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Platelet Immunology in China: Research and Clinical Applications
Transfusion Medicine Reviews xxx (2016) xxx–xxx
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Transfusion Medicine Reviews journal homepage: www.tmreviews.com
Platelet Immunology in China: Research and Clinical Applications Guoguang Wu a,⁎, Yan Zhou a, Lilan Li a, Zhoulin Zhong a, Hengchong Li a, Haiyan Li a, Mei Yu a, Weidong Shen a, Heyu Ni b a b
Nanning Institute of Transfusion Medicine, Nanning Blood Center, Nanning, China Canadian Blood Services and Department of Laboratory Medicine and Pathobiology, St Michael's Hospital, University of Toronto, Toronto, Ontario, Canada
a r t i c l e
i n f o
Available online xxxx Keywords: Platelet immunology Human platelet alloantigens Immune-mediated thrombocytopenia Anti-CD36 Chinese population
a b s t r a c t Immunization against human platelet alloantigens (HPAs) is associated with a number of clinical complications. The detection and identification of clinically relevant platelet antibodies are important for the diagnosis and management of patients affected with immune-mediated thrombocytopenias. Human platelet alloantigen frequencies and the characteristics of antiplatelet antibodies vary widely between ethnic groups. Since 2008, the importance of platelet immunology in the field of transfusion medicine has gained greater recognition by clinical laboratories in China. Laboratories in China have established and improved methods for platelet antibody detection and HPA genotyping techniques, which are used for the diagnosis of alloimmune platelet disorders in clinic and research environments. Research has revealed the frequencies of HPA alleles in different Chinese ethnic groups and compared the differences in HPA gene frequencies between the Chinese Han and other ethnic groups of the world. Production of anti-CD36 isoantibodies is an important risk factor for immune-mediated thrombocytopenia in the Chinese population. Advances in research and clinical application of platelet immunology have significantly improved the clinical diagnosis, treatment including transfusion support, and prevention of alloimmune platelet disorders in the Chinese population. © 2016 Published by Elsevier Inc.
Contents Platelet Immunology in China . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Techniques for Platelet Antibody Detection and HPA Genotyping in China. . . . . . . . . . . . . . . . . . . . . . . Frequencies of HPA Alleles in the Chinese Population . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clinical Detection of Platelet Antibodies in the Chinese Population . . . . . . . . . . . . . . . . . . . . . . . . . . Anti-CD36 Isoantibodies Are an Important Risk Factor for Immune-Mediated Thrombocytopenia in the Chinese Population Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of Interest. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Platelets are one of the most important cellular products issued by blood centers in China. Platelet products are often prescribed for the prophylactic treatment to reduce the risk of bleeding in hematooncology and for the treatment of bleeding in patients with a wide range of conditions. Platelets have important functions in hemostasis, in which they adhere to damaged blood vessels, aggregate en masse, and through cross-links with fibrinogen or other proteins, form a fibrin clot to prevent further blood loss [1-2]; in addition, platelets are also ⁎ Corresponding author at: Guoguang Wu, Nanning Institute of Transfusion Medicine, Nanning Blood Center, No. 18, Keyuan Ave, Nanning, Guangxi 530003, China. E-mail address: [email protected] (G. Wu).
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involved in inflammation, innate and adaptive immunity and diseases ranging from heart disease to autoimmunity and even cancer [3-5]. Platelets perform their functions through ligand-receptor interactions involving the glycoproteins (GP) expressed on their cell surface membranes. Platelet membrane GPs can be expressed in polymorphic forms caused by single-nucleotide polymorphisms in the genes that encode them. The amino acid changes resulting from these singlenucleotide polymorphisms induce changes in GP structure to form antigens that can elicit antibody generation through exposure from pregnancy, platelet transfusions, or, rarely, transplantation [6-7]. To date, 36 human platelet alloantigens (HPAs) have been identified (HPA-1– HPA-29bw and Lap a) and are known to be expressed on 6 different
http://dx.doi.org/10.1016/j.tmrv.2016.12.001 0887-7963/© 2016 Published by Elsevier Inc.
Please cite this article as: Wu G, et al, Platelet Immunology in China: Research and Clinical Applications, Transfus Med Rev (2016), http:// dx.doi.org/10.1016/j.tmrv.2016.12.001
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platelet GPs: GPIIb, GPIIIa, GPIbα, GPIbβ, GPIa, and CD109 [8-36]. In addition to HPAs, platelets express other antigens, including CD36 (Naka, GPIV), GPVI,blood group antigens (I, P, and ABO(H)), and human leukocyte antigens (HLA I classes A, B, and, to a lesser degree, C). Human platelet antigens show variation in genotype frequency across populations [37]. Immunization against HPAs is associated with a number of clinical conditions, including fetal and neonatal alloimmune thrombocytopenia (NAIT), platelet transfusion refractoriness (PTR), posttransfusion purpura (PTP), passive alloimmne thrombocytopenia, transplantationassociated alloimmune thrombocytopenia, and other platelet immune disorders [38-40]. The detection and identification of clinically relevant platelet antibodies are important for the diagnosis and management of patients affected with immune-mediated thrombocytopenias. Human platelet alloantigen frequencies and the characteristics of antiplatelet antibodies vary widely between ethnic groups. The most commonly reported alloimmune thrombocytopenia–associated HPA alloantibody in white populations is anti–HPA-1a, followed by anti–HPA-5b. In contrast, anti–HPA-4 antibodies are the most common in Japanese patients with immune thrombocytopenia[41-45]. Understanding the characteristics of clinically relevant platelet antibodies in the Chinese population and developing the ability to detect relevant platelet antibodies in Chinese blood centers and hospitals are important for improving care for patients affected with immune-mediated thrombocytopenia in China. Summarizing results from literature searches using PubMed Database, Chinese BioMedical Literature Database, and Chinese Core Journal of Peking University Directory, this review introduces recent research and clinical advances in the field of platelet immunology in China. Platelet Immunology in China With the request from the International Society of Blood Transfusion and International Society of Blood Transfusion Working Party of Platelet