Fetal and neonatal immune thrombocytopenia caused by maternal alloantibodies and isoantibodies in Caucasian and Asian populations: a narrative review

Human platelet antigens (HPAs) associated with fetal neonatal and alloimmune thrombocytopenia (FNAIT)

Common HPAs

Alloantigens

Twelve well-established HPAs are included in six diallelic systems: HPA-1, HPA-2, HPA-3, HPA-4, HPA-5 and HPA-15. HPAs are numbered in their order of discovery, with the higher frequency antigen designated as ‘a’ and the lower frequency antigen designated as ‘b’. The lower frequency antigens arose from single nucleotide mutations on the respective gene leading to missense amino acid exchanges and resulting in new antigenic determinants (epitopes). The frequencies of HPAs were intensively studied in Caucasian populations, and investigated in other ethnic groups.

Nonself antigens causing immune responses in members of the same species are called alloantigens or isoantigens. Alloantigens (such as HPA) differ only in the polymorphic structure caused by mutational changes (e.g., single amino acid substitutions) of glycoprotein, and isoantigens are recognized by individuals lacking an entire cellular glycoprotein present in cells of normal individuals. Accordingly, the corresponding immune responses are called alloimmunization or isoimmunization. Until today, isoantigens have not been included in the HPA nomenclature.

Three transmembrane glycoprotein complexes, namely, αIIbβ3, α2β1, and GPIb/IX/V, and a glycosylphosphatidylinositol (GPI)-linked glycoprotein, CD109, are known as carriers of antigenic determinants. HPA-1, HPA-3, and HPA-4 reside on αIIbβ3, whereas HPA-5 resides on α2β1, and HPA-15 is found on CD109. In the last three decades, a large number of rare HPAs have been identified. This progress is due in particular to the introduction of a platelet crossmatch between maternal serum and paternal platelets (carrier of rare antigens) in the antigen capture assay (MAIPA), in addition to antibody screening of maternal serum using standard platelet panels. As a result, the first low-frequency HPA (HPA-8b) could be discovered (1). Most of them are located on the extracellular domain of the integrin αIIbβ3 (https://www.versiti.org/medical-professionals/precision-medicine-expertise/platelet-antigen-database/hpa-gene-database).

Alloantibodies and FNAIT

In this section, we will discuss the recent progress on the most clinically important human platelet antigens, namely, HPA-1, -3, and -4 residing on integrins αIIbβ3, and HPA-5 on α2β1 (Figure 1A,1B) as well as HPA-2 and HPA-15 located on GPIb/IX/V complex and CD109, respectively. We present the following article in accordance with the Narrative Review reporting checklist (available at https://dx.doi.org/10.21037/aob-21-47).

Figure 1 Integrins carrying human platelet alloantigens (HPAs). (A) Integrins αIIbβ3 and αvβ3 on platelets and endothelium carrying HPA -1, -3, and -4. The positions of amino acid exchanges (L33P; R143Q and I843S) located on β3 and αIIb subunits responsible for the formation of HPA-1, HPA-4, and HPA-3 are indicated. Alloimmunization during pregnancy can lead to the development of different anti-HPA-1a antibody types and FNAIT. Left panel: two different types of anti-HPA-1a antibodies (type 1 and type 2) recognizing the polymorphic β3 subunits independent from α subunits (neither αIIb nor αv) were found [Zhi et al., 2018, (2)]. In contrast to type 1, type 2 anti-HPA-1a antibodies recognize epitopes formed by not only the PSI but also the EGF-1 domain. Theoretically, mothers could also develop anti-HPA-1a antibodies reacting with compound epitopes formed by platelet αIIb and α3 subunits (type 4). Right panel: the third type of anti-HPA-1a antibodies (type 3) react with compound epitopes formed by αv and α3 subunits expressed predominantly in the endothelium [Santoso et al., 2016, (3)]. (B) Integrin α2β1 on platelets carrying HPA-5. The positions of amino acid exchange E534K located on the b-propeller domain of α2 subunits responsible for the formation of HPA-5 are indicated. In contrast to αIIb, the α2 integrin subunit contains a α I-domain.

HPA-1 and HPA-4 on β3 integrin

HPA-1 is the most relevant alloantigen system associated with FNAIT in Caucasians. Alloantibodies against HPA-1a are responsible for approximately 80% of FNAIT cases (4,5). The incidence of FNAIT is about 1:1,000 in newborns (6). In a retrospective study, intracranial hemorrhage (ICH) was encountered in approximately 15% of these cases (4), which may lead to fetal death or persistent neurological sequelae (7). In a prospectively studied cohort of pregnancies, the incidence of ICH was lower. In 79 newborn babies with FNAIT (anti-HPA-1a), 2 (2.5%) developed ICH. In both cases, platelet counts were <50×10⁹/L (8). Among Caucasian populations, the frequency of the rare HPA-1b allele ranges from 0.133 to 0.190. In contrast, HPA-1b gene frequencies are much lower in East Asian populations (ranging from 0.002 to 0.012) (9). Accordingly, alloimmunization against HPA-1a is unlikely in Asian populations. Recently, the first case of FNAIT due to anti-HPA-1a antibodies was found in a blood-related Chinese family (10).

HPA-1a and -1b are controlled by the point mutation leucine > proline at position 33 (Leu33Pro) located on the PSI (plexins, semaphorins and integrins) domain of the β3 integrin subunit (Figure 1A). According to the allele distribution, the estimated risk of an antigenic incompatibility allowing immunization against HPA-1b is higher compared to HPA-1a (13.51% versus 2.17% for a first pregnancy). However, alloimmunization against HPA-1a is much more common than immunization against HPA-1b during pregnancy. In addition, only a few cases of FNAIT caused by anti-HPA-1b were reported (11), whereas, anti-HPA-1b antibodies are encountered more frequently than anti-HPA-1a in patients immunized by blood transfusion. Until today, the reason for this discrepancy is unclear.

