12 and 13) by c.1248+5g>a in OXCT1 Gene: Study on intermediates of OXCT1 transcripts in fibroblasts. Hum Mutat 2013; 34: 473-480.