Immunology, the 14th International Society of Blood Transfusion Platelet Immunology Workshop and co-research projects were organized and designed by Dr Guo-Guang Wu and the Nanning Institute of Transfusion Medicine in China in 2007 to 2008. The aims of the Platelet Immunology Workshop were to evaluate and share the latest knowledge and techniques in platelet immunology for the laboratory diagnosis of platelet immune disorders and to reach a consensus regarding various standards in platelet immunology and molecular testing. Five main techniques were addressed, including serological testing, genotyping, and the detection for the drug-dependent antibodies against platelet. Forty-two laboratories from 23 countries participated in the workshop, including 7 laboratories from China [46]. This successful global collaboration stimulated and accelerated both clinical and research projects relating to platelet immunology in the field of transfusion medicine in China. Several large blood centers, including Beijing, Shanghai, Zhejiang, Guangzhou, Shenzhen, Qingdao, and Nanning Blood Center, established specific platelet immunology laboratories for the diagnosis of platelet immune disorders and for in-house development of platelet serologic and molecular testing techniques. Some blood centers created their own HPA-typed donor registries which helped to improve the outcomes of patients receiving platelet transfusions therapy with compatible platelet products in China. The importance of platelet immunology also continues to gain recognition by hospital clinical departments in China. Techniques for Platelet Antibody Detection and HPA Genotyping in China Serologic methods that are used in China's laboratories for the detection and identification of platelet antibodies are divided into “Whole” (Intact) Platelet Methods and Platelet Membrane Glycoprotein Capture techniques, which are platelet immunofluorescence test–flow cytometry, solid-phase red cell adherence assay, mixed passive hemagglutination, monoclonal antibody-specific immobilization of platelet antigens,
and modified antigen-capture enzyme-linked immunosorbent assays. Commercial kits used by some of laboratories are MASPAT kits (Sanquin, Amsterdam, the Netherlands), LIFECODES Pak Series kits (Immucor, Norcross, GA), and Capture P kits (Immucor). The molecular HPA genotyping techniques used by laboratories in China include DNA-base polymerase chain reaction with sequencespecific primers (PCR-SSP), TaqMan Real-Time PCR (TaqMan), sequencing-based typing (SBT), and PCR followed by Luminex bead detection. Some laboratories have developed and published their new techniques for PCR-SSP and SBT [47-48], as well as for real-time PPCR for HPA genotyping [49]. The commercial kits that are used by laboratories are G&T Multi-PCR HPA Genotyping Kit (G&T, Los Angeles, CA). The immortal lymphoblastiod cell lines of rare human platelet–specific alloantigen and CD36 have been established and studied in the Nanning Institute of Transfusion Medicine. These cell lines can be used to provide reference DNA for routine laboratory reagents and perpetual research materials for long-term studies [50]. Frequencies of HPA Alleles in the Chinese Population The frequencies of several human platelet antigens (HPAs) vary between different populations and are a major determinant for the prevalence of HPA alloimmunization and its clinical associated entities. Study HPA allele frequencies and comparing between different ethnic populations can help to elucidate the potential alloimmunization risk associated with pregnancy and transfusion in each ethnic group in Chinese population. China is the most populated country in the world and is a multiethnic nation. Of the 56 ethnic groups, the Han group is the largest, accounting for 91.59% of the total population, and the Zhuang group is the second largest, according to the Chinese National census conducted in 2000 [51]. Table 1 shows the frequencies of HPA alleles in Han (Shanghai area), Zhuang (Guangxi area), Miao (Guizhou area), Dong (Guizhou area), Khalkhas (Xinjiang area), Li (Hainan area), Uighurs (Xinjiang area), Zang (Lhasa area), people from Hong Kong, and Taiwanese (Taiwan area) [47,52-60]. All blood samples were collected from unrelated blood donors who confirmed their ethnic group. Genotype frequencies were compared between Han and other ethnic groups using a χ 2 or Fisher exact test; gray boxes in Table 1 indicate a statistically significant difference (where b.05 was considered statistically significant). The genotype distribution in the Han group was similar to that in the Zhuang group, except for HPA-3 and HPA-4. By contrast, significant differences of multiple HPA allele frequencies were found between Han and Miao, Dong, Khalkhas, Li, Uighurs, Zang, and Taiwanese groups. In the Chinese ethnic groups that investigated, an individual with either homozygous for the HPA-1b, HPA-2b, HPA-3b, HPA-4b, HPA-5b, or HPA-6bw allele was rare. The other low-frequency antigens of HPA-7bw, HPA-8bw, HPA-9bw, HPA-11bw, HPA-12bw, HPA-13bw, HPA-14bw, and HPA-16bw were first detected in whites and exhibited private antigens that were not detected in the studied Chinese ethnic groups. This suggests that the risk of platelet alloimmunzation caused by these HPAs is extremely low in the Chinese population. The gene frequency of HPA-4b in Chinese populations is present from 0.0000 to 0.045. The gene frequency of the HPA-15a is higher than that of HPA-15b in the Han, Zhuang, Miao, Khalkhas, Zang, and Taiwanese groups, whereas HPA-15b is more frequent than HPA-15a among the Li and Uighurs groups. The prevalence of HPAs in a given population is a major determinant for the prevalence of HPA alloimmunization and its clinically associated entities: fetal alloimmune thrombocytopenia, NAIT, PTR, PTP, transplantation-associated alloimmune thrombocytopenia, posttransfusion passive alloimmune thrombocytopenia, and platelet transfusion in the Chinese population. A comparison of HPA genotype frequencies between Chinese Han and European whites in Germany [61], American whites in the United States [62], Vietnamese (Kinh) in Vietnam [63], Koreans in Korea [64], Parsis in Indian [65], Argentineans in Rosario of Argentina [66], and African Beninese in sub-Saharan [67] is shown in Table 2. Statistically significant differences were found for the genotype distribution of
Please cite this article as: Wu G, et al, Platelet Immunology in China: Research and Clinical Applications, Transfus Med Rev (2016), http:// dx.doi.org/10.1016/j.tmrv.2016.12.001
G. Wu et al. / Transfusion Medicine Reviews xxx (2016) xxx–xxx
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Table 1 Distribution of HPA in different ethnic group of the Chinese population
Gray boxes indicate statistically significant differences in χ2 test with the same HPA system in the Chinese Han population at Shanghai.