Although the Leu33Pro mutation responsible for the formation of HPA-1a and -1b could be identified, little is known about the exact epitopes recognized by anti-HPA-1a antibodies. Accumulated data demonstrated that the epitopes of anti-HPA-1a antibodies are heterogeneous. Some anti-HPA-1a react solely with the PSI domain carrying the polymorphic amino acid residue 33 (called type 1), and some recognize conformational epitopes formed by the PSI-together with the epidermal growth factor-1 (EGF-1) domain (called type 2) (2,12-14) (Figure 1A). Recent studies showed that both antibody types bind independently from the α subunits (neither αIIb nor αv) (15). Furthermore, current evidence indicated that most anti-HPA-1a represent type 2 antibodies (13). Therefore, it is tempting to speculate that type 1 and type 2 antibodies represent successive affinity maturation stages during the course of the immune response (13). A study demonstrated that anti-HPA-1a antibodies are also heterogeneous in their ability to interfere with fibrinogen binding and consequently have a different impact on bleeding in FNAIT (16). It is currently unclear whether this functional heterogeneity is related to type 1 and type 2 anti-HPA-1a antibodies.

It is known that the integrin β3 common subunits can form heterodimers with either αIIb or αv chains and function as a receptor for fibrinogen (αIIbβ3) and vitronectin (αvβ3), respectively (Figure 1A). Recently, another type of anti-HPA-1a antibody recognizing compound epitopes formed by the αv, and the polymorphic β3 subunit was found in FNAIT cases, predominantly found in FNAIT cases with ICH. However, the exact position and conformation of binding sites of this antibody type are not known. In comparison to the previous antibody types, this anti-HPA-1a type could alter angiogenesis (3). Similar observations were made in an animal model suggesting that maternal anti-β3 antibodies suppressed fetal angiogenesis and caused trophoblasts destruction by natural killer cells leading to ICH, placental dysfunction and miscarriage (17,18). It remains to be elucidated which types of anti-β3 antibodies produced by immunized mice in this animal model are directly responsible for this dysfunction.

Recent observations indicated that anti-HPA-1a antibodies recognizing the αvβ3 complex did not significantly induce platelet clearance by macrophages, most probably due to the low copy number of αvβ3 on the platelet surface when compared to αIIbβ3 (500 versus 50,000 molecules/platelet) (Santoso et al., in preparation). HPA-1a antibodies have been shown to suppress megakaryopoiesis by inducing early cell death (19). Later, Zeng et al. demonstrated that anti-αvβ3 autoantibodies from patients with immune thrombocytopenia (ITP) could aggravate thrombocytopenia by impeding megakaryocytes migration and adhesion to the vascular niche (20). Thus, maternal anti-HPA-1a reacting specifically with fetal αvβ3 may alter fetal/neonatal platelet counts by inhibiting thrombocytopoiesis.

Finally, although the three-dimensional structures of the isolated PSI domain in αvβ3 and αIIbβ3 are nearly superimposable, this domain showed distinct conformational states when placed in the context of the entire β3 pairing either with αv or αIIb subunit. This structural difference could be recognized by the immune system (3). Therefore, it is possible that different patterns of anti-HPA-1 antibody types may develop by immunization with platelets or endothelial cells.

Recent data indicated that maternal immunization to HPA-1a occurs during pregnancy by exposure to β3 on syncytiotrophoblast or platelets (Figure 2). In addition, immunization by fetal platelets may occur from obstetrical, trauma complications, or at parturition (6). As HPA-1a is expressed on αvβ3 integrin in the fetal trophoblast, one might speculate that contact of maternal blood with trophoblast or circulating microparticles in maternal blood result in maternal alloimmunization against HPA-1a on β3 and αvβ3 complex (21-23). In addition, if immunization occurs to HPA-1a fetal platelets residing on αIIbβ3, anti-HPA-1a antibodies against β3 and αIIbβ3 complex may develop (Figure 1A).

Figure 2 Possible alloimmunization of HPA-1a (−) mother by HPA-1a (+) fetus [Vanderpuye et al., Biochem J 1991, (21); Kumpel B et al., Transfusion 2008, (22)]. Simplified representation of fetal-maternal placenta interface is illustrated. HPA-1a (+) fetal and HPA-1a (−) maternal platelets expressed abundantly on αIIbβ3, but little on αvβ3 is indicated. The expression of HPA-1a (+) on αvβ3 in syncytiotrophoblast is shown. Theoretically, sensitization of the mother may occur by direct contact of maternal blood with syncytiotrophoblast or/and through the shedding of trophoblast microparticles into the maternal circulation or by fetal platelets resulting from obstetrical, trauma related complications or at parturition. HPA, human platelet alloantigen.

In the Japanese population, anti-HPA-4b is the most frequent maternal αIIbβ3 antibody in FNAIT (24). The allelic frequency of HPA-4b among the Japanese is 0.00854, whereas the HPA-4 polymorphism is nearly nonexistent in Caucasian populations. Surprisingly, two FNAIT cases caused by anti-HPA-4b have been reported in Caucasian families (25,26). HPA-4a and -4b are formed by the point mutation arginine > glutamine at position 143 located on the β I-domain of the β3 integrin subunit (Figure 1A). Currently, it is unknown whether different types of anti-HPA-4 antibodies recognizing different epitopes exist.

HPA-3 on αIIb integrin

In comparison to HPA-1, a greater variation of HPA-3 frequencies was found among different populations. The frequency of HPA-3a and HPA-3b ranges from 0.50 to 0.61 and 0.39 to 0.50, respectively (27). Despite these balanced allele frequencies, anti-HPA-3 antibodies are rarely detected in the sera of women with thrombocytopenic newborns. However, ICH related to anti-HPA-3 antibodies was reported (28-32). Several serological studies showed that anti-HPA-3 antibodies are difficult to detect, most probably because of the heterogeneity of HPA-3 epitopes (33).