HPA-1, HPA-2, and HPA-5 between Chinese Han and whites (both in Germany and the United States); this finding indicates important differences in the potential risk of HPA alloimmunization associated with transfusion and pregnancy between Chinese and whites. HPA-1a and HPA-5b are the most important platelet antigen systems involved in platelet alloimmunization in whites [43]. Within Asia, the frequencies of HPA genotypes of Chinese Han were similar to Vietnamese (Kinh) and Koreans, with the exception of HPA-3 between Han and Vietnamese and HPA-2 between Han and Koreans. In contrast, a statistically significant difference of all HPAs studied was found between Han and Parsis in Indian. Chinese Han populations show significantly lower frequencies of HPA-1b, HPA-2b, and HPA-6a than in both Argentineans and African Beninese. The low frequency or absence of the HPA-4b allele in Chinese Han populations was similar in Vietnamese, Koreans, Argentineans, and African Beninese. The HPA-4 is dimorphic in some Asian populations, and most of the platelet immunizations against HPA-4a or HPA-4b have been reported in Japan [44].
This study of the frequencies of HPA alleles in the Chinese population has developed the DNA techniques (PCR-SSP, TaqMan, and SBT) for HPA genotyping and provided HPA allele data to establish an effective HPAtyped donor registry in China. Some of the larger blood centers, such as Shanghai, Beijing, Guangzhou, Zhejiang, and Nanning Blood Center, established their own HPA-type donor registries and they share their data with each other. The registry in Nanning Blood Center collects and stores HPA and HLA-typing information for 1072 platelet donors, which is used to identify matched unrelated donors for patients requiring platelet transfusion. The blood center also provides compatible platelets products for improved management of patients affected with platelet immune disorders. Clinical Detection of Platelet Antibodies in the Chinese Population We reviewed a total of 478 cases diagnosed as NAIT (24 cases), PTR (453 cases), and normal donors with antibodies (1 case) by various
Please cite this article as: Wu G, et al, Platelet Immunology in China: Research and Clinical Applications, Transfus Med Rev (2016), http:// dx.doi.org/10.1016/j.tmrv.2016.12.001
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Table 2 Comparison of the distribution of HPA in Chinese Han population and other racial groups in the world
Gray boxes indicate statistically significant differences in χ2 test with the same HPA system in the Chinese Han population at Shanghai.
Please cite this article as: Wu G, et al, Platelet Immunology in China: Research and Clinical Applications, Transfus Med Rev (2016), http:// dx.doi.org/10.1016/j.tmrv.2016.12.001
G. Wu et al. / Transfusion Medicine Reviews xxx (2016) xxx–xxx
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Table 3 Specificities of platelet antibodies associated with NAIT, PTR, and PTP Cases in Chinese Specificities of platelet antibodies Cases
NAIT PTR Donor with antibody Total
Anti– HPA-2b
Anti– HPA-3a
Anti– HPA-4b
Anti– HPA-5a
Anti– HPA-5b
Anti– HPA-15b
AntiHLA
AntiHLA + HPA-15b
2 4
1
1
1 1
3
7 297
1
1
1
6
1
1
2
3
304
1
Table 4 Incidence of platelet antibodies associated in the 478 cases Platelet antibodies
Appeared proportion (%)
Anti-HLA Anti-CD36 Anti-CD36 + HLA Anti–HPA-3a Anti–HPA-15b Anti-HLA + HPA-15b Anti–HPA-5b Anti–HPA-5a Anti–HPA-2b Anti–HPA-4b Unknown anti-HPA Anti-HLA + unknown anti-HPA
304/478 (63.60) 15/478 (3.14) 2/478 (0.42) 6/478 (1.26) 3/478 (0.63) 1/478 (0.21) 2/478 (0.42) 1/478 (0.21) 1/478 (0.21) 1/478 (0.21) 52/478 (10.88) 90/478 (18.83)
platelet immunology laboratories in China between 2008 and 2015 [6895]. The cases published before 2008 were excluded due to the difficulty in validating the clinical and experimental data from the earlier publications. The overall specificity of the platelet antibodies in 478 cases of NAIT, PTR, and normal donor with antibodies is shown in Table 3. Table 4 shows the incidence of relevant platelet antibodies associated with all 478 cases and evaluates the apparent frequency of specificities of platelet antibodies in these alloimmunization cases. After the incidence of anti-HLA and unknown-specificity HPA antibodies, the most frequently identified platelet antibody was anti-CD36 (17/478 [3.56%] ), followed by anti–HPA-3a (6/478 [1.26%]), anti–HPA-15 (including anti–HPA-15a and anti–HPA-15b; 4/478 [0.84%]), and anti–HPA-5 (including anti–HPA-5a and anti–HPA-5b; 3/478 [0.63%]). Both anti– HPA-2 (anti–HPA-2b) and anti–HPA-4 (anti–HPA-4b) were reported in 1 case (each 1/478 [0.21%]). In 142 cases (142/478 [29.7%]), including 90 cases containing anti-HLA antibodies, the laboratories could not identify the specificity of the antiplatelet antibodies. Anti-CD36 Isoantibodies Are an Important Risk Factor for ImmuneMediated Thrombocytopenia in the Chinese Population CD36 (GPIV, Naka) is an 88-kDa membrane GP expressed on platelets, monocytes, macrophages, nucleated erythrocytes, and other tissues. Recent studies indicate that CD36 is a class B scavenger receptor capable of interacting with types I and IV collagen, malaria-infected red blood cells, oxidized low-density lipoprotein, long-chain fatty
AntiHLA + unknown HPA
AntiCD36
AntiCD36 + HLA
Unknown anti-HPA
Total
90
7 7 1
1 1
5 47
24 452 1
90
15
2
52
478
acids, and thrombospondin. Two types of CD36 deficiency have been described. Individuals with type I deficiency lack CD36 on platelets and monocytes, whereas individuals with type II deficiency lack CD36 on platelets only. Despite the apparently wide-ranging functions of this protein, CD36 deficiency has not been linked definitively to any disease state in humans. CD36-deficient individuals exposed to normal platelets can produce anti-CD36 antibodies. Anti-CD36, also named anti-Nak a, was first described in a Japanese woman with PTR shown to be an isoantibody in CD36 deficiency individuals and implicated in cases of NAIT, PTR, and PTP [96]. CD36 deficiency varies widely between ethnic groups, with a frequency of 3% to 11% in Asians, 8% in subSaharan Africans, and less than 0.4% in whites [97-98]. The incidence of CD36 deficiency in the Chinese population was studied in different areas including Guangxi, Guangzhou, Zhejiang, Shanghai, and Shenzhen (Table 5) [88,99-103]. The incidence of CD36 deficiency in Chinese populations ranges from 1.8% (18/998, in Guangzhou) to 4.13% (190/4621, in Guangxi). Novel CD36 gene mutations that lead to CD36 deficiency were frequently identified in the Guangxi population [92,95,104]. The overall proportion of type I CD36 deficiency in the Guangxi population was 41.03%, whereas that of type II was 58.97% [99]. Of 17 identified anti-CD36 cases, 10 cases (4 PTR [90] and 6 NAIT [91-93] were identified in the Nanning, Guangxi population and 7 cases (3 PTR, 3 NAIT, and 1 blood donor [88-89]) were reported by Guangzhou blood Center. The total number of anti-CD36 cases reported in Guangxi was higher than that in other regions in China, and may be associated with the high incidence of CD36 deficiency in Guangxi population. One anti-CD36 case was detected from a female blood donor who was most probably immunized during her pregnancy [88]. Together, these studies reveal an important difference in the detection of clinically relevant antiplatelet antibodies between Chinese and other populations. Anti-CD36 isoantibodies are an important risk factor for immune-mediated thrombocytopenia in the Chinese population. Conclusions Since 2008, the importance of platelet immunology has been gaining greater recognition by clinical laboratories in China. Currently, laboratory diagnosis of alloimmune platelet disorders has continued to improve owing to advances in assay technology and to the growing experience of laboratories. Research findings indicate that the frequencies of HPAs vary among different Chinese ethnic groups. The results of clinical
Table 5 Incidence of CD36 deficiency in Chinese population Population
No. of donors studied
Frequency of CD36 deficiency (%)
Type I CD36 deficiency (%)
Type II CD36 deficiency (%)
Reference
Guangxi Guangzhou Zhejiang Shanghai Shenzhen Guangzhou Total
4621 998 192 1022 327 249 7409
4.13 1.8 3.65 2.16 3.06 2.81 3.45
41.03 41.67 0 9.09 10 NT
58.97 58.34 100 90.91 90 NT
Zhong et al [99] Xu et al [88] Xu et al [100] Li et al [101] Li et al [102] Wang et al [103]
Abbreviation: NT, not test.
Please cite this article as: Wu G, et al, Platelet Immunology in China: Research and Clinical Applications, Transfus Med Rev (2016), http:// dx.doi.org/10.1016/j.tmrv.2016.12.001
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applications of platelet immunology suggest that anti-CD36 isoantibodies are an important risk factor for immune-mediated thrombocytopenia in the Chinese population, whereas anti–HPA-1a and anti–HPA-5b are the most important HPA alloantibodies in whites and anti–HPA-4 plays the major role in Japanese for immune thrombocytopenias. However, of the 478 cases reviewed in this article, antibody specificity could not be identified in 142 cases by laboratories in China (142/478 [29.7%]), suggesting that there are currently disparities in testing capabilities. To improve consistent testing standards among laboratories, we need to (1) expand the exchange of knowledge and clinical expertise between laboratories worldwide; (2) standardize and harmonize techniques; and (3) according to the characteristics of platelet immunology in the local population, establish appropriate panel cell standards including those that express low-frequency or rare HPAs and prepare the reference reagents both for platelet serology and genotyping. Finally, improvements in platelet immunology testing in China have the potential to impact and guide the clinical diagnosis, prevention, and treatment of alloimmune platelet disorders in the Chinese population. With an increasingly heterogeneous global patient population, diagnostic laboratories should be aware of each patient's ethnic origin when considering the possibility of immunization to platelet antigens, including anti-HLA, anti-HPA, and anti-CD36 [105]. Conflict of Interest The authors have no conflicts of interest to declare. Acknowledgments The authors would like to thank Dr Xiaohong Ruby Xu and Mrs Alexandra H. Marshall (Li Ka Shing Knowledge Institute of St Michael's Hospital, Toronto, Canada) for their help with manuscript editing. The authors also acknowledge our colleagues of the Nanning Institute of Transfusion Medicine, China, for their work in compiling the data from the publications. References [1] Leslie M. Cell biology. Beyond clotting: the powers of platelets. Science 2010; 328(5978):562–4. [2] Hou Y, Carrim N, Wang Y, Gallant RC, Marshall A, Ni H. Platelets in hemostasis and thrombosis: novel mechanisms of fibrinogen-independent platelet aggregation and fibronectin-mediated protein wave of hemostasis. J Biomed Res 2015;29(6):437–44. [3] Semple JW, Italiano Jr JE, Freedman J. Platelets and the immune continuum. Nat Rev Immunol 2011;11(4):264–74. [4] Li C, Li J, Li Y, Lang S, Yougbare I, Zhu G, et al. Crosstalk between platelets and the immune system: old systems with new discoveries. Adv Hematol 2012;2012: 384685. [5] Peng J, Ma SH, Liu J, Hou Y, Liu XM, Niu T, et al. Association of autoantibody specificity and response to intravenous immunoglobulin G therapy in immune thrombocytopenia: a multicenter cohort study. J Thromb Haemost 2014;12(4):497–504. [6] Curtis BR, McFarland JG. Human platelet antigens—2013. Vox Sang 2014;106(2): 93–102. [7] Zdravic D, Yougbare I, Vadasz B, Li C, Marshall AH, Chen P, et al. Fetal and neonatal alloimmune thrombocytopenia. Semin Fetal Neonatal Med 2016;21(1):19–27. [8] Newman PJ, Derbes RS, Aster RH. The human platelet alloantigens, PlA1 and PlA2, are associated with a leucine33/proline33 amino acid polymorphism in membrane glycoprotein IIIa, and are distinguishable by DNA typing. J Clin Invest 1989;83(5): 1778–81. [9] Kuijpers RW, Faber NM, Cuypers HT, Ouwehand WH, von dem Borne AE. NH2terminal globular domain of human platelet glycoprotein Ib alpha has a methionine 145/threonine145 amino acid polymorphism, which is associated with the HPA-2 (Ko) alloantigens. J Clin Invest 1992;89(2):381–4. [10] Lyman S, Aster RH, Visentin GP, Newman PJ. Polymorphism of human platelet membrane glycoprotein IIb associated with the Baka/Bakb alloantigen system. Blood 1990;75(12):2343–8. [11] Wang R, Furihata K, McFarland JG, Friedman K, Aster RH, Newman PJ. An amino acid polymorphism within the RGD binding domain of platelet membrane glycoprotein IIIa is responsible for the formation of the Pena/Penb alloantigen system. J Clin Invest 1992;90(5):2038–43. [12] Santoso S, Kalb R, Walka M, Kiefel V, Mueller-Eckhardt C, Newman PJ. The human platelet alloantigens Br(a) and Brb are associated with a single amino acid polymorphism on glycoprotein Ia (integrin subunit alpha 2). J Clin Invest 1993;92(5): 2427–32.