HPA-3a and -3b result from the single amino acid Ile843Ser substitution located near the carboxyl terminus of the αIIb extracellular domain (34). Early biochemical studies identified serine 837 as a major O-glycosylation site required for anti-HPA-3a antibody binding (35) (Figure 1A). In this respect, some anti-HPA-3 alloantibodies required intact epitopes formed by O-linked carbohydrates structures or terminal sialic acids that can be lost during platelet storage and platelets’ isolation process for antibody testing (28,29,36-38). A similar phenomenon was observed with the rare alloantigen HPA-9 (Val837Met) located six amino acids away from the HPA-3 dimorphism (39). Recently, a rare platelet antigen on αIIb (HPA-30bw) associated with FNAIT was reported. This antigen is formed by the point mutation Glu806His located within the calf-2 domain and also depends on the carbohydrate composition of αIIb subunit. Similar to some anti-HPA-3a, anti-HPA-30bw alloantibodies are sensitive to O-glycanase treatment (40). However, O-glycosylation is regulated differently in non-human, human cell lines, or human platelets, which are likely to express completely different glycan chains. In accordance, anti-HPA-30b antibodies did react with HPA-30b expressed in human (HEK293) cell line but not in non-human (CHO-K1) cells (40). Recently, bioengineered induced pluripotent stem cells (iPSC)-derived megakaryocytes for the detection of HPA-3 and HPA-9bw were generated (41). In the future, the development of in vitro-generated HPA-defined iPSC-derived platelets carrying endogenous carbohydrates moieties may improve the detection of challenging platelet antibodies.

The αIIb and αv subunits of the β3 integrin family are apparently different, although both share significant homology (42). The αIIbβ3 integrin is expressed on platelets but not on endothelial cells (43). Earlier studies demonstrated that anti-HPA-3a did not react with endothelial cells compared to anti-HPA-1a antibodies (44). In the mature protein, the single heavy chain of αIIb (GPIIbα) is disulfide-bonded to the light chain (GPIIbβ). Biochemical studies demonstrated the existence of two GPIIbβ isoforms, which may lead to the dual proteolytic processing of αIIb (45). Whether this phenomenon may alter αIIb expression on different cells and consequently the binding of some anti-HPA-3 antibodies has not been clarified. Although αIIb is claimed to be a platelet-specific integrin, Rout et al. reported high αIIb expression on invasive trophoblast cells in the mice. Together with other integrins, αIIbβ3 coordinately regulate the adhesion and migration of the differentiating mouse trophoblast (46). Ongoing study in animal models using αIIb deficient and human αIIb transgenic mice indicated that maternal anti-αIIb may target trophoblast cells and lead to placenta dysfunction (47).

It is becoming more and more apparent that different antibody types produced as a polyclonal response by the mother during the pregnancy may determine the severity of the disease. Therefore, the development of serological identification and functional analysis of such antibody type is an important area to improve the prediction of severity in FNAIT cases.

HPA-5 on α2 integrin

Anti-HPA-5b antibodies were first identified in the maternal sera of patients with FNAIT (48,49). In Caucasian populations, anti-HPA-5b is the second most frequent alloantibody type (9–19%) encountered with FNAIT (5,50,51). Compared to anti-HPA-1a, anti-HPA-5 antibodies were found in higher frequency in unselected female blood donors with at least one pregnancy screened for platelet antibodies (52). Our data showed that 1.7% and 0.1% of female blood donors with at least one previous pregnancy present anti-HPA-5b and anti-HPA-1a, respectively (53). However, the chance for a thrombocytopenic child in immunized pregnant women with anti-HPA-5b is low. This observation is in accordance with a previous prospective study in a large cohort of 933 pregnant women screened to develop platelet alloantibodies. Seventeen of 933 mothers (1.8%) formed anti-HPA-5b, but in all cases the newborns’ platelet counts were above 150×10⁹/L (54). In a Japanese cohort of FNAIT cases, anti-HPA-5b was also found as the most frequent platelet antibody (24). Although thrombocytopenia in HPA-5b-FNAIT is often moderate, cases with ICH have been observed (55,56). Anti-HPA-5a, directed against the antithetic antigen, has been found in FNAIT and platelet transfusion refractoriness (PTR) (57,58).

HPA-5a and -5b result from the single amino acid substitution Glu534Lys, which is located on the β-propeller-domain of the a2 subunit of the α2β1 integrin (Figure 1B). α2β1, originally characterized on long-term activated T-cells, has been subsequently found on several cell types, including platelets, fibroblast, epithelial cells, and endothelial cells depending on differentiation and activation state. The α2β1 integrin mainly acts as a receptor for collagens, but other non-collagenous proteins, including laminin, proteoglycans, and viruses, have been described as ligands as well (59).

In contrast to αIIbβ3, only a few copies of the α2β1 integrin (2,000–6,000 copies/platelet) were found on platelets. Similar to the α-subunits of β2-integrin, α2 has a 191-amino acid insert (called the I-domain), which is highly homologous to the A-domain found in the von Willebrand factor (VWF) (60). There are several consistent pieces of evidence for the heterogeneity of α2 expression on platelets. First, two spots with different isoelectric points corresponding to α2 integrin subunits were found (61). Then, a different copy number of α2β1 on the platelet surface associated with an α2 gene polymorphism was reported. Individuals carrying the 807T/873A allele express high levels of platelet α2β1 when compared to individuals carrying the 807C/873G allele (62). Further studies showed a linkage between HPA-5b with C807 (low expresser) and HPA-5a with either C807 or T807 (low and high expresser). This observation indicated that some HPA-5a positive individuals expressed α2β1 in high density on the platelet surface. The HPA-5 polymorphism did not alter platelet adhesion onto collagens (63) but attenuated the adhesion of platelets onto decorin, a small leucine-rich proteoglycan (64).