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Contents lists available at ScienceDirect
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Platelet Immunology in China: Research and Clinical Applications Guoguang Wu a,⁎, Yan Zhou a, Lilan Li a, Zhoulin Zhong a, Hengchong Li a, Haiyan Li a, Mei Yu a, Weidong Shen a, Heyu Ni b a b
Nanning Institute of Transfusion Medicine, Nanning Blood Center, Nanning, China Canadian Blood Services and Department of Laboratory Medicine and Pathobiology, St Michael's Hospital, University of Toronto, Toronto, Ontario, Canada
a r t i c l e
i n f o
Available online xxxx Keywords: Platelet immunology Human platelet alloantigens Immune-mediated thrombocytopenia Anti-CD36 Chinese population
a b s t r a c t Immunization against human platelet alloantigens (HPAs) is associated with a number of clinical complications. The detection and identification of clinically relevant platelet antibodies are important for the diagnosis and management of patients affected with immune-mediated thrombocytopenias. Human platelet alloantigen frequencies and the characteristics of antiplatelet antibodies vary widely between ethnic groups. Since 2008, the importance of platelet immunology in the field of transfusion medicine has gained greater recognition by clinical laboratories in China. Laboratories in China have established and improved methods for platelet antibody detection and HPA genotyping techniques, which are used for the diagnosis of alloimmune platelet disorders in clinic and research environments. Research has revealed the frequencies of HPA alleles in different Chinese ethnic groups and compared the differences in HPA gene frequencies between the Chinese Han and other ethnic groups of the world. Production of anti-CD36 isoantibodies is an important risk factor for immune-mediated thrombocytopenia in the Chinese population. Advances in research and clinical application of platelet immunology have significantly improved the clinical diagnosis, treatment including transfusion support, and prevention of alloimmune platelet disorders in the Chinese population. © 2016 Published by Elsevier Inc.
Contents Platelet Immunology in China . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Techniques for Platelet Antibody Detection and HPA Genotyping in China. . . . . . . . . . . . . . . . . . . . . . . Frequencies of HPA Alleles in the Chinese Population . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clinical Detection of Platelet Antibodies in the Chinese Population . . . . . . . . . . . . . . . . . . . . . . . . . . Anti-CD36 Isoantibodies Are an Important Risk Factor for Immune-Mediated Thrombocytopenia in the Chinese Population Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of Interest. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Platelets are one of the most important cellular products issued by blood centers in China. Platelet products are often prescribed for the prophylactic treatment to reduce the risk of bleeding in hematooncology and for the treatment of bleeding in patients with a wide range of conditions. Platelets have important functions in hemostasis, in which they adhere to damaged blood vessels, aggregate en masse, and through cross-links with fibrinogen or other proteins, form a fibrin clot to prevent further blood loss [1-2]; in addition, platelets are also ⁎ Corresponding author at: Guoguang Wu, Nanning Institute of Transfusion Medicine, Nanning Blood Center, No. 18, Keyuan Ave, Nanning, Guangxi 530003, China. E-mail address: [email protected] (G. Wu).
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involved in inflammation, innate and adaptive immunity and diseases ranging from heart disease to autoimmunity and even cancer [3-5]. Platelets perform their functions through ligand-receptor interactions involving the glycoproteins (GP) expressed on their cell surface membranes. Platelet membrane GPs can be expressed in polymorphic forms caused by single-nucleotide polymorphisms in the genes that encode them. The amino acid changes resulting from these singlenucleotide polymorphisms induce changes in GP structure to form antigens that can elicit antibody generation through exposure from pregnancy, platelet transfusions, or, rarely, transplantation [6-7]. To date, 36 human platelet alloantigens (HPAs) have been identified (HPA-1– HPA-29bw and Lap a) and are known to be expressed on 6 different
http://dx.doi.org/10.1016/j.tmrv.2016.12.001 0887-7963/© 2016 Published by Elsevier Inc.
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platelet GPs: GPIIb, GPIIIa, GPIbα, GPIbβ, GPIa, and CD109 [8-36]. In addition to HPAs, platelets express other antigens, including CD36 (Naka, GPIV), GPVI,blood group antigens (I, P, and ABO(H)), and human leukocyte antigens (HLA I classes A, B, and, to a lesser degree, C). Human platelet antigens show variation in genotype frequency across populations [37]. Immunization against HPAs is associated with a number of clinical conditions, including fetal and neonatal alloimmune thrombocytopenia (NAIT), platelet transfusion refractoriness (PTR), posttransfusion purpura (PTP), passive alloimmne thrombocytopenia, transplantationassociated alloimmune thrombocytopenia, and other platelet immune disorders [38-40]. The detection and identification of clinically relevant platelet antibodies are important for the diagnosis and management of patients affected with immune-mediated thrombocytopenias. Human platelet alloantigen frequencies and the characteristics of antiplatelet antibodies vary widely between ethnic groups. The most commonly reported alloimmune thrombocytopenia–associated HPA alloantibody in white populations is anti–HPA-1a, followed by anti–HPA-5b. In contrast, anti–HPA-4 antibodies are the most common in Japanese patients with immune thrombocytopenia[41-45]. Understanding the characteristics of clinically relevant platelet antibodies in the Chinese population and developing the ability to detect relevant platelet antibodies in Chinese blood centers and hospitals are important for improving care for patients affected with immune-mediated thrombocytopenia in China. Summarizing results from literature searches using PubMed Database, Chinese BioMedical Literature Database, and Chinese Core Journal of Peking University Directory, this review introduces recent research and clinical advances in the field of platelet immunology in China. Platelet Immunology in China With the request from the International Society of Blood Transfusion and International Society of Blood Transfusion Working Party of Platelet Immunology, the 14th International Society of Blood Transfusion Platelet Immunology Workshop and co-research projects were organized and designed by Dr Guo-Guang Wu and the Nanning Institute of Transfusion Medicine in China in 2007 to 2008. The aims of the Platelet Immunology Workshop were to evaluate and share the latest knowledge and techniques in platelet immunology for the laboratory diagnosis of platelet immune disorders and to reach a consensus regarding various standards in platelet immunology and molecular testing. Five main techniques were addressed, including serological testing, genotyping, and the detection for the drug-dependent antibodies against platelet. Forty-two laboratories from 23 countries participated in the workshop, including 7 laboratories from China [46]. This successful global collaboration stimulated and accelerated both clinical and research projects relating to platelet immunology in the field of transfusion medicine in China. Several large blood centers, including Beijing, Shanghai, Zhejiang, Guangzhou, Shenzhen, Qingdao, and Nanning Blood Center, established specific platelet immunology laboratories for the diagnosis of platelet immune disorders and for in-house development of platelet serologic and molecular testing techniques. Some blood centers created their own HPA-typed donor registries which helped to improve the outcomes of patients receiving platelet transfusions therapy with compatible platelet products in China. The importance of platelet immunology also continues to gain recognition by hospital clinical departments in China. Techniques for Platelet Antibody Detection and HPA Genotyping in China Serologic methods that are used in China's laboratories for the detection and identification of platelet antibodies are divided into “Whole” (Intact) Platelet Methods and Platelet Membrane Glycoprotein Capture techniques, which are platelet immunofluorescence test–flow cytometry, solid-phase red cell adherence assay, mixed passive hemagglutination, monoclonal antibody-specific immobilization of platelet antigens,
and modified antigen-capture enzyme-linked immunosorbent assays. Commercial kits used by some of laboratories are MASPAT kits (Sanquin, Amsterdam, the Netherlands), LIFECODES Pak Series kits (Immucor, Norcross, GA), and Capture P kits (Immucor). The molecular HPA genotyping techniques used by laboratories in China include DNA-base polymerase chain reaction with sequencespecific primers (PCR-SSP), TaqMan Real-Time PCR (TaqMan), sequencing-based typing (SBT), and PCR followed by Luminex bead detection. Some laboratories have developed and published their new techniques for PCR-SSP and SBT [47-48], as well as for real-time PPCR for HPA genotyping [49]. The commercial kits that are used by laboratories are G&T Multi-PCR HPA Genotyping Kit (G&T, Los Angeles, CA). The immortal lymphoblastiod cell lines of rare human platelet–specific alloantigen and CD36 have been established and studied in the Nanning Institute of Transfusion Medicine. These cell lines can be used to provide reference DNA for routine laboratory reagents and perpetual research materials for long-term studies [50]. Frequencies of HPA Alleles in the Chinese Population The frequencies of several human platelet antigens (HPAs) vary between different populations and are a major determinant for the prevalence of HPA alloimmunization and its clinical associated entities. Study HPA allele frequencies and comparing between different ethnic populations can help to elucidate the potential alloimmunization risk associated with pregnancy and transfusion in each ethnic group in Chinese population. China is the most populated country in the world and is a multiethnic nation. Of the 56 ethnic groups, the Han group is the largest, accounting for 91.59% of the total population, and the Zhuang group is the second largest, according to the Chinese National census conducted in 2000 [51]. Table 1 shows the frequencies of HPA alleles in Han (Shanghai area), Zhuang (Guangxi area), Miao (Guizhou area), Dong (Guizhou area), Khalkhas (Xinjiang area), Li (Hainan area), Uighurs (Xinjiang area), Zang (Lhasa area), people from Hong Kong, and Taiwanese (Taiwan area) [47,52-60]. All blood samples were collected from unrelated blood donors who confirmed their ethnic group. Genotype frequencies were compared between Han and other ethnic groups using a χ 2 or Fisher exact test; gray boxes in Table 1 indicate a statistically significant difference (where b.05 was considered statistically significant). The genotype distribution in the Han group was similar to that in the Zhuang group, except for HPA-3 and HPA-4. By contrast, significant differences of multiple HPA allele frequencies were found between Han and Miao, Dong, Khalkhas, Li, Uighurs, Zang, and Taiwanese groups. In the Chinese ethnic groups that investigated, an individual with either homozygous for the HPA-1b, HPA-2b, HPA-3b, HPA-4b, HPA-5b, or HPA-6bw allele was rare. The other low-frequency antigens of HPA-7bw, HPA-8bw, HPA-9bw, HPA-11bw, HPA-12bw, HPA-13bw, HPA-14bw, and HPA-16bw were first detected in whites and exhibited private antigens that were not detected in the studied Chinese ethnic groups. This suggests that the risk of platelet alloimmunzation caused by these HPAs is extremely low in the Chinese population. The gene frequency of HPA-4b in Chinese populations is present from 0.0000 to 0.045. The gene frequency of the HPA-15a is higher than that of HPA-15b in the Han, Zhuang, Miao, Khalkhas, Zang, and Taiwanese groups, whereas HPA-15b is more frequent than HPA-15a among the Li and Uighurs groups. The prevalence of HPAs in a given population is a major determinant for the prevalence of HPA alloimmunization and its clinically associated entities: fetal alloimmune thrombocytopenia, NAIT, PTR, PTP, transplantation-associated alloimmune thrombocytopenia, posttransfusion passive alloimmune thrombocytopenia, and platelet transfusion in the Chinese population. A comparison of HPA genotype frequencies between Chinese Han and European whites in Germany [61], American whites in the United States [62], Vietnamese (Kinh) in Vietnam [63], Koreans in Korea [64], Parsis in Indian [65], Argentineans in Rosario of Argentina [66], and African Beninese in sub-Saharan [67] is shown in Table 2. Statistically significant differences were found for the genotype distribution of
Please cite this article as: Wu G, et al, Platelet Immunology in China: Research and Clinical Applications, Transfus Med Rev (2016), http:// dx.doi.org/10.1016/j.tmrv.2016.12.001
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Table 1 Distribution of HPA in different ethnic group of the Chinese population
Gray boxes indicate statistically significant differences in χ2 test with the same HPA system in the Chinese Han population at Shanghai.
HPA-1, HPA-2, and HPA-5 between Chinese Han and whites (both in Germany and the United States); this finding indicates important differences in the potential risk of HPA alloimmunization associated with transfusion and pregnancy between Chinese and whites. HPA-1a and HPA-5b are the most important platelet antigen systems involved in platelet alloimmunization in whites [43]. Within Asia, the frequencies of HPA genotypes of Chinese Han were similar to Vietnamese (Kinh) and Koreans, with the exception of HPA-3 between Han and Vietnamese and HPA-2 between Han and Koreans. In contrast, a statistically significant difference of all HPAs studied was found between Han and Parsis in Indian. Chinese Han populations show significantly lower frequencies of HPA-1b, HPA-2b, and HPA-6a than in both Argentineans and African Beninese. The low frequency or absence of the HPA-4b allele in Chinese Han populations was similar in Vietnamese, Koreans, Argentineans, and African Beninese. The HPA-4 is dimorphic in some Asian populations, and most of the platelet immunizations against HPA-4a or HPA-4b have been reported in Japan [44].