It is conceivable that the expression of HPA-5 on different cells, depending on the surface density, different state and activation of α2β1 integrin, may enhance antibody binding, alter cellular functions leading to severe cases of FNAIT.

Isoantibodies against αIIbβ3 and FNAIT

Isoantibodies against αIIbβ3 produced in mothers with Glanzmann thrombasthenia (GT) are responsible for fetal and neonatal ITP. GT is a rare autosomal recessive disorder of platelet aggregation caused by mutations in the ITGA2B or/and ITGB3 genes encoding the integrin αIIbβ3. Three types of GT based on αIIbβ3 expression/function have been described: type I with absent αIIbβ3 expression (<5% of normal), type II with reduced expression (5–20% of normal), and type III, which has normal expression but is characterized by non-functional αIIbβ3. Recurrent bleeding episodes and platelet immunization are common complications of this disease (65). In rare cases, isoantibodies against αIIbβ3 developed by GT mothers (type I) before or during the pregnancy could cause FNAIT. Such isoantibodies reacted with all platelets derived from healthy blood donors (66-69). A systematic review of the literature among 31 cases comprising 40 pregnancies showed maternal isoimmunization in 73% of pregnancies and was associated with four neonatal deaths (70).

Recently, a unique mutation in the ITGA2B gene (G > A substitution at the splice donor site of intron 15) was found within the French Gypsy that showed a strong linkage to the HPA-1b allele (71). Based on the αIIb defect, these homozygous HPA-1bb Gypsy patients fail to express the αIIbβ3 heterodimer on the platelet surface, but can still express αvβ3 carrying HPA-1b epitopes. Interestingly, these GT patients developed two types of anti-HPA-1a alloantibodies, one that reacted with β3, and another that recognized the αvβ3 complex (14).

Isoantibodies against CD36 in immune-mediated disorders

Three decades ago, a new platelet antigen (designated Nak^a) involved in PTR was reported for the first time (72,73). By immunochemical analysis, the authors demonstrated that anti-Nak^a antibodies reacted with platelet membrane glycoprotein IV (GPIV, today designated as CD36) from normal donors but not from Nak^a negative subjects. Further study showed that platelets from Nak^a negative platelets failed to express CD36 (CD36null) on the cell surface, suggesting that Nak^a is an isoantigen rather than an alloantigen. Consequently, only transfusions with Nak^a negative platelets were able to raise the platelet counts of the patients. Several cases of PTR associated with anti-CD36 antibodies, primarily in Asian and African populations were reported from this time forward. However, PTR cases caused by anti-CD36 were also found in individuals of Mediterranean descent, including Lebanon, Egypt, Oman, and Palestine (74-81).

Meanwhile, several anti-CD36 immune-mediated diseases were described, including thrombotic thrombocytopenic purpura (TTP) (82-84), hemolytic uremic syndrome (HUS) (85), adverse transfusion reactions (86,87), post-transfusion purpura (PTP) (88), and FNAIT (89,90). Interestingly, transfusion-related acute lung injury (TRALI) associated with plasma transfusions containing anti-CD36 antibodies has also been reported (91).

Scavenger receptor CD36

CD36 is a multifunctional membrane receptor highly expressed on vascular and hematopoietic cells, including vascular smooth muscle cells, endothelial cells, macrophages, platelets and fetal erythrocytes. The class B scavenger receptor family, binds to many different ligands, including thrombospondin, oxidized phospholipids, oxidized low-density lipoprotein (oxLDL), and long-chain fatty acids. Furthermore, CD36 also mediates the adhesion of Plasmodium falciparum, Staphylococcus, and Mycobacterium to infected erythrocytes. Accordingly, CD36 is involved in diverse physiological and pathological processes, including thrombosis/hemostasis, atherogenesis, the innate immune defense, and diabetes (92-94).

The human CD36 gene is located on chromosome 7q11.2 and is encoded by 15 exons, but only exons 3 to 14 encode a 472 amino acid peptide [~molecular weight (MW) 50 kDa] (95,96). The protein harbors two transmembrane domains, a large extracellular domain containing ligand-binding sites and a single short cytoplasmic tail at each terminal (N and C terminal). The extracellular domain includes a hydrophobic region between amino acids 184–204 that may interact with the plasma membrane (Figure 3). The extracellular domain is heavily glycosylated; 9/10 putative N-linked glycosylation sites are glycosylated. Different CD36 molecular weights were reported for CD36 isolated from platelets, epithelial cells, and erythroblasts [relative molecular mass (Mr) ranging from 78 to 88 kDa], indicating cell type-specific glycosylation (92). Phylogenetic studies of the CD36 gene among vertebrates, including humans, mice, chickens and zebrafish, indicated that the CD36 gene appeared early in evolution, before the emergency of bony fish more than 500 million years ago. Human and mouse CD36 share high homology (more than 80%), leading to strong similarities in the structure and tissue distribution (97). Accordingly, several monoclonal antibodies (mAbs) against human CD36 showed cross-reactivity with mouse CD36 and vice versa (98).

Figure 3 Schematic diagram of the multifunctional receptor CD36. The binding pocket of different ligands and two possible entrances for fatty acid associated with different diseases are illustrated. The region of immunodominant epitopes (amino acid residues 155–183) recognized by several monoclonal antibodies and anti-Nak^a is shown. Another region (amino acid residues 30–76) recognized by mAb 13/15 is indicated.

Besides the transmembrane form of CD36, a soluble form of CD36 (sCD36) associated with microparticles was identified. Elevated sCD36 plasma concentration was detected in patients with cardiovascular disease and diabetes (99). However, little is currently known about the function of sCD36. Recent data demonstrated that type I CD36 deficient individuals characterized by the absence of CD36 on platelets and monocytes failed to produce sCD36 in plasma. This allows rapid identification of these subjects by analyzing plasma samples using a solid-phase sandwich ELISA (100).