This study of the frequencies of HPA alleles in the Chinese population has developed the DNA techniques (PCR-SSP, TaqMan, and SBT) for HPA genotyping and provided HPA allele data to establish an effective HPAtyped donor registry in China. Some of the larger blood centers, such as Shanghai, Beijing, Guangzhou, Zhejiang, and Nanning Blood Center, established their own HPA-type donor registries and they share their data with each other. The registry in Nanning Blood Center collects and stores HPA and HLA-typing information for 1072 platelet donors, which is used to identify matched unrelated donors for patients requiring platelet transfusion. The blood center also provides compatible platelets products for improved management of patients affected with platelet immune disorders. Clinical Detection of Platelet Antibodies in the Chinese Population We reviewed a total of 478 cases diagnosed as NAIT (24 cases), PTR (453 cases), and normal donors with antibodies (1 case) by various
Please cite this article as: Wu G, et al, Platelet Immunology in China: Research and Clinical Applications, Transfus Med Rev (2016), http:// dx.doi.org/10.1016/j.tmrv.2016.12.001
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Table 2 Comparison of the distribution of HPA in Chinese Han population and other racial groups in the world
Gray boxes indicate statistically significant differences in χ2 test with the same HPA system in the Chinese Han population at Shanghai.
Please cite this article as: Wu G, et al, Platelet Immunology in China: Research and Clinical Applications, Transfus Med Rev (2016), http:// dx.doi.org/10.1016/j.tmrv.2016.12.001
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Table 3 Specificities of platelet antibodies associated with NAIT, PTR, and PTP Cases in Chinese Specificities of platelet antibodies Cases
NAIT PTR Donor with antibody Total
Anti– HPA-2b
Anti– HPA-3a
Anti– HPA-4b
Anti– HPA-5a
Anti– HPA-5b
Anti– HPA-15b
AntiHLA
AntiHLA + HPA-15b
2 4
1
1
1 1
3
7 297
1
1
1
6
1
1
2
3
304
1
Table 4 Incidence of platelet antibodies associated in the 478 cases Platelet antibodies
Appeared proportion (%)
Anti-HLA Anti-CD36 Anti-CD36 + HLA Anti–HPA-3a Anti–HPA-15b Anti-HLA + HPA-15b Anti–HPA-5b Anti–HPA-5a Anti–HPA-2b Anti–HPA-4b Unknown anti-HPA Anti-HLA + unknown anti-HPA
304/478 (63.60) 15/478 (3.14) 2/478 (0.42) 6/478 (1.26) 3/478 (0.63) 1/478 (0.21) 2/478 (0.42) 1/478 (0.21) 1/478 (0.21) 1/478 (0.21) 52/478 (10.88) 90/478 (18.83)
platelet immunology laboratories in China between 2008 and 2015 [6895]. The cases published before 2008 were excluded due to the difficulty in validating the clinical and experimental data from the earlier publications. The overall specificity of the platelet antibodies in 478 cases of NAIT, PTR, and normal donor with antibodies is shown in Table 3. Table 4 shows the incidence of relevant platelet antibodies associated with all 478 cases and evaluates the apparent frequency of specificities of platelet antibodies in these alloimmunization cases. After the incidence of anti-HLA and unknown-specificity HPA antibodies, the most frequently identified platelet antibody was anti-CD36 (17/478 [3.56%] ), followed by anti–HPA-3a (6/478 [1.26%]), anti–HPA-15 (including anti–HPA-15a and anti–HPA-15b; 4/478 [0.84%]), and anti–HPA-5 (including anti–HPA-5a and anti–HPA-5b; 3/478 [0.63%]). Both anti– HPA-2 (anti–HPA-2b) and anti–HPA-4 (anti–HPA-4b) were reported in 1 case (each 1/478 [0.21%]). In 142 cases (142/478 [29.7%]), including 90 cases containing anti-HLA antibodies, the laboratories could not identify the specificity of the antiplatelet antibodies. Anti-CD36 Isoantibodies Are an Important Risk Factor for ImmuneMediated Thrombocytopenia in the Chinese Population CD36 (GPIV, Naka) is an 88-kDa membrane GP expressed on platelets, monocytes, macrophages, nucleated erythrocytes, and other tissues. Recent studies indicate that CD36 is a class B scavenger receptor capable of interacting with types I and IV collagen, malaria-infected red blood cells, oxidized low-density lipoprotein, long-chain fatty
AntiHLA + unknown HPA
AntiCD36
AntiCD36 + HLA
Unknown anti-HPA
Total
90
7 7 1
1 1
5 47
24 452 1
90
15
2
52
478
acids, and thrombospondin. Two types of CD36 deficiency have been described. Individuals with type I deficiency lack CD36 on platelets and monocytes, whereas individuals with type II deficiency lack CD36 on platelets only. Despite the apparently wide-ranging functions of this protein, CD36 deficiency has not been linked definitively to any disease state in humans. CD36-deficient individuals exposed to normal platelets can produce anti-CD36 antibodies. Anti-CD36, also named anti-Nak a, was first described in a Japanese woman with PTR shown to be an isoantibody in CD36 deficiency individuals and implicated in cases of NAIT, PTR, and PTP [96]. CD36 deficiency varies widely between ethnic groups, with a frequency of 3% to 11% in Asians, 8% in subSaharan Africans, and less than 0.4% in whites [97-98]. The incidence of CD36 deficiency in the Chinese population was studied in different areas including Guangxi, Guangzhou, Zhejiang, Shanghai, and Shenzhen (Table 5) [88,99-103]. The incidence of CD36 deficiency in Chinese populations ranges from 1.8% (18/998, in Guangzhou) to 4.13% (190/4621, in Guangxi). Novel CD36 gene mutations that lead to CD36 deficiency were frequently identified in the Guangxi population [92,95,104]. The overall proportion of type I CD36 deficiency in the Guangxi population was 41.03%, whereas that of type II was 58.97% [99]. Of 17 identified anti-CD36 cases, 10 cases (4 PTR [90] and 6 NAIT [91-93] were identified in the Nanning, Guangxi population and 7 cases (3 PTR, 3 NAIT, and 1 blood donor [88-89]) were reported by Guangzhou blood Center. The total number of anti-CD36 cases reported in Guangxi was higher than that in other regions in China, and may be associated with the high incidence of CD36 deficiency in Guangxi population. One anti-CD36 case was detected from a female blood donor who was most probably immunized during her pregnancy [88]. Together, these studies reveal an important difference in the detection of clinically relevant antiplatelet antibodies between Chinese and other populations. Anti-CD36 isoantibodies are an important risk factor for immune-mediated thrombocytopenia in the Chinese population. Conclusions Since 2008, the importance of platelet immunology has been gaining greater recognition by clinical laboratories in China. Currently, laboratory diagnosis of alloimmune platelet disorders has continued to improve owing to advances in assay technology and to the growing experience of laboratories. Research findings indicate that the frequencies of HPAs vary among different Chinese ethnic groups. The results of clinical
Table 5 Incidence of CD36 deficiency in Chinese population Population
No. of donors studied
Frequency of CD36 deficiency (%)
Type I CD36 deficiency (%)
Type II CD36 deficiency (%)
Reference
Guangxi Guangzhou Zhejiang Shanghai Shenzhen Guangzhou Total
4621 998 192 1022 327 249 7409
4.13 1.8 3.65 2.16 3.06 2.81 3.45
41.03 41.67 0 9.09 10 NT
58.97 58.34 100 90.91 90 NT
Zhong et al [99] Xu et al [88] Xu et al [100] Li et al [101] Li et al [102] Wang et al [103]
Abbreviation: NT, not test.