Immunodominant epitopes on CD36

The first IgG mAb against CD36, designated as FA6-152, was generated by immunizing with fetal erythrocytes. mAb FA6-152 binds to fetal monocytes, platelets, reticulocytes, but not lymphocytes and granulocytes. Interestingly, this mAb agglutinated fetal, but not adult erythrocytes (101). Shortly after that, several mAbs against CD36 were assigned by the International Workshop of Leukocyte Typing (102). Some anti-CD36 mAb (5F1; IgM) lysed platelets in plasma and some (ES IVC7; IgG) induced platelet aggregation, and most of them inhibited collagen-induced platelet aggregation.

Using human-mouse chimeric expressing cells, Daviet et al. could identify two different immunodominant epitopes recognized by mAbs (103). The majority of mAbs, including FA6-152, recognized epitopes within the domain comprising amino acids 155–183. One unique mAb, 13/10, bound another domain that spans amino acids 30–76. MAbs against the 155–183 domain is functionally important regarding their capability to inhibit ligand binding, platelet function, and adhesion of P. falciparum-infected erythrocytes onto CD36 (103,104).

Further studies showed that all mAbs recognizing the 155–183 domain inhibited the binding of anti-CD36 antibodies in human sera, whereas mAb against the 30–76 domain did not. These observations indicate that the 155–183 amino acid sequence is important for the binding of anti-CD36 antibodies (105). Therefore, detection of anti-CD36 by an antigen-capture assay using mAb as capture antibody (such as MAIPA) frequently leads to false-negative results caused by competitive inhibition between anti-CD36 mAb and human serum (106). Thus, the selection of appropriate capture mAb is important to eliminate the drawback of the antigen-capture assay for the identification of anti-CD36 antibodies in serum samples. This fact, however, could be useful for the development of therapeutic antibodies: modified mAbs against CD36 competing for the same binding site could be used to displace the binding of human anti-CD36 antibodies preventing the pathogenic effects of these antibodies (98).

CD36 deficiency

The existence of CD36 deficient (Nak^a negative) subjects was described for the first time in Japan. Among the Japanese population, around 3–11% of healthy blood donors were Nak^a negative lacking CD36 expression on the platelet surface (72,107). Further studies analyzing CD36 expression on monocytes showed two different types of CD36 deficiency. Type I individuals are characterized by the absence of CD36 both on platelets and monocytes whereas type II subjects fail to express CD36 on platelets only (108). Two features are unique to the CD36 deficiency. First, the incidence of CD36 deficiency is relatively high as compared with other glycoprotein deficiencies, such αIIbβ3 in GT and GPIb/IX in Bernard-Soulier syndrome (BSS) patients (109,110), who present with hemostatic problems. Second, CD36 deficient individuals are apparently healthy without evidence of hemostatic abnormalities (72,107,111). However, studies in humans and mice showed defective uptake and utilization of long fatty acids, indicating a causal link between defective myocardial fatty acids uptake and CD36 deficiency (94,112).

Population studies have shown that the incidence of CD36 deficiency varies among different ethnic groups. CD36 deficiency is very rare in Caucasians (<0.3%) and is more common in African and Asian populations (4–8%) (74,75,113). A higher frequency of CD36-deficient individuals (type I and type II) was reported in Japan (6.8%) (113). In China, the frequency of CD36 deficiency on platelets ranges from 1.8% to 3.6% in the largest ethnic group, the Han population (81,114,115). Similar frequency (2.64%) was reported in the Arabian population (116).

More than 30 mutations in the coding region of the CD36 gene responsible for type I CD36 deficiency have been described (115). Three common mutations, C268T, 949insA, and 329–330 delAC, have been identified in Japanese individuals (117). Although the C268T mutation represents the most frequent substitution (>50%), this polymorphism did not lead to the production of anti-CD36 isoantibodies in reported cases (Table S1). In contrast, 329–330 delAC and 1,228–1,239 delATTGTGCCTATT are the most common mutations in Chinese individuals (81). In Thailand, A1163T seems to be the most frequent mutation associated with CD36 deficiency (100). Because of these heterogenous mutations, a practicable genotyping approach for identifying individuals with CD36 deficiency is difficult to develop.

Anti-CD36 isoantibodies and FNAIT

Shortly after the discovery of anti-CD36 antibodies as a cause of PTR in Japan (72), the first case of FNAIT due to anti-CD36 antibodies was reported in Thailand (89). After that, the clinical relevance of maternal anti-CD36 antibodies was reinforced by other new cases of FNAIT, three from African-American mothers and one from a mother with Italian ancestry (90). Meanwhile, several FNAIT cases due to anti-CD36 antibodies were identified in China (118). Recently, anti-CD36 associated with FNAIT was found in Arabic populations living in Germany (116). Table S1 provides a synopsis of previously published clinical cases, their diagnostics, and treatments (81,89,90,116,119-124). Serological diagnostics of the CD36 antigen and antibody will be discussed separately in another review chapter.

Pathomechanisms of anti-CD36 mediated FNAIT

Similar to previously known alloantibody-mediated FNAIT cases, the degree of thrombocytopenia caused by anti-CD36 isoantibodies varies widely from moderate to severe. ICH was also reported. Besides thrombocytopenia, fetal anemia frequently accompanies the clinical picture of the fetus.

In contrast to anti-HPA-1a, anti-CD36 antibodies react with platelets and endothelial cells, and also erythrocytes and monocytes of the fetus. Former studies applying mAbs (clones FA6-152 and 5F1) demonstrated the expression of CD36 solely on fetal but not on adult erythrocytes. The CD36 expression was related to the differentiation stage of the erythroid progenitors. It is expressed on mature BFU-E with an antigenic density increasing until day five CFU-E (101). It is well known that antigen-antibody-mediated red cell hemolysis (e.g., against Rhesus D) can cause anemic hydrops fetalis (AHF), leading to widespread soft-tissue edema and/or the accumulation of fluid in the fetal body cavities (125). Several studies reported an association between anti-CD36 antibodies and AHF (119,121,124). Recently, we found AHF caused by anti-CD36 in a case of severe FNAIT. Maternal anti-CD36 antibodies caused a significant reduction of BFU-E/CFU-E formation associated with an increased number of apoptotic CD34⁺ erythroid/myeloid precursor cells (124). This mechanism may be responsible for fetal anemia and consecutive AHF. Nevertheless, intrauterine transfusion with washed red blood cells (RBCs) should be taken into account to prevent fetal anemia and improve fetal survival (121).