Please cite this article as: Wu G, et al, Platelet Immunology in China: Research and Clinical Applications, Transfus Med Rev (2016), http:// dx.doi.org/10.1016/j.tmrv.2016.12.001
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applications of platelet immunology suggest that anti-CD36 isoantibodies are an important risk factor for immune-mediated thrombocytopenia in the Chinese population, whereas anti–HPA-1a and anti–HPA-5b are the most important HPA alloantibodies in whites and anti–HPA-4 plays the major role in Japanese for immune thrombocytopenias. However, of the 478 cases reviewed in this article, antibody specificity could not be identified in 142 cases by laboratories in China (142/478 [29.7%]), suggesting that there are currently disparities in testing capabilities. To improve consistent testing standards among laboratories, we need to (1) expand the exchange of knowledge and clinical expertise between laboratories worldwide; (2) standardize and harmonize techniques; and (3) according to the characteristics of platelet immunology in the local population, establish appropriate panel cell standards including those that express low-frequency or rare HPAs and prepare the reference reagents both for platelet serology and genotyping. Finally, improvements in platelet immunology testing in China have the potential to impact and guide the clinical diagnosis, prevention, and treatment of alloimmune platelet disorders in the Chinese population. With an increasingly heterogeneous global patient population, diagnostic laboratories should be aware of each patient's ethnic origin when considering the possibility of immunization to platelet antigens, including anti-HLA, anti-HPA, and anti-CD36 [105]. Conflict of Interest The authors have no conflicts of interest to declare. Acknowledgments The authors would like to thank Dr Xiaohong Ruby Xu and Mrs Alexandra H. Marshall (Li Ka Shing Knowledge Institute of St Michael's Hospital, Toronto, Canada) for their help with manuscript editing. The authors also acknowledge our colleagues of the Nanning Institute of Transfusion Medicine, China, for their work in compiling the data from the publications. References [1] Leslie M. Cell biology. Beyond clotting: the powers of platelets. Science 2010; 328(5978):562–4. [2] Hou Y, Carrim N, Wang Y, Gallant RC, Marshall A, Ni H. Platelets in hemostasis and thrombosis: novel mechanisms of fibrinogen-independent platelet aggregation and fibronectin-mediated protein wave of hemostasis. J Biomed Res 2015;29(6):437–44. [3] Semple JW, Italiano Jr JE, Freedman J. Platelets and the immune continuum. Nat Rev Immunol 2011;11(4):264–74. [4] Li C, Li J, Li Y, Lang S, Yougbare I, Zhu G, et al. Crosstalk between platelets and the immune system: old systems with new discoveries. Adv Hematol 2012;2012: 384685. [5] Peng J, Ma SH, Liu J, Hou Y, Liu XM, Niu T, et al. Association of autoantibody specificity and response to intravenous immunoglobulin G therapy in immune thrombocytopenia: a multicenter cohort study. J Thromb Haemost 2014;12(4):497–504. [6] Curtis BR, McFarland JG. Human platelet antigens—2013. Vox Sang 2014;106(2): 93–102. [7] Zdravic D, Yougbare I, Vadasz B, Li C, Marshall AH, Chen P, et al. Fetal and neonatal alloimmune thrombocytopenia. Semin Fetal Neonatal Med 2016;21(1):19–27. [8] Newman PJ, Derbes RS, Aster RH. The human platelet alloantigens, PlA1 and PlA2, are associated with a leucine33/proline33 amino acid polymorphism in membrane glycoprotein IIIa, and are distinguishable by DNA typing. J Clin Invest 1989;83(5): 1778–81. [9] Kuijpers RW, Faber NM, Cuypers HT, Ouwehand WH, von dem Borne AE. NH2terminal globular domain of human platelet glycoprotein Ib alpha has a methionine 145/threonine145 amino acid polymorphism, which is associated with the HPA-2 (Ko) alloantigens. J Clin Invest 1992;89(2):381–4. [10] Lyman S, Aster RH, Visentin GP, Newman PJ. Polymorphism of human platelet membrane glycoprotein IIb associated with the Baka/Bakb alloantigen system. Blood 1990;75(12):2343–8. [11] Wang R, Furihata K, McFarland JG, Friedman K, Aster RH, Newman PJ. An amino acid polymorphism within the RGD binding domain of platelet membrane glycoprotein IIIa is responsible for the formation of the Pena/Penb alloantigen system. J Clin Invest 1992;90(5):2038–43. [12] Santoso S, Kalb R, Walka M, Kiefel V, Mueller-Eckhardt C, Newman PJ. The human platelet alloantigens Br(a) and Brb are associated with a single amino acid polymorphism on glycoprotein Ia (integrin subunit alpha 2). J Clin Invest 1993;92(5): 2427–32.
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Please cite this article as: Wu G, et al, Platelet Immunology in China: Research and Clinical Applications, Transfus Med Rev (2016), http:// dx.doi.org/10.1016/j.tmrv.2016.12.001
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