CD36 is found on the placental membranes, microvillus, and basal membrane (126). The central role of CD36 (also known as fatty acid translocase) as a high-affinity receptor for fatty acid uptake and lipid metabolism has been well documented (127,128). During the third trimester of pregnancy, the placenta’s preferential transport of maternal plasma FA is critical for fetal growth and development (129). Disturbance of placenta vascular development and function could dramatically alter fetal growth development and thereby neonatal survival. In this process, placental vascularization and angiogenesis play critical roles (130,131). Recently, we found in the mouse FNAIT model a significant reduction of the placental labyrinth area and decreased fetal capillary numbers in immunized Cd36^−/− mothers compared to the naïve cohort. This phenomenon depends on FcγRIIa (CD32) expressed on placenta microvascular endothelial cells (132). It is conceivable that crosslinking between endothelial and blood cells by anti-CD36 antibodies may enhance the inflammatory response leading to severe FNAIT and even fetal death by affecting placenta angiogenesis (98).

Natural history of maternal immunization

Prospective studies on FNAIT in Caucasian populations provided information on the natural history of FNAIT. Cumulative data from ten prospective studies (133) show that 9.7% of all HPA-1a (−) negative mothers are immunized during pregnancy. The chance that a HPA-1a (−) mother gives birth to a HPA-1a (+) child is approximately 84%, given a gene frequency of 0.839 for HPA-1a (134). In the large Norwegian study (8), 34.2% of all HPA-1a (+) neonates of immunized mothers were severely thrombocytopenic (platelet counts <50×10⁹/L), whereas 47.2% had normal counts with platelets >150×10⁹/L. In this study the rate of FNAIT cases with ICH (platelet counts <150×10⁹/L) was 2.4%. This rate may be the consequence of the screening and treatment strategy applied by the investigators: as children of all immunized mothers were delivered 2 to 4 weeks prior to term by cesarean section. Furthermore, HPA-1a immunization is strongly correlated with the HLA-DRB3*01:01 class II major histocompatibility antigen (135). In HPA-1a (−) women giving birth to HPA-1a (+) progeny, the risk of immunization is about 25 times higher if the mothers are a carrier of HLA-DRB3*01:01 (136). Accordingly, the outcome of the neonates is associated with the HLA-DRB3*01:01 (137).

Little is known about the natural history of maternal immunization against other platelet alloantigens and isoantigens until today. Therefore, such a study is important to predict the risk of immunization.

Current therapies of FNAIT

Antenatal prophylactic and postnatal therapeutic interventions aim to reduce the risk of ICH and other serious bleeding complications in the fetus and the newborn. Most therapeutic recommendations and guidelines on prenatal therapy refer to anti-HPA-1a mediated FNAIT. In HPA-1a immunized women with at least one previously affected child, the risk for the next pregnancy depends upon the paternal genotype (HPA-1aa or HPA-1ab). In case of heterozygous father (HPA-1ab) the fetal HPA genotype should be determined, preferably by (noninvasive) typing of cell free fetal DNA in maternal plasma (138-140). The risk of fetal ICH is enhanced, if a previous sibling with FNAIT suffered from ICH (141) and the clinical outcome of the newborn seems to be worse, if the mother carries the DRB3*01:01 antigen (142). For pregnancies at risk, maternal intravenous immunoglobulin (IVIG) therapy (1 g/kg once a week) is considered to be effective in avoiding cerebral bleeding. Due to the lack of randomized studies with a control group, maternal IVIG for preventing fetal ICH in NAIT is used off-label. It is not clear whether additional maternal therapy with corticosteroids is effective (143). In the past, high-risk patients have been subjected to fetal blood sampling and platelet counting followed by intrauterine transfusion of compatible platelets in case of thrombocytopenia. However, owing to the high risk of fetal complications, the non-invasive approach with weekly IVIG infusions is now preferred (143).

Normally, pregnant women in their first pregnancy are not aware of the risk of immunization. Therefore, the screening program for platelet alloimmunization is deliberately performed, but it is still intensively debated. If thrombocytopenic newborns of alloimmunized mothers are at risk of serious bleeding, including ICH, the therapy of choice is the transfusion of antigen-compatible platelets, including maternal platelets (144). However, in urgent situations, platelet concentrates from random donors are usually also effective (144,145). In case platelet concentrates are not available, IVIG may be used (144).

Consensus for standard pre- and postnatal therapies for other antibodies, except HPA-1, is not yet available.

New therapeutic approaches

Although the use of IVIG for the prevention/treatment of FNAIT during pregnancy is increasing, the precise mechanism of IVIG action is still unclear (143). Several mechanisms have been proposed, including decreasing of maternal antibody production by inducing immune tolerance or reduction of placental transfer, and enhancement of maternal IgG catabolism via the FcRn receptor (146-148). However, such strategies may inhibit the transfer of immune-protective maternal IgG, with potential increased risk of infections by the locally dominant pathogens during pregnancy and during the first weeks after birth. Therefore, more specific and effective antenatal therapies are desirable.

The first concept is the development of FcRn inhibitors. Studies in mouse models demonstrated that anti-FcRn antibodies could decrease miscarriages and improve angiogenesis by inhibiting fetal FcRn (17,131,149-151). FcRn is a pH-dependent FcγR that only binds IgG at acidic pH (152). Following pinocytosis into endosomes of endothelial cells, IgG binds to FcRn (due to acidic milieu) and thereby escapes rapid degradation. The FcRn-IgG complex can be translocated back to the cell surface, and IgG can be released after dissociation from FcRn (due to neutral milieu). This recycling process is responsible for the relatively long half-life of IgG. Consequently, inhibition by anti-FcRn leads to rapid IgG degradation and clearance from the circulation (152). This effect reduces anti-platelet antibodies, which has been shown in ITP patients treated with high-dose IVIG (153). Thus, anti-FcRn antibodies may have two modes of action in FNAIT; reduction of maternal antibody concentration and inhibition of FcRn-mediated transfer via the placenta into the fetus (154).

Currently, a clinical trial with the inhibitory anti-FcRn blocking mAb nipocalimab (M281) has been initiated for the therapy of hemolytic disease of the fetus and newborn (HDFN). Therefore, it seems warranted to consider this therapy for FNAIT when this approach turns out to be effective for the therapy of HDFN (154).

An attractive alternative strategy would be to administer non-destructive IgG, which shares the allospecificity of maternal antibodies and can inhibit the binding of pathogenic maternal alloantibody to fetal platelets. Such a therapeutic agent should not trigger effector function by inability to interact with fetal FcγRs, but still retain the ability to be transported across the placenta. Ghevaert et al. introduced such a strategy by developing human recombinant anti-HPA-1a (termed B2G1Δnab) (155). These modified mAb against HPA-1a would be an excellent candidate for treatment of FNAIT if it could be shown in humans that it is able to cross the placenta in sufficient amounts and can displace effectively bound to fetal platelets (155).

In recent years, the therapeutic potential of deglycosylated IgG (deg-IgG) antibodies for treatment of autoimmune disorders has been widely recognized (156). Removal of the N-glycan (linked to asparagine 297), located on the Fc part, leads to a significant reduction of IgG binding with the FcγRs expressed on macrophages and its ability to activate complement C1q. Interestingly, these deg-IgG antibodies could still be transported from the maternal circulation to the fetus via FcRn (157). Accordingly, our previous in vivo study in mice demonstrated that deg-mAb specific for HPA-1a (mAb SZ21) could cross the placenta and prevent the clearance of fetal platelets mediated by maternal anti-HPA-1a antibodies. This observation indicates that the use of epitope-specific antibodies for the antenatal therapy of severe FNAIT is feasible (158).

Recently, we evaluated this treatment strategy in mice model of anti-CD36-mediated FNAIT. By the antenatal administration (5 mg/kg body weight) of deglycosylated mouse mAb 32-106 (deg-32-106), the high frequency of fetal death could be significantly reduced (40% to 2%) However, similar antenatal treatment with IVIG administered in a dose of 1 g/kg body weight on days 10, 15, and 20 after breeding did not increase platelet counts. Furthermore, it did not reduce fetal death rates (40%). Only IVIG administration three days earlier at days 7, 12, and 17 instead at days 10, 15, and 20 reduced fetal death (40% to 13%) (98). Our results indicated that deg-32-106 could prevent placenta angiogenesis caused by maternal antibodies (98). Interestingly, deg-32-106 reacted with human CD36. Thus, the development of humanized deg-32-106 as a drug to prevent severe FNAIT caused by anti-CD36 could be envisaged.

Another strategy to prevent fetal bleeding complications is to reduce the risk of alloimmunization by administering antibodies to eliminate fetal platelets and fetal cellular particles from the maternal circulation. This has been attempted by administration of anti-HPA-1a antibodies (159). It is assumed that anti-D causes rapid clearance of D positive fetal RBCs from the maternal circulation (160). Tiller et al. were able to transfer this situation of antibody-mediated immune suppression (AMIS) to a mouse model for FNAIT: they reduced the immunizing effects of human platelet transfusions to β3^−/− mice with infusions of human anti-HPA-1a and with infusions of mouse monoclonal anti-β3 antibodies (161). First results from a clinical trial show (EudraCT number 2019-003459-12) show that NAITgam is able to reduce the half life of HPA-1a positive platelets transfused to HPA-1a-negative subjects (162). However, more trials are mandatory to show both safety and efficiency of this prophylactic therapy.

Other HPAs

HPA-2 on GPIbα

Immunization against antigens of the biallelic HPA-2 system residing on platelet GPIb/IX/V complex can lead to the production of anti-HPA-2a and anti-HPA-2b alloantibodies. The HPA-2 polymorphism, discovered in Caucasians, also exists in other Asian populations (118) and in sub-Saharan African populations (163). The rarer allele, HPA-2b, has a frequency of 0.088 in the Western European population (134). In Han Chinese, the frequency of this antigen is 0.0485 and in Koreans 0.077 (118). In sub-Saharan populations, HPA-2b frequencies vary from 0.224 to 0.393 (163). Alloantibodies against HPA-2b were first discovered in a Dutch patient, who had received blood transfusions (164). Later anti-HPA-2b antibodies were found in a multi-transfused Japanese patient (165). These antibodies have been also found in rare cases of FNAIT (166-168). An atypical case of neonatal amegakaryocytic thrombocytopenia associated with anti-HPA-2b was reported (169).

The antigenic determinants of HPA-2a and HPA-2b are formed by substitution of threonine into methionine at amino acid position 145 located on the amino terminal domain of GPIbα subunit (170). The GPIbα contains a N-terminal ligand binding domain (LBD), an anionic and sulfated region, a macroglycopeptide region and a mechanosensory domain (MSD) (171). This Thr145Met dimorphism resides in the LBD domain within VWF and alters their binding (172). However, little is known about the impact of anti-HPA-2 antibodies on platelet function. Platelet GPIbα is sensitive for protease cleavage (173). A soluble extracellular fragment of GPIbα (glycocalicin) containing anti-HPA-2 binding sites is continuously released due to proteolytic cleavage by ADAM17 metalloproteinase (171). This fact may hamper the detection of anti-HPA-2 antibodies and may explain the rarity of these antibodies.

The glycoprotein GPIb-IX-V complex is expressed exclusively on platelets and megakaryocytes. After integrin αIIbβ3, GPIb/IX/V complex is the second most abundant receptor on human platelets (171). Early study reported that human endothelial cells in culture also expressed GPIb/IX/V complex (174). In contrast to β3 integrin carrying HPA-1a epitopes (22,175), GPIb/X/V complex is not found on trophoblast. One might speculate that this is reason for the rare immunization against HPA-2 system in FNAIT.

HPA-15 on CD109

Immunization against the biallelic HPA-15 system residing on GPI-anchored CD109 glycoprotein can lead to the production of anti-HPA-15a and anti-HPA-15b alloantibodies. These alloantibodies were found in different clinical settings of immune mediated thrombocytopenia including PTR and FNAIT (176-180).

The gene frequencies of HPA-15a and -15b were 0.512 and 0.488 in Caucasians (181), while 0.532 and 0.468 in Asian populations (182,183). Although the gene frequencies of HPA-15a and HPA-15b are similar, anti-HPA-15b was found more frequently than anti-HPA-15a both in PTR and FNAIT cases (51,180,181). The reason for this phenomenon is currently unknown.

Anti-HPA-15 antibodies were originally discovered by radioimmunoprecipitation (176). Meanwhile, anti-HPA-15 can also be detected using antigen capture assay (184). This approach, however, seems to be insensitive when platelets are used for testing due to the low copy number of CD109 on platelets. The use of cell lines stably expressing high CD109 copy number could reduce the rate of false negative result obtained with platelets (185).

CD109 is expressed in fetal and adult CD34 positive bone marrow cell subsets, activated T lymphoblast, activated platelets, endothelium, megakaryoblastic cell leukemia cells, and human tumor cell lines (186-189). Upregulation of CD109 was observed in several tumor cells (190,191). Cuppini and coworkers reported that CD109 positive circulating endothelial cells was associated with increased progression free survival and overall survival suggesting the role CD109 on the mechanism of tumor progression (192).

On platelets, CD109 is not constitutively expressed on the cell surface, but appears as early activation marker. After agonist-induced activation, such as low-dose ADP and epinephrine, CD109 is rapidly displayed on the platelet surface. In resting platelets, CD109 resides in α-granules, co-distributed with P-selectin and within the open canicular system (OPS). Accordingly, only low expression level of CD109 (500–2,000 molecules/platelet) was detectable on the platelet surface (193). In addition, marked inter-individual differences in the copy number of CD109 were observed on platelets (184,194). However, the physiological role of this differential expression is still unknown.

Since CD109 is a platelet activation antigen, it is remarkable that anti-HPA-15 antibodies, although rare, could also be found in FNAIT cases. Among 213 patients with FNAIT only two (0.94%) were related to anti-HPA-15 antibodies (181). In the same study, HPA-15 antibodies were much more common in sera of transfused patients (27.7%). Interestingly, ICH associated with anti-HPA-15b antibodies has been reported (51,178,184). Currently, little is known about the function of anti-CD109 antibodies. Initial studies demonstrated that CD109 antibodies abrogated responder cell proliferation in a mixed lymphocyte response assay (195). Recently, Ye and coworkers reported that knockdown of CD109 suppressed cell migration resulted in reduction of endothelial tube formation (196). The question whether anti-HPA-15 bound to CD109 on endothelial cells could inhibit cell migration and suppress endothelial tube formation is currently not known.

Conclusions and perspectives

Apart from the well-known platelet alloantibodies, isoantibodies against platelet glycoproteins play an important role in the pathomechanism of FNAIT, particularly anti-CD36 antibodies. Although they seem to be uncommon in the Caucasian population, anti-CD36 isoantibodies are of clinical importance in Asian and other populations. Meanwhile, in the course of world globalization, anti-CD36 mediated FNAIT has been reported in Western countries.

Platelet alloantibodies and isoantibodies not only bind to platelets, as confirmed previously, but also interact with endothelial cells (such as anti-HPA-1a) as well as other blood cells (such as anti-CD36). All these antibody-mediated effects can trigger FNAIT by different mechanisms leading to different clinical pictures and consequently require adapted treatment strategies. For example, the IVIG standard therapy for anti-HPA-1a does not seem effective for anti-CD36, at least in the animal model.

In addition, recent evidence indicated that maternal antibodies are also heterogeneous with respect to their epitopes, and their ratio may differ from one case to other, reflecting the various clinical pictures of FNAIT. Therefore, further improvement on laboratory diagnostics, both on serological and functional analysis of platelet antibodies, is mandatory for the better prediction and management of FNAIT.

To achieve this goal, a further understanding of the nature of the pathogenic antibodies will be necessary. Concerning anti-CD36 antibodies, visible progress has been made in the last few years. However, there are several open questions, namely, on the incidence, natural history, antibody titer/types, severity/clinical pictures in FNAIT, and the involvement of anti-CD36 in other antibody-mediated platelet disorders and TRALI.

Acknowledgments

XZX is a PhD candidate at the University of Giessen, Germany. This work is submitted in partial fulfillment of the requirements of the PhD.

Funding: This work was supported in part by grants from the National Natural Science Foundation of China (81601451 and 81970169).

Footnote

Provenance and Peer Review: This article was commissioned by the Guest Editor (Brian R. Curtis) for the series “Thrombocytopenia Due to Immunization Against CD36” published in Annals of Blood. The article has undergone external peer review.

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://dx.doi.org/10.21037/aob-21-47

Peer Review File: Available at https://dx.doi.org/10.21037/aob-21-47

Conflicts of Interest: The authors have completed the ICMJE uniform disclosure form (available at https://dx.doi.org/10.21037/aob-21-47). The series “Thrombocytopenia Due to Immunization Against CD36” was commissioned by the editorial office without any funding or sponsorship. